Salts and other solid forms of cyclopropylmethylamine serotonin receptor modulators

Abstract

Disclosed herein are salts and solid forms of certain cyclopropylmethylamine compounds as well as methods of preparation, methods of treatment, and pharmaceutical compositions comprising the same.

Description

[0001] Attorney Docket No: 01312-0023-00PCT

[0002] SALTS AND OTHER SOLID FORMS OF CYCLOPROPYLMETHYLAMINE SEROTONIN RECEPTOR MODULATORS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 721 ,476, filed on November 16, 2024, U.S. Provisional Application No. 63 / 783,426, filed on April 4, 2025, and U.S. Provisional Application No. 63 / 801 ,949, filed on May 8, 2025, each of which are incorporated herein by reference in their entirety for any purpose.

[0005] SUMMARY

[0006] Disclosed herein are solid forms of a compound selected from (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d2, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d4, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d2, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d5 and (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-alpha-d2. In some embodiments, the solid form may be a salt, and / or solvate thereof. In some embodiments, the solid form is a polymorph of the solid forms. In some embodiments, the solid form is not the hydrofumarate or fumarate of any of the foregoing compounds.

[0007] Also disclosed are methods for making the solid forms and methods for using the solid forms of a compound selected from (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d2, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d4, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d2, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d5 and (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-alpha-d2. In some embodiments, the solid form is a polymorph of the free base form of the compound. In other embodiments, the solid form is a salt, and in some embodiments, a polymorph of the salt. The salt may be formed from an acid selected from hydrochloric acid, fumaric acid, galactaric (mucic) acid, naphthalene-1,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane-1 ,2-disulfonic acid, lactobionic acid, p-toluenesulfonic acid, D- glucoheptonic acid, thiocyanic acid, (-)-L- Attorney Docket No: 01312-0023-00PCT

[0008] pyroglutamic acid, methanesulfonic acid, L- malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D-gluconic acid, benzenesulfonic acid, D,L-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, T, -aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, xinafoic acid, hydrobromic acid, or a combination thereof. In any embodiments, a stoichiometric ratio of acid to the free base of the compound is from about 0.4 to about 2.2, such as from about 0.5 to about 2, or from about 0.5 to about 1 or about 2.

[0009] In any embodiment, the solid form may be a crystalline solid, a hydrate, a solvate, or a combination thereof. The crystalline solid may be substantially a single form, such as a polymorph form. In some embodiments, the polymorph may be selected to have one or more desired properties, for example improved properties, such as physical properties, chemical properties, pharmacokinetic properties, or a combination thereof. The one or more desired properties may comprise a desirable melting point temperature, glass transition temperature, flowability, thermal stability, mechanical stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

[0010] Also disclosed herein are pharmaceutical compositions comprising at least one solid form of a disclosed compound, and a pharmaceutically acceptable excipient.

[0011] Also disclosed herein are methods of treating a disease and / or disorder comprising administering to a subject in need thereof a therapeutically effective amount of at least one solid form of a compound selected from (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d2, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d4, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d2, (+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d5 and (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-alpha-d2. In some embodiments, the method comprises administering to the subject in need thereof a pharmaceutical composition comprising at least one solid form of a disclosed compound, and a pharmaceutically acceptable excipient.

[0012] In some embodiments, the subject is suffering from a neurological disease or a Attorney Docket No: 01312-0023-00PCT

[0013] psychiatric disorder, or both, such as a neurodegenerative disorder. In some embodiments, the neurological disorder or psychiatric disorder, or both, may comprise depression, addiction, anxiety, or a post-traumatic stress disorder, and / or the neurological disorder or psychiatric disorder, or both, may comprise seizure disorders, epilepsy, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, Prader-Willi Syndrome (PWS), obesity or other eating disorders (e.g., hyperphagia), or a substance use disorder such as alcohol abuse, tobacco abuse, opioid abuse, amphetamine abuse, and methamphetamine abuse. In some embodiments, the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

[0014] In some embodiments, the method comprises further administering an effective amount of an empathogenic agent and / or a 5-HT2A antagonist to the subject. The 5-HT2A antagonist may be selected from MDL-11 ,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin.

[0015] In some embodiments, the method comprises administering at least one compound described herein to modulate one or more serotonin receptor subtypes in a synergistic manner (e.g., a synergistic therapeutic effect via modulation of at least two serotonin receptor subtypes). In certain embodiments, the method comprises administering at least one compound selected from (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d2, (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d4, (+) (2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine, (+) (2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d2, (+) (2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d5 and (+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-alpha-d2. In certain embodiments, the at least one compound is a 5-HT2Creceptor agonist, as well as a 5-HT2and / or 5-HT2Breceptor antagonist or partial agonist.

[0016] In any embodiment, administering the solid form of the compound comprises oral, intravenous, parenteral, or topical administration. In certain embodiments, oral administration is used, but in other embodiments, administration is by injection, inhalation, intraocular, intravaginal, intrarectal ortransdermal route. The foregoing and other objects, features, and advantages of the present disclosure will become more apparent from the following detailed description. Attorney Docket No: 01312-0023-00PCT

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a single crystal structure drawing of Solid Form C of Compound I HCI, as described in Example 48.

[0019] Figure 2 shows a single crystal structure drawing of Solid Form A of Compound VII HCI, as described in Example 49.

[0020] Figure 3 shows an XRPD pattern of Solid Form C of Compound I HCI, as described in Example 50.

[0021] Figure 4A shows an XRPD pattern of Solid Form C of Compound I HCI with Reitveld refinement as described in Example 50.

[0022] Figure 4B shows a difference plot and Rwp value corresponding to Figure 4A.

[0023] Figure 5 shows an XRPD pattern of Solid Form A of Compound VII HCI, as described in Example 50.

[0024] Figure 6 shows an XRPD pattern of Solid Form A of Compound VII HCI with Reitveld refinement, as described in Example 50.

[0025] DETAILED DESCRIPTION

[0026] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms "a," "an," and "the" refer to one or more than one, unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference in their entirety, unless otherwise specified.

[0027] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims, are to be understood as being modified by the term "about." Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and / or limits of detection under standard test conditions / methods. When directly and explicitly distinguishing embodiments from discussed art, the embodiment numbers are not approximates unless the word "about" is expressly recited.

[0028] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this Attorney Docket No: 01312-0023-00PCT

[0029] disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0030] "Administering" refers to any suitable mode of administration, including, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini- osmotic pump, to the subject.

[0031] “Disease” and “disorder” may be used interchangeably herein.

[0032] "(+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine" refers to Compound I having the following structure:

[0033]

[0034] Compound I

[0035] "(+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d2" refers to Compound II having the following structure:

[0036]

[0037] Compound II

[0038] "(+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-d4" refers to Compound III having the following structure: Attorney Docket No: 01312-0023-00PCT

[0039]

[0040] Compound III

[0041] "(+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine" refers to Compound IV having the following structure:

[0042]

[0043] Compound IV

[0044] "(+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d2" refers to Compound V having the following structure:

[0045]

[0046] Compound V

[0047] "(+)-(2-(2-(Allyloxy)-5-fluorophenyl)cyclopropyl)methanamine-d5" refers to Compound Attorney Docket No: 01312-0023-00PCT

[0048] VI having the following structure:

[0049]

[0050] &

[0051] Compound VI

[0052] "(+) (2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methanamine-alpha-d2" refers to Compound VII having the following structure:

[0053]

[0054] Compound VII

[0055] "Subject" refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject.

[0056] The terms "therapeutically effective amount," "effective amount," "therapeutically sufficient amount," "effective or sufficient amount" and the like are used interchangeably herein and refer to a dose of a pharmaceutical agent that produces a therapeutic effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.

[0057] "Neuronal plasticity" refers to the ability of the brain to change its structure and / or function continuously throughout a subject's life. Examples of the changes to the brain include, Attorney Docket No: 01312-0023-00PCT

[0058] but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.

[0059] "Brain disorder" refers to a neurological disorder which affects the brain's structure and / or function. Brain disorders can include, but are not limited to, seizures, epilepsy, Alzheimer's, Parkinson's disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, stroke, traumatic brain injury, and substance use disorder (e.g., alcohol abuse, tobacco abuse, opioid abuse, amphetamine abuse, and methamphetamine).

[0060] "Combination therapy" refers to a method of treating a disease and / or disorder, wherein two or more different pharmaceutical agents are administered to a subject in need thereof. In some embodiments, the two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. In some embodiments, the compounds of the present disclosure can be used in a combination therapy with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy comprises administration of two or more drugs during a single cycle or course of therapy.

[0061] "Neurotrophic factors" refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.

[0062] The terms "modulate," "modulating," "modulation," and the like refer to an increase or decrease in the amount, quality, or effect of a particular activity, function and / or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5-HT2c) are modulators of the receptor.

[0063] "Agonism" refers to the activation of a receptor or enzyme by a modulator, such as a full agonist or partial agonist, to produce a biological response.

[0064] "Agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, "5-HT2c agonist" can be used to refer to a compound that exhibits an ECso with respect to 5-HT2Cactivity of no more than about 1.00 nM. In some embodiments, the term "agonist" includes full agonists or partial agonists. "Full agonist" refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. "Partial agonist" refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximum response, at the receptor relative to a full agonist. Attorney Docket No: 01312-0023-00PCT

[0065] "Positive allosteric modulator" refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances and / or amplifies the effect of an agonist.

[0066] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator, such as a full or partial antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.

[0067] "Antagonist" or "neutral antagonist" refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

[0068] The terms "composition," “formulation,” “preparation” and the like are used interchangeably herein and refer to a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts. A "pharmaceutically acceptable" ingredient is a carrier, diluent or excipient that is compatible with the other ingredients of the formulation.

[0069] "Pharmaceutically acceptable excipient" refers to a substance that aids the administration of an active agent to a subject and / or aids in absorption by a subject.

[0070] Pharmaceutical excipients useful in the compositions disclosed herein include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the disclosed compositions.

[0071] In certain embodiments, the compounds described herein may be administered for treating seizure disorders. In certain embodiments, the seizure disorder may comprise absence seizures (brief staring spells and / or loss of awareness), sometimes lasting a few seconds. In certain embodiments, the absence seizures may occur several times a day. In some embodiments, the absence seizures are, unlike most types of convulsive seizure disorders, non-convulsive in nature. As referenced herein and unless context dictates otherwise, “non-convulsive” seizures include those such as absence seizures that do not involve convulsive movements (e.g., rhythmic jerking or stiffening of muscles). While subtle motor signs such as eye fluttering or blinking, slight lip smacking, or minor hand movements may be observed in subjects presenting absence seizures, these movements would not generally be considered convulsive in nature.

[0072] In certain embodiments, it is believed that staring spells and / or loss of awareness are generally associated with a thalamocortical circuit disruption or thalamocortical oscillations. For example, in some embodiments, absence seizures are believed to arise from abnormal Attorney Docket No: 01312-0023-00PCT

[0073] rhythmic oscillations between the thalamus and cerebral cortex. The thalamus, a relay center for sensory and motor signals, plays a key role in regulating consciousness and attention. In certain embodiments, these oscillations are driven by T-type calcium channels in thalamic relay neurons, which become hyperactive during seizures, leading to excessive synchronized firing. As further discussed herein, impaired GABAergic and glutamatergic signaling, ion channel dysregulation, cortical network hyperexcitability, and genetic contributions can also be associated with thalamocortical circuit disruptions.

[0074] Thalamocortical oscillations and thalamocortical circuit disruptions both involve the functional relationship between the thalamus and the cerebral cortex, yet they represent distinct physiological processes with different implications for brain function and disease.

[0075] Thalamocortical oscillations refer to rhythmic patterns of neural activity that regulate various brain states, including sleep, wakefulness, and sensory processing. These oscillations arise from the dynamic interplay between thalamic relay neurons and cortical networks, producing characteristic waveforms such as sleep spindles (12-16 Hz), delta waves (1 -4 Hz), and gamma oscillations (30-100 Hz). While these oscillations are essential for normal cognition and consciousness, their dysregulation can contribute to neurological disorders. In the case of absence seizures, excessive and hypersynchronous thalamocortical oscillations — particularly in the 3 Hz spike-and-wave range — are a hallmark feature. These abnormal oscillations may lead to brief periods of impaired consciousness, causing the characteristic staring spells and lack of awareness associated with the condition.

[0076] Thalamocortical circuit disruptions, on the other hand, typically involve structural or functional impairments in the connectivity between the thalamus and the cortex. Unlike oscillations, which can be part of normal physiology, circuit disruptions generally indicate pathology and are linked to a wide range of neurological conditions, including epilepsy, neurodevelopmental disorders, and neurodegenerative diseases. A disruption in this circuitry can impair the transmission of sensory, cognitive, and / or motor information, leading to deficits in attention, awareness, and sensory perception. In the context of absence seizures, while the disorder is primarily characterized by abnormal oscillations, some researchers suggest that underlying thalamocortical circuit dysfunction may contribute to the generation and propagation of these seizures. A breakdown in inhibitory or excitatory control within the thalamocortical network may predispose the system to enter the pathological rhythmic activity seen during absence seizures.

[0077] In certain embodiments, it has been surprisingly discovered that the compounds described herein may be effective for treating both non-convulsive seizure disorders (e.g., Attorney Docket No: 01312-0023-00PCT

[0078] absence seizures) and convulsive seizure disorders (e.g., epileptic seizures). This finding is both surprising and unexpected due to the fundamental neurophysiological and mechanistic differences between these seizure types. For example, convulsive epileptic seizures, such as tonic-clonic or focal motor seizures, are characterized by widespread cortical excitability, excessive neuronal firing, and synchronized hyperexcitability across broad cortical and subcortical networks. These seizures typically originate in the cortex and propagate to motor regions, leading to involuntary muscle contractions, loss of postural control, and violent convulsions. Historically, treatments for convulsive seizures often focus on suppressing cortical excitability, enhancing GABAergic inhibition, or blocking sodium or calcium channels to prevent excessive neuronal firing. In contrast, absence seizures, a form of non-convulsive seizures, arise from abnormal thalamocortical oscillations rather than cortical hyperexcitability. These seizures are typically characterized by 3 Hz spike-and-wave discharges and are thought to result from dysregulated interactions between the thalamus and cortex, specifically involving T-type calcium channel activity and aberrant GABAergic signaling within the reticular thalamic nucleus. Unlike convulsive seizures, which manifest through motor involvement, absence seizures present as brief staring episodes, loss of awareness, and behavioral arrest without significant motor convulsions.

[0079] Given the divergent neurophysiological mechanisms underlying convulsive seizures and non-convulsive absence seizures, it would not be expected that a compound effective for convulsive seizures — likely targeting cortical excitability — would also be effective in absence seizures, which arise from thalamocortical circuit dysfunction and / or oscillations rather than generalized cortical hyperexcitability. Indeed, it has been previously known that convulsive and non-convulsive seizure disorders are subject to distinct pathophysiologies and drug targets. For example, most known drugs for treating convulsive seizures act on sodium channels (e.g., phenytoin, carbamazepine), GABA-A receptors (e.g., benzodiazepines), or glutamate receptors to suppress high-frequency cortical firing. In contrast, absence seizures have been previously known to respond preferentially to drugs that modulate T-type calcium channels (e.g., ethosuximide) or selectively alter thalamocortical rhythm generation. Many known first-line convulsive seizure treatments fail to control absence seizures and, in some cases, worsen them (e.g., phenytoin and carbamazepine can exacerbate absence seizures).

[0080] Moreover, historical precedent has largely suggested that there is limited - if any -overlap in the known treatments for convulsive and non-convulsive seizure disorders. Clinical and pharmacological data suggest that many drugs previously described as being effective for convulsive seizures are ineffective or even counterproductive in treating absence seizures. For Attorney Docket No: 01312-0023-00PCT

[0081] example, sodium channel blockers, which suppress cortical excitability in convulsive epilepsy, do not typically prevent the synchronized thalamocortical oscillations seen in absence seizures. Given this precedent, the expectation would be that compounds described herein, if effective in convulsive seizures, would not necessarily modulate thalamocortical network dysfunction in a way that otherwise treats or controls absence seizures. However, contrary to this understanding, in some embodiments, Applicant has surprisingly discovered that compounds described herein may be effective in treating broad seizure types (e.g., convulsive and non-convulsive), suggesting an unanticipated and novel mode of action that is distinct from conventional anti-seizure medications. Additionally, this further suggests that patients with mixed seizure types (e.g., juvenile absence epilepsy with occasional convulsive episodes) could benefit from treating with compounds described herein rather than requiring multiple drugs, which is often necessary to manage absence seizures separately from convulsive seizures.

[0082] Given the well-established mechanistic divergence between convulsive and non-convulsive seizure types, it was not predictable that a compound having efficacy against convulsive seizures could also be effective against absence seizures (e.g., in some embodiments, via suppression of thalamocortical oscillatory disruptions). This surprising discovery further supports the novel therapeutic potential of the compounds described herein.

[0083] Treatment-resistant absence seizures, also known as refractory or drug-resistant absence seizures, occurs when absence seizures fail to respond adequately to first-line antiepileptic drugs (AEDs) despite optimal treatment. In certain embodiments, this means that seizures persist even after trials of at least two appropriately chosen and dosed AEDs, either alone or in combination.

[0084] Thus, in certain embodiments, disclosed herein are methods of treating seizures (e.g., convulsive and / or non-convulsive) comprising administering to a subject in need thereof a therapeutically effective amount of at least one solid form of a compound disclosed herein, the method comprises administering to the subject in need thereof at least one solid form of a disclosed compound.

[0085] Also, disclosed herein are solid forms of Compounds I, II, III, IV, V, VI and VII that are useful to treat various disorders, such as brain disorders. Also disclosed are methods for making the solid forms of Compounds I through VII and methods of administering the solid forms of Compounds I through VII.

[0086] In some embodiments, the solid form of the compound is a crystalline form of the compounds described herein. In some embodiments, the solid form of the compound is a salt Attorney Docket No: 01312-0023-00PCT

[0087] of the compound. In some embodiments, the solid form of a compound selected from Compounds I, II, III, IV, V, VI and VII is a polymorph, such as a polymorph of the free base compound or a polymorph of the salt. In some embodiments, the solid form of the compound is a crystalline salt form of the compound, such as an acid addition salt form.

[0088] In some embodiments, the solid form of a compound selected from Compounds I, II, III, IV, V, VI and VII comprises a salt of said compound. Suitable salts include a pharmaceutically acceptable salt of at least one of Compounds I, II, III, IV, V, VI and VII. In some embodiments, the salt may be formed from a suitable pharmaceutically acceptable acid, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, fumaric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. In some embodiments, the salt may be formed from fumaric acid, hydrobromic acid, or hydrochloric acid. In some embodiments, the salt may be formed from hydrochloric acid.

[0089] In other embodiments, the salt of a compound selected from Compounds I, II, III, IV, V, VI and VII may be formed from a suitable pharmaceutically acceptable base, including, without limitation, inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Additional information concerning pharmaceutically acceptable salts can be found in, for example, S. M. Berge, etal., "Pharmaceutical Salts," J Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.

[0090] In some embodiments, the salt may be formed using an acid from Table 1.

[0091] Table 1

[0092]

[0093] Attorney Docket No: 01312-0023-00PCT

[0094]

[0095] In some embodiments, the solid form disclosed herein is an HCI salt of a compound selected from Compounds I, II, III, IV, V, VI and VII. In some embodiments, the solid form is selected from Solid Form A of Compound I HCI, Solid Form B of Compound I HCI, or Solid Form C of Compound I HCI. Attorney Docket No: 01312-0023-00PCT

[0096] In some embodiments, the solid form is selected from Solid Form A of Compound II HCI, Solid Form B of Compound II HCI, or Solid Form C of Compound II HCI.

[0097] In some embodiments, the solid form is selected from Solid Form A of Compound III HCI or Solid Form B of Compound I HCI.

[0098] In some embodiments, the solid form is selected from Solid Form A of Compound IV HCI or Solid Form B of Compound IV HCI.

[0099] In some embodiments, the solid form is selected from Solid Form A of Compound V HCI or Solid Form B of Compound V HCI.

[0100] In some embodiments, the solid form is selected from Solid Form A of Compound VI HCI, Solid Form B of Compound VI HCI, or Solid Form C of Compound VI HCI.

[0101] In some embodiments, the solid form is selected from Solid Form A of Compound VII HCI, Solid Form B of Compound VII HCI, or Solid Form C of Compound VII HCI.

[0102] In some embodiments, Solid Form C of Compound I HCI has an X-ray powder diffraction pattern comprising one, two, three or more peaks selected from peaks at 6.87 ± 0.20, 9.11 ± 0.20, 11.42 ± 0.20, 14.11 ± 0.20, 16.51 ± 0.20, 18.27 ± 0.20, and 23.90 ± 0.20.

[0103] In some embodiments, Solid Form A of Compound VII HCI has an X-ray powder diffraction pattern comprising one, two, three or more peaks selected from peaks at 6.95 ± 0.20, 9.19 ± 0.20, 9.82 ± 0.20, 11.49 ± 0.20, 14.18 ± 0.20, 16.60 ± 0.20, and 22.73 ± 0.20.

[0104] The acid salts of the compounds disclosed herein can have any suitable stoichiometric ratio of acid to the compound. In one embodiment, the molar ratio of acid to the compound is from about 0.4 to about 2.2, such as forms wherein the salt has a stoichiometric ratio of acid to the compound of from about 0.5 to about 2, such as from about 0.5 to about 1 or from about 0.5 to about 2.

[0105] In some embodiments, any one of Compounds I, II, III, IV, V, VI and VII of the present disclosure are in a solid form. The solid form may be a crystalline form or an amorphous form. In some embodiments, the solid form is a crystalline form, such as a polymorph. In some embodiments, the solid form of the compound is a salt. And in certain embodiments, the solid form is a crystalline salt form of the compound. Solid forms of Compounds I, II, III, IV, V, VI and VII such as crystalline forms including salt and non-salt crystalline forms of the compounds, may exist in more than one crystal form. Such different forms are referred to as polymorphs. In some embodiments, the disclosed compounds are particular polymorphs of Compounds I, II, III, IV, V, VI and VII or a salt form of Compounds I, II, III, IV, V, VI and VII.

[0106] In some embodiments, the solid form of the compounds disclosed herein is selected to be a crystalline form, such as a particular polymorph of a crystalline form of a disclosed Attorney Docket No: 01312-0023-00PCT

[0107] compound that provides one or more desired properties. In one embodiment, the crystalline form offers advantages over the amorphous form of the molecule. In another embodiment, the disclosed polymorph offers improved properties as compared to another polymorph of the target compound. The compound may be a salt or free base (e.g., zwitterionic) compound. The one or more desired properties may include, but are not limited to, physical properties, including but not limited to, melting point temperature, glass transition temperature, flowability, and / or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc.; chemical properties, such as, but not limited to, hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles; and / or pharmacokinetic properties, such as, but not limited to, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and / or half-life.

[0108] The desired polymorph may be produced by techniques include, but are not limited to, crystallization in particular solvents and / or at particular temperatures, supersaturation, using a precipitation agent, such as a salt, glycol, alcohol, etc., co-crystallization, lyophilization, spray drying, freeze drying, and / or complexing with an inert agent.

[0109] Techniques to identify a particular solid form of Compounds I, II, III, IV, V, VI and VII include, but are not limited to, X-ray crystallography, X-ray diffraction, electron crystallography, powder diffraction, including X-ray, neutron, or electron diffraction, X-ray fiber diffraction, small-angle X-ray scattering, and / or melting point.

[0110] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more of the solid forms of Compounds I, II, III, IV, V, VI and VII and a pharmaceutically acceptable excipient. Such compositions are suitable for administration to a subject, such as a human subject.

[0111] The presently disclosed pharmaceutical compositions can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, capsules, lozenges, cachets, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present disclosure can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present disclosure can be administered transdermally. The compositions of this disclosure can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J Clin. Pharmacol.

[0112] 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the Attorney Docket No: 01312-0023-00PCT

[0113] present disclosure also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the solid form a compound of the present disclosure.

[0114] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").

[0115] In powders, the carrier may be a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets contain, in some embodiments, from about 5% to about 70% or about 10% to about 70% of the compounds of the present disclosure.

[0116] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.

[0117] If desired, disintegrating or solubilizing agents may be added, such as the cross- linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0118] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compounds of the present disclosure are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0119] Liquid form preparations include solutions and suspensions, for example, water or water / propylene glycol suspensions.

[0120] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation Attorney Docket No: 01312-0023-00PCT

[0121] product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0122] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include suspensions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0123] Oil suspensions can be formulated by suspending the compound of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0124] The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J Biomater Sci. Polym. Ed 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J Phann. Pharmacol. 49:669-674, 1997). Both transdermal Attorney Docket No: 01312-0023-00PCT

[0125] and intradermal routes can afford constant delivery for weeks or months.

[0126] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for parenteral administration may, in some embodiments, comprise a solution or suspension of the compounds of the present disclosure dissolved or suspended in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions or suspensions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pharmaceutical formulation intermediate (pFI) adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present disclosure in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1 ,3-butanediol.

[0127] In some embodiments, the formulations of the compounds of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, for example, by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin.

[0128] Biotechnol. 6:698-708, 1995; Ostro,Am. J Hosp. Pharm. 46:1576-1587, 1989).

[0129] The compositions of the present disclosure can be administered by any suitable Attorney Docket No: 01312-0023-00PCT

[0130] means, including oral, parenteral and topical methods. Transdermal administration methods, by atopical route, can be formulated as applicator sticks, suspensions, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0131] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such a form, the preparation is subdivided into unit doses containing appropriate quantities of the compounds of the present disclosure. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. In some embodiments, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0132] The compound of the present disclosure can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease and / or disorder, and the like as is known to those of ordinary skill in the art. Suitable dosage ranges for the compounds disclosed herein include from about 0.1 mg to about 10,000 mg, or from about 1 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 250 mg. Suitable dosages for the compound of the present disclosure include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0133] The compounds disclosed herein can be administered at any suitable frequency, interval and duration. For example, the compounds can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2, 3, 4, 5, 6, or 7 days, so as to provide the preferred dosage level. When the compound of the present disclosure is administered more than once a day, representative intervals include 5, 10, 15, 20, 30, 45 and 60 minutes, as well as 1 , 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compound of the present disclosure can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.

[0134] The composition can also contain other compatible therapeutic agents. In some embodiments, the compounds described herein can be used in combination with other active agents known to be useful in modulating a glucocorticoid receptor or glucagon-like peptide-1 (GLP-1) with adjunctive agents that may not be effective alone, but may contribute to the Attorney Docket No: 01312-0023-00PCT

[0135] efficacy of the active agent.

[0136] In some embodiments, the compounds of the present disclosure can be coadministered with a second active agent. In some embodiments, the second active agent may be an agent known to be useful in modulating a glucocorticoid receptor or glucagon-like peptide-1 (GLP-1). Co-administration includes administering the compound of the present disclosure and the second active agent within 0.5, 1 , 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Co-administration also includes administering the compound of the present disclosure and the second active agent simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.

[0137] Moreover, the compound of the present disclosure and the second active agent can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.

[0138] In some embodiments, co-administration can be accomplished by co-formulation, such as by preparing a single pharmaceutical composition including both the compound of the present disclosure and the second active agent. In other embodiments, the compound of the present disclosure and the second active agent can be formulated separately.

[0139] The disclosed compounds and the second active agent can be present in the compositions of the present disclosure in any suitable weight ratio, such as from about 1 :100 to about 100:1 (w / w), or from about 1 :50 to about 50:1 , or from about 1 :25 to about 25:1 , or from about 1 :10 to about 10:1 , or from about 1 :5 to about 5:1 (w / w). In some embodiments, the compound of the present disclosure and the second active agent are present in a suitable weight ratio, such as about 1 :100 (w / w), 1 :50, 1 :25, 1:10, 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , 5:1, 10:1, 25:1, 50:1 or 100:1 (w / w). Other dosages and dosage ratios of the compound of the present disclosure and the second active agent are suitable in the compositions and methods disclosed herein.

[0140] In certain embodiments, the solid forms described herein may be a solvate, such as a hydrate. As used herein, the term “hydrate” refers to a substance that is formed by the addition of water to a substance pre-existing in the solid-state, e.g. nilotinib hydrochloride. The water molecules may be absorbed, adsorbed and / or contained within the crystal lattice of the solid compound and are usually present in a defined stoichiometric ratio. The notation for a hydrated compound (M) may be M.n W, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate, n is 1 ; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on. Thus, in certain embodiments, the solid forms described herein may comprise a stoichiometric or non-stoichiometric hydrate.

[0141] As used herein, the term “non-stoichiometric hydrate” denotes a crystalline solid in Attorney Docket No: 01312-0023-00PCT

[0142] which water molecules occupy disordered or partially occupied sites within the crystal lattice or reside in lattice channels or voids, such that the overall water content is variable rather than constant. A non-stoichiometric hydrate retains its crystallinity and lattice structure across a range of water contents, and is therefore distinguishable from a stoichiometric hydrate, in which water occupies well-defined and fixed stoichiometric positions. For purposes of the present disclosure, the term “non-stoichiometric hydrate” includes partial hydrates, i.e. , hydrates containing less than one mole of water per mole of compound, including but not limited to hydrates having 0.01 to 0.99 moles of water per mole of compound.

[0143] As used herein, the term “channel hydrate” refers to a crystalline hydrate in which one or more water molecules reside within continuous one-dimensional or two-dimensional channels, tunnels, or grooves formed by the packing arrangement of the compound in the crystal lattice. The water molecules may be ordered or disordered and may interact with the lattice through hydrogen bonding, van der Waals forces, electrostatic interactions, or ion coordination. Channel hydrates may be stoichiometric or non-stoichiometric and may exhibit reversible water uptake or release as a function of temperature or relative humidity while retaining the same fundamental crystalline framework. Channel hydrates may be identified by visualization of the extended crystalline network. Additionally, or in the alternative, channel hydrates may be identified by one or more analytical characteristics, including gradual and reversible water uptake in dynamic vapor sorption (DVS) analysis, variable but reproducible water content by Karl Fischer titration or thermogravimetric analysis, and substantially consistent XRPD patterns despite changes in hydration level.

[0144] As used herein, the term “pore hydrate” (also known as a “void” or “cage” hydrate) refers to a crystalline hydrate in which water molecules occupy isolated voids, cavities, or pockets within the crystal lattice that do not form continuous channels. The enclosed water molecules are typically stabilized by local hydrogen bonding or electrostatic interactions but are spatially confined and not part of a continuous network through the lattice. In some embodiments, pore / cage hydrates may more commonly exhibit fixed (stoichiometric) water content and may undergo stepwise dehydration accompanied by phase transitions or loss of crystallinity when water is removed.

[0145] As used herein, the term “ion-coordinated hydrate” refers to a crystalline solid form in which one or more water molecules are coordinated to ionic species present in the lattice, including cations (e.g., protonated amines, alkali metals, alkaline earth metals) or anions (e.g., halides, sulfonates, phosphates). Coordination may occur through hydrogen bonding, electrostatic interaction, or direct coordination and may involve water molecules located at defined lattice sites or within lattice channels, pores, or voids. An ion-coordinated hydrate may Attorney Docket No: 01312-0023-00PCT

[0146] be stoichiometric or non-stoichiometric and includes hydrates in which water contributes to the stabilization of ionic interactions within the crystal lattice.

[0147] The solid forms of any of the compounds of the present disclosure can be used for increasing neuronal plasticity. The solid forms of any of the compounds of the present disclosure can also be used to treat any brain disease. The solid forms of any of the compounds of the present disclosure can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.

[0148] In some embodiments, a solid form of any of the compounds of the present disclosure is used to treat neurological diseases. In some embodiments, the compounds have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is selected from migraines, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Alzheimer’s psychosis, Parkinson's disease, psychological disorders, treatment resistant depression, suicidal ideation, major depressive disorders, bipolar disorders, schizophrenia, strokes, traumatic brain injuries, and addictions (e.g., substance use disorders). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.

[0149] In some embodiments, a compound of the present disclosure is used for increasing neuronal plasticity. In some embodiments, the compounds described herein are used for treating a brain disorder. In some embodiments, the compounds described herein are used for Attorney Docket No: 01312-0023-00PCT

[0150] increasing at least one of translation, transcription, or secretion of neurotrophic factors.

[0151] In some embodiments, the present disclosure provides a method of treating a disease and / or disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the disease and / or disorder is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, and muscle cramps. In some embodiments, the present invention provides a method of treating a disease and / or disorder of women's reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.

[0152] In some embodiments, the compounds of the present disclosure have activity as 5-HT2C, 5-HT2A and / or 5-HT2Bmodulators. In some embodiments, the compounds of the present disclosure elicit a biological response by activating the 5-HT2Creceptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2Creceptor), while antagonizing the 5-HT2and / or 5-HT2Breceptors. In some embodiments, the compounds of the present disclosure elicit a biological response by activating the 5-HT2Areceptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2Areceptor). In some embodiments, the compounds of the present disclosure are 5- HT2Amodulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds of the present disclosure are selective tyrosine kinase B (TrkB) modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.

[0153] In some embodiments, the compounds of the present disclosure are 5-HT2Amodulators (e.g., 5-HT2Aagonists) that are non-hallucinogenic. In some embodiments, the non-hallucinogenic 5-HT2Amodulators (e.g., 5-HT2Aagonists) are used to treat neurological diseases, which modulators do not elicit dissociative side-effects. In some embodiments, the compounds of the present disclosure are 5-HT2Amodulators (e.g., 5-HT2Aantagonists) that are non-hallucinogenic. In some embodiments, the non-hallucinogenic 5-HT2Amodulators (e.g., 5-HT2Aantagonists) are used to treat neurological diseases, which modulators do not elicit dissociative side-effects.

[0154] In some embodiments, the compounds of the present disclosure are 5-HT2Cmodulators (e.g., 5-HT2Cagonists) that are non-hallucinogenic. In some embodiments, the Attorney Docket No: 01312-0023-00PCT

[0155] non-hallucinogenic 5-HT2c modulators (e.g., 5-HT2c agonists) are used to treat neurological diseases, which modulators do not elicit dissociative side-effects.

[0156] In some embodiments, the compounds described herein are 5-HT2Cagonists (e.g., full or partial agonists) that exhibit antagonistic activity (e.g., full or partial) at 5-HT2. In some embodiments, the compounds described herein are 5-HT2Cagonists (e.g., full or partial agonists) that exhibit antagonistic activity (e.g., full or partial) at 5-HT2B.

[0157] In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs. In some embodiments, the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.

[0158] In some embodiments, serotonin receptor modulators, such as modulators of serotonin receptor 2C (5-HT2Cmodulators, e.g., 5-HT2Cagonists), are used to treat a brain disorder. The presently disclosed compounds can function as 5-HT2Cagonists alone, or in combination with a second therapeutic agent that also is a 5-HT2Cmodulator. In such cases, the second therapeutic agent can be an agonist or an antagonist. Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein include, without limitation, MDL- 11 ,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, MDL-100,907, pimavanserin, nelotanserin and lorcaserin. In some embodiments, the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about four hours prior to administration of a compound disclosed herein. In some embodiments, the serotonin receptor modulator is administered at most about one hour prior to administration of a compound disclosed herein. Thus, in some embodiments of combination therapy with the presently disclosed compounds, the second therapeutic agent is a serotonin receptor modulator. In some embodiments, the second therapeutic agent is a serotonin receptor modulator and is provided at a dose of from about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg. In certain such embodiments, a compound of the present disclosure is provided at a dose of from about 10 mg to about 100 mg, or from about 20 mg to about 200 mg, or from about 15 mg to about 300 mg, and the serotonin Attorney Docket No: 01312-0023-00PCT

[0159] receptor modulator is provided at a dose of about 10 mg to about 100 mg.

[0160] In some embodiments, the compounds of the present disclosure are non-hallucinogenic 5-HT2c modulators (e.g., 5-HT2c agonists) that are used to treat a neurological disease. In some embodiments, the neurological disease comprises decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2Creceptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.

[0161] In some embodiments, the compounds of the present disclosure are non-hallucinogenic 5-HT2Cmodulators (e.g., 5-HT2Cagonists) that are used for increasing neuronal plasticity. In some embodiments, the compounds of the present disclosure are

[0162] non-hallucinogenic 5-HT2Cmodulators (e.g., 5-HT2Cagonists) that are used for treating a brain disorder. In some embodiments, the compounds of the present disclosure are non-hallucinogenic 5-HT2Cmodulators (e.g., 5-HT2Cagonists) that are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, the compounds of the present disclosure are the 5-HT2Cmodulators that increase neuronal activity and / or can be used for treating a brain disorder by modulating a TrkB receptor (e.g., TrkB agonist).

[0163] Without being bound to any particular theory, it has been surprisingly discovered that, in some embodiments, compounds of the present disclosure are “multifunctional” 5-HT2Cagonists that also exhibit antagonistic activity at 5-HT2A, which induces a synergistic effect that can be therapeutically effective at treating certain diseases and disorders, such as psychotic disorders (e.g., schizophrenia) and addiction (e.g., cocaine and / or methamphetamine use disorder(s)). In certain embodiments, the compounds of the present disclosure are 5-HT2Cagonists that also exhibit antagonistic activity at 5-HT2B.

[0164] In some embodiments, the presently disclosed compounds are given to patients in a dose that is lower than would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit. This dose range is predicted to be between 200 pg (micrograms) and 2 mg.

[0165] As noted above, the compounds of the present disclosure can be used for increasing neuronal plasticity. Neuronal plasticity refers to the ability of the brain to change structure and / or function throughout a subject's life. New neurons can be produced and integrated into the central nervous system throughout the subject's life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing Attorney Docket No: 01312-0023-00PCT

[0166] dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.

[0167] In some embodiments, increasing neuronal plasticity is achieved by treating a subject with one or more of the disclosed compounds. In certain embodiments, increasing neuronal plasticity can effectively treat certain neurodegenerative disorders, such as Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis, stroke, traumatic brain injury, or substance use disorder.

[0168] In some embodiments, the present disclosure provides methods for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of the present disclosure. In some embodiments, increasing neuronal plasticity improves a brain disorder described herein.

[0169] In some embodiments, the compounds of the present disclosure used to increase neuronal plasticity have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, decreased neuronal plasticity is associated with a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.

[0170] In some embodiments, the experiment or assay to determine increased neuronal plasticity of any compound of the present disclosure is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentrationresponse experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2Abinding assay, a 5-HT2Cagonist assay, a5-HT2Cantagonist assay, aTrkB agonist assay, aTrkB antagonist assay, or a 5-HT2Ablocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay.

[0171] In some embodiments, the present disclosure provides a method of treating a disease and / or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described in the present disclosure. In some Attorney Docket No: 01312-0023-00PCT

[0172] embodiments, the disease and / or disorder is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps. In some embodiments, the present disclosure provides a method of treating a disease and / or disorder of women's reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described in the present disclosure. In some embodiments, the present disclosure provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides a method of treating a brain disorder with combination therapy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure and at least one additional therapeutic agent.

[0173] In some embodiments, the compounds of the present disclosure are 5-HT2A modulators (e.g., 5-HT2A agonists) 5-HT2Cmodulators (e.g., 5-HT2Cagonists), and / or TrkB modulators (e.g., TrkB agonists) that are used to treat a brain disorder. In some embodiments, the brain disorders comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2Areceptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.

[0174] In some embodiments, a compound of the present disclosure is used to treat brain disorders. In some embodiments, the compounds have, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidality, schizophrenia, Alzheimer’s psychosis, and addiction (e.g., substance abuse disorders such as amphetamine use and methamphetamine use). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.

[0175] In some embodiments, the present disclosure provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein. In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, Attorney Docket No: 01312-0023-00PCT

[0176] suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

[0177] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's, or Parkinson's disease. In some embodiments, the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is alcohol use disorder.

[0178] In some embodiments, the method further comprises administering one or more additional therapeutic agent selected from lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Ability), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), and clonazepam (Klonopin).

[0179] In certain embodiments of the method for treating a brain disorder with a solid form disclosed herein, a second therapeutic agent that is an empathogenic agent is administered. Examples of suitable empathogenic agents for use in combination with the present solid forms include phenethylamines, such as 3,4-methylene-dioxymethamphetamine (MDMA), and analogs thereof. Other suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation:

[0180] N-Allyl-3,4-methylenedioxy-amphetamine (MDAL);

[0181] N-Butyl-3,4-methylenedioxyamphetamine (MDBU);

[0182] N-Benzyl-3,4-methylenedioxyamphetamine (MDBZ);

[0183] N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM); Attorney Docket No: 01312-0023-00PCT

[0184] N,N-Dimethyl-3,4-methylenedioxyamphetamine (MDDM);

[0185] N-Ethyl-3,4-methylenedioxyamphetamine (MDE; MDEA);

[0186] N-(2-Hydroxyethyl)-3,4-methylenedioxy amphetamine (MDHOET);

[0187] N-lsopropyl-3,4-methylenedioxyamphetamine (MDIP);

[0188] N-Methyl-3,4-ethylenedioxyamphetamine (MDMC);

[0189] N-Methoxy-3,4-methylenedioxyamphetamine (MDMEO);

[0190] N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET);

[0191] alpha, alpha, N-Trimethyl-3,4-methylenedioxyphenethylamine (MDMP; 3,4-Methylenedioxy-N-methylphentermine);

[0192] N-Hydroxy-3,4-methylenedioxyamphetamine (MDOH);

[0193] 3,4-Methylenedioxyphenethylamine(MDPEA);

[0194] alpha, alpha-Dimethyl-3,4-methylenedioxyphenethylamine (MDPH; 3,4-methyl enedioxyphentermine);

[0195] N-Propargyl-3,4-methylenedioxyamphetamine (MDPL);

[0196] Methylenedioxy-2-aminoindane (MDAI);

[0197] 1.3-Benzodioxolyl-N-methylbutanamine MBDB;

[0198] N-methyl-1 ,3-benzodioxolylbutanamine, MBDB;

[0199] 3.4-methylenedioxy-N-methyl-a-ethylphenylethylamine;

[0200] 3.4-Methylenedioxyamphetamine MDA);

[0201] Methylone (also known as "3,4-methylenedioxy-N-methylcathinone) Ethylone, also known as 3,4-methylenedioxy-N-ethylcathinone;

[0202] GHB or Gamma Hydroxybutyrate or sodium oxybate;

[0203] N-Propyl-3,4-methylenedioxyamphetamine (MDPR), and the like.

[0204] In some embodiments, the compounds of the present disclosure are used in combination with the standard of care therapy for a neurological disease described herein. Non-limiting examples of the standard of care therapies, may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, and aripiprazole. Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, and sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the Attorney Docket No: 01312-0023-00PCT

[0205] art.

[0206] Methods of increasing at least one of translation, transcription, or secretion of neurotrophic factors are also described herein. Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons. Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can increase neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can promote neuronal growth, promote neuritogenesis, promote synaptogenesis, promote dendritogenesis, increase dendritic arbor complexity, and / or increase dendritic spine density.

[0207] In some embodiments, the compounds described herein are used to increase at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, increasing at least one of translation, transcription or secretion of neurotrophic factors treats a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

[0208] In some embodiments, the experiment or assay used to determine an increase in the translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry. In some embodiments, the experiment or assay used to determine increased transcription of neurotrophic factors includes gene expression assays, PCR, and microarrays. In some embodiments, the experiment or assay used to determine increased secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.

[0209] In some embodiments, the present disclosure provides a method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound disclosed herein.

[0210] EXEMPLARY ENUMERATED EMBODIMENTS

[0211] 1. A solid form of a compound selected from Compounds I, II, III, IV, V, VI, and VII, wherein the selected compound exhibits at least one improved property compared Attorney Docket No: 01312-0023-00PCT

[0212] to previously known solid forms of said compound.

[0213] 2. The solid form of Embodiment 1 , wherein the solid form of the compound is a salt.

[0214] 3. The solid form of Embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-1 ,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane-1,2-disulfonic acid, lactobionic acid, p- toluenesulfonic acid, D-glucoheptonic acid, thiocyanic acid, (-)-L-pyroglutamic acid, methanesulfonic acid, L-malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D-gluconic acid, benzenesulfonic acid, D,L-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2- hydroxy, glutaric acid, L-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)-camphoric acid, glutamic acid, acetic acid, fumaric acid, xinafoic acid, hydrobromic acid, hydrochloric acid, or a combination thereof.

[0215] 4. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

[0216] 5. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

[0217] 6. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is selected from about 0.5 to about 1 molar equivalent of the acid or from about 0.5 to about 2 molar equivalents of the acid.

[0218] 7. The solid form of Embodiment 1 , wherein the solid form is a free base form of the selected compound.

[0219] 8. The solid form of any one of Embodiments 1 -7, wherein the solid form is a crystalline solid.

[0220] 9. The solid form of Embodiment 8, wherein the crystalline solid is a substantially single polymorph.

[0221] 10. The solid form of any one of Embodiments 1-9, wherein the solid form is a hydrate.

[0222] 11. Solid Form A of Compound I HCI.

[0223] 12. Solid Form B or Solid Form C of Compound I HCI.

[0224] 13. Solid Form A of Compound II HCI.

[0225] 14. Solid Form B or Solid Form C of Compound II HCI.

[0226] 15. Solid Form A of Compound III HCI.

[0227] 16. Solid Form B of Compound III HCI. Attorney Docket No: 01312-0023-00PCT

[0228] 17. Solid Form A of Compound IV HCI.

[0229] 18. Solid Form B or Solid Form C of Compound IV HCI.

[0230] 19. Solid Form A of Compound V HCI.

[0231] 20. Solid Form B of Compound V HCI.

[0232] 21. Solid Form A of Compound VI HCI.

[0233] 22. Solid Form B of Compound VI HCI.

[0234] 23. Solid Form A of Compound VII HCI

[0235] 24. Solid Form B of Compound VII HCI

[0236] 25. Solid Form C of Compound VII HCI

[0237] 26. The solid form of any one of Embodiments 1-25, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

[0238] 27. The solid form of Embodiment 26, wherein the at least one improved property comprise an improvement in melting point temperature, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

[0239] 28. The solid form according to any one of Embodiments 1-27, wherein the solid form comprises a hydrate.

[0240] 29. The solid form according to Embodiment 28, wherein the solid form comprises a non-stoichiometric hydrate.

[0241] 30. The solid form according to any one of Embodiments 28-29, wherein said solid form comprises about 0.1 to about 0.25 mol of H2O per formula unit.

[0242] 31. The solid form according to any one of Embodiments 28-30, wherein said solid form comprises about 0.12 to about 0.20 mol of H2O per formula unit.

[0243] 32. The solid form according to any one of Embodiments 28-31 , wherein said solid form comprises about 0.5 to about 2 w / w % water.

[0244] 33. The solid form according to any one of Embodiments 28-31 , wherein said solid form comprises about 0.6 to about 1.8 w / w % water.

[0245] 34. The solid form according to any one of Embodiments 28-33, wherein the solid form comprises a channel hydrate.

[0246] 35. The solid form according to any one of Embodiments 28-33, wherein the solid form comprises a cage hydrate. Attorney Docket No: 01312-0023-00PCT

[0247] 36. The solid form according to any one of Embodiments 28-35, wherein the solid form comprises an ion-coordinated hydrate.

[0248] 37. The solid form according to Embodiment 36, wherein the solid form comprises an ion-coordinated channel hydrate.

[0249] 38. The solid form according to Embodiment 35, wherein the solid form comprises an ion-coordinated cage hydrate.

[0250] 39. A pharmaceutical composition comprising a solid form of a compound according to any one of Embodiments 1-38, and a pharmaceutically acceptable excipient. 40. A method of treating a disease and / or disorder, comprising administering to a subject a therapeutically effective amount of a solid form of a compound according to any one of Embodiments 1 -38, or a pharmaceutical composition according to Embodiment 39.

[0251] 41. The method of Embodiment 40, wherein the subject has a neurological disease or a psychiatric disorder, or both.

[0252] 42. The method of Embodiment 41 , wherein the neurological disorder is a neurodegenerative disorder.

[0253] 43. The method of Embodiment 41 , wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.

[0254] 44. The method of Embodiment 41 , wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis or substance use disorder.

[0255] 45. The method of Embodiment 41 , wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

[0256] 46. The method of any one of Embodiments 40-45, wherein administering comprises oral administration, parenteral administration, or intravenous administration.

[0257] 47. The method of any one of Embodiments 40-45, wherein administering comprises oral administration.

[0258] 48. The method of any one of Embodiments 40-45, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

[0259] 49. The method of any one of Embodiments 40-48, further comprising administering to the subject a therapeutically effective amount of an empathogenic agent. Attorney Docket No: 01312-0023-00PCT

[0260] 50. The method of Embodiment 41 , wherein the neurological disorder or psychiatric disorder, or both, is a substance use disorder.

[0261] 51. The method of Embodiment 50, wherein the substance use disorder is amphetamine use disorder.

[0262] 52. The method of Embodiment 50, wherein the substance use disorder is methamphetamine use disorder.

[0263] 53. The method of Embodiment 50, wherein the substance use disorder is cocaine use disorder.

[0264] 54. The method of any one of Embodiments 40 or 46-49, wherein the disease or disorder is a seizure disorder.

[0265] 55. The method of Embodiment 54, wherein the disease or disorder is an epilepsy.

[0266] 56. The method of Embodiment 54, wherein the disease or disorder comprises staring spells and / or loss of awareness associated with thalamocortical oscillations.

[0267] 57. The method of Embodiment 56, wherein the staring spells and / or loss of awareness associated with thalamocortical oscillations are associated with absence seizures.

[0268] 58. The method of Embodiment 57, wherein the absence seizures comprise refractory absence seizures.

[0269] 59. The method of any one of Embodiments 40 or 46-49, wherein the disease or disorder comprises hyperphagia.

[0270] 60. The method of any one of Embodiments 40, 46-49, or 59 wherein the disease or disorder is Prader-Willi Syndrome.

[0271] EXAMPLES

[0272] Example 1. Salt Screen

[0273] Compound I is synthesized in accordance with the synthetic procedures set forth herein (see, e.g., Example 12). The resulting Compound I is isolated as a solid and is characterized to evaluate its physical properties. The evaluation is performed by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption / desorption (DYS), and / or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size / morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the free base is a solvate or hydrate, and to evaluate thermal stability. DYS data is Attorney Docket No: 01312-0023-00PCT

[0274] used to evaluate hygroscopicity of the free base and if hydrates can be formed at high relative humidity. About 10 to 15 solvents are selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

[0275] Table 2

[0276]

[0277]

[0278] Attorney Docket No: 01312-0023-00PCT

[0279]

[0280] The information obtained is used for designing the subsequent salt screen. The salt screen is performed by reacting the free base with pharmaceutically acceptable acids under various conditions in attempts to generate crystalline salts. Pharmaceutically acceptable acids that may be used are listed below. Specific acids are selected based on the pKa of the free base, and typically 15 to 20 acids are selected. Experiments are performed using 0.5 molar equivalent, 1 molar equivalent and / or 2 molar equivalents of the acid.

[0281] Table 3 Exemplary Acids

[0282]

[0283] Attorney Docket No: 01312-0023-00PCT

[0284]

[0285] Solvent systems for the salt crystallization experiments are selected based on the solubility of the free base and the selected acid. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques that are used for salt crystallization are chosen based on the solvent selected and properties of the free base. The following techniques (or combination of techniques) may be used for salt crystallization:

[0286] • Free base and acid are dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

[0287] • Free base and acid are dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled to a sub-ambient temperature (between -78 °C to 15 °C). The cooling method can be a fast cooling (by plunging the sample into an ice bath or a dry ice / acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

[0288] • Free base and acid are dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

[0289] • Free base and acid are added to a solvent or mixture of solvents, where one or both components are not fully dissolved. The slurry is agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and dried (air dried or vacuum dried). The same experiment can be Attorney Docket No: 01312-0023-00PCT

[0290] also performed in solvent systems where the solvents are not miscible.

[0291] • Free base and acid are milled together (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

[0292] • Free base and acid are melted together and cooled to various temperatures using various cooling rates.

[0293] • If an amorphous form of a salt is obtained, the amorphous salt will be exposed to elevated humidity, or elevated temperature (or combination of both), or solvent vapors at various temperatures to form crystalline salts.

[0294] The stoichiometric ratio of acid to the selected compound is confirmed by1H NMR, HPLC, or both as is known to those of ordinary skill in the art.

[0295] The salts obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated / solvated, and by1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on salts that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the salt and if hydrated form is present.

[0296] Example 2. Additional Salt Screen

[0297] Compounds II, III, and IV can be prepared as described herein (see, e.g., Examples 18 and 21). Compounds V and VI can be prepared according to the methods described in PCT Patent Application No. PCT / US25 / 22435, which is incorporated herein by reference in its entirety for all purposes. The procedures of Example 1 are repeated separately with each of Compounds II, III, IV, V, VI, and VII to isolate salt forms of those compounds.

[0298]

[0299] Polymorph Screen

[0300] The active pharmaceutical ingredient (API) of Compound I, which may be a free base or a salt, is characterized to evaluate its physical properties. The evaluation is performed by X- ray powder diffraction (XRPD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), thermogravimetry (TG), dynamic vapor sorption / desorption (DVS), and / or solubility testing in organic solvents, water, and mixed solvent systems. XRPD data is used to assess crystallinity. PLM data is used to evaluate crystallinity and particle size / morphology. DSC data is used to evaluate melting point, thermal stability, and crystalline form conversion. TG data is used to evaluate if the API is a solvate or hydrate, and to evaluate thermal stability. DVS data is used to evaluate hygroscopicity of the API and if hydrates can be formed at high relative humidity. About 10 to 15 solvents may be selected from the list below, based on their properties (polarity, dielectric constant and dipole moment).

[0301] Table 4 Attorney Docket No: 01312-0023-00PCT

[0302]

[0303] The information obtained is used for designing the subsequent polymorph screen. Solvents are used as a single solvent or as solvent mixtures, some containing water. The techniques used for the polymorph screen are chosen based on the solvent selected and properties of the API. The following techniques (or a combination of techniques) may be used for the polymorph screening: Attorney Docket No: 01312-0023-00PCT

[0304] • API is dissolved in a solvent or mixture of solvents, and the solvents are evaporated at different rates (slow evaporation or fast evaporation) and at different temperatures (ambient or elevated).

[0305] • API is dissolved in a solvent or mixture of solvents (at ambient temperature or an elevated temperature), and the final solution is cooled (between -78 °C to 20 °C). The cooling method can be a fast cooling (by plunging the sample to an ice bath or a dry ice / acetone bath), or slow cooling. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

[0306] • API is dissolved in a solvent or mixture of solvents, and an antisolvent is added to precipitate the salt. The solids formed will be recovered by filtration and dried (air dried or vacuum dried).

[0307] • API is added to a solvent or mixture of solvents, where the API is not fully dissolved.

[0308] The slurry will be agitated at different temperatures for a number of days. The solids formed will be recovered by filtration and (air dried or vacuum dried).

[0309] • API is milled (by mechanical milling or by mortar and pestle), with a drop of solvent, or without any solvent.

[0310] • API is melted and cooled (at different cooling rates, fast and slow, and cooled to different temperatures) to obtain solids.

[0311] • API is suspended in a solvent or mixture of solvents, and the slurry is placed in a heating / cooling cycle for multiple cycles. The remaining solids after the final cooling cycle will be filtered and (air dried or vacuum dried).

[0312] • API is processed to obtain an amorphous form (by melting, milling, solvent evaporation, spray drying or lyophilization). The amorphous form will then be exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

[0313] • API is exposed to elevated humidity (or elevated temperature, or combination thereof), or to solvent vapors for extended period of days.

[0314] • Two or more polymorphs of the API are mixed in a solvent or solvent systems (some solvent mixtures containing variable amount of water) to obtain a slurry, and the slurry will be agitated (at various temperatures) for an extended period of time (days). The solvent system used can be pre-saturated with the APL. The final solids will be filtered and dried (air dried or vacuum dried).

[0315] • API is heated to a specific temperature and cooled (at ambient conditions or in a dry box). Attorney Docket No: 01312-0023-00PCT

[0316] The solids obtained are analyzed by XRPD to determine if they are crystalline and, if so, by DSC to see the melting point and by TG to see if they are hydrated / solvated, and by1H NMR spectroscopy to ensure chemical integrity. KF water titration is performed on forms that are hydrated. DVS analysis is performed to evaluate hygroscopicity of the form and if hydrated form is present. In particular variable temperature analyses, including variable temperature XRPD, are performed to assess the stability of each physical form as well as its crystallinity.

[0317] Differential scanning calorimetry (DSC) thermograms are obtained using a DSC Q 100 (TA Instruments, New Castle, DE). The temperature axis and cell constant of the DSC cell are calibrated with indium (10 mg, 99.9% pure, melting point 156.6°C, heat of fusion 28.4 Jig). Samples (2.0 - 5.0 mg) are weighed in aluminum pans on an analytical balance. Aluminum pans without lids are used for the analysis. The samples are equilibrated at 25°C and heated to 250 - 300 °c at a heating rate of 10°C / min under continuous nitrogen flow. TG analysis of the samples is performed with a Q 50(TA Instruments, New Castle, DE). Samples (2.0 - 5.0 mg) are analyzed in open aluminum pans under a nitrogen flow (50 mL / min) at 25°C to 210°C with a heating rate of 10°C / min.

[0318] The sample for moisture analysis is allowed to dry at 25 °C for up to 4 hours under a stream of dry nitrogen. The relative humidity is then increased stepwise from 10 to 90% relative humidity (adsorption scan) allowing the sample to equilibrate for a maximum of four hours before weighing and moving on to the next step. The desorption scan is measured from 85 to 0% relative humidity with the same equilibration time. The sample is then dried under a stream of dry nitrogen at 80 °C for 2 hours or until no weight loss is observed. X-ray powder diffraction data are collected using a Miniflex Tabletop XRD system (Rigaku / MSC, The Woodlands, TX) from 5° to 45° 20 with steps of 0.1°, and the measuring time is 1.0 second / step. All samples are ground to similar size before exposure to radiation. The powder samples are illuminated using CuKa radiation().= 1.54056A) at 30 kV and 15 mA.

[0319] Variable temperature XRPD data are collected using a Huber Imaging Plate Guinier Camera 670 employing Ni-filtered CuKal radiation (A= 1.5405981 A) produced at 40 kV and 20 mA by a Philips PW1120 / 00 generator fitted with a Huber long fine-focus tube PW2273 / 20 and a Huber Guinier Monochromator Series 611 / 15. The original powder is packed into a Lindemann capillary (Hilgenberg, Germany) with an internal diameter of 1 mm and a wall thickness of 0.01 mm. The sample is heated at an average rate of 5 Kmin-1using a Huber High Temperature Controller HTC 9634 unit with the capillary rotation device 670.2. The temperature is held constant at selected intervals for 10 min while the sample is Attorney Docket No: 01312-0023-00PCT

[0320] exposed to X- rays and multiple scans were recorded. A 28-range of 4.00 - 100.0° is used with a step size of 0.005° 28.

[0321] In certain embodiments, wherein the solid form is a solvate, such as a hydrate, the DSC thermogram reveals endothermic transitions. In accordance with the observed DSC transitions, TGA analysis indicates stages of weight change corresponding to desolvation or dehydration and / or melting of the sample. In the case of hydrates, these results are in harmony with Karl Fisher titration data which indicate the water content of the sample.

[0322] The moisture sorption profile of a sample can be generated to assess the stability of a solid form is stable over a range of relative humidities. In certain embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is small. In other embodiments, the change in moisture content over 10.0 to 95.0 % relative humidity is reversible. In certain embodiments, the XRPD pattern of a sample of solid form indicates that the sample has a well defined crystal structure and a high degree of crystallinity.

[0323]

[0324] Further Polymorph Screening

[0325] The procedures of Example 3 are repeated separately with each of Compounds II, III, IV, V, VI, and VII to isolate salt forms of those compounds.

[0326]

[0327] Evaluation of Metabolic Stability in Human Liver Microsomes

[0328] Microsomal Assay: Human liver microsomes (20 mg / mL) are obtained from Xenotech, LLC (Lenexa, KS). B-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCh), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.

[0329] Determination of Metabolic Stability: 7.5 mM stock preparations of test compounds of the disclosed compounds are prepared in a suitable solvent, such as DMSO. The 7.5 mM stock preparations are diluted to 12.5-50 pMin acetonitrile (ACN). The 20 mg / mL human liver microsomes are diluted to 0.625 mg / mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCh. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 pL aliquot of the 12.5-50 pM test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 4.0 mg / mL human liver microsomes, 0.25 pM test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCb. The reaction mixtures are incubated at 37 °C, and 50 pL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallowwell 96-well plates which contain 50 pL of ice-cold ACN (acetonitrile) with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 pL of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Attorney Docket No: 01312-0023-00PCT

[0330] Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the positive control, 7-ethoxycoumarin (1 pM). Testing is done in triplicate.

[0331] Data analysis: The in vitro V / 2S for test compounds are calculated from the slopes of the linear regression of% parent remaining (In) vs incubation time relationship.

[0332] in vitro V / 2 = 0.693 / k

[0333] k = -[slope of linear regression of% parent remaining (In) vs incubation time] The apparent intrinsic clearance is calculated using the following equation:

[0334] CLint (mL / min / kg) = (0.693 I in vitro T) (Incubation Volume / mg of microsomes) (45 mg microsomes I gram of liver) (20 gm of liver I kg b.w.)

[0335] Data analysis is performed using Microsoft Excel Software.

[0336] In these experiments, values equal to or more than a 15% increase in half-life are considered to be a significant difference if the apparent intrinsic clearance ratio (e.g., solid form of Compound I, II, III, IV, V, VI or VII vs. comparator solid form) is > 1.15 or <0.85, then there is considered to be significant differentiation.

[0337] Example 6.

[0338]

[0339] To a solution of the starting phenol (2.8 g, 20 mmol) and 2-iodo-1 -fluoroethane (2 equiv) in anhydrous DMF (1 M) was added CS2CO3 (2 equiv) at room temperature. The reaction mixture was heated at 50 °C until the reaction was complete as indicated by TLC analysis. The reaction mixture was allowed to cool to room temperature and diluted with water and diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether (x3). The combined organic extracts were washed with water (x2) and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to provide a crude solid that was used in the next step without purification.

[0340] Example 7.

[0341]

[0342] Attorney Docket No: 01312-0023-00PCT

[0343] To a vigorously stirred suspension of NaH (60% mineral oil, 1.4 equiv) in THF (50 mL) was slowly added triethyl phosphonoacetate (1.2 equiv) dropwise at room temperature.

[0344] Following the cessation of gas evolution, a 1 M THF solution of crude product of Example 16 was added dropwise at room temperature. The reaction was quenched after 30 min by the careful addition of water and diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether (x3). The combined organic extracts were combined and washed with water (x2) and brine, and dried with anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to provide the crude solid product that was used in the next step without purification.

[0345] Example 8.

[0346]

[0347] To a vigorously stirred suspension of trimethylsulfoxonium iodide (1.5 equiv) in DMSO (0.2 M) was added portion wise NaH (60% mineral oil, 1.5 equiv) at room temperature. The reaction mixture was allowed to stir until the reaction mixture became homogeneous (ca. 45-60 min) at which point a 1 M DMSO solution of the crude product produced in Example 7 was added dropwise. The reaction mixture was allowed to stir for at least 2 hours (or sooner if TLC indicated a complete reaction) and quenched by the addition of water and diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether (x3). The combined organic extracts were combined and washed with water (x2) and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to provide a crude oil that was purified by a flash silica gel plug (dry load, hexane then 15% EA / Hex) to provide 1.26 g of the desired ester product as colorless oil (36% yield over 3 steps).

[0348] Example 9.

[0349]

[0350] To a stirred solution of the ester product of Example 8 in THF (20 mL) was added an aqueous solution of lithium hydroxide monohydrate (3.0 equiv) in water (20 mL). The reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was then allowed to cool to room temperature and diluted with diethyl ether. The phases were separated and the Attorney Docket No: 01312-0023-00PCT

[0351] organics washed with sat. aq. sodium bicarbonate (x2). The combined aqueous extracts were acidified to pH = 1 and extracted with dichloromethane (x3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrate in vacuo to afford the acid product as a white solid.

[0352] Example 10.

[0353]

[0354] To a stirred solution of 365 mg of the acid product from Example 9 in DMF (0.1 M) at room temperature was added 1 ,1 '-carbonyldiimidazole (2.0 equiv). The reaction mixture was allowed to stir at room temperature for 30 min before ammonium acetate (10 equiv) and triethyl amine (5 equiv) are added. The reaction mixture is allowed to stir at room temperature overnight before being quenched by the addition of diethyl ether and 1M HCI. The phases were separated and the aqueous was extracted with diethyl ether (x3). The combined organic extracts were washed with 1M HCI, sat. aq. sodium bicarbonate, water, and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the amide product which was used in the next step without additional purification.

[0355] Example 11.

[0356]

[0357] To a stirred solution of the amide produced in Example 10 in THF (0.1 M) was added dropwise BH3 -THF (1 M solution in THF, 5 equiv). The reaction mixture was refluxed for 4 hours before cooling to room temperature and quenching with methanol. The reaction mixture was concentrated to dryness, diluted with methanol (0.1 M) and 6 M HCI (3 mL), and refluxed for 30 min. After cooling to room temperature, the methanol was removed in vacuo and the crude mixture was basified with 3 M NaOH aqueous solution and extracted with DCM (x5). The combined organic extracts were washed with brine and dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the target as solid. Formation of the free base target compound was confirmed by HRMS (M+H)+(Found: 228.1204 m / z; Calc’d: 228.1194 m / z) and1H NMR (600 MHz, d4-MeOH) 56.94 (dd, J = 9.0, 4.6 Hz, 1H), 6.89 (ddd, J = 9.0, 8.0, 3.0 Hz, 1H), 6.76 (dd, J = 9.4, 3.0 Hz, 1H), 4.92 -4.70 (m, 2H), 4.38-4.16 (m, 2H), 3.02 (d, J = 7.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.16 (dt, J = 9.0, 5.3 Hz, 1H), 1.31 - 1.22 (m, 1H), 1.18 (dt, J = Attorney Docket No: 01312-0023-00PCT

[0358] 8.5, 5.5 Hz, 1 H), 1.04 (dt, J = 9.0, 5.2 Hz, 1 H).

[0359] Example 12.

[0360]

[0361] The racemate free base product prepared according to the method of Example 11 was separated by chiral HPLC, hexane / iPrOH / DEA, 90 / 10 (0.1% diethylamine), 5 pl injection, flowrate of 10 mL / min, A = 280 nm, using Chiralpak AD-H column to afford the (+)-isomer (Compound I; 20 min) and the (-)-isomer (25 min).

[0362] Example 13.

[0363]

[0364] To a stirred solution of the amide produced in Example 10 in THF (0.1 M) in an ice bath was added dropwise lithium aluminium deuteride (10 equiv) portion wise. The reaction mixture was allowed to warm to room temperature and additional lithium aluminum deuteride (5 equiv) was added. The reaction mixture was quenched at 0 °C by the addition of water and basified with 3 M KOH solution. The aqueous phase was extracted with DCM (x5) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the d2 free base racemate of the desired product as a white solid. Formation of the target d2 free base was confirmed by HRMS (ESI+) calc’d for Ci2Hi4D2F2NO+[M+H]+: 230.1320; found: 230.1310; and1H NMR (600 MHz, d4-MeOH) 56.94 (dd, J = 9.0, 4.6 Hz, 1 H), 6.89 (ddd, J = 9.0, 8.0, 3.0 Hz, 1H), 6.76 (dd, J= 9.4, 3.0 Hz, 1 H), 4.95 -4.69 (m, 2H), 4.35 -4.17 (m, 2H), 2.16 (dt, J = 9.0, 5.3 Hz, 1 H), 1.25 (dt, J = 9.7, 4.9 Hz, 1H), 1.18 (dt, J = 8.5, 5.5 Hz, 1 H), 1.04 (dt, J = 9.0, 5.2 Hz, 1H). Attorney Docket No: 01312-0023-00PCT

[0365] Example 14.

[0366]

[0367] The racemate free base product prepared according to the method of Example 13 was separated by chiral HPLC, hexane / iPrOH / DEA, 90 / 10 (0.1% diethylamine), 5 pl injection, flowrate of 10 mL / min, A = 280 nm) using Chiralpak AD-H column to afford the (+)-isomer (Compound VII, 20 min) and the (-)-isomer (25 min).

[0368] Example 15.

[0369]

[0370] To a solution of ethyl fluoroacetate (10 mmol) in diethyl ether (50 mL) was added an excess of lithium aluminum deuteride (3.0 equiv) portion wise at 0 °C. Upon completion of the reaction as indicated by TLC, the reaction mixture was quenched carefully with water and acidified with 1 M HCI. The phases were separated, and the aqueous phase was extracted with DCM (x3). The combined organic extracts were dried over anhydrous sodium sulfate and filtered. To the filtrate was added tosyl chloride (1.7 equiv), triethylamine (2.0 equiv) and 5 mol% DMAP. The reaction mixture was allowed to stir overnight before being concentrated and dry loaded onto a silica gel column (elution: 5, 10, 15, 25% ethyl acetate in hexane) to provide 2-fluoroethyl-1 , 1 -d24-methylbenzenesulfonate as a colorless oil (73% yield).

[0371] Example 16.

[0372]

[0373] The procedure of Example 6 was repeated, except 2-iodo-1 -fluoroethane was replaced Attorney Docket No: 01312-0023-00PCT

[0374] with TSOCD2CH2F prepared according to Example 15 to afford the free base of the target d2 product.

[0375] Example 17.

[0376]

[0377] The procedure of Example 7 was repeated, except the aldehyde was replaced with the d2 aldehyde produced according to Example 16. The procedures of Examples 8 through 11 were then followed with the d2 intermediates to afford the free base of the target d2 racemate. Formation of the desired product was confirmed by HRMS (ESI+) calc’d for Ci2Hi4D2F2NO+[M+H]+: 230.1320; found 230.1314; and1H NMR (600 MHz, d4-MeOH) 56.94 (dd, J = 9.0, 4.6 Hz, 1 H), 6.89 (ddd, J = 9.0, 8.0, 3.1 Hz, 1 H), 6.76 (dd, J = 9.4, 3.0 Hz, 1 H), 4.90 - 4.72 (m, 2H), 3.07 -2.98 (m, 2H), 2.16 (dt, J = 9.0, 5.3 Hz, 1H), 1.30 - 1.21 (m, 1H), 1.18 (dt, J = 8.5, 5.5 Hz, 1H), 1.04 (dt, J = 9.0, 5.2 Hz, 1H).

[0378] Example 18.

[0379]

[0380] The racemate free base product prepared according to the method of Example 17 was separated by chiral HPLC, hexane / iPrOH / DEA, 90 / 10 (0.1% diethylamine), 5 ul injection, flowrate of 10 mL / min, A = 280 nm) using Chiralpak AD-H column to afford the (+)-isomer (Compound II, 20 min) and the (-)-isomer (25 min). Attorney Docket No: 01312-0023-00PCT

[0381] Example 19.

[0382]

[0383] The procedure of Example 6 was repeated, except 2-iodo-1 -fluoroethane was replaced with TSOCD2CD2F prepared according to the method set forth in W02020 / 260196A1 (incorporated herein by reference in its entirety), to afford the free base of the target d4 aldehyde product.

[0384] Example 20.

[0385]

[0386] The procedure of Example 7 was repeated, except the aldehyde was replaced with the d4 aldehyde produced according to Example 19. The procedures of Examples 8 through 11 were then followed with the d4 intermediates to afford the free base of the target d4 racemate. Formation of the desired product was confirmed by HRMS (ESI+) calc’d for CI2HI2D4F2NO+[M+H]+: 232.1446; found 232.1440; and1H NMR (600 MHz, d4-MeOH) 56.94 (dd, J = 9.0, 4.6 Hz, 1 H), 6.89 (ddd, J = 9.0, 8.0, 3.1 Hz, 1 H), 6.76 (dd, J = 9.4, 3.1 Hz, 1 H), 3.09 - 2.97 (m, 2H), 2.16 (dt, J = 9.0, 5.3 Hz, 1 H), 1.30 - 1.23 (m, 1 H), 1.18 (dt, J = 8.5, 5.5 Hz, 1 H)1.04 (dt, J = 9.0, 5.2 Hz, 1H). Attorney Docket No: 01312-0023-00PCT

[0387] Example 21.

[0388]

[0389] The racemate free base product prepared according to the method of Example 20 was separated by chiral HPLC, hexane / iPrOH / DEA, 90 / 10 (0.1% diethylamine), 5 ul injection, flowrate of 10 mL / min, A = 280 nm) using Chiralpak AD-H column to afford the (+)-isomer (Compound III, 20 min) and the (-)-isomer (25 min).

[0390] Example 22. Formation of HCI Salt of Compound VII

[0391]

[0392] To a solution of Compound VII free base prepared according to the method of Example 14 (400 mg) in methanol (4 mL) was added dropwise 6 M HCI until pH paper indicated pH = 1. The volatiles were removed in vacuo and diluted with a minimal amount of methanol. The material was triturated by the addition of dichloromethane (4 mL) followed by hexane (8 mL). The volatiles were removed in vacuo. Toluene was added to the resulting residue and sonicated for 1 min before removal of the solvent in vacuo (x3). The solid was dried to a constant mass to provide the HCI salt of Compound VII as a white powder.

[0393] Example 23. Recrystallization of HCI Salt of Compound VII

[0394] Compound VII HCI (100 mg) was dissolved in a minimal amount of hot isopropanol. A 3X volume of hexanes was carefully layered on top of the solution. The mixture was allowed stand at room temperature and slowly diffuse overnight to afford colorless needles (Solid Form A of Compound VII HCI).

[0395] Example 24. Recrystallization of HCI Salt of Compound VII. Attorney Docket No: 01312-0023-00PCT

[0396] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound VII, yielding crystalline Solid Form B of Compound VII HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0397] Example 25. Recrystallization of HCI Salt of Compound VII.

[0398] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Compound VII, yielding crystalline Solid Form C of Compound VII HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0399] Example 26. Formation of HCI Salt of Compound I

[0400] The procedure of Example 22 was repeated, except Compound VII free base was replaced with the free base of Compound I, to afford the HCI salt of Compound I as a white powder.

[0401] Example 27. Recrystallization of HCI Salt of Compound I.

[0402] Compound I HCI prepared in Example 26 (700 mg) in DCM (15 mL) is added a minimal amount of MeOH until complete dissolution of Compound I HCI. Hexane (50 mL) is carefully layered on top of DCM / MeOH solution, the vessel is sealed, and allowed to stand without disturbance at room temperature for 24 hours. Compound I HCI forms as a crystalline solid (Solid Form A of Compound I HCI). The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0403] Example 28. Recrystallization of HCI Salt of Compound I.

[0404] A swirled suspension of 100 mg of Compound I HCI in toluene (10 mL) is heated to ca.

[0405] 90-100 °C (just below boiling) using a heat gun. Methanol (ca. 0.5 mL) is added dropwise with swirling to the hot suspension until complete dissolution of the solid. The solution is allowed to cool to room temperature overnight and then placed in a -20 °C freezer. Compound I HCI forms as a crystalline solid (Solid Form B of Compound I HCI). The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0406] Example 29. Formation of HCI Salt of Compound II

[0407] The procedure of Example 22 was repeated, except Compound VII free base was replaced with the free base of Compound II, to afford the HCI salt of Compound II as a white powder.

[0408] Example 30. Recrystallization of HCI Salt of Compound II.

[0409] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound II, yielding crystalline Solid Form A of Compound II HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0410] Example 31. Recrystallization of HCI Salt of Compound II.

[0411] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Attorney Docket No: 01312-0023-00PCT

[0412] Compound II, yielding crystalline Solid Form B of Compound II HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0413] Example 32. Formation of HCI Salt of Compound III

[0414] The procedure of Example 22 was repeated, except Compound VII free base was replaced with the free base of Compound III, to afford the HCI salt of Compound III.

[0415] Example 33. Recrystallization of HCI Salt of Compound III.

[0416] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound III, yielding crystalline Solid Form A of Compound III HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0417] Example 34. Recrystallization of HCI Salt of Compound III.

[0418] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Compound III, yielding crystalline Solid Form B of Compound III HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0419] Example 35. Formation of HCI Salt of Compound IV

[0420] The procedure of Example 22 was repeated, except Compound VII free base was replaced with the free base of Compound IV (see Example 53), to afford the HCI salt of Compound IV as a white powder.

[0421] Example 36. Recrystallization of HCI Salt of Compound IV.

[0422] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound IV, yielding crystalline Solid Form A of Compound IV HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0423] Example 37. Recrystallization of HCI Salt of Compound IV.

[0424] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Compound IV, yielding crystalline Solid Form B of Compound IV HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0425] Example 38. Formation of HCI Salt of Compound V

[0426] The procedure of Example 22 was repeated, except Compound V free base prepared by known methods (see, e.g., PCT Patent Application No. PCT / US25 / 22435, which is incorporated herein by reference in its entirety for all purposes) is used instead of the free base of Compound VII, to afford the HCI salt of Compound V.

[0427] Example 39. Recrystallization of HCI Salt of Compound V.

[0428] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound V, yielding crystalline Solid Form A of Compound V HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained. Attorney Docket No: 01312-0023-00PCT

[0429] Example 40. Recrystallization of HCI Salt of Compound V.

[0430] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Compound V, yielding crystalline Solid Form B of Compound V HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0431] Example 41. Formation of HCI Salt of Compound VI.

[0432] The procedure of Example 22 was repeated, except Compound VI free base prepared by known methods (see, e.g., PCT Patent Application No. PCT / US25 / 22435, which is incorporated herein by reference in its entirety for all purposes) is used instead of the free base of Compound VII, to afford the HCI salt of Compound VI.

[0433] Example 42. Recrystallization of HCI Salt of Compound VI.

[0434] The recrystallization procedure set forth in Example 27 is performed on the HCI salt of Compound VI, yielding crystalline Solid Form A of Compound VI HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0435] Example 43. Recrystallization of HCI Salt of Compound VI.

[0436] The recrystallization procedure set forth in Example 28 is performed on the HCI salt of Compound VI, yielding crystalline Solid Form B of Compound VI HCI. The solid form is analyzed by XRPD and a list of prominent peaks is obtained.

[0437] Example 44. Recrystallization of HCI Salt of Compound I.

[0438] Compound I HCI (100 mg) was dissolved in a minimal amount of hot isopropanol. A 3X volume of hexanes was carefully layered on top of the solution. The mixture was allowed stand at room temperature and slowly diffuse overnight to afford colorless needles (Solid Form C of Compound I HCI).

[0439] Example 45. Recrystallization of HCI Salt of Compound II.

[0440] Compound II HCI (102 mg) was dissolved in a minimal amount of hot isopropanol. A 3X volume of hexanes was carefully layered on top of the solution. The mixture was allowed stand at room temperature and slowly diffuse overnight to afford colorless needles (Solid Form C of Compound II HCI).

[0441] Example 46. Recrystallization of HCI Salt of Compound IV.

[0442] Compound IV HCI (100 mg) was dissolved in a minimal amount of hot isopropanol. A 3X volume of hexanes was carefully layered on top of the solution. The mixture was allowed stand at room temperature and slowly diffuse overnight to afford colorless needles (Solid Form C of Compound IV HCI).

[0443] Example 47. Single Crystal X-ray Diffraction (SCXRD) Analysis of Solid Form C of Compound IV HCI Attorney Docket No: 01312-0023-00PCT

[0444] A crystal of Solid Form C of Compound IV HCI having approximate dimensions of 0.100x0.120x0.550 mm is mounted on a Mitegen micromesh mount in a random orientation. Data are collected from a shock-cooled single crystal at 150(2) K on a Broker AXS D8 Quest three circle diffractometer with a fine focus sealed tube X-ray source using a Triumph curved graphite crystal as monochromator and a Photon II charge-integrating pixel array (CPAD) detector. The diffractometer uses MoKaradiation (A = 0.71073 A). All data are integrated with SAINT V8.40B and a multi-scan absorption correction using TWINABS 2012 / 1 was applied. See Broker, SAINT, V8.40B, Broker AXS Inc., Madison, Wisconsin, USA; L . Krause, R. Herbst-Irmer, G. M. Sheldrick, D. Stalke, J. Appl. Cryst. 2015, 48, 3-10,

[0445] doi:10.1107 / S1600576714022985.

[0446] The structure is solved by dual methods with SHELXT and refined by full-matrix leastsquares methods against P using SHELXL-2019 / 2. SeeG. M. Sheldrick, Acta Cryst. 2015, A71, 3-8, doi:10.1107 / S2053273314026370; and G. M. Sheldrick, Acta Cryst. 2015, C71, 3-8, doi:10.1107 / S2053229614024218. All non-hydrogen atoms are refined with anisotropic displacement parameters. All hydrogen atoms are refined with isotropic displacement parameters. Some of their coordinates are refined freely and some on calculated positions using a riding model with their Utsovalues constrained to 1.5 times the L / eqof their pivot atoms for terminal sp3carbon atoms and 1.2 times for all other carbon atoms.

[0447] This method is then repeated for each of solid forms A, B and C for each of Compounds I, II, III, IV, V, VI and VII.

[0448] Single Crystal X-ray Diffraction (SCXRD) Analysis of Solid Form C of Compound I

[0449]

[0450] A colorless needle shaped crystal of Solid Form C of Compound I HCI having approximate dimensions of 0.100x0.120x0.550 mm was mounted on a Mitegen micromesh mount in a random orientation. Data were collected from a shock-cooled single crystal at 150(2) K on a Bruker AXS D8 Quest three circle diffractometer with a fine focus sealed tube X-ray source using a Triumph curved graphite crystal as monochromator and a Photon II charge-integrating pixel array (CPAD) detector. The diffractometer used Mo / <aradiation (A = 0.71073 A). All data were integrated with SAINT V8.40B and a multi-scan absorption correction using TWINABS 2012 / 1 was applied. See Bruker, SAINT, V8.40B, Bruker AXS Inc., Madison, Wisconsin, USA; L . Krause, R. Herbst-lrmer, G. M. Sheldrick, D. Stalke, J. Appl. Cryst. 2015, 48, 3-10, doi:10.1107 / S1600576714022985.

[0451] The structure was solved by dual methods with SHELXT and refined by full-matrix leastsquares methods against P using SHELXL-2019 / 2. SeeG. M. Sheldrick, Acta Cryst. 2015, A71, 3-8, doi:10.1107 / S2053273314026370; and G. M. Sheldrick, Acta Cryst. 2015, C71, 3-8, Attorney Docket No: 01312-0023-00PCT

[0452] doi:10.1107 / S2053229614024218. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were refined with isotropic displacement parameters. Some of their coordinates were refined freely and some on calculated positions using a riding model with their Utsovalues constrained to 1.5 times the L / eq of their pivot atoms for terminal sp3carbon atoms and 1.2 times for all other carbon atoms.

[0453] Table 5 provides crystal data and structure refinement for Solid Form C of Compound I HCI, which was determined to be a partial hydrate (approx, monohydrate, non-stoichiometric). Visualization of the extended crystalline network suggests Solid Form C of Compound I HCI is a pore / cage hydrate.

[0454] Table 5

[0455] < <

[0456] < <

[0457] < <

[0458]

[0459] Attorney Docket No: 01312-0023-00PCT

[0460] >

[0461]

[0462] Figure 1 is a single crystal structure drawing of Solid Form C of Compound I HCI generated using FinalCif. See D. Kratzert, FinalCif, V139, https: / / dkratzert.de / finalcif.html.

[0463] Example 49. Single Crystal X-ray Diffraction (SCXRD) Analysis of Solid Form A of Compound VII HCI

[0464] A colorless, needle-shaped crystal of Solid Form A of Compound VII HCI having approximate dimensions of 0.080x0.090x0.420 mm was mounted on a Mitegen micromesh mount in a random orientation. Data were collected from a shock-cooled single crystal at 150(2) K on a Broker AXS D8 Quest three circle diffractometer with a fine focus sealed tube X-ray source using a Triumph curved graphite crystal as monochromator and a Photon II chargeintegrating pixel array (CPAD) detector. The diffractometer used MoKaradiation (A = 0.71073 A). All data were integrated with SAINT V8.40B and a multi-scan absorption correction using SADABS 2016 / 2 was applied. See Broker, SAINT, V8.40B, Broker AXS Inc., Madison, Wisconsin, USA; L . Krause, R. Herbst-lrmer, G. M. Sheldrick, D. Stalke, J. Appl. Cryst. 2015, 48, 3-10, doi:10.1107 / S1600576714022985.

[0465] The structure was solved by direct methods with SHELXT and refined by full-matrix Attorney Docket No: 01312-0023-00PCT

[0466] least-squares methods against P using SHELXL-2019 / 2. See . M. Sheldrick, Acta Cryst. 2015, A71, 3-8, doi:10.1107 / S2053273314026370; and G. M. Sheldrick, Acta Cryst. 2015, C71, 3-8, doi:10.1107 / S2053229614024218. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were refined with isotropic displacement parameters. Some of their coordinates were refined freely and some on calculated positions using a riding model with their Utsovalues constrained to 1 .5 times the L / eq of their pivot atoms for terminal sp3carbon atoms and 1 .2 times for all other carbon atoms. Refined as a 2-component twin. The unit cell does metrically fit an orthorhombic C-centered cell double the size and is twinned by that symmetry (180-degree rotation around the a-axis). Application of the twin matrix 1 00 0 -1 0 -0.969 0 -1 (Rotax) yielded a BAS value of 0.282(1).

[0467] Table 6 provides crystal data and structure refinement for Solid Form A of Compound VII HCI, which was determined to be a partial hydrate (approx, monohydrate, non-stoichiometric). Visualization of the extended crystalline network suggests Solid Form C of Compound I HCI is a channel hydrate in which the water molecules are ion coordinated.

[0468] Table 6

[0469]

[0470] Attorney Docket No: 01312-0023-00PCT

[0471] < <

[0472] < <

[0473] < <

[0474]

[0475] Figure 2 is a single crystal structure drawing of Solid Form A of Compound VII HCI generated using FinalCif. See D. Kratzert, FinalCif, V139, dkratzert.de / finalcif.html.

[0476] Example 50. X-ray powder diffraction analysis (XRPD or PXRD) of Solid Form C of Compound I HCI and Solid Form A of Compound VII HCI Attorney Docket No: 01312-0023-00PCT

[0477] Data Collection-. Samples of Solid Form C of Compound I HCI and Solid Form A of Compound VII HCI were ground to powders in agate mortar and pestle.

[0478] X-ray powder diffraction (XRPD) data were collected in focusing mode on a Panalytical Empyrean X-ray diffractometer equipped with Bragg-Brentano HD optics, a sealed tube copper X-ray source (X = 1.54178 A), soller slits on both the incident and receiving optics sides, and a PixCel3D Medipix detector.

[0479] The ground samples were packed in a 15 mm wide and 0.2 mm deep zero background holder (Malvern Panalytical 32 mm Low background Insert). 1 / 4° anti-scatter slits and 1 / 16° divergence slits as well as a 4 mm mask were chosen based on sample area and starting 0 angle. Data were collected between 4 and 90° (for Solid Form C of Compound I HCI) or 5 and 90° (for Solid Form A of Compound VII HCI) in 20 using the Panalytical Data Collector software (Data Collector, XRD Data Collection software, Version 6.1b, PANalytical B.V., Almelo, The Netherlands, 2019).

[0480] Data Analysis: Data were analyzed using the HighScore software of Panalytical (HighScore, Version 4.9, PANalytical B.V., Almelo, The Netherlands, 2020). Visual comparison of experimental patterns and of powder patterns simulated from previously determined single crystal data (see Figures 1 and 2) indicated phase pure material.

[0481] Rietveld refinements were performed against the models of the single crystal structure data sets using the HighScore software of Panalytical. The “Expanded Rietveld Phase Fit” option of Highscore was used. Refinement of preferred orientation was included using a spherical harmonics model. For the profile fit, split width and shape refinement was included.

[0482] Unit cell parameters refined to the following values are below in Tables 7 and 8 (150 K equivalents from the single crystal data given for comparison).

[0483] Table 7 - Solid Form C of Compound I HCI

[0484]

[0485] Attorney Docket No: 01312-0023-00PCT

[0486]

[0487] Table 8 - Solid Form A of Compound VII HCI

[0488]

[0489] The XRPD pattern of Solid Form C of Compound I HCI is shown in Figure 3. The corresponding pattern with Reitveld refinement is shown in Figure 4A with the difference plot and Rwp value in Figure 4B.

[0490] The XPRD pattern of Solid Form A of Compound VII HCI is shown in Figure 5. The corresponding pattern with Reitveld refinement is shown in Figure 6.

[0491] Observed peaks and prominent peaks were identified from the XRPD pattern of Solid Form C of Compound I HCI and the XPRD pattern of Solid Form A of Compound VII HCI. The prominent peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying non-overlapping low angle peaks with strong intensity. Under most circumstances, peaks within a range of up to about 30° 20 are presented. Rounding was used to round each peak to the nearest 0.01° 20. Peak position variabilities are given to within ± 0.2° 20. The wavelength used to calculate d-spacings was 1.5417 A.

[0492] Table 9 provides a list of observed peaks from the XRPD pattern of Solid Form C of Compound I HCI. Table 10 lists the prominent peaks from the XRPD pattern of Solid Form C of Compound I HCI.

[0493] Table 9

[0494]

[0495] Attorney Docket No: 01312-0023-00PCT

[0496]

[0497] Attorney Docket No: 01312-0023-00PCT

[0498]

[0499] Table 10

[0500]

[0501] Table 11 provides a list of observed peaks from the XRPD pattern of Solid Form A of Compound VII HCI. Table 12 lists the prominent peaks from the XRPD pattern of Solid Form A of Compound VII HCI.

[0502] Table 11

[0503]

[0504] Attorney Docket No: 01312-0023-00PCT

[0505]

[0506] Table 12

[0507]

[0508] Example 51 . Synthesis of Compound IV Attorney Docket No: 01312-0023-00PCT

[0509]

[0510] The procedure of Example 6 was repeated, except 2-iodo-1 -fluoroethane was replaced with allyl iodide (3-iodo-1 -propene) afford the free base of the target product.

[0511] Example 52.

[0512]

[0513] The procedure of Example 7 was repeated, except the aldehyde was replaced with the aldehyde produced according to Example 51. The procedures of Examples 8 through 11 were then followed with the intermediate to afford the free base of the target racemate.

[0514] Example 53.

[0515]

[0516] The racemate free base product prepared according to the method of Example 52 was separated by chiral HPLC, hexane / iPrOH / DEA, 90 / 10 (0.1% diethylamine), 5 ul injection, flowrate of 10 mL / min, A = 280 nm) using Chiralpak AD-H column to afford the (+)-isomer (Compound IV, 22 min) and the (-)-isomer (26 min). Attorney Docket No: 01312-0023-00PCT

[0517] Biological Examples

[0518]

[0519] Response (HTR) Experiments.

[0520] Dose-response studies. Dose-response studies for Compounds I, II, III, IV, V, VI and / or VII are performed in four consecutive steps:

[0521] (a). Formulation work. A suitable (non-toxic) vehicle will be identified that can be used to dissolve the compound.

[0522] (b). Pilot dose-finding study. HTR-inducing drugs typically have biphasic bell-shaped (inverted U-shaped) dose-response functions, with ascending and descending phases. To quantify the potency of a drug in a HTR dose-response study, doses covering the entire extent of the ascending phase should be included, as well as at least one dose that falls on the descending phase. A pilot dose-finding study is performed to identify a set of doses that matches those requirements. For the pilot, male C57BL / 6J mice will be injected with a range of doses (typically 0.3-30 mg / kg) by the IP or SC route and then behavior will be recorded in a magnetometer chamber for up to 150 minutes.

[0523] (c). Dose-response study. Groups of male C57BL / 6J mice with a magnet implant are injected with vehicle or 4-5 doses of the compound (n=5-7 mice / group) by the IP or SC route and then behavior will be recorded in a magnetometer chamber for at least 30 minutes.

[0524] (d). Repeated testing. Although potency can typically be quantified based on a single dose-response study, in some instances repeated testing may be necessary. For example, the doses selected for testing may not have been ideal to calculate the median effective dose (ED50 value). If necessary, a second or third dose-response study will be performed.

[0525] Analysis: The following analyses will be performed for dose-response studies:

[0526] HTR counts will be analyzed using a 1-way ANOVA followed by a post-hoc test (Dunnett’s test).

[0527] The median effective dose (ED5o value) for the compounds (in mg / kg or moles / kg) will calculated by nonlinear regression using a gaussian or sigmoidal model. The potencies of compounds and other reference compounds can also be compared statistically using an extra-sum-of-squares F-test.

[0528] HTR counts can be binned (e.g., blocks of 1 , 2, 5, or 10 minutes) and analyzed using a 2-way ANOVA (drug x time) followed by a post-hoc test (Dunnett’s test or Tukey’s test).

[0529] 5-HT2A Antagonist blockade studies. Four groups of male C57BL / 6J mice with a magnet implant are pretreated SC with the selective 5-HT2A antagonist M 100907 (vehicle, 0.001 , 0.01 , or 0.1 mg / kg). Twenty minutes later, all of the animals will be injected IP or SC with one dose of the compound (n=5-7 mice / group) and then behavior will be recorded in a magnetometer chamber for 30 minutes. Attorney Docket No: 01312-0023-00PCT

[0530] 5-HTIA Antagonist blockade studies. Four groups of male C57BL / 6J mice (n=5-7 mice / group) with a magnet implant are pretreated SC with the selective 5-HTI antagonist WAY-100635 (vehicle or 1 mg / kg). Twenty minutes later, the animals will be injected IP or SC with vehicle or one dose of the compound and then behavior will be recorded in a magnetometer chamber for at least 30 minutes.

[0531] Extended time-course studies. Male C57BL / 6J mice with a magnet implant are injected IP or SC with up to three different treatments (n=5-6 mice / group) and then behavior will be recorded in a magnetometer chamber for up to 5 hours (the exact assessment period used will depend on the duration-of-action of the Material being tested).

[0532] Brain penetration testing. These studies are used to test whether 5-HT2A ligands that do not induce the HTR are brain penetrant in mice. Male C57BL / 6J mice with a magnet implant are pretreated IP or SC with vehicle or three doses of the 5-HT2A ligand (n=5-7 mice / group); 20 minutes later, all of the mice are injected IP with 1 mg / kg (±)-DOI HCI, and then behavior will be recorded in a magnetometer chamber for 20-30 minutes.

[0533] hERG inhibition studies.

[0534] All experiments are conducted manually using a HEKA EPC-10 amplifier at room temperature in the whole-cell mode of the patch-clamp technique. HEK293 cells stably expressing hKv11.1 (hERG) under G418 selection can be sourced from the University of Wisconsin, Madison. Cells are cultured in DMEM containing 10% fetal bovine serum, 2 mM glutamine, 1 mM sodium pyruvate, 100 U ml-1 streptomycin, and 500 mg ml-1 penicillin, 100 pg ml-1 G418. The cell line is not authenticated or tested for mycoplasma contamination.

[0535] Before experiments, cells are grown to 60-80% confluency, lifted using TrypLE, and plated onto poly-l-lysine-coated coverslips. Patch pipettes are pulled from soda lime glass (microhaematocrit tubes) and should exhibit resistances of 2-4 MQ. For the external solution, normal sodium Ringer is used (160 mM NaCI, 4.5 mM KCI, 2 mM CaCh, 1 mM MgCh, 10 mM HEPES, pH 7.4 and 290-310 mOsm). The internal solution used is potassium fluoride with ATP (160 mM KF, 2 mM MgCI2, 10 mM EGTA, 10 mM HEPES, 4 mM NaATP, pH = 7.2 and 300-320 mOsm). A two-step pulse (applied every 10 s) from -80 mV initially to 40 mV for 2 s and then to -60 mV for 4 s, is used to elicit hERG currents. The percentage reduction of tail current amplitude by the compounds that are tested is determined and data are shown as mean ± s.d. (n = 3-4 per data point). For all experiments, solutions of the drugs are prepared fresh from 10 mM stocks in DMSO. The final DMSO concentration never exceeds 1%.

[0536] Serotonin and opioid receptor functional assays.

[0537] Functional assay screens at 5-HT and opioid receptors are performed in parallel using the same compound dilutions and 384-well-format high-throughput assay platforms. Assays are Attorney Docket No: 01312-0023-00PCT

[0538] used to assess activity at all human isoforms of the receptors, except where noted for the mouse 5-HT2A receptor. Receptor constructs in pcDNA vectors are generated from the Presto-Tango GPCR Iibrary39 with minor modifications. All tested compounds are serially diluted in drug buffer (HBSS, 20 mM HEPES, pH 7.4 supplemented with 0.1% bovine serum albumin and 0.01% ascorbic acid) and dispensed into 384-well assay plates using a FLIPR Tetra automated dispenser head (Molecular Devices). Every plate includes a positive control such as 5-HT (for all 5-HT receptors), DADLE (DOR), salvinorin A (KOR), and DAMGO (MOR). For measurements of 5-HT2A 5-HT2B, and 5-HT2CGq-mediated calcium flux function, HEK Flp-ln 293, T-Rex stable cell lines (Invitrogen) are loaded with Fluo-4 dye for one hour, stimulated with compounds and read for baseline (0-10 s) and peak fold-over-basal fluorescence (5 min) at 25 °C on the FLIPR Tetra system. For measurement of 5-HT6Gs and 5-HT7afunctional assays, -mediated cAMP accumulation is detected using the split-luciferase GloSensor assay in HEKT cells measuring luminescence on a Microbeta Trilux (Perkin Elmer) with a 15 min drug incubation at 25 °C. For 5-HTIA, 5-HTIB, 5-HTIF, MOR, KOR and DOR functional assays, Gi / o, -mediated cAMP inhibition is measured using the split-luciferase GloSensor assay in HEKT cells, conducted similarly to that above, but in combination with either 0.3 pM isoproterenol (5-HTIA, 5-HTIB, 5-HTIF ) or 1 pM forskolin (MOR, KOR and DOR) to stimulate endogenous cAMP accumulation. For measurement of 5-HTID, 5-HTIE, 5-HT , and 5-HT5A functional assays, -arrestin2 recruitment is measured by the Tango assay using HTLA cells expressing tobacco etch virus (TEV) fused-p-arrestin2, as described previously with minor modifications. Cell lines were not authenticated, but they ae purchased mycoplasma-free and tested for mycoplasma contamination. Data for all assays are plotted and nonlinear regression is performed using “log(agonist) vs. response” in GraphPad Prism to yield estimates of the efficacy (Emax and half-maximal effective concentration (ECso)).

[0539] Pharmacokinetic studies.

[0540] Male and female C57 / BL6J mice (12 weeks old) are administered separately for each of solid forms A, B, and / or C of the compounds described herein via i.p. injection at doses of either 50 mg kg— 1 , 10 mg kg— 1 or 1 mg kg— 1. Mice are euthanized 15 min or 3 h after injection by cervical dislocation. Two males and two females are used per dose and time point. Brain and liver are collected, flash-frozen in liquid nitrogen, and stored at -80 °C until metabolomic processing. Whole brain and liver sections are lyophilized overnight to complete dryness, then homogenized with 3.2mm diameter stainless-steel beads using a GenoGrinder for 50 s at 1 ,500 rpm. Ground tissue is then extracted using 225 pl cold methanol, 190 pl water, 750 pl methyl tert-butyl ether (MTBE). Seven method blanks and seven quality-control samples (pooled human serum, BiolVT) are extracted at the same time as the samples. The nonpolar fraction of Attorney Docket No: 01312-0023-00PCT

[0541] MTBE is dried under vacuum and reconstituted in 60 pl of 90:10 (v / v) methanol: toluene containing 1-cyclohexyldodecanoic acid urea as an internal standard. Samples are then vortexed, sonicated and centrifuged before analysis.

[0542] For analysis of the tested compound in liver and brain, samples are randomized before injection with method blanks and quality-control samples are analyzed between every ten study samples. A six-point calibration curve is analyzed after column equilibration using blank injections, and then after all study samples. Blanks are injected after the calibration curve to ensure no that none of the tested compound is retained on the column and carried over to samples. Reconstituted sample (5 pl) is injected onto a Waters Acquity LIPLC CSH C18 column (100 mm x 2.1 mm, 1.7 pm particle size) with an Acquity LIPLC CSH C18 VanGuard precolumn (Waters) using a Vanquish LIHPLC coupled to a TSQ Altis triple quadrupole mass spectrometer (Thermo Fisher Scientific). Mobile phase A consists of 60:40 v / v acetonitrile / water with 10 mM ammonium formate and 0.1% formic acid. Mobile phase B consists of 90:10 v / v isopropanol / acetonitrile with 10 mM ammonium formate and 0.1% formic acid. Gradients are run from 0-2 min at 15% B; 2-2.5 min 30% B; 2.5-4.5 min 48% B; 4.5-7.3 min 99% B; 7.3-10 min 15% B. The flow rate is 0.600 ml / min and the column is heated to 65 °C. Mass spectrometer conditions are optimized for the target compound by direct infusion. Selected reaction monitoring is performed for the top five ions, with collision energy, source fragmentation, and radiofrequency optimized for the test compound. Data are processed with T raceFinder 4.1 (Thermo Fisher Scientific). Organ weights are recorded. The concentration in the brain is calculated using the experimentally determined number of moles of the target compound in the whole organ divided by the weight of the organ.

[0543] 5-HT Receptor Functional Assays.

[0544] Various assays for measuring serotonin receptor activation are known to those of skill in the art, including those methods described in Olsen et al., Nat. Chem. Biol., 2020 Aug.;

[0545] 16(8):841 -49, incorporated herein by reference in its entirety for all purposes. The assays described therein may be utilized to measure the functional activity of any of the serotonin receptor subtypes described herein, including 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C. In certain embodiments, serotonin (5-hydroxytryptamine) is used as the reference compound.

[0546] Cell culture

[0547] HEK293T cells are maintained, passaged, and transfected in DMEM medium containing 10% FBS, 100 Units / mL penicillin, and 100pg / mL streptomycin (Gibco-ThermoFisher, Waltham, MA) in a humidified atmosphere at 37°C and 5% CO2. After transfection, cells are plated in DMEM containing 1% dialyzed FBS, 100 Units / mL penicillin, and 100pg / mL streptomycin for BRET2, calcium, and GloSensor assays. Attorney Docket No: 01312-0023-00PCT

[0548] BRET2 assays

[0549] Cells are plated either in six-well dishes at a density of 700,000-800,000 cells / well, or 10-cm dishes at 7-8 million cells / dish. Cells are transfected 2-4 hours later, using a 1 :1 :1 :1 DNA ratio of receptor:Ga-RLuc8:Gp:Gy-GFP2 (100 ng / construct for six-well dishes, 750 ng / construct for 10-cm dishes), except for the Gy-GFP2 screen, where an ethanol coprecipitated mixture of Gpi-4- is used at twice its normal ratio (1 :1 :2:1). Transit 2020 (Mirus Biosciences, Madison, Wl) is used to complex the DNA at a ratio of 3 pL Transit / pg DNA, in OptiMEM (Gibco-ThermoFisher, Waltham, MA) at a concentration of 10 ng DNA / pL OptiMEM. The next day, cells are harvested from the plate using Versene (0.1 M PBS + 0.5 mM EDTA, pH 7.4), and plated in poly-D-lysine-coated white, clear bottom 96-well assay plates (Greiner Bio-One, Monroe, NC) at a density of 30,000-50,000 cells / well.

[0550] One day after plating in 96-well assay plates, white backings (Perkin Elmer, Waltham, MA) are applied to the plate bottoms, and growth medium is carefully aspirated and replaced immediately with 60 pL of assay buffer (1x HBSS + 20 mM HEPES, pH 7.4), followed by a 10 pL addition of freshly prepared 50 pM coelenterazine 400a (Nanolight Technologies, Pinetop, AZ). After a five-minute equilibration period, cells are treated with 30 pL of drug for an additional 5 minutes. Plates are then read in an LB940 Mithras plate reader (Berthold Technologies, Oak Ridge, TN) with 395 nm (RLuc8-coelenterazine 400a) and 510 nm (GFP2) emission filters, at 1 second / well integration times. Plates are read serially six times, and measurements from the sixth read were used in all analyses. BRET2 ratios are computed as the ratio of the GFP2 emission to RLuc8 emission.

[0551] Calcium Mobilization Assays

[0552] Cells are plated in 10-cm plates as described in the BRET2 protocol and co-transfected with receptor (1 pg) and Ga-subunit (1 pg) cDNA. The next day, cells are plated at 15,000 cells / well in poly-D-lysine coated black, clear bottom 384-well plates (Greiner Bio-One, Monroe, NC). The following day, growth medium are aspirated and replaced with 20 pL assay buffer containing 1x Fluo-4 Direct Calcium Dye (ThermoFisher Scientific, Waltham, MA) and incubated for 60 minutes at 37°C (no CO2). Plates were brought to RT for 10 minutes in the dark before being loaded into a FLIPR Tetra® liquid-handling robot and plate reader (Molecular Devices, San Jose, CA). Baseline fluorescence measurements were taken for 10 seconds followed by robotic drug addition (10 pL) and a 60-second measurement (1 measurement / second). For antagonist assays, cells are first treated with antagonist and kept in the dark at room temperature for ten minutes before agonist addition by the FLIPR Tetra® robot. Maximal response during this time is used to calculate amplitude of the calcium transients.

[0553] Measurements were analyzed as percentage of maximum signal amplitude for the construct. Attorney Docket No: 01312-0023-00PCT

[0554] Giosensor cAMP Assays

[0555] Cells are plated in 10-cm plates as previously described. Cells are transfected with plasmids encoding cDNA for the Giosensor reporter (Promega, Madison, Wl), receptor, and Ga-subunit at a ratio of 2:1 :1 (2 pg: 1 pg: 1 pg). The next day, cells are plated in black, clear-bottom, 384-well white plates. After aspiration of the medium on the day of the assay, cells are incubated for 60 minutes at 37°C with 20 pL of 5 mM luciferin substrate (GoldBio, St. Louis, MO) freshly prepared in assay buffer. For Gas activity, 10 pL of drugs are added using the FLIPR Tetra® liquid-handling robot and read after 15 minutes in a Spectramax luminescence plate reader (Molecular Devices, San Jose, CA) with a 0.5 second signal integration time. For Gai activity, 10 pL of drugs are added for a 15-minute incubation period. Subsequently, 10 pL of isoproterenol (final concentration of 200 nM) are added and incubated for an additional 15-minute period before reading. Attorney Docket No: 01312-0023-00PCT

[0556] ADDITIONAL EXEMPLARY ENUMERATED EMBODIMENTS

[0557] 1. A solid form of a compound selected from Compounds I, II, III, IV, V, VI and VII, wherein the selected compound exhibits at least one improved property compared to previously known solid forms of said compound.

[0558] 2. The solid form of Embodiment 1 , wherein the solid form of the compound is a salt.

[0559] 3. The solid form of Embodiment 2, wherein the salt is formed from an acid selected from galactaric (mucic) acid, naphthalene-1,5-disulfonic acid, citric acid, sulfuric acid, d-glucuronic acid, ethane-1 ,2-disulfonic acid, lactobionic acid, p- toluenesulfonic acid, D-glucoheptonic acid, thiocyanic acid, (-)-L-pyroglutamic acid, methanesulfonic acid, L-malic acid, dodecylsulfuric acid, hippuric acid, naphthalene-2-sulfonic acid, D-gluconic acid, benzenesulfonic acid, D,L-lactic acid, oxalic acid, oleic acid, glycerophosphoric acid, succinic acid, ethanesulfonic acid 2-hydroxy, glutaric acid, L-aspartic acid, cinnamic acid, maleic acid, adipic acid, phosphoric acid, sebacic acid, ethanesulfonic acid, (+)- camphoric acid, glutamic acid, acetic acid, fumaric acid, xinafoic acid, hydrobromic acid, hydrochloric acid, or a combination thereof.

[0560] 4. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is from about 0.4 molar equivalent to about 2.2 molar equivalents of the acid.

[0561] 5. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is from about 0.5 molar equivalent to about 2 molar equivalents of the acid.

[0562] 6. The solid form of Embodiment 3, wherein the stoichiometric ratio of acid to the selected compound is selected from about 0.5 to about 1 molar equivalent of the acid or from about 0.5 to about 2 molar equivalents of the acid.

[0563] 7. The solid form of Embodiment 1 , wherein the solid form is a free base form of the selected compound.

[0564] 8. The solid form of any one of Embodiments 1 -7, wherein the solid form is a crystalline solid.

[0565] 9. The solid form of Embodiment 8, wherein the crystalline solid is a substantially single polymorph.

[0566] 10. The solid form of any one of Embodiments 1-9, wherein the solid form is a Attorney Docket No: 01312-0023-00PCT

[0567] hydrate.

[0568] 11. Solid Form A of Compound I HCI.

[0569] 12. Solid Form B of Compound I HCI.

[0570] 13. Solid Form C of Compound I HCI.

[0571] 14. Solid Form A of Compound II HCI.

[0572] 15. Solid Form B of Compound II HCI.

[0573] 16. Solid Form C of Compound II HCI.

[0574] 17. Solid Form A of Compound III HCI.

[0575] 18. Solid Form B of Compound III HCI.

[0576] 19. Solid Form A of Compound IV HCI.

[0577] 20. Solid Form B or Solid Form C of Compound IV HCI.

[0578] 21. Solid Form A of Compound V HCI.

[0579] 22. Solid Form B of Compound V HCI.

[0580] 23. Solid Form A of Compound VI HCI.

[0581] 24. Solid Form B or Solid Form C of Compound VI HCI.

[0582] 25. Solid Form A of Compound VII HCI.

[0583] 26. Solid Form B of Compound VII HCI.

[0584] 27. Solid Form C of Compound VII HCI.

[0585] 28. The solid form of any one of Embodiments 1-27, wherein the solid form comprises a hydrate.

[0586] 29. The solid form of Embodiment 28, wherein the hydrate is a partial hydrate. 30. The solid form of Embodiment 28, wherein the hydrate is a monohydrate.

[0587] 31. The solid form of any one of Embodiments 1-30, wherein the at least one improved property is selected from physical properties, chemical properties, pharmacokinetic properties, or a combination thereof.

[0588] 32. The solid form of Embodiment 31 , wherein the at least one improved property comprise an improvement in melting point temperature, glass transition temperature, flowability, thermal stability, shelf life, stability against polymorphic transition, hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles, bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, half-life, or a combination thereof.

[0589] 33. The solid form according to any one of Embodiments 1-32, wherein the solid form comprises a non-stoichiometric hydrate.

[0590] 34. The solid form according to any one of Embodiments 1-33, wherein said solid Attorney Docket No: 01312-0023-00PCT

[0591] form comprises about 0.1 to about 0.25 mol of H2O per formula unit.

[0592] 35. The solid form according to any one of Embodiments 1-34, wherein said solid form comprises about 0.12 to about 0.20 mol of H2O per formula unit.

[0593] 36. The solid form according to any one of Embodiments 1-35, wherein said solid form comprises about 0.5 to about 2 w / w % water.

[0594] 37. The solid form according to any one of Embodiments 1-36, wherein said solid form comprises about 0.6 to about 1.8 w / w % water.

[0595] 38. The solid form according to any one of Embodiments 1-37, wherein the solid form comprises a channel hydrate.

[0596] 39. The solid form according to any one of Embodiments 1-37, wherein the solid form comprises a cage hydrate.

[0597] 40. The solid form according to any one of Embodiments 1-37, wherein the solid form comprises an ion-coordinated hydrate.

[0598] 41. The solid form according to Embodiment 38, wherein the solid form comprises an ion-coordinated channel hydrate.

[0599] 42. The solid form according to Embodiment 39, wherein the solid form comprises an ion-coordinated cage hydrate.

[0600] 43. A pharmaceutical composition comprising a solid form of a compound according to any one of Embodiments 1-42, and a pharmaceutically acceptable excipient.

[0601] 44. A method of treating a disease and / or disorder, comprising administering to a subject a therapeutically effective amount of a solid form of a compound according to any one of Embodiments 1 -42, or a pharmaceutical composition according to claim 43.

[0602] 45. The method of Embodiment 44, wherein the subject has a neurological disease or a psychiatric disorder, or both.

[0603] 46. The method of Embodiment 45, wherein the neurological disorder is a neurodegenerative disorder.

[0604] 47. The method of Embodiment 45, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.

[0605] 48. The method of Embodiment 45, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, Alzheimer’s psychosis or substance use disorder.

[0606] 49. The method of Embodiment 45, wherein the neurological disorder or psychiatric Attorney Docket No: 01312-0023-00PCT

[0607] disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.

[0608] 50. The method of any one of Embodiments 44-49, wherein administering comprises oral administration, parenteral administration, or intravenous administration.

[0609] 51. The method of any one of Embodiments 44-49, wherein administering comprises oral administration.

[0610] 52. The method of any one of Embodiment 44-49, wherein administering comprises administering by injection, inhalation, intraocular, intravaginal, intrarectal or transdermal routes.

[0611] 53. The method of any one of Embodiments 44-52, further comprising administering to the subject a therapeutically effective amount of an empathogenic agent. 54. The method of any one of Embodiments 45 or 50-52, wherein the neurological disorder or psychiatric disorder, or both, is a substance use disorder.

[0612] 55. The method of Embodiment 54, wherein the substance use disorder is amphetamine use disorder.

[0613] 56. The method of Embodiment 54, wherein the substance use disorder is methamphetamine use disorder.

[0614] 57. The method of Embodiment 54, wherein the substance use disorder is cocaine use disorder.

[0615] 58. The method of any one of Embodiments 45 or 50-52, wherein the disease or disorder is a seizure disorder.

[0616] 59. The method of any one of Embodiments 45 or 50-52, wherein the disease or disorder is an epilepsy.

[0617] 60. The method of any one of Embodiments 45 or 50-52, wherein the epilepsy is a convulsive epilepsy.

[0618] 61. The method of any one of Embodiments 48 or 50-52, wherein the disease or disorder is absence seizures.

[0619] 62. The method of any one of Embodiments 44 or 50-52, wherein the disease or disorder comprises hyperphagia.

[0620] 63. The method of any one of Embodiments 44, 50-52, or 62 wherein the disease or disorder is Prader-Willi Syndrome.

[0621] 64. Solid Form C of Compound I HCI, characterized by at least one of: (i) an x-ray powder diffraction (XRPD) pattern substantially similar to Figure 1 , or (ii) an x- ray powder diffraction (XRPD) pattern characterized by at least two peaks Attorney Docket No: 01312-0023-00PCT

[0622] selected from the listing in Table 10.

[0623] Solid Form A of Compound VII HCI, characterized by at least one of: (i) an x-ray powder diffraction (XRPD) pattern substantially similar to Figure 3, or (ii) an x-ray powder diffraction (XRPD) pattern characterized by at least two peaks selected from the listing in Table 12.

Claims

Attorney Docket No: 01312-0023-00PCTWhat is claimed:

1. A solid form of crystalline Compound I:Compound Iwherein the solid form comprises a non-stoichiometric hydrate.

2. The solid form according to claim 1 , wherein said solid form comprises about 0.1 mol to about 0.25 mol of H2O per formula unit.

3. The solid form according to claim 1 , wherein said solid form comprises about 0.12 mol to about 0.20 mol of H2O per formula unit.

4. The solid form according to claim 1 , wherein said solid form comprises about 0.5 w / w % to about 2 w / w % water.

5. The solid form according to claim 1 , wherein said solid form comprises about 0.6 w / w % to about 1.8 w / w % water.

6. The solid form according to claim 1 , wherein said solid form comprises a cage hydrate.

7. The solid form according to claim 1 , wherein said solid form comprises an ion-coordinated hydrate.

8. A pharmaceutical composition comprising the solid form according to claim 1 and at least one GLP-1 agonist.

9. A solid form of crystalline Compound VII:Compound VIIwherein the solid form comprises a non-stoichiometric hydrate.

10. The solid form of claim 9, wherein said solid form comprises about 0.1 mol toAttorney Docket No: 01312-0023-00PCTabout 0.25 mol of H2O per formula unit.

11. The solid form according to claim 9, wherein said solid form comprises about 0.12 mol to about 0.20 mol of H2O per formula unit.

12. The solid form according to claim 9, wherein said solid form comprises about 0.5 w / w % to about 2 w / w % water.

13. The solid form according to claim 9, wherein said solid form comprises about 0.6 w / w % to about 1.8 w / w % water.

14. The solid form according to claim 9, wherein the solid form comprises a channel hydrate.

15. The solid form according to claim 9, wherein the solid form comprises an ion- coordinated hydrate.

16. A pharmaceutical composition comprising the solid form of claim 9 and at least one GLP-1 agonist.

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