Crystalline forms of neuroactive steroids

Abstract

The present disclosure relates to Compound 1 as well as crystalline solid forms and solid dosage forms thereof. The present disclosure also provides methods of making and using the crystalline solid forms of Compound 1, as well as solid dosage forms thereof. # imgabs0 # (compound 1)

Description

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

[0002] NMDA receptors are heteromeric complexes consisting of NR1, NR2 and / or NR3 subunits and have different recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and CNS, where they participate in excitatory synaptic transmission. Activating these receptors helps synaptic plasticity in some cases and excitotoxicity in other cases. These receptors allow Ca to bind to glutamate and glycine after the binding. 2+ Entering ligand-gated ion channels and are the basis of excitatory neurotransmission and normal CNS function. Positive modulators can be used as therapeutic agents with potential clinical use as cognitive enhancers and in the treatment of psychiatric disorders with reduced or defective glutamatergic transmission (see, e.g., 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, a proper balance must be achieved between various properties, including affinity for the NMDA receptor, positive allosteric modulatory activity, duration of activity, oral bioavailability, tissue distribution, and stability (e.g., shelf life, dispensability, and crystallizability). A properly balanced combination of such properties can improve NMDA receptor PAMs in terms of efficacy, safety, tolerability, patient compliance, and manufacturing. Therefore, solid forms of compound 1 with appropriate properties (including chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, grinding properties, and stability during tableting) and large-scale commercial preparations of their corresponding solid dosage forms face many challenges.

[0004] Thus, there is a need for one or more solid forms of NMDA receptor PAMs (eg, Compound 1) that possess a suitable balance of these properties and that can be used to prepare pharmaceutically acceptable solid dosage forms thereof. Summary of the invention

[0005] Various polymorphic forms of compound 1

[0006] Disclosed herein is (Compound 1)

[0007] and solid dosage forms comprising said forms of Compound 1 and methods of making and using said forms of Compound 1.

[0008] In one aspect, the present disclosure provides a crystalline form of Compound 1:

[0009]

[0010] (Compound 1)

[0011] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0012] 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;

[0013] 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;

[0014] 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;

[0015] 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;

[0016] 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

[0017] 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.

[0018] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0019] 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;

[0020] b) crystalline 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;

[0021] c) crystalline 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;

[0022] 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, 17.0 ± 0.2, and 21.4 ± 0.2 degrees 2θ;

[0023] e) crystalline 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; and

[0024] f) crystalline 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.

[0025] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0026] a) crystalline 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;

[0027] b) crystalline 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;

[0028] c) crystalline 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;

[0029] d) crystalline 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;

[0030] e) crystalline 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; and

[0031] f) crystalline 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.

[0032] In some embodiments, the crystalline form is an anhydrate.

[0033] In some embodiments, the crystalline form is crystalline Form A, characterized in that its XRPD pattern comprises peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ. In some embodiments, the XRPD pattern of the 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 in that its XRPD pattern comprises 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 in that its XRPD pattern comprises 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. Figure 1A XRPD pattern depicted.

[0034] In some embodiments, the crystalline Form A has substantially Figure 1B Thermogravimetric analysis (TGA) thermogram depicted. In some embodiments, the crystalline Form A has substantially Figure 1B A differential scanning calorimetry (DSC) thermogram is depicted. In some embodiments, the DSC thermogram comprises an endothermic peak at about 203°C.

[0035] In some embodiments, the crystalline form is crystalline Form B, characterized in that its XRPD pattern comprises peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ. In some embodiments, the XRPD pattern of the 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 in that its XRPD pattern comprises 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 in that its XRPD pattern comprises 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. Figure 2A XRPD pattern depicted.

[0036] In some embodiments, the crystalline Form B has substantially Figure 2B In some embodiments, the crystalline Form B has substantially Figure 2B Depicted DSC thermogram. In some embodiments, the DSC thermogram comprises an endothermic peak at about 204°C.

[0037] 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.

[0038] In some embodiments, the crystalline form is crystalline Form D, characterized in that its XRPD pattern comprises peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD pattern of the crystalline Form D further comprises 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 in that its XRPD pattern has 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 in that its XRPD pattern comprises peaks at substantially Figure 3A XRPD pattern depicted.

[0039] In some embodiments, the crystalline Form D has substantially Figure 3B In some embodiments, the crystalline Form D has substantially Figure 3B In some embodiments, the DSC thermogram comprises an endothermic peak at about 204° C. In some embodiments, the DSC thermogram comprises an endothermic peak at about 127° C.

[0040] In some embodiments, the crystalline form is an n-BuOH solvate. In some embodiments, the crystalline form is a crystalline form E, characterized in that its XRPD pattern comprises 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 the 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 a crystalline form E, characterized in that its XRPD pattern has 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 a crystalline form E, characterized in that it is substantially as Figure 4A XRPD pattern depicted.

[0041] In some embodiments, the crystalline Form E has substantially Figure 4B In some embodiments, the crystalline Form E has substantially Figure 4B Depicted is a differential scanning calorimetry (DSC) thermogram. 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.

[0042] In some embodiments, the crystalline form is crystalline Form F, characterized in that its XRPD pattern comprises 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 the 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 in that its XRPD pattern comprises 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 in that it is substantially as Figure 5A XRPD pattern depicted.

[0043] In some embodiments, the crystalline form is crystalline Form G, characterized in that its XRPD pattern comprises 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 the 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 in that its XRPD pattern comprises 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 in that its XRPD pattern comprises 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. Figure 5A XRPD pattern depicted.

[0044] In some embodiments, the crystalline form is selected from the group consisting of:

[0045] a) Crystalline Form A, characterized in that it is substantially as follows Figure 1A The XRPD pattern depicted;

[0046] b) Crystalline Form B, characterized in that it is substantially as follows Figure 2A The XRPD pattern depicted;

[0047] c) Crystalline Form D, characterized in that it is substantially as follows Figure 3A The XRPD pattern depicted;

[0048] d) Crystalline Form E, characterized in that substantially Figure 4A The XRPD pattern depicted;

[0049] e) Crystalline Form F, characterized in that substantially Figure 5A the XRPD pattern depicted; and

[0050] f) Crystalline Form G, characterized in that substantially Figure 5A XRPD pattern depicted.

[0051] In a second aspect, the present disclosure provides a solid dosage form comprising a crystalline form of Compound 1 as disclosed herein and at least one pharmaceutically acceptable carrier.

[0052] 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 as 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 disorders, 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 depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including disorders involving mutations in the Shank proteome), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis complex), 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 forms of epilepsy such as Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease), disease and Parkinson's disease) and tinnitus.

[0053] 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 as disclosed herein or a solid dosage form comprising a crystalline form of Compound 1 as disclosed herein.

[0054] In a fifth aspect, the present disclosure provides a method for preparing a crystalline form of Compound 1. In some embodiments, the method for preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0055] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0056] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0057] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0058] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: a) adding Compound 1 to a solvent to form a solution; b) adding the solution to an antisolvent; c) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is BuOH. In some embodiments, the antisolvent is n-heptane.

[0059] In some embodiments, the method for preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0060] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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; c) cooling the filtrate to about −20° C.; d) precipitating a solid; and e) isolating the solid. In some embodiments, the solvent is acetone.

[0061] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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 rate in step b) is selected from the group consisting of about 2°C / min, about 10°C / min, and about 50°C / min.

[0062] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0063] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0064] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises the following steps: 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.

[0065] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising the steps of: 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 antisolvent; d) adding Form X of Compound 1 seeds and aging the mixture at about 50°C; e) cooling the mixture to about 20°C for at least 3 hours and maintaining the mixture at 20°C (optionally wet milling) to precipitate a solid; and f) isolating the solid. In some embodiments, the solvent is acetone. In some embodiments, the antisolvent is acetone / water. In some embodiments, the antisolvent is acetone / water (1:1 v / v).

[0066] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: a) adding crude Compound 1 to a solvent to form a mixture and heating to about 80°C; b) concentrating the mixture by distillation; c) adding a solvent to the mixture; d) adjusting the temperature of the mixture to about 80°C; e) adding Form E of Compound 1 seeds; 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

[0067] Figure 1A An exemplary XRPD pattern of Form A is depicted.

[0068] Figure 1B Exemplary TGA (upper) and DSC (lower) thermogram curves of Form A are depicted.

[0069] Figure 1C An exemplary hot stage image of Form A is depicted.

[0070] Figure 1D An exemplary DVS diagram of Form A is depicted.

[0071] Figure 1E Depicted are exemplary XRPD overlays of Form A before and after DVS testing.

[0072] Figure 2A An exemplary XRPD pattern of Form B is depicted.

[0073] Figure 2B Exemplary TGA (upper) and DSC (lower) thermogram curves of Form B are depicted.

[0074] Figure 3A An exemplary XRPD pattern of Form D is depicted.

[0075] Figure 3B Exemplary TGA (upper) and DSC (lower) thermogram curves of Form D are depicted.

[0076] Figure 3C Depicted are exemplary XRPD overlays of Form D before and after heating.

[0077] Figure 4A An exemplary XRPD pattern of Form E is depicted.

[0078] Figure 4B Exemplary TGA (upper) and DSC (lower) thermogram curves of Form E are depicted.

[0079] Figure 4C Depicted are exemplary XRPD overlays of Form E before and after heating.

[0080] Figure 4D Depicts an exemplary embodiment of Form E 1 H-NMR spectrum.

[0081] Figure 5AAn exemplary XRPD pattern of Form F is depicted: T XRPD patterns of Compound 1 samples: Form X: Reference; Form A: Compound 1 Reference. Form F: Oven No. 1 dried at 40 °C); Form G: Reference No. 2, heated at 90 °C.

[0082] Figure 5B Depicted is an exemplary TGA thermogram of Form F converted to slurry after drying in a vacuum oven at 40°C.

[0083] Figure 5C Depicted is an exemplary DSC thermogram of Form F converted to slurry after drying in a vacuum oven at 40°C. DETAILED DESCRIPTION

[0084] General Definition

[0085] The term "herein" means the entire application.

[0086] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meaning commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Generally, the nomenclature used in conjunction with the compounds, compositions and methods described herein is the nomenclature well known and commonly used in the art.

[0087] It should be understood that any embodiment described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in examples), can be combined with one or more other embodiments of the disclosure unless expressly denied or inappropriate. The combination of embodiments is not limited to those specific combinations claimed by multiple dependent claims. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same basic claim. In the case where the elements are presented in a list format such as a Markush group format, each subgroup of the elements is also disclosed, and any one or more elements can be removed from the group.

[0088] Throughout the present specification, the word "comprise" or variations such as "comprises" or "comprising" should be understood to imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0089] Throughout the specification, when a composition is described as having, including or comprising (or variations thereof) a specific component, it is contemplated that the composition may also consist essentially of or consist of the component. Similarly, when a method or process is described as having, including or comprising a specific process step, the process may also consist essentially of or consist of the process step. In addition, it should be understood that the order of steps or the order in which certain actions are performed is unimportant, as long as the compositions and methods described herein remain operable. In addition, two or more steps or actions may be performed simultaneously.

[0090] As used herein, the term "comprising" means "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. Thus, these terms will be understood to imply the inclusion of the stated integers (or components) or groups of integers (or components) but not the exclusion of any other integers (or components) or groups of integers (or components).

[0091] As used herein, "about" or "approximately" means within an acceptable error range for the 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, ie, the limitations of the measurement system.

[0092] The use of the terms "a" and "an" and "the" and similar referents in the context of describing elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0093] As used herein, the term "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0094] Unless otherwise indicated herein, the description of the range of values ​​herein is intended only to be used as a shorthand method for individually referring to each individual value falling within the range and including endpoints, and each individual value is incorporated into this specification as if the individual value is individually described herein. Unless otherwise indicated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise indicated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the embodiments without limiting the scope of the claims. None of the language in this specification should be interpreted as indicating that any unrequired element is essential.

[0095] All publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In the event of a conflict, this specification (including its specific definitions) will prevail. In addition, any specific embodiment of the present disclosure that falls within the scope of the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly stated herein. Any specific embodiment of the present disclosure may be excluded from any claim for any reason, whether or not it is related to the existence of the prior art.

[0096] The terms "active ingredient," "active agent," and "active substance" refer to a compound that is administered to a subject alone or together with one or more pharmaceutically acceptable excipients for the treatment, prevention, or amelioration of the symptoms of one or more conditions, disorders, or diseases. As used herein, an "active ingredient," "active agent," and "active substance" may be an optically active isomer of a compound described herein.

[0097] The terms "drug" and "therapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to a subject for the treatment, prevention, or amelioration of the symptoms of one or more conditions, disorders, or diseases.

[0098] As used herein, the term "polymorph" refers to a crystalline form of a compound or its salt, hydrate or solvate in a specific crystal packing arrangement. All polymorphs have the same elemental composition. The term "polymorph" includes pseudopolymorphs, which are generally different solvates of the same material and therefore have different properties. Therefore, each different polymorph and pseudopolymorph disclosed herein is considered to be a different single crystalline form.

[0099] As used herein, the term "crystallization" refers to a solid state form consisting of orderly arranged structural units. The different crystalline forms of the same compound or its salt, hydrate or solvate are derived from the different stacking of solid molecules, which leads to different crystal symmetries and / or unit cell parameters. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. See, for example, Remington's Pharmaceutical Science, 18th edition, Mack Publishing, Easton Pa, 173 (1990); The United States Pharmacopeia, 23rd edition, 1843-1844 (1995) (incorporated herein by reference). As used herein, the terms "crystalline form," "single crystalline form," "crystalline solid form," and "polymorph" are used interchangeably; these terms distinguish between crystals having different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0100] The term "substantially pure" refers to the composition of a specific crystalline solid form of Compound 1, which may 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 crystalline solid form 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.

[0101] Crystalline forms are often characterized by X-ray powder diffraction (XRPD). The reflections (peaks, usually expressed in degrees 2θ) of the XRPD pattern are often considered to be the fingerprint of a particular crystalline form. The relative intensities of the XRPD peaks may vary, among other things, depending on the sample preparation technique, crystal size distribution, filters, sample installation procedures, and the specific instrument employed. In some cases, there may be more peaks (i.e., new peaks) or fewer peaks (i.e., peaks may disappear) in the XRPD pattern, depending on the type or setup of the instrument. In some cases, any particular peak in the XRPD pattern may appear as a single peak, double peak, triple peak, quadruple peak, or multiple peaks, depending on the type or setup of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystalline form. In some cases, any particular peak in the XRPD may exhibit a symmetrical shape or an asymmetrical shape, for example, with a shoulder. In addition, instrument variations and other factors may affect the 2θ value. A technician who is aware of these variations is able to use XRPD and other known physicochemical techniques to identify or determine the defining features or characteristics of a particular crystalline form.

[0102] When referring to peaks in the XRPD pattern of the crystalline form of Compound 1, the term "characteristic peaks" refers to a collection of certain peaks whose 2θ values ​​in the range of 0°-40° are uniquely attributed to one crystalline form of Compound 1 as a whole.

[0103] The term "amorphous" as applied to chemical compounds refers to a state in which the material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on the temperature. Typically, such materials do not produce a characteristic X-ray diffraction pattern and, although exhibiting the properties of a solid, are more formally described as liquids. Upon heating, a change in properties from solid to liquid occurs, which is characterized by a change of state, usually a secondary change ("glass transition").

[0104] The terms "anhydrate" or "anhydrous" are used interchangeably and, when applied to a compound, refer to the solid state of the compound that contains no structural water or other solvent molecules within the crystal lattice.

[0105] The term "solvate" refers to a compound or salt thereof provided herein, which further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces (e.g., hydrogen bonds). When the solvent is water, the solvate is a hydrate. When the solvent comprises ethanol, the compound can be an ethanol solvate.

[0106] 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.

[0107] The crystalline form of Compound 1 described herein (e.g., Form A) may melt at a specific temperature or within a temperature range. Such a specific temperature or temperature range may be determined by the onset temperature (T) of the melting endothermic peak in the DSC curve of the crystalline form. 起始 ). In some embodiments, at such starting temperatures, a sample of the crystalline form of Compound 1 melts and undergoes concurrent side processes, such as recrystallization or chemical decomposition. In some embodiments, at such starting temperatures, the crystalline form of Compound 1 melts in the absence of other concurrent processes.

[0108] The present disclosure provides forms of Compound 1 that have 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, grinding properties, and stability during tableting).

[0109] The present disclosure relates to the solid form of Compound 1

[0110] (Compound 1)

[0111] 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 single crystalline forms of the present disclosure are Forms A, B, D, E, F, and G.

[0112] Compound 1 and its chemical synthesis are disclosed in U.S. Patent No. 10227375 / PCT Application Publication No. WO2014160480.

[0113] In some embodiments, as disclosed herein, a crystal structure of the present disclosure can be identified by having one or more characteristic peaks in an XRPD spectrum.

[0114] In some embodiments, as disclosed herein, the crystal structures of the present disclosure can be identified by having one or more characteristic endothermic peaks in a differential scanning calorimetry (DSC) thermogram.

[0115] In some embodiments, as disclosed herein, the crystal structures of the present disclosure can be identified by having one or more characteristic endothermic peaks in a thermogravimetric analysis (TGA) thermogram.

[0116] In some embodiments, as disclosed herein, the crystal structures 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.

[0117] In some embodiments, the crystal structures of the present disclosure can be identified by having one or more characteristic peaks in an XRPD spectrum, combined with one or more characteristic endothermic peaks in a differential scanning calorimetry thermogram and / or a thermogravimetric analysis (TGA) thermogram.

[0118] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0119] 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;

[0120] 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;

[0121] 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;

[0122] 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;

[0123] 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

[0124] 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.

[0125] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0126] 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;

[0127] b) crystalline 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;

[0128] c) crystalline 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;

[0129] 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, 17.0 ± 0.2, and 21.4 ± 0.2 degrees 2θ;

[0130] e) crystalline 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; and

[0131] f) crystalline 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.

[0132] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0133] a) crystalline 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;

[0134] b) crystalline 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;

[0135] c) crystalline 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;

[0136] d) crystalline 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;

[0137] e) crystalline 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; and

[0138] f) crystalline 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.

[0139] In some embodiments, the crystalline form of Compound 1 is selected from the group consisting of:

[0140] a) crystalline Form A, wherein Form A is characterized by being substantially Figure 1A X-ray powder diffraction (XRPD) pattern shown;

[0141] b) crystalline Form B, wherein Form B is characterized by being substantially Figure 2A The XRPD pattern shown;

[0142] c) crystalline Form D, wherein Form D is characterized by XRPD pattern 3A;

[0143] d) crystalline Form E, wherein Form E is characterized by being substantially as Figure 4A The XRPD pattern shown;

[0144] e) crystalline Form F, wherein Form F is characterized by being substantially Figure 5A The XRPD pattern shown; and

[0145] f) crystalline Form G, wherein Form G is characterized by being substantially as Figure 5A XRPD pattern shown.

[0146] 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 a n-butanol solvate.

[0147] A. Crystalline Form A

[0148] In some embodiments, the present disclosure relates to crystalline Form A of Compound 1. In some embodiments, the anhydrous crystalline form of Compound 1 is Form A. In some embodiments, Form A has one or more characteristics selected from the group consisting of:

[0149] a) an XRPD pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ;

[0150] b) Basically Figure 1A The XRPD pattern shown;

[0151] c) DSC thermogram curve, which includes an endothermic peak at about 203 °C;

[0152] d) Basically Figure 1B The DSC thermogram curve shown;

[0153] e) a TGA curve showing a loss of at least about 0.04 wt % between about 25°C and about 190°C; and

[0154] f) Basically Figure 1B TGA curve shown.

[0155] In some embodiments, Form A is characterized in that its XRPD pattern comprises peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ. In some embodiments, Form A is characterized in that its XRPD pattern comprises peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ and 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, Form A is characterized in that its XRPD pattern comprises 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 being substantially as Figure 1A XRPD pattern depicted.

[0156] In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 0.04 wt % of Form A between about 25° C. and about 190° C. In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 0.04 wt % of Form A between about 25° C. and about 190° C. In some embodiments, Form A is characterized by being substantially Figure 1B Thermogravimetric analysis (TGA) thermogram depicted.

[0157] In some embodiments, Form A is characterized by being substantially Figure 1B Depicted differential scanning calorimetry (DSC) thermogram. In some embodiments, Form A is characterized in that its DSC thermogram comprises an endotherm at about 203 °C. In some embodiments, Form A is characterized in that its DSC thermogram comprises a melting endotherm at about 203 °C.

[0158] In some embodiments, Form A is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form A is 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, the polymorphic purity of Form A is at least 90%. In some embodiments, the polymorphic purity of Form A is at least 92%. In some embodiments, the polymorphic purity of Form A is at least 94%. In some embodiments, the polymorphic purity of Form A is at least 96%. In some embodiments, the polymorphic purity of Form A is at least 98%. In some embodiments, the polymorphic purity of Form A is at least 99%.

[0159] B. Crystalline Form B

[0160] In some embodiments, the present disclosure relates to crystalline Form B of Compound 1. In some embodiments, the anhydrous crystalline form of Compound 1 is Form B. In some embodiments, Form B has one or more characteristics selected from the group consisting of:

[0161] a) an XRPD pattern comprising peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ;

[0162] b) Basically Figure 2A The XRPD pattern shown;

[0163] c) DSC thermogram curve, which includes an endothermic peak at about 204 °C;

[0164] d) Basically Figure 2B The DSC thermogram curve shown;

[0165] e) a TGA curve showing a loss of at least about 0.2 wt % between about 70°C and about 150°C; and

[0166] f) Basically Figure 2B TGA curve shown.

[0167] In some embodiments, Form B is characterized in that its XRPD pattern comprises peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ. In some embodiments, Form B is characterized in that its XRPD pattern comprises peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ and 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, Form B is characterized in that its XRPD pattern comprises 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 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. In some embodiments, the crystalline Form B is characterized by being substantially as Figure 2A XRPD pattern depicted.

[0168] In some embodiments, Form B is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 0.2 wt % of Form B between about 70° C. and about 150° C. In some embodiments, Form B is characterized by being substantially as Figure 2B Thermogravimetric analysis (TGA) thermogram depicted.

[0169] In some embodiments, Form B is characterized by being substantially as follows Figure 2B Depicted differential scanning calorimetry (DSC) thermogram. In some embodiments, Form B is characterized in that its DSC thermogram comprises an endotherm at about 204°C. In some embodiments, Form B is characterized in that its DSC thermogram comprises a melting endotherm at about 204°C.

[0170] In some embodiments, Form B is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form B is 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, the polymorphic purity of Form B is at least 90%. In some embodiments, the polymorphic purity of Form B is at least 92%. In some embodiments, the polymorphic purity of Form B is at least 94%. In some embodiments, the polymorphic purity of Form B is at least 96%. In some embodiments, the polymorphic purity of Form B is at least 98%. In some embodiments, the polymorphic purity of Form B is at least 99%.

[0171] C. Crystalline Form F

[0172] In some embodiments, the present disclosure relates to crystalline Form F of Compound 1. In some embodiments, the anhydrous crystalline form of Compound 1 is Form F. In some embodiments, Form F has one or more characteristics selected from the group consisting of:

[0173] 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;

[0174] b) Basically Figure 5A The XRPD pattern shown;

[0175] c) DSC thermogram curve, which includes an endothermic peak at about 203 °C;

[0176] d) Basically Figure 5B The DSC thermogram curve shown; and

[0177] e) Basically Figure 5C TGA curve shown.

[0178] In some embodiments, Form F is characterized in that its XRPD pattern comprises 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 is characterized in that its XRPD pattern comprises peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ and 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, 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. In some embodiments, crystalline Form F is characterized by being substantially as Figure 5A XRPD pattern depicted.

[0179] In some embodiments, Form F is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form F is 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, the polymorphic purity of Form F is at least 90%. In some embodiments, the polymorphic purity of Form F is at least 92%. In some embodiments, the polymorphic purity of Form F is at least 94%. In some embodiments, the polymorphic purity of Form F is at least 96%. In some embodiments, the polymorphic purity of Form F is at least 98%. In some embodiments, the polymorphic purity of Form F is at least 99%.

[0180] D. Crystalline Form G

[0181] 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 has one or more characteristics selected from the group consisting of:

[0182] 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

[0183] b) Basically Figure 5A XRPD pattern shown.

[0184] In some embodiments, Form G is characterized in that its XRPD pattern comprises 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 is characterized in that its XRPD pattern comprises peaks at 9.1 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, and 17.2 ± 0.5 degrees 2θ and 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, 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, the crystalline Form G is characterized by being substantially as Figure 5A XRPD pattern depicted.

[0185] In some embodiments, Form G is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form G is 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, the polymorphic purity of Form G is at least 90%. In some embodiments, the polymorphic purity of Form G is at least 92%. In some embodiments, the polymorphic purity of Form G is at least 94%. In some embodiments, the polymorphic purity of Form G is at least 96%. In some embodiments, the polymorphic purity of Form G is at least 98%. In some embodiments, the polymorphic purity of Form G is at least 99%.

[0186] E. Crystalline Form D

[0187] 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 has one or more characteristics selected from the group consisting of:

[0188] a) an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ;

[0189] b) Basically Figure 3AThe XRPD pattern shown;

[0190] c) DSC thermogram curve, which includes an endothermic peak at about 204 °C;

[0191] d) DSC thermogram curve, which includes an endothermic peak at about 127 °C;

[0192] e) Basically Figure 3B The DSC thermogram curve shown;

[0193] f) a TGA curve showing a loss of at least about 14 wt % between about 60° C. and about 150° C.; and

[0194] g) Basically Figure 3B TGA curve shown.

[0195] In some embodiments, Form D is characterized in that its XRPD pattern comprises peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ. In some embodiments, Form D is characterized in that its XRPD pattern comprises peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ and further comprises 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 in that its XRPD pattern comprises 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 being substantially as Figure 3A XRPD pattern depicted.

[0196] In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 14 wt % of Form D between about 60° C. and about 150° C. In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 14-15 wt % of Form D between about 60° C. and about 150° C. In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of about 14 wt % of Form D between about 60° C. and about 150° C. In some embodiments, Form D is characterized by substantially Figure 3B Thermogravimetric analysis (TGA) thermogram depicted.

[0197] In some embodiments, Form D is characterized by being substantially as Figure 3B Depicted differential scanning calorimetry (DSC) thermograms. In some embodiments, Form D is characterized in that its DSC thermogram comprises an endotherm at about 204°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises an endotherm at about 127°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises endotherms at about 127°C and about 204°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises a desolvation endotherm at about 127°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises a melting endotherm at about 204°C.

[0198] In some embodiments, Form D is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form D is 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, the polymorphic purity of Form D is at least 90%. In some embodiments, the polymorphic purity of Form D is at least 92%. In some embodiments, the polymorphic purity of Form D is at least 94%. In some embodiments, the polymorphic purity of Form D is at least 96%. In some embodiments, the polymorphic purity of Form D is at least 98%. In some embodiments, the polymorphic purity of Form D is at least 99%.

[0199] F. Crystalline Form E

[0200] In some embodiments, the crystalline form of Compound 1 is a solvate. In some embodiments, the solvate is nBuOH solvate.

[0201] 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:

[0202] 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;

[0203] b) Basically Figure 4AThe XRPD pattern shown;

[0204] c) DSC thermogram curve, which includes an endothermic peak at about 203 °C;

[0205] d) DSC thermogram curve, which includes an endothermic peak at about 87 °C;

[0206] e) Basically Figure 4B The DSC thermogram curve shown;

[0207] f) a TGA curve showing a loss of at least about 7 wt % between about 22° C. and about 100° C.; and

[0208] f) Basically Figure 4B TGA curve shown.

[0209] In some embodiments, Form E is characterized in that its XRPD pattern comprises 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 in that its XRPD pattern comprises peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, and 17.0 ± 0.2 degrees 2θ and 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, Form E is characterized in that its XRPD pattern comprises 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 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. In some embodiments, crystalline Form E is characterized by being substantially as Figure 4A XRPD pattern depicted.

[0210] In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA) thermogram showing a loss of at least about 7 wt % of Form E between about 22° C. and about 100° C. In some embodiments, Form E is characterized by being substantially as Figure 4B Thermogravimetric analysis (TGA) thermogram depicted.

[0211] In some embodiments, Form E is characterized by being substantially as follows Figure 4B Depicted differential scanning calorimetry (DSC) thermograms. In some embodiments, Form E is characterized in that its DSC thermogram comprises an endotherm at about 203°C. In some embodiments, Form E is characterized in that its DSC thermogram comprises an endotherm at about 87°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises endotherms at about 87°C and about 203°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises a desolvation endotherm at about 87°C. In some embodiments, Form D is characterized in that its DSC thermogram comprises a melting endotherm at about 203°C.

[0212] In some embodiments, Form E is substantially free of other polymorphic forms. In some embodiments, the polymorphic purity of Form E is 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, the polymorphic purity of Form E is at least 90%. In some embodiments, the polymorphic purity of Form E is at least 92%. In some embodiments, the polymorphic purity of Form E is at least 94%. In some embodiments, the polymorphic purity of Form E is at least 96%. In some embodiments, the polymorphic purity of Form E is at least 98%. In some embodiments, the polymorphic purity of Form E is at least 99%.

[0213] Pharmaceutical composition

[0214] In one aspect, the present invention provides a pharmaceutical composition, which is a solid dosage form comprising a solid form of Compound 1 as 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.

[0215] Solid dosage forms suitable for oral administration include solid formulations such as tablets, capsules, capsules, powders, lozenges (including liquid fills), sachets and the like.

[0216] The solid dosage forms disclosed herein include a carrier, which may include one or more pharmaceutically acceptable excipients, including but not limited to binders, surfactants, diluents or fillers, buffers, anti-adhesive agents, glidants, hydrophilic or hydrophobic polymers, retarders, stabilizers or stabilizers, disintegrants or ultra-micro disintegrants, dispersants, antioxidants, defoamers, fillers, flavors, colorants, lubricants, adsorbents, preservatives, plasticizers, coatings or sweeteners, or mixtures thereof, as well as other excipients known in the art. For example, the excipient may be a binder, such as microcrystalline cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, tragacanth gum or gelatin; a diluent, such as mannitol, microcrystalline cellulose, maltodextrin, starch or lactose; a disintegrant, such as alginic acid, PRIMOGEL ® , sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, 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, cetyl triethylammonium bromide, polyethylene oxide-polypropylene oxide copolymer, or CREMOPHOR ®EL; an antioxidant such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, tocopherol or tocopherol acetate, sodium sulfite or sodium metabisulfite, a coating comprising one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, methacrylate copolymers, cellulose acetate, hydroxypropyl methylcellulose acetate succinate, shellac; a sweetener such as sucrose, sucralose, acesulfame K, aspartame sodium or saccharin; or a flavoring such as mint, methyl salicylate or orange flavoring. Any well-known pharmaceutical excipients can be incorporated into the dosage form and can be found in the following documents: FDA's "Inactive Ingredients Guide", "Remington: The Science and Practice of Pharmacy", 22nd Edition, (Pharmaceutical Press, 2005); "Handbook of Pharmaceutical Excipients", 6th Edition (Pharmaceutical Press, 2009); all documents in the documents are incorporated by reference. In some embodiments, the solid dosage form disclosed herein includes any one or more of the following excipients: low moisture microcrystalline cellulose, silicified low moisture microcrystalline cellulose type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate and opadry AMB II 88A180040 white. In some embodiments, the solid dosage forms disclosed herein comprise: low moisture microcrystalline cellulose, silicified low moisture microcrystalline cellulose type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and opadry AMB II 88A180040 white. In some embodiments, the solid dosage forms disclosed herein comprise: low moisture microcrystalline cellulose, silicified low moisture microcrystalline cellulose type 90, mannitol, sodium starch glycolate, and sodium stearyl fumarate.

[0217] How to use

[0218] Compound 1 as described herein is generally designed to be a positive allosteric modulator of NMDA function, and thus is useful for treating and preventing, for example, CNS-related conditions in a subject.

[0219] In some embodiments, Compound 1 as described herein is generally designed to penetrate the blood-brain barrier (eg, designed to be transported across the blood-brain barrier). In some embodiments of the present disclosure, Compound 1 acts as a positive allosteric modulator (PAM) of NMDA and enhances NMDA receptor function.

[0220] In one aspect, the present disclosure provides a method for treating a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1 or a solid dosage form as disclosed herein.

[0221] 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 of Compound 1 or a solid dosage form as disclosed herein.

[0222] In one aspect, the present disclosure provides a method for preventing a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1 or a solid dosage form as disclosed herein.

[0223] 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 of Compound 1 or a solid dosage form as disclosed herein.

[0224] 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 of Compound 1 or a solid dose as disclosed herein.

[0225] In one aspect, the present disclosure provides a crystalline form of Compound 1 or a solid dosage form as disclosed herein for use in treating a disease, disorder, or condition requiring positive allosteric NMDA modulation in a subject.

[0226] In one aspect, a crystalline form of Compound 1 of the present disclosure or a solid dosage form as disclosed herein is used to treat a CNS-related condition in a subject.

[0227] In one aspect, the present disclosure provides a crystalline form of Compound 1 or a solid dosage form as disclosed herein for use in preventing a disease, disorder, or condition requiring positive NMDA modulation in a subject.

[0228] In one aspect, the present disclosure provides a crystalline form of Compound 1 or a solid dosage form as disclosed herein for use in preventing a CNS-related condition in a subject.

[0229] In one aspect, the present disclosure provides a crystalline form of Compound 1 or a solid dosage form as disclosed herein for use in inducing sedation or anesthesia in a subject.

[0230] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid dosage form as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject.

[0231] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid dosage form as disclosed herein for the manufacture of a medicament for treating a CNS-related condition in a subject.

[0232] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid dosage form as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring positive allosteric NMDA modulation in a subject.

[0233] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid dosage form as disclosed herein for the manufacture of a medicament for preventing a CNS-related condition in a subject.

[0234] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid dosage form as disclosed herein for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

[0235] In some embodiments, the condition is cancer. In some embodiments, the condition is diabetes. In some embodiments, the condition is a sterol synthesis disorder. In some embodiments, the condition is a gastrointestinal (GI) condition, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the GI, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. In some embodiments, the condition is inflammatory bowel disease.

[0236] In some embodiments, the condition is Smith-Lemli-Opitz Syndrome (SLOS). In some embodiments, the condition is desmosterolosis. In some embodiments, the condition is sitosterolemia. In some embodiments, the condition is cerebrotendinous xanthomatosis (CTX). In some embodiments, the condition is mevalonate kinase deficiency (MKD). In some embodiments, the condition is SC4MOL gene mutation (SMO deficiency). In some embodiments, the condition is Niemann-Pick disease. In some embodiments, the condition is autism spectrum disorder (ASD). In some embodiments, the condition is associated with phenylketonuria.

[0237] Exemplary conditions associated with 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), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis, and CNS conditions, e.g., as described herein.

[0238] Exemplary CNS conditions associated with positive NMDA modulation include, but are not limited to, 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 forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including disorders involving mutations in the Shank proteome (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome (Rett syndrome), syndrome), multiple sclerosis, steroidogenesis disorders, pain (including acute and chronic pain; headaches such as migraine), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet disease and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

[0239] In certain embodiments, the crystalline form of Compound 1 or a solid dose as disclosed herein can be used to induce sedation or anesthesia. In certain embodiments, the crystalline form of Compound 1 or a solid dose as disclosed herein can be used to treat or prevent adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, steroid synthesis disorders, pain, epileptic seizure disorders, stroke, traumatic brain injury, movement disorders and visual impairment, hearing loss and tinnitus. In some embodiments, the disease is Huntington's disease. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is an inflammatory disease (e.g., lupus).

[0240] In another aspect, provided is a method of 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 a crystalline form of Compound 1 or a solid dose as disclosed herein.

[0241] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure (e.g., a crystalline form of Compound 1) and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent, or they can also be administered in combination with other agents. The combined administration can be performed using any technique that is obvious to those skilled in the art, for example, including separate administration, sequential administration, simultaneous administration, and alternating administration.

[0242] Diseases and conditions

[0243] Movement disorders

[0244] Also described herein are methods for treating movement disorders. As used herein, "movement disorders" refer to various diseases and conditions associated with excessive movement disorders and associated muscle control abnormalities. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's syndrome (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0245] Tremor is an involuntary, sometimes rhythmic contraction and relaxation of muscles that can involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremor includes inherited, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (narcolepsy, tricyclic drugs, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (ie, rubrospongal tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, psychogenic tremor, or rubrospongal tremor.

[0246] Cerebellar tremor or intention tremor is a slow, widespread tremor of a limb that occurs after a purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, such as tumors, stroke, disease (e.g., multiple sclerosis, genetic degenerative disorders).

[0247] Dystonic tremors occur in individuals affected by dystonia (a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions). Dystonic tremors may affect any muscle in the body. Dystonic tremors occur irregularly and are often relieved by complete rest.

[0248] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild, and some are non-progressive, and can be slowly progressive, starting on one side of the body but usually affecting both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease as a person ages, but the severity may increase. Aggravated emotions, stress, fever, physical fatigue, or low blood sugar may trigger tremors and / or increase their severity. Symptoms usually progress over time and can be obvious and persistent after they occur.

[0249] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs, and patients may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor.

[0250] Parkinson's disease tremor is caused by damage to structures in the brain that control movement. Parkinson's disease tremor is often a precursor to Parkinson's disease and is often seen as a "ball rolling" movement of the hands, which may also affect the jaw, lips, legs and trunk. The onset of Parkinson's disease tremor usually begins after the age of 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0251] Physiologic tremors occur in normal individuals but are of no clinical significance. Physiologic tremors are seen in all voluntary muscle groups. Physiologic tremors can be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. The usual frequency of tremors is about 10 Hz.

[0252] Psychogenic or hysterical tremors can occur at rest or during postural or dynamic movements. People with psychogenic tremors may have conversion disorder or another psychiatric disorder.

[0253] Rubrostral tremor is characterized by a coarse, slow tremor that can be present at rest, in posture, and with intent. The tremor is associated with conditions that affect the red nucleus in the midbrain, typically an unusual stroke.

[0254] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinson's disease is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinson's disease shares the same symptoms as Parkinson's disease, but is a complex disorder rather than a progressive neurodegenerative disease.

[0255] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that result in abnormal, often repetitive movements or postures. Dystonic movements may be patterned, distorted, and may be trembling. Dystonia is often triggered or exacerbated by voluntary movements and is associated with overflow muscle activation.

[0256] Chorea is a neurological disorder characterized by jerky, involuntary movements that typically affect the shoulders, hips, and face.

[0257] Huntington's disease is a genetic disorder that causes nerve cells in the brain to fail. Symptoms include loss of control of movements, clumsiness and problems with balance. Huntington's disease can make it harder to walk, talk and swallow.

[0258] Ataxia is the loss of complete control over body movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0259] Myoclonus and startle are responses to sudden and unexpected stimulation, which may be sound, touch, vision, or vestibular stimulation.

[0260] A tic is an involuntary movement that is usually sudden, brief, repetitive, but without rhythm, often mimicking normal behavior and often occurring against the background of normal activity. Tics can be divided into motor tics, which are associated with movement, and vocal tics, which are associated with sound. Tics can be characterized as simple or complex. For example, a simple motor tic involves only a few muscles localized to a specific body part.

[0261] Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood characterized by multiple motor tics and at least one vocal tic.

[0262] Restless legs syndrome is a neurological sensorimotor disorder characterized by a strong urge to move the legs when at rest.

[0263] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and stiffness of the muscles, usually involving the lower back and legs. It usually results in a stiff-leg gait and exaggerated lumbar hyperflexion. Characteristic abnormalities in the activity of the sequential motor units of the paraxial muscles of the spine are usually observed on EMG recordings. Variants include "stiff limb syndrome," which produces focal stiffness, usually affecting the distal legs and feet.

[0264] Gait disorders are abnormalities in the pattern or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system responsible for the abnormal movement and include hemiplegic gait, diplegic gait, neuropathy gait, myopathy gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0265] Mood disorders

[0266] Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression due to a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0267] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), major depressive disorder, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel anxious and irritable. Clinical depression affects how an individual feels, thinks, and acts, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities and may feel as if life is not worth living.

[0268] Postpartum 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 sleeping and eating habits, loss of libido, crying episodes, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., refractory depression as described herein).

[0269] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression experience an increased risk of PND.

[0270] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and motivation, significant weight gain or increased appetite. Patients with AD may also have excessive sleep or sleepiness (hypersomnia), a sense of heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0271] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood that is more pronounced than sadness or loss, and excessive weight loss or excessive guilt.

[0272] Psychotic major depression (PMD) or psychotic depression denotes a major depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0273] Catatonic depression refers to major depressive disorder that involves disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, and be immobile or display meaningless or strange movements.

[0274] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which individuals have a seasonal pattern of depressive episodes in the fall or winter.

[0275] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These problems are less severe and tend to be more persistent (eg, at least 2 years).

[0276] Double depression is defined as a period of severe depressed mood (dysthymia) lasting at least 2 years and marked by a phase of major depressive disorder.

[0277] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0278] Recurrent brief depressive disorder (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting 2 weeks or less, and usually less than 2-3 days.

[0279] Minor depressive disorder or minor depression means depression in which at least 2 symptoms are present for 2 weeks.

[0280] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During mania, individuals may feel or appear unusually happy, energetic, or irritable. They often make poorly thought-out decisions with little regard for the consequences. The need for sleep is often reduced. During depression, there may be tearfulness, poor eye contact with others, and a negative outlook on life. People with this condition have a high risk of suicide within 20 years, greater than 6%, while the incidence of self-harm is 30-40%. Other mental health issues, such as anxiety disorders and substance use disorders are often associated with bipolar disorder.

[0281] Depression due to a chronic medical condition means depression caused by a chronic medical condition (such as cancer or chronic pain, chemotherapy, chronic stress).

[0282] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) have not relieved the depressive symptoms of an individual with treatment-resistant depression. In some cases, an individual with treatment-resistant depression improves symptoms but relapses. Refractory depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or antianxiety drugs), as well as nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0283] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual preoccupations with suicide. The range of suicidal ideation varies greatly, from, for example, fleeting thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social situations, preoccupying oneself with death, feeling confused or hopeless about a situation, increasing use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if they will never be seen again.

[0284] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, lack of positive thoughts or plans, excessive sleep, excessive eating, decreased appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0285] Anxiety disorders

[0286] Methods for treating anxiety disorders are provided herein. Anxiety disorders are an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a variety of anxiety disorders.

[0287] Generalized anxiety disorder is a common chronic condition characterized by long-term anxiety that is not focused on any particular object or situation. People with generalized anxiety disorder experience nonspecific, persistent fears and worries and an excessive focus on everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0288] People with panic disorder experience brief episodes of intense fear and apprehension, often characterized by shaking, trembling, confusion, dizziness, nausea, and difficulty breathing. According to the APA, a panic attack is a sudden onset of fear or discomfort that peaks within ten minutes, can last for hours, and can be triggered by stress, fear, or even exercise; but the specific cause is not always obvious. In addition to recurring, unexpected panic attacks, a diagnosis of panic disorder requires that the attack have long-term consequences: worry about the potential effects of the attack, persistent fear of future attacks, or significant changes in behavior related to the attack. As a result, people with panic disorder experience symptoms even outside of specific panic attacks. People with panic disorder often notice changes in their normal heartbeat and believe that they have a heart problem or are about to have another panic attack. In some cases, a high level of vigilance (hypervigilance) of bodily functions occurs during a panic attack, in which any perceived physiological changes are interpreted as potentially life-threatening (i.e., extreme hypochondriasis).

[0289] Obsessive-compulsive disorder is a type of anxiety disorder characterized by repetitive compulsions (distressing, persistent, and intrusive thoughts or images) and compulsions (the urge to perform specific behaviors or rituals). OCD thought patterns can be compared to superstitions in that it involves believing in a cause-and-effect relationship that does not actually exist. The process is often completely illogical; for example, the compulsion to follow a certain pattern may be used to relieve an obsession with impending harm. In many cases, the compulsion is completely inexplicable and is simply a nervous urge to complete a ritual. In a few cases, people with OCD may have obsessions without obvious compulsions; even fewer have only compulsions.

[0290] Phobias are the largest category of anxiety disorders and include all fears and anxieties that are triggered by specific stimuli or situations. The sufferer typically anticipates frightening consequences from encountering the phobic object, which can be any animal, place, or bodily fluid.

[0291] Post-traumatic stress disorder, or PTSD, is an anxiety disorder caused by a traumatic experience. Post-traumatic stress reactions can result from extreme situations, such as combat, rape, hostage situations, or even serious accidents. Long-term (chronic) exposure to severe stressors can also lead to the condition, for example, a soldier who endures individual combat situations but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0292] epilepsy

[0293] Epilepsy is a brain disorder characterized by long-term recurrent seizures. Types of epilepsy include, but are not limited to, systemic epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal seizures during awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0294] Epilepsy

[0295] Epileptogenesis is the process by which a normal brain gradually develops into epilepsy (a chronic condition characterized by seizures). Epileptogenesis results from neuronal damage caused by an initial insult (e.g., status epilepticus).

[0296] Status epilepticus (SE)

[0297] Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic lateral epileptic discharges. Convulsive status epilepticus is characterized by the occurrence of convulsive status epilepticus attacks, and may include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. The treatment of early status epilepticus adopts first-line therapy. Established status epilepticus is characterized by the continued onset of status epilepticus despite the use of first-line therapy, and therefore second-line therapy is applied. Refractory status epilepticus is characterized by the continued onset of status epilepticus despite the use of first-line and second-line therapy, and general anesthetics are generally applied. Super-refractory status epilepticus is characterized by the continued onset of status epilepticus after 24 hours or more of treatment with first-line therapy, second-line therapy, and general anesthetics.

[0298] Non-convulsive status epilepticus can 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 absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus or typical absence non-convulsive status epilepticus, late absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus or typical absence non-convulsive status epilepticus.

[0299] Seizures

[0300] A seizure is a physical symptom or behavior change that follows an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is a rapid, uncontrolled shaking of a person's body. During a convulsion, a person's muscles repeatedly contract and relax.

[0301] Based on the type of behavior and brain activity, seizures are divided into two main categories: generalized and partial (also called localized or focal). Classifying seizure types helps doctors diagnose whether a person has epilepsy.

[0302] Whereas generalized seizures are produced by electrical impulses from the entire brain, partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain where the seizure occurs is sometimes called the focus.

[0303] There are six types of generalized seizures. The most common and violent, and the best known, are the generalized convulsions, also called grand mal seizures. In this type of seizure, the person loses consciousness and usually collapses. After the loss of consciousness, the whole body becomes rigid (called the "tonic" phase of the seizure) for 30 to 60 seconds, followed by violent convulsions (the "clonic" phase) for 30 to 60 seconds, after which the person falls into a deep sleep (the "postictal" or post-seizure phase). During a grand mal seizure, injuries and accidents can occur, such as tongue biting and urinary incontinence.

[0304] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Sufferers are usually children, who typically stop moving and stare blankly. These seizures start and end suddenly and can occur several times a day. Sufferers are usually unaware that they are having a seizure, except that they may be aware of "losing time."

[0305] Myoclonic seizures involve sporadic twitching, usually on both sides of the body. Patients sometimes describe the twitching as brief electric shocks. If severe, these seizures may cause objects to be dropped or thrown involuntarily.

[0306] Clonic seizures are repetitive, rhythmic twitches that involve both sides of the body at the same time.

[0307] Tonic seizures are characterized by muscle rigidity.

[0308] Atonic seizures involve a sudden and generalized loss of muscle tone, especially in the arms and legs, often resulting in a fall.

[0309] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; prolonged seizures; recurrent seizures; status epilepticus, such as: refractory convulsive status epilepticus, non-convulsive status epilepticus; 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; affective seizures; focal seizures; gelatinous seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; large bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvan seizures seizure); visual reflex seizure; or withdrawal seizure. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox-Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome, or PCDH19 female pediatric epilepsy.

[0310] Sterol synthesis disorders

[0311] In one embodiment, the present invention describes a method for treating sterol synthesis disorder. Cholesterol plays a vital role in growth and development. It is a membrane lipid and a precursor of many molecules, which play an important role in cell growth and differentiation, protein glycosylation and signal transduction pathways. The biosynthesis of cholesterol involves a variety of enzymes and intermediates. The disease caused by the deficiency of any enzyme involved in cholesterol biosynthesis can lead to the accumulation of intermediates and the imbalance of biomacromolecules, thereby causing diseases including congenital skeletal deformities, facial feature deformities, psychomotor retardation and dysplasia. In one embodiment, compounds as described herein can be used to treat sterol synthesis disorder or the symptoms of sterol synthesis disorder, such as NMDA receptor modulating compounds as described herein, to the subject suffering from sterol synthesis disorder. Other disease descriptions are as follows.

[0312] Smith-Lemli-Opitz syndrome

[0313] In one embodiment, methods for treating Smith-Lemly-Opitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency) are described herein. SLOS is an inborn error in cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, hyperesthesia, behavioral stereotypy, dysmorphic facial features, and syndactyly of the second / third toes, one of the characteristics of the disease is a decrease in the level of a brain sterol (24(S)-hydroxycholesterol). SLOS is an autosomal recessive genetic disease that results in low or low-to-normal plasma cholesterol levels and elevated levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC) due to a deficiency in the last enzyme in the cholesterol synthesis pathway. 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 drugs that promote cholesterol production and / or proliferation; and reduce the accumulation of 7DHC and 8DHC, a potentially toxic precursor of cholesterol.

[0314] Cholesterolosis

[0315] Decholesterolemia is a dehydrocholesterol reductase deficiency disorder and has a phenotype similar to SLOS. In one embodiment, described herein are methods of treating decholesterolemia using the compounds described herein.

[0316] Sitosterolemia

[0317] Sitosterolemia is a rare autosomal recessive disorder caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia promotes intestinal absorption of plant sterols and cholesterol. Patients often have tendon and tuberous xanthomas and premature coronary artery disease. In one embodiment, methods of treating sitosterolemia with the compounds described herein are described herein.

[0318] Cerebrotendinous xanthomatosis (CTX)

[0319] In one embodiment, methods of treating cerebrotendinous xanthomas (also known as cerebrocholesterolosis or Van Bogaert-Scherer-Epstein syndrome) with the compounds described herein are described herein. CTX can be caused by mutations in the CYP27A1 gene, which produces sterol 27-hydroxylase. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid), which are important for the absorption of fats in the intestine. Enzyme dysfunction may lead to cholesterol accumulation in tissues. CTX is characterized by childhood diarrhea, cataracts, tendon xanthomas, intellectual impairment, and motor abnormalities in adults.

[0320] Mevalonate kinase deficiency syndrome (MKD)

[0321] Mevalonate kinase deficiency (also known as mevalonic aciduria, a more severe form of MKD, or hyper-IgD syndrome (HIDS or hyperimmunoglobulinemia D) with periodic fever syndrome, a more benign form of MKD) causes mevalonic acid to accumulate in the urine due to insufficient mevalonate kinase activity. MKD may cause developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and overall poor development. Mevalonic aciduria is characterized by physical and mental developmental delay, poor development, recurrent fever with vomiting and diarrhea, enlarged liver, spleen and lymph nodes, microcephaly (small head circumference), cataracts, low muscle tone, short stature, distinct facial features, ataxia, and anemia. HIDS is characterized by recurrent fever with swollen lymph nodes, joint pain, gastrointestinal problems, and rash. In one embodiment, described herein are methods for treating MKD with the compounds described herein.

[0322] SC4MOL gene mutation (SMO deficiency)

[0323] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthetic 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, which can be detected in blood, skin scrapings, or primary skin fibroblasts. In one embodiment, described herein are methods for treating SMO deficiency with the compounds described herein.

[0324] Niemann-Pick disease

[0325] Niemann-Pick disease is a lysosomal storage disorder caused by a gene mutation that affects metabolism. Niemann-Pick disease results in an abnormal buildup of cholesterol and other fatty substances (lipids) because the body is unable to transport these substances. The buildup damages the affected area.

[0326] Autism

[0327] In one embodiment, methods for treating autism spectrum disorder or autism are described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex brain development disorders. Autism is typically characterized by difficulties in social interaction, such as difficulties in verbal and nonverbal communication. Individuals with autism also often have repetitive behaviors. Autism may be associated with intellectual disability, motor coordination and attention difficulties, and physical health problems (e.g., sleep and gastrointestinal disorders). Individuals with autism may also excel in visual skills, music, mathematics, and art. Autism may refer to autistic disorder, childhood disorganization disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Autism may also refer to monogenic causes of autism, such as synaptopathy, such as Rett syndrome, fragile X syndrome, and Angelman syndrome.

[0328] Conditions associated with phenylketonuria

[0329] In one embodiment, methods for treating conditions associated with phenylketonuria (e.g., cognitive impairment) with compounds described herein are described herein. Phenylketonuria may lead to hypocholesterolemia and reduced vitamin D levels. Compared with subjects without phenylketonuria, subjects with phenylketonuria have been found to have reduced total low-density cholesterol and 25-hydroxyvitamin D (Clin. Chim. Acta 2013, 416: 54-59). In subjects with phenylketonuria, 24S-hydroxycholesterol and 27S-hydroxycholesterol and 7α-hydroxycholesterol (e.g., representing peripheral and liver cholesterol elimination, respectively) have been shown to be significantly reduced, while in subjects with phenylketonuria, 7β-hydroxycholesterol (e.g., reflecting oxidative stress) is significantly increased. In subjects with phenylketonuria, changes in 24S-OHC and 7β-hydroxycholesterol levels are associated with phenylalanine levels, and 27S-hydroxycholesterol levels may be associated with 25-hydroxyvitamin D levels.

[0330] Process for preparing the crystalline form

[0331] In one aspect, the present disclosure provides a method of preparing a crystalline form of Compound 1 as disclosed herein.

[0332] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0333] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0334] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0335] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0336] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising the steps of: a) adding Compound 1 to a solvent to form a solution; b) adding the solution to an antisolvent; c) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is BuOH. In some embodiments, the antisolvent is n-heptane.

[0337] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0338] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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; c) cooling the filtrate to about −20° C.; d) precipitating a solid; and e) isolating the solid. In some embodiments, the solvent is acetone.

[0339] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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 rate in step b) is selected from the group consisting of 2°C / min, 10°C / min, and 50°C / min.

[0340] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0341] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0342] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising the following steps: 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.

[0343] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: 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.

[0344] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising the steps of: 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 antisolvent; d) adding Form X of Compound 1 seeds and aging the mixture at about 50°C; e) cooling the mixture to about 20°C for at least 3 hours and maintaining the mixture at 20°C (optionally wet milling) to precipitate a solid; and f) isolating the solid. In some embodiments, the solvent is acetone. In some embodiments, the antisolvent is acetone / water. In some embodiments, the antisolvent is acetone / water (1:1 v / v).

[0345] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: a) adding Form E of Compound 1 to acetone to form a mixture; b) heating the mixture to about 50°C; c) adding acetone / water antisolvent (1:1 v / v); d) adding Form X of Compound 1 seeds and aging the mixture at about 50°C; e) adding acetone / water antisolvent; f) cooling the mixture to about 20°C over at least 3 hours and maintaining the mixture at 20°C (optionally wet milling) to precipitate solids; and g) isolating the solids.

[0346] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: a) adding crude Compound 1 to a solvent to form a mixture and heating to about 80°C; b) concentrating the mixture by distillation; c) adding a solvent to the mixture; d) adjusting the temperature of the mixture to about 80°C; e) adding Form E of Compound 1 seeds; 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.

[0347] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, the method comprising the following steps: a) adding crude Compound 1 to n-BuOH to form a mixture and heating to about 80°C; b) concentrating the mixture by distillation; c) adding n-BuOH to the mixture; d) adjusting the temperature of the mixture to about 80°C; e) adding Form E of Compound 1 seed crystals; 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.

[0348] Examples

[0349] In order that the invention described herein may be more fully understood, the following examples are set forth. These examples are provided for illustration of the crystalline solid forms provided herein and should not be construed in any way as limiting the scope thereof.

[0350] Example 1. Instruments and methods

[0351] AX-Ray Powder Diffraction (XRPD)

[0352] X-ray diffraction patterns as 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. Table 1 lists the XRPD parameters used.

[0353] Table 1. XRPD test parameters

[0354]

[0355] B. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0356] TGA data were collected using a TA Discovery 550 / Q500 TGA from TA Instrument. DSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated using an indium reference standard and the TGA was calibrated using a nickel reference standard. Detailed parameters are provided in Table 2:

[0357] Table 2. Parameters of TGA and DSC tests

[0358]

[0359] C. Polarized Light Microscopy (PLM) and Hot Stage

[0360] Polarized light micrographs were captured at room temperature using a Nikon DS-Fi2 upright microscope. The hot stage was performed on a Linkam.

[0361] D. Chemical purity determination (HPLC)

[0362] Purity analysis and stoichiometry were performed using an Agilent 1100 HPLC as detailed in Table 3:

[0363] Table 3. HPLC method used for purity testing

[0364]

[0365] E. Dynamic Vapor Sorption (DVS)

[0366] DVS was measured using an SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25°C was calibrated for the deliquescent points of LiCl, Mg(NO3)2, and KCl. The parameters used for the DVS testing are provided in Table 4.

[0367] Table 4. Parameters of DVS test

[0368]

[0369] F. Nuclear Magnetic Resonance (NMR)

[0370] Solution NMR spectra were collected on a Bruker 400M NMR spectrometer. Samples were prepared in DMSO-d6.

[0371] Example 2. Abbreviations

[0372] Solvent abbreviations are provided in Table 5.

[0373] Table 5. Abbreviations

[0374]

[0375] Example 3. Polymorph Screening

[0376] Polymorph screening experiments were performed using different crystallization or solid transformation methods. Table 6 summarizes the methods used and the crystalline forms identified.

[0377] Table 6. Methods and crystalline forms

[0378]

[0379] A. Anti-solvent addition

[0380] About 15 mg of the starting material (Compound 1) was dissolved in 0.1-0.9 mL of solvent to obtain a clear solution. The solution was magnetically stirred and then 0.2 mL of antisolvent was added in each step until a precipitate appeared or the total amount of antisolvent reached 15.0 mL. The results in Table 7 (below) show the form obtained.

[0381] Table 7. Summary of antisolvent addition experiments

[0382]

[0383] *After stirring the clear solution at -20 °C, a solid was obtained.

[0384] B. Slurry at room temperature

[0385] Slurry conversion experiments were performed in different solvent systems at room temperature. About 15 mg of the starting material (Compound 1) was suspended in 0.2 mL of solvent in a glass vial. After magnetic stirring of the suspension at room temperature for 7 days, the remaining solid was separated. The results are summarized in Table 8 below.

[0386] Table 8. Summary of slurry conversion experiments performed at room temperature

[0387]

[0388] C. Slurry at 40°C

[0389] Slurry conversion experiments were also performed in different solvent systems at 40°C. About 10 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a glass vial. After the suspension was stirred at 40°C for about 7 days, the remaining solid was separated. The results are summarized in Table 9.

[0390] Table 9. Summary of slurry conversion experiments at 40 °C

[0391]

[0392] D. Solid vapor diffusion

[0393] Solid vapor diffusion experiments were performed using different solvents. Approximately 10 mg of the starting material (Compound 1) was weighed into a 3 mL vial, which was placed in a 20 mL vial with 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.

[0394] Table 10. Summary of solid vapor diffusion experiments

[0395]

[0396] E. Liquid vapor diffusion

[0397] About 15 mg of the starting material (Compound 1) was dissolved in an appropriate solvent to obtain a clear solution in a 3 mL vial. This solution was then placed in a 20 mL vial with 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.

[0398] Table 11. Summary of liquid vapor diffusion experiments

[0399]

[0400] F. Slow evaporation

[0401] Briefly, about 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 for the following steps. The visually clear solution was filtered using a Parafilm with 6 pinholes. ® Cover and allow to evaporate at room temperature. The results are summarized in Table 12.

[0402] Table 12. Summary of slow evaporation experiments

[0403]

[0404] G. Slow cooling

[0405] About 20 mg of the starting material (Compound 1) was suspended in 0.5-1.0 mL of solvent in a 3 mL glass vial at room temperature. The suspension was then heated to 50°C, equilibrated for about two hours and filtered using a PTFE membrane (pore size of 0.22 μm). The filtrate was slowly cooled to 5°C at a rate of 0.1°C / min. No solid was obtained in any system, and the solution was then transferred to -20°C. If no precipitation was observed, the solution was subjected to evaporation at room temperature. The results are summarized in Table 13.

[0406] Table 13. Summary of slow cooling experiments

[0407]

[0408] H. Heating experiment

[0409] About 10 mg of the starting material (Compound 1) was weighed into the DSC pan. The sample was heated to 205°C at 30°C / min and then cooled to 25°C at different rates (2, 10, 50°C / min). The heated samples were tested by XRPD. The results are summarized in Table 14.

[0410] Table 14. Summary of heating-cooling experiments

[0411]

[0412] I. High temperature slurry

[0413] High temperature slurry conversion experiments were performed at 90°C in different solvent systems. About 100 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a glass vial. After magnetic stirring of the suspension at 90°C for 24 hours, the remaining solid was separated for XRPD analysis. The results are summarized in Table 15.

[0414] Table 15. Summary of high temperature slurries

[0415]

[0416] J. Wet grinding

[0417] About 20 mg of Form A and 0.2 mL of solvent were added to a mortar and ground for 10 minutes. The remaining solid was tested by XRPD. The results are summarized in Table 16.

[0418] Table 16. Summary of wet grinding

[0419]

[0420] Example 4

[0421] Several crystalline forms were obtained through screening, including two anhydrates (Forms A and B), two hydrates (Forms X and D), and one solvate (Form E). Detailed characterization data for each form are provided in Table 17.

[0422] Table 17. Characterization of crystalline forms

[0423]

[0424] Figure 1A-5A XRPD patterns for each form are provided in. These crystalline forms exhibit suitable properties for preparing solid dosage forms (e.g., chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, milling properties, and stability during tableting).

[0425] Example 5. Preparation and characterization of Form A

[0426] Form A was used directly for polymorph screening. Figure 1A The XRPD pattern of Form A is provided in , and the characteristic peaks are summarized in Table 18. The chemical purity of Form A is about 98% as determined by HPLC. Figure 1B TGA and DSC data for Form A are provided in and show a weight loss of 0.04% up to 190° C. and an endothermic peak due to melting at 203.0° C. (peak temperature). Based on these results, Form A is believed to be an anhydrate.

[0427] The crystals disappeared after heating to 205°C, indicating evaporation after melting. Figure 1C To investigate the solid form stability as a function of humidity, a DVS isotherm was collected for Form A at 25°C. The results showed a water uptake of 0.05% at 25°C / 80% RH with no form change after DVS testing. Figure 1D and Figure 1E , indicating that Form A is non-hygroscopic.

[0428] Table 18. Observed XRPD Peaks of Form A

[0429]

[0430] Example 6: Preparation and Characterization of Form B

[0431] Form B is produced by heating Form X. Figure 2A The XRPD pattern of Form B is shown in , and the characteristic peaks are summarized in Table 19. The chemical purity of Form B is about 99% as determined by HPLC. Figure 2BTGA and DSC data for Form B are provided in and show a weight loss of 0.2% up to 150° C. The DSC data show a sharp melting peak at 203.7° C. (peak temperature). Given these results, Form B is believed to be an anhydrate.

[0432] Table 19. Observed XRPD Peaks of Form B

[0433]

[0434] Example 7: Preparation of Form X

[0435] Form A was prepared by mixing with EtOH / H2O (0.927 / 0.073, a w =0.4) to produce form X.

[0436] Example 8: Preparation and Characterization of Form D

[0437] Form D is produced by vacuum drying Form X. Figure 3A The XRPD pattern of Form D is provided in , and the characteristic peaks are summarized in Table 20. The chemical purity of Form D is about 98% as determined by HPLC. Figure 3B TGA and DSC data for Form D are provided in and show a weight loss of 13.8% up to 150°C and a desolvation endotherm at 127.1°C (peak temperature) followed by a possible melting peak at 204.0°C (peak temperature). After heating to 150°C and then cooling to room temperature under nitrogen and re-exposure to ambient conditions, Form D converts to Form A (see Figure 3C ).

[0438] Table 20. Observed XRPD Peaks of Form D

[0439]

[0440] Example 9: Preparation and Characterization of Form E

[0441] Form E was generated by liquid diffusion in BuOH / n-heptane at room temperature. Figure 4A The XRPD pattern of Form E is provided in , and the characteristic peaks are summarized in Table 21. The chemical purity of Form E is about 98% as determined by HPLC. Figure 4BTGA and DSC data for Form E are provided in and show a weight loss of 7.2% up to 100°C and a desolvation endotherm at 86.7°C (peak temperature) followed by a possible melting peak at 203.1°C (peak temperature). After heating to 140°C and then cooling to room temperature under nitrogen and re-exposure to ambient conditions, Form E converts to Form B (see Figure 4C ). As in Figure 4D Through 1 Form E is believed to be an n-butanol solvate, as evidenced by the presence of n-butanol methylene protons detected by H NMR at ~3.7 ppm (1.5:1, n-butanol / API molar ratio).

[0442] Table 21. Observed XRPD Peaks of Form E

[0443]

[0444] Example 10: Preparation and Characterization of Form F

[0445] Form F is produced by the following process:

[0446] 1.1 Conversion at different concentrations at 80°C

[0447] Three slurries were set up at 50 g, 100 g, and 150 g of BuOH solvate of compound 1 / L heptane at 1-2 mL scale. The slurries were placed on a temperature controlled shaker at 80°C and stirred at 600 rpm overnight. After overnight conditioning, the wet cake in the slurries was tested by XRPD, which all gave patterns consistent with the target anhydrous Form F.

[0448] The 150 g / L slurry was very thick and cake-like, while the 100 g / L and 50 g / L slurries were homogenous and free-flowing slurries. 100 g / L is a suitable concentration for the slurry conversion process.

[0449] 1. Conversion kinetics at 280°C

[0450] The conversion kinetics at 80°C were probed from 2 mL tests at -100 g / L (in a T controlled shaker). Samples taken at the 1.5 hour and 3 hour time points (0.5 mL slurry samples) were centrifuged to separate the solids, and the wet cake solids were immediately analyzed by XRPD.

[0451] XRPD results showed (data not shown) that the conversion process was completed very quickly. At the 1.5 hour time point, the sample had converted to anhydrous Form F with high crystallinity.

[0452] 1.3 Characterization of slurry conversion products after drying at 40 °C

[0453] The wet cake of anhydrous Form F converted from the slurry over 4 days at 60°C 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 XRPD characteristic peaks are summarized in Table 22.

[0454] The sample after overnight drying gave the same XRPD pattern as the wet cake, indicating the feasibility of removing n-heptane in a vacuum oven at elevated temperatures. After drying overnight at 40 °C, no residual solvent (BuOH or n-heptane) was detected in the sample by TGA, DSC.

[0455] Table 22. Observed XRPD Peaks of Form F

[0456]

[0457] Example 11: Preparation and Characterization of Form G

[0458] XRPD

[0459] Form G is characterized by XRPD (see Figure 5A ; and Table 23).

[0460] Table 23. Observed XRPD Peaks of Form G

[0461]

Claims

1. A crystalline form of Compound 1: Compound 1.

2. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is selected from the group consisting of: 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) 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.

3. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is selected from the group consisting of: 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; b) crystalline 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; c) crystalline 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; 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, 17.0 ± 0.2, and 21.4 ± 0.2 degrees 2θ; e) crystalline 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; and f) crystalline 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.

4. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is selected from the group consisting of: a) crystalline 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; b) crystalline 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; c) crystalline 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; d) crystalline 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; e) crystalline 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; and f) crystalline 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.

5. The crystalline form according to any one of claims 1 to 4, wherein the crystalline form is an anhydrate.

6. The crystalline form according to claim 5, wherein the crystalline form is crystalline form A, characterized in that Its XRPD pattern comprises peaks at 15.3 ± 0.2, 16.6 ± 0.2 and 17.9 ± 0.2 degrees 2θ.

7. The crystalline form of claim 6, wherein the XRPD pattern 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.

8. The crystalline form according to claim 7, wherein the crystalline form is crystalline form A, characterized in that Its XRPD pattern comprises 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 crystalline form according to any one of claims 1 to 8, wherein the crystalline form is crystalline form A, characterized in that An XRPD pattern substantially as depicted in Figure 1A.

10. The crystalline form according to any one of claims 1 to 9, wherein the crystalline form has a thermogravimetric analysis (TGA) thermogram substantially as depicted in Figure 1B.

11. The crystalline form of any one of claims 1 to 10, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 1B.

12. The crystalline form of claim 11, wherein the DSC thermogram comprises an endothermic peak at about 203°C.

13. The crystalline form according to claim 5, wherein the crystalline form is crystalline form B, characterized in that Its XRPD pattern comprises peaks at 14.4 ± 0.2, 16.8 ± 0.2 and 18.5 ± 0.2 degrees 2θ.

14. The crystalline form of claim 13, wherein the XRPD pattern 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.

15. The crystalline form according to claim 14, wherein the crystalline form is crystalline form B, characterized in that Its XRPD pattern comprises 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 crystalline form according to any one of claims 1 to 5 or 13 to 15, wherein the crystalline form is crystalline form B, characterized in that An XRPD pattern substantially as depicted in Figure 2A.

17. The crystalline form of any one of claims 1 to 5 or 13 to 16, wherein the crystalline form has a TGA thermogram substantially as depicted in Figure 2B.

18. The crystalline form of any one of claims 1 to 5 or 13 to 17, wherein the crystalline form has a DSC thermogram substantially as depicted in Figure 2B.

19. The crystalline compound of claim 18, wherein the DSC thermogram comprises an endothermic peak at about 204°C.

20. The crystalline form according to any one of claims 1 to 4, wherein the crystalline form is a solvate.

21. The crystalline form of claim 20, wherein the crystalline form is a hydrate.

22. The crystalline form of claim 21, wherein the crystalline form is a monohydrate.

23. The crystalline form according to any one of claims 1 to 4 or 20 to 22, wherein the crystalline form is crystalline form D, characterized in that Its XRPD pattern comprises peaks at 15.2 ± 0.2, 17.4 ± 0.2 and 17.7 ± 0.2 degrees 2θ.

24. The crystalline form of claim 23, wherein the XRPD pattern further comprises 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 crystalline form of claim 24, wherein the crystalline form is crystalline form D, characterized in that Its XRPD pattern has 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 crystalline form according to any one of claims 1 to 4, 20 to 25, wherein the crystalline form is crystalline form D, characterized in that An XRPD pattern substantially as depicted in Figure 3A.

27. The crystalline form of any one of claims 1 to 4, 20 to 26, wherein the crystalline form has a TGA thermogram substantially as depicted in Figure 3B.

28. The crystalline form of any one of claims 1 to 4, 20 to 27, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram substantially as in Figure 3B.

29. The crystalline form of claim 28, wherein the DSC thermogram comprises an endothermic peak at about 204°C.

30. The crystalline form of claim 28 or 29, wherein the DSC thermogram comprises an endothermic peak at about 127°C.

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

32. The crystalline form of claim 31, wherein the crystalline form is crystalline Form E, characterized in that Its XRPD pattern comprises peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2 and 17.0 ± 0.2 degrees 2θ.

33. The crystalline form of claim 32, wherein the XRPD pattern 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.

34. The crystalline form of claim 32, wherein the crystalline form is crystalline Form E, characterized in that Its XRPD pattern has 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 crystalline form according to any one of claims 1 to 4, 20 or 31 to 34, wherein the crystalline form is crystalline Form E, characterized in that An XRPD pattern substantially as depicted in Figure 4A.

36. The crystalline form of any one of claims 1 to 4, 20, or 31 to 35, wherein the crystalline form has a TGA thermogram substantially as depicted in Figure 4B.

37. The crystalline form of any one of claims 1 to 4, 20, or 31 to 36, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 4B.

38. The crystalline form of claim 37, wherein the thermogram comprises an endothermic peak at about 203 °C.

39. The crystalline form of claim 37 or 38, wherein the DSC thermogram comprises an endothermic peak at about 87°C.

40. The crystalline form of claim 5, wherein the crystalline form is crystalline Form F, characterized in that Its XRPD pattern comprises peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5 and 22.9 ± 0.5 degrees 2θ.

41. The crystalline form of claim 40, wherein the XRPD pattern 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.

42. The crystalline form of claim 41, wherein the crystalline form is crystalline Form F, characterized in that Its XRPD pattern comprises 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 crystalline form according to any one of claims 1 to 4 and 40 to 42, wherein the crystalline form is crystalline Form F, characterized in that An XRPD pattern substantially as depicted in Figure 5A.

44. The crystalline form of claim 5, wherein the crystalline form is crystalline Form G, characterized in that Its XRPD pattern comprises peaks at 9.1 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5 and 17.2 ± 0.5 degrees 2θ.

45. The crystalline form of claim 44, wherein the XRPD pattern 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.

46. ​​The crystalline form of claim 44, wherein the crystalline form is crystalline Form G, characterized in that Its XRPD pattern comprises 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 crystalline form according to any one of claims 1 to 4 and 44 to 46, wherein the crystalline form is crystalline Form G, characterized in that An XRPD pattern substantially as depicted in Figure 5A.

48. The crystalline form of claim 1, wherein the crystalline form is selected from the group consisting of: a) Crystalline form A, characterized in that An XRPD pattern substantially as depicted in Figure 1A; b) crystalline Form B characterized by an XRPD pattern substantially as depicted in Figure 2A; c) crystalline Form D characterized by an XRPD pattern substantially as depicted in Figure 3A; d) crystalline Form E characterized by an XRPD pattern substantially as depicted in Figure 4A; e) crystalline Form F characterized by an XRPD pattern substantially as depicted in Figure 5A; and f) Crystalline Form G characterized by an XRPD pattern substantially as depicted in Figure 5A.

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

50. A method of treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of the crystalline form of any one of claims 1 to 48 or the solid dosage form of claim 48.

51. The method of claim 50, wherein the CNS-related condition is selected from the group consisting of adjustment disorders, 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 depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including disorders involving mutations in the Shank proteome), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis complex), 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 forms of epilepsy such as Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease), disease and Parkinson's disease) and tinnitus.

52. A method of inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of the crystalline form of any one of claims 1 to 48 or the solid dosage form of claim 49.

53. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) dissolving compound 1 in at least one solvent to form a solution; b) adding an antisolvent until a precipitate forms; and c) isolating the precipitate.

54. The method of claim 53, wherein the solvent is selected from the group consisting of THF, 1,4-dioxane, and MEK.

55. The method of claim 53 or 54, wherein the antisolvent is selected from the group consisting of H2O and ACN.

56. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to allow precipitation of solids; and c) isolating the solid.

57. The method of claim 56, wherein the solvent is selected from the group consisting of: DME, acetone, nBuOH, EtOAc, IPAc, BuOAc, diethyl ether, and ACN.

58. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at about 40° C. to precipitate solids; and c) isolating the solid.

59. The method of claim 58, wherein the solvent is selected from the group consisting of IPAc, BuOAc, ACN, and n-heptane.

60. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: 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.

61. The method of claim 60, wherein the solvent is selected from the group consisting of: DME, MEK, diethyl ether, and t-BuOH.

62. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a solution; b) adding the solution to an antisolvent; c) aging the mixture at room temperature to precipitate solids; as well as d) isolating the solid.

63. The method of claim 62, wherein the solvent is BuOH.

64. The method of claim 62 or 63, wherein the antisolvent is n-heptane.

65. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: 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) allowing solids to precipitate; and e) isolating the solid.

66. The method of claim 65, wherein the solvent is selected from the group consisting of IPAc and t-BuOH.

67. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: 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) allowing solids to precipitate; and f) isolating the solid.

68. The method of claim 67, wherein the solvent is acetone.

69. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: 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.

70. The method of claim 69, wherein 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.

71. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) aging the mixture at about 90° C. to precipitate solids; and c) isolating the solid.

72. The method of claim 71, wherein the solvent is n-heptane.

73. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding compound 1 to a solvent to form a mixture; b) grinding the mixture to provide a solid; and c) isolating the solid.

74. The method of claim 73, wherein the solvent is acetone / MIBK.

75. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: 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 allow solids to precipitate; and g) isolating the solid.

76. The method of claim 75, wherein the first solvent is heptane.

77. The method of claim 75 or 76, wherein the second solvent is n-BuOH.

78. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding Form E of Compound 1 to a solvent to form a mixture; b) heating the mixture to about 50° C.; c) adding antisolvent; d) adding Form X of Compound 1 seeds and aging the mixture at about 50°C; e) cooling the mixture to about 20°C over at least 3 hours and maintaining the mixture at 20°C (optionally with wet grinding) to allow solids to precipitate; and f) isolating the solid.

79. The method of claim 78, wherein the solvent is acetone.

80. The method of claim 78 or 79, wherein the antisolvent is acetone / water.

81. A method for preparing a crystalline form of Compound 1, the method comprising the steps of: a) adding crude compound 1 to a solvent to form a mixture and heating to about 80° C.; b) concentrating the mixture by distillation; c) adding a solvent to the mixture; d) adjusting the temperature of the mixture to about 80° C.; e) adding seed crystals of Compound 1 in Form E; f) cooling the mixture to about 15-25° C.; g) aging the mixture at about 15-25° C. for about 4-18 hours to allow solids to precipitate; and h) isolating the solid.

82. The method of claim 81, wherein the solvent is n-BuOH.

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