Salts of isochromanyl compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

Abstract

To provide salts and new forms of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine as well as pharmaceutical composition for treating a neurological or psychiatric disease or disorder.SOLUTION: There is provided a pharmaceutical composition comprising (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate or a hydrate or solvate thereof, or a solid or crystal thereof, and a pharmaceutically acceptable excipient. There is also provided a method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate characterized by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine with phosphoric acid.SELECTED DRAWING: None

Description

Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 818,256, filed on March 14, 2019, the entire content of which is incorporated herein by reference.

Technical Field

[0002] This application relates to salts and crystals of (R)-1-(8 - Fluoroisochroman - 1 - yl)-N - methylmethanamine (Compound 1), and methods for their preparation, therapeutic uses, and pharmaceutical compositions.

Background Art

[0003] Diseases and disorders of the central nervous system affect a wide range of populations and vary in severity. Neurological and psychiatric diseases and disorders include major depression, schizophrenia, bipolar disorder, obsessive - compulsive disorder (OCD), panic disorder, and post - traumatic stress disorder (PTSD), among others. These diseases and disorders can affect a person's thinking, mood, behavior, and social interactions, and can significantly impair the functions of daily life. See, for example, Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (2000) ("DSM - IV - TR"); Diagnostic and Statistical Manual of Mental Disorders, 5th Ed., American Psychiatric Association (2013)("DSM - 5"). Furthermore, neuropsychiatric symptoms such as anhedonia, depression, anxiety, cognitive impairment, psychosis, aggressive behavior, agitated excitement, impulse control disorders, and sleep disorders are currently recognized as core disorders in neurological diseases and disorders such as Alzheimer's disease and Parkinson's disease.

[0004] For the treatment of CNS diseases (central nervous system diseases), various drugs are currently under development. For example, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine reported in U.S. Patent No. 10,196,403 (all of which are incorporated herein by reference) is useful for the treatment of CNS disorders. In order to facilitate the production of safe, effective, and high-quality pharmaceuticals, salts and novel forms of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine are sought.

Summary of the Invention

[0005] (Summary of the Invention) This specification provides salts and crystals of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine. The compound (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1) has the following structure:

Chemical Formula

[0006] In some embodiments, a method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1), or a salt or crystal thereof, is provided.

[0007] In some embodiments, a method of using (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1), or a salt or crystal thereof, in the treatment of CNS diseases is provided.

[0008] In some embodiments, a pharmaceutical composition comprising (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1) described herein, or a salt or crystal thereof, and one or more pharmaceutically acceptable excipients is provided.

Brief Description of the Drawings

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[0010] (Detailed Description of the Invention) The method of the present invention relates to the use of the compounds and compositions disclosed herein for treating neurological or psychiatric diseases, disorders or deficiencies. In certain embodiments, the neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, stimulant disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, Alzheimer's disease, Parkinson's disease or cognitive impairment. In one embodiment, the disease or disorder is depression, particularly treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder. In certain embodiments, the dysfunction in neurological diseases or disorders such as Alzheimer's disease and Parkinson's disease includes neuropsychiatric symptoms such as anhedonia, depression, anxiety, cognitive dysfunction, psychosis, aggressive behavior, agitated excitement, impulse control disorder and / or sleep disorder.

[0011] A detailed description is provided to facilitate understanding of the various embodiments disclosed herein, but the disclosure is not intended to limit the claims to specific embodiments, and it should be understood that the disclosure is illustrative of the content recited in the claims. Accordingly, the specific embodiments disclosed herein can be combined with other specific embodiments disclosed herein, including those under various headings provided for simplicity and editing, but none of them should be construed as limiting the claims.

[0012] All publications cited herein are hereby incorporated by reference in their entirety.

[0013] (Definitions) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0014] As used herein, the singular forms of the articles "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0015] As used herein, unless otherwise indicated, the term "about" is used in connection with a numerical value or range of numerical values provided to describe a particular solid form (e.g., a particular temperature or temperature range, such as in the description of melting, dehydration, or glass transition; a mass change, such as a mass change as a function of temperature or humidity; a solvent or water content, such as with respect to mass or percentage; or a peak position, such as 13 in connection with analysis by 13C NMR, DSC, TGA, and XRPD, etc.), indicating that it may deviate from the numerical value or range of numerical values by up to what is considered reasonable to one of ordinary skill in the art when describing a particular solid form. Specifically, the term "about", when used in this context, indicates that the numerical value or range of numerical values may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the recited value or range of values while still describing the particular solid form. In certain embodiments, the numerical value may be about 5% different. The term "about", when used with a °2θ value, refers to ±0.3°2θ or ±0.2°2θ. In certain embodiments, "about" refers to a °2θ value of ±0.2°2θ. In certain embodiments, "about" refers to a temperature of ±3 °C.

[0016] As used herein, the term "alkali metal bicarbonate" is used alone or in combination with another term to mean a base represented by the formula: M(HCO3) where M refers to an alkali metal such as lithium, sodium, or potassium. Examples of alkali metal bicarbonates include, but are not limited to, lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate.

[0017] As used herein, the term "alkali metal alkoxide" is used alone or in combination with another term and means a base represented by the formula: M(O-alkyl) (wherein M refers to an alkali metal such as lithium, sodium or potassium). Examples of alkali metal alkoxides include, but are not limited to, lithium alkoxide, sodium alkoxide and potassium alkoxide.

[0018] As used herein, the term "metal hydroxide base" is used alone or in combination with another term and means a base having the formula: MOH (wherein M refers to an alkali metal such as lithium, sodium or potassium). Examples of alkali metal hydroxide bases include, but are not limited to, lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0019] As used herein, the terms "comprising" and "including" or grammatical variations thereof are considered to specify a stated feature, integer, step or component, but do not preclude the addition of one or more other features, integers, steps, components or groups thereof. These terms include the term "consisting of".

[0020] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature of the order of the temperature of the room in which the reaction is carried out, for example, a temperature of about 20 °C to about 30 °C.

[0021] As used herein, the terms "amorphous" or "amorphous form" are intended to mean that the substance, component or product of interest is not crystalline as determined, for example, by XRPD, or that the substance, component or product of interest is not birefringent when observed, for example, with a microscope. For example, amorphous essentially means that there is no regular repeating sequence of molecules, or no long-range order like that of a crystal, i.e., an amorphous form means non-crystalline. Also, an amorphous form does not exhibit a distinct X-ray diffraction pattern with sharp maxima. In certain embodiments, a sample containing an amorphous form of a substance may be substantially free of other amorphous forms and / or crystals. For example, an amorphous substance can be identified by an XRPD spectrum with no readily distinguishable reflections.

[0022] As used herein, the terms "chemical purity" or "purity" mean the measured value of a pure compound. In certain embodiments, the compounds described herein can be isolated with a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In certain embodiments, the compounds described herein can be isolated with an enantiomeric purity of greater than about 90%. In certain embodiments, the compounds described herein can be isolated with an enantiomeric purity of greater than about 95%. In certain embodiments, the compounds described herein can be isolated with an enantiomeric purity of greater than about 99%. The measured values can be determined by methods well known in the art, such as elemental analysis, column chromatography, NMR spectroscopy, and the like.

[0023] As used herein, the terms "crystal" or "crystalline form / crystalline morphology" mean crystalline solids of a single component or multiple components, including, but not limited to, crystal forms such as solvates, hydrates, inclusion hydrates and co-crystals. For example, "crystal" means that the molecules are arranged in a regular repetition, the molecules are regularly arranged, and it has a distinguishable crystal lattice. Also, "crystalline form" means a specific lattice arrangement of a crystalline substance. Even for the same substance, it has various different crystal lattices (unit cells), shows different physical properties due to the crystal lattice, and in some cases, the water or solvent content may be different. Different crystal lattices can be identified by solid state property evaluation methods such as X-ray powder diffraction (XRPD). Other property evaluation methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), etc., are not only more useful for identifying the crystalline form, but also useful for determining stability and solvent / water content.

[0024] As used herein, the terms "% crystallinity" or "crystalline purity" mean the proportion of the crystalline form in a preparation or sample that may include an amorphous form of the same compound or at least one other crystalline form of the compound, or a mixture thereof. In certain embodiments, the crystalline form can be isolated with a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In certain embodiments, the crystalline form can be isolated with a purity higher than about 90%. In certain embodiments, the crystalline form can be isolated with a purity higher than about 95%. In certain embodiments, the crystalline form can be isolated with a purity higher than about 99%.

[0025] As used herein, "delaying" the onset of a disorder means delaying, interfering with, taking time, stabilizing, and / or extending the onset of the disorder. Delaying can vary in length of time depending on the disease history and / or the individual receiving treatment.

[0026] As used herein, the term "disorder" or a particular disorder disclosed herein (e.g., CNS disorder) refers to a disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0027] As used herein, the term "enantiomeric purity" refers to a measure of the purity of a chiral compound. In some embodiments, the compounds described herein can be isolated with an enantiomeric purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the compounds described herein can be isolated with an enantiomeric purity greater than about 99%. In some embodiments, the compounds described herein can be isolated with an enantiomeric purity greater than about 90%. In some embodiments, the compounds described herein can be isolated with an enantiomeric purity greater than about 95%. The measure can be determined by methods well known in the art, such as specific rotation, chiral column chromatography, NMR spectroscopy, and the like.

[0028] As used herein, the term "hydrate" is meant to refer to a solid form (e.g., a crystal) of a compound 1 and its salts that contains water. The water in the hydrate can be present in a stoichiometric amount with respect to the amount of salt in the solid, or can be present in various amounts as seen in channel-type hydrates.

[0029] The reactions of the processes described herein can be carried out in a suitable solvent that can be readily and easily selected by one of ordinary skill in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates or products within the temperature range at which the reaction is carried out, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of two or more solvents. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected. In some embodiments, the reaction can be carried out in the absence of a solvent, such as when at least one of the reagents is a liquid or a gas. As used herein, the term "organic solvent" refers to a carbon-based solvent (i.e., they contain carbon in their structure) used to dissolve or disperse one or more of the compounds described herein.

[0030] Suitable solvents include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (methylene chloride), tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, 1,1,1-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, and mixtures thereof.

[0031] Suitable solvents include ether solvents such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, and mixtures thereof.

[0032] Suitable solvents include protic solvents (e.g., polar protic solvents), such as water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2- or 3-pentanol, neopentyl alcohol, tert-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol or glycerol, but are not limited thereto.

[0033] Suitable solvents include aprotic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene or hexamethylphosphoramide, but are not limited thereto.

[0034] Suitable solvents include hydrocarbon solvents, such as benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o- or p-xylene, octane, indane, nonane or naphthalene.

[0035] As used herein, the terms "peak" or "characteristic peak" refer to a reflection having a relative height / intensity of at least about 3% of the height / intensity of the maximum peak.

[0036] As used herein, the terms "pharmaceutically acceptable" or "physiologically acceptable" refer to compounds (e.g., in solid form), compositions, dosage forms, and other materials useful in manufacturing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0037] "Pharmaceutically acceptable excipients" refer to non-toxic binders, fillers, adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, emulsifiers, anti-caking agents, fragrances, desiccants, plasticizers, vehicles, disintegrants, or lubricants, etc., which do not impair the pharmacological activity of the compound being formulated. Examples of pharmaceutically acceptable excipients that can be used in the composition include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of vegetable saturated fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin, etc.

[0038] As used in the specification, "prevention" or "prevention of" means a regimen that defends against the onset of a disorder so that the clinical symptoms of the disorder do not develop. Thus, "prevention" relates to performing a treatment method, including administration of a compound disclosed herein, on a subject before detectable signs of a disease in the subject become detectable (e.g., administering a compound disclosed herein to a subject in a state without detectable symptoms of a disorder). The subject is considered to be at risk of developing a disorder. As used herein, a "at-risk" subject is a subject at risk of developing a disorder to be treated. This may be, for example, a measurable parameter that correlates with the onset of a disorder and may be indicated by one or more risk factors known in the art.

[0039] The production of the compound may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups (PGs) can be readily determined by those skilled in the art. The chemical properties of the protecting groups are described, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006, the entire contents of which are incorporated herein by reference. The production of the compound may also include a leaving group (LG), which is a molecular fragment that detaches by cleavage of a bond. The leaving group is an anion or a neutral fragment and can stabilize another electron density that causes cleavage of the bond. Representative leaving groups are halides (e.g., Cl, Br, I, etc.) and esters of sulfonates (e.g., tosylate (TsO), triflate (TfO), mesylate (MsO), etc.).

[0040] As used herein, the terms "reaction", "contact" or "treatment" when describing a particular process are used as known in the art and generally mean bringing chemical reagents together in a manner that allows for interaction at the molecular level to achieve a chemical or physical transformation. In certain embodiments, a reaction includes two reagents, and for the first reagent, one equivalent or more of the second reagent is used. The reaction steps of the methods described herein can be carried out at times and under conditions suitable for the production of the identified product.

[0041] The term "salt" as used in the specification refers to a substance resulting from the combination of a compound with an acid or a base. For example, the free base compound 1 can be combined with the desired acid in a solvent or in a melt to produce a salt of compound 1. In some embodiments, the acid addition salts of compound 1 can be converted to different acid addition salts by anion exchange. Salts produced in a solvent system can be isolated by precipitation from the solvent. Precipitation and / or crystallization can be obtained, for example, by evaporation, temperature reduction, addition of an antisolvent, or combinations thereof.

[0042] The term "solid form" as used herein refers to the compounds provided herein in either an amorphous state or a crystalline state (e.g., a crystal), and thus the crystalline state compounds provided herein may optionally contain a solvent or water within the crystal lattice to form, for example, a solvated or hydrated crystal. In some embodiments, the compounds provided herein exist in a crystalline state as described herein.

[0043] A "solvate" as used herein is formed by the interaction of a solvent with a compound.

[0044] As used herein, the term "subject" to which administration is intended includes, but is not limited to, humans [i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, elderly adults)] and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals (e.g., including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats and / or dogs) and / or birds (e.g., including commercially relevant birds such as chickens, ducks, geese, quails and / or turkeys). A "subject" may have been independently diagnosed with a disorder as defined herein, may currently be experiencing symptoms associated with the disorder, may have experienced symptoms in the past, may be at risk of developing the disorder, or may exhibit one or more symptoms of the disorder even if undiagnosed. In some embodiments, the subject is a human who may have been independently diagnosed with a disorder as defined herein, may currently be experiencing symptoms associated with the disorder, may have experienced symptoms in the past, may be at risk of developing the disorder, or may exhibit one or more symptoms of the disorder even if undiagnosed.

[0045] As used herein, the term "substantially" when describing characteristic forms of crystals such as XRPD patterns, DSC thermograms, TGA thermograms, etc. means that the figure of interest, even if not identical to the reference figure depicted herein, falls within the limits of experimental error and thus can be judged by one of ordinary skill in the art to be obtained from the same crystal as that disclosed herein. For example, the term "substantially" as used in the context of XRPD herein means encompassing the deviations disclosed herein (e.g., device deviations, measurement deviations, etc.).

[0046] As used herein, the term "substantially amorphous" means that the majority of the weight of a sample or preparation (e.g., a salt of Compound 1) is amorphous and the remainder of the sample is crystalline of the same compound. In some embodiments, a substantially amorphous sample has a crystallinity of less than about 5% (e.g., about 95% of the amorphous form of the same compound), preferably less than about 4% crystallinity (e.g., about 96% of the amorphous form of the same compound), more preferably less than about 3% crystallinity (e.g., about 97% of the amorphous form of the same compound), still more preferably less than about 2% crystallinity (e.g., about 98% of the amorphous form of the same compound), still more preferably less than about 1% crystallinity (e.g., about 99% of the amorphous form of the same compound), and most preferably about 0% crystallinity (e.g., about 100% of the amorphous form of the same compound). In some embodiments, the term "completely amorphous" means a crystallinity of less than about 99% or about 0%.

[0047] As used herein, the term "substantially crystalline" means that the majority of the weight of a sample or preparation (e.g., a salt of Compound 1) is crystalline and the remainder of the sample is in an amorphous form (e.g., an amorphous form) of the same compound. In some embodiments, a substantially crystalline sample has a crystallinity of at least about 95% (e.g., about 5% of the amorphous form of the same compound), preferably at least about 96% crystallinity (e.g., about 4% of the amorphous form of the same compound), more preferably at least about 97% crystallinity (e.g., at least about 96% crystallinity (e.g., about 3% of the amorphous form of the same compound), still more preferably at least about 98% crystallinity (e.g., about 2% of the amorphous form of the same compound), still more preferably at least about 99% crystallinity (e.g., about 1% of the amorphous form of the same compound), most preferably about 100% crystallinity (e.g., about 100% of the amorphous form of the same compound). In some embodiments, the term "completely crystalline" means a crystallinity of at least about 99% or about 100%.

[0048] The term "substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition containing many of the compounds, salts, hydrates, solvates or solid forms provided herein. Substantial separation can include a composition containing the compounds, salts, hydrates, solvates or solid forms provided herein at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight or at least about 99% by weight.

[0049] As used herein, the terms "therapeutically effective amount" or "effective amount" mean an amount effective to induce the desired biological or medical response, and when administered to a subject for treating a disorder, includes an amount of the compound sufficient to effectively effect treatment of such disorder. The effective amount varies depending on the compound, the disorder, its severity and the age, weight, etc. of the subject to be treated. The effective amount may be a single or multiple dosages (e.g., one or more administrations may be required to achieve the endpoint of the desired treatment). The effective amount should be administered in an effective amount when used in combination with one or more other agents such that the desired or beneficial result is obtained or achieved. The appropriate dosage of any co-administered compound may be reduced, if desired, due to the combined, additive or synergistic effects of the compounds.

[0050] As used herein, the terms "treatment," "treating," and "treatment" mean an approach for obtaining beneficial or desirable results, including, but not limited to, therapeutic benefits. Therapeutic benefits include eradication and / or amelioration of the underlying disorder being treated; and eradication and / or amelioration of one or more symptoms associated with the underlying disorder such that an improvement is observed in the subject, even though the subject may still be afflicted with the underlying disorder. In certain embodiments, "treatment" or "treating" includes one or more of the following: (a) suppressing a disorder (e.g., reducing one or more symptoms caused by the disorder and / or reducing the degree of the disorder), (b) delaying or arresting the onset of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or delaying the worsening or progression of the disorder) and / or (c) alleviating the disorder (e.g., causing regression of clinical symptoms, improving the disorder, delaying the progression of the disorder, and / or enhancing the quality of life). In some embodiments, treatment can be administered after one or more symptoms have developed. In another embodiment, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history and / or genetic or other susceptibility factors). Also, treatment may be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0051] As used herein, the term "treatment-resistant depression" is also referred to as "treatment-resistant depression" and refers to a situation of major depressive disorder (MDD) in which a subject shows an insufficient response to treatment with at least two antidepressants (e.g., standard marketed antidepressant treatment). An insufficient response may include no response. Also, an insufficient response may occur when the subject does not show complete remission of symptoms or when a physician or clinician determines that the subject's response is inappropriate. The symptoms of treatment-resistant depression vary from mild to severe. Factors contributing to an insufficient response include, but are not limited to, early termination of treatment, insufficient dosage, non-compliance by the patient, misdiagnosis, and comorbid mental disorders.

[0052] EtOAc (ethyl acetate); g (gram); h (hour); HCl (hydrochloric acid); M (mole); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimole); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); nM (nanomole); Ph (phenyl); μg (microgram); μL (microliter); μM (micromole); wt% (weight %).

[0053] Salts and their crystalline forms This specification provides (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1) and its crystalline forms. Compound (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1) has the following structure:

Chemical formula

[0054] Compound 1 is described in US Patent Application No. 15 / 663,688 (Patent), all of which are hereby incorporated by reference into this specification.

[0055] (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine of Compound 1 is named or identified using other generally recognized nomenclatures. For example, the compound may be named or identified by a common name, a systematic name, or a non-systematic name. Nomenclatures generally recognized in the field of chemistry include, but are not limited to, Chemical Abstracts Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). In this specification, the IUPAC name provided by ChemDraw Professional 15.0 is used for Compound 1.

[0056] Compound 1 may be produced as a salt. In some embodiments, Compound 1 may be produced as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include malates, tartrates, citrates, phosphates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, hydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, benzenesulfonates, toluenesulfonates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, lactates, γ-hydroxybutyrates, glycolates, and mandelates. A list of other suitable pharmaceutically acceptable salts is described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0057] In some embodiments, the salt of Compound 1 is the hydrochloride salt of Compound 1. The hydrochloride form of Compound 1 is referred to herein as "Compound 1 hydrochloride". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride.

[0058] In some embodiments, the salt of Compound 1 is the phosphate salt of Compound 1. The phosphate form of Compound 1 is referred to herein as "Compound 1 phosphate". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate.

[0059] In some embodiments, the salt of Compound 1 is the L-tartrate salt of Compound 1. The L-tartrate form of Compound 1 is referred to herein as "Compound 1 L-tartrate". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate.

[0060] In some embodiments, the salt of Compound 1 is the D-tartrate salt of Compound . The D-tartrate form of Compound 1 is referred to as "Compound 1 D-tartrate". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate.

[0061] In some embodiments, the salt of Compound 1 is the fumarate salt of Compound 1. The fumarate form of Compound 1 is denoted as "fumarate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumaric acid salt.

[0062] In some embodiments, the salt of Compound 1 is the citrate salt of Compound 1. The citrate form of Compound 1 is denoted as "citrate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citric acid salt.

[0063] In some embodiments, the salt of Compound 1 is the succinate salt of Compound 1. The succinate form of Compound 1 is denoted as "succinate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinic acid salt.

[0064] In some embodiments, the salt of Compound 1 is the glutarate salt of Compound 1. The glutarate form of Compound 1 is denoted as "glutarate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutaric acid salt.

[0065] In some embodiments, the salt of Compound 1 is the L-malate salt of Compound 1. The L-malate form of Compound 1 is denoted as "the malate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine malate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate.

[0066] In some embodiments, the salt of Compound 1 is the benzenesulfonate salt of Compound 1. The benzenesulfonate form of Compound 1 is denoted as "the besylate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine besylate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine benzenesulfonate.

[0067] In some embodiments, the salt of Compound 1 is the p-toluenesulfonate salt of Compound 1. The p-toluenesulfonate form of Compound 1 is denoted as "the tosylate of Compound 1". Another name for the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine p-toluenesulfonate.

[0068] The salts described herein can have, for Compound 1, about half, about 1, about 2, about 3 equivalents, etc. of acid. In some embodiments, the salts described herein contain about half an equivalent of acid relative to Compound 1. In some embodiments, the salts described herein contain about 1 equivalent of acid relative to Compound 1. In some embodiments, the salts described herein contain about 2 equivalents of acid relative to Compound 1. In some embodiments, the salts described herein contain about 3 equivalents of acid relative to Compound 1. One skilled in the art will recognize that there is an equilibrium where protons may be present between the acid and Compound 1, depending on conditions (e.g., solvent, temperature, etc.) and the strength of the acid. For example, under some conditions, the acid can become a counteranion by losing one or more protons to Compound 1, and Compound 1 becomes a countercation. Under certain conditions, the protons of the acid form a weak interaction with the basic site of Compound 1, such that the protons can be shared between the acid and Compound 1.

[0069] The salts described herein can have less than about 1 equivalent, about 2 equivalents, about 3 equivalents, about 4 equivalents, less than about 5 equivalents, or 6 equivalents or more of solvent or hydrate relative to the salt. In some embodiments, the described salts have less than about 1 equivalent of solvent or hydrate relative to the salt. In some embodiments, the described salts have less than about 1 equivalent of hydrate relative to the salt. In some embodiments, the described salts have about 2 equivalents of solvent or hydrate relative to the salt. In some embodiments, the described salts have about 2 equivalents of hydrate relative to the salt. In some embodiments, the described salts have about 3 equivalents of solvent or hydrate relative to the salt. In some embodiments, the described salts have about 3 equivalents of hydrate relative to the salt.

[0070] In some embodiments, the salts described herein are anhydrous.

[0071] The salts of Compound 1 can be isolated as one or more crystals. Different crystal forms of the same substance can have various bulk properties, such as hygroscopicity, solubility, stability, etc. Crystal forms with a high melting point have high thermodynamic stability and may be advantageous for extending the shelf life of formulations containing such crystal forms. Crystal forms with a low melting point have low thermodynamic stability but are considered advantageous in terms of improved water solubility and enhanced drug bioavailability. Weakly hygroscopic crystal forms are preferable in terms of stability to heat or humidity and may be less likely to deteriorate during long-term storage. The crystals described herein have many advantages, such as having desirable properties. Furthermore, the crystal forms disclosed herein are considered useful for improving the properties of pharmaceuticals, such as dissolution profiles, shelf life, bioavailability, etc.

[0072] Different crystals of a specific substance, such as Compound 1 described herein, include both the anhydrous form of the substance and the solvated / hydrated forms of the substance, and each of the anhydrous form and the solvated / hydrated form can be distinguished from each other by different XRPD patterns or another solid property evaluation method and can exhibit different crystal lattices. In some examples, a single crystal (e.g., identified by a unique XRPD pattern) may have a varying water or solvent content, and despite the change in the composition regarding water and / or solvent, the lattice does not substantially change (and the same is true for the XRPD pattern).

[0073] The reflections (peaks) in an XRPD pattern are generally considered to be the fingerprint of a particular crystal. It is well known that the relative intensities of XRPD peaks can vary greatly depending, inter alia, on the sample preparation technique, the crystal size distribution, the filter used, the sample mounting procedure, and the particular equipment employed. Also, depending on the type or setting of the apparatus (e.g., whether a Ni filter is used), new peaks may be observed or existing peaks may disappear. Furthermore, equipment variations and other factors can affect the 2θ values. Accordingly, the peak assignments as reported herein may vary by plus or minus (±) approximately 0.2° (2θ) or approximately 0.3° (2θ).

[0074] Similarly, temperature measurements related to DSC, TGA, or other thermal experiments can vary by approximately ±3 °C depending on the equipment, particular settings, sample conditioning, etc. Accordingly, the crystals reported herein that exhibit a “substantial” DSC thermogram as shown in any of the figures are understood to be those that accommodate such variations.

[0075] Crystals of a substance can be obtained by a number of methods as is known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives such as cocrystallizing pairs of molecules, desolvation, dehydration, rapid evaporation, quenching, slow cooling, vapor diffusion, sublimation, exposure to moisture, milling, and solvent-drop milling.

[0076] Compound 1 and its salts can be produced in batches, samples, or preparations, referred to herein as batches. A batch, sample, or preparation can contain Compound 1 and its salts in any of the crystalline or amorphous forms described herein, including the hydrated and non-hydrated forms and mixtures thereof.

[0077] One or more of the constituent elements of the compounds provided herein (e.g., salts of Compound 1) can also include all isotopes of the atoms present in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds provided herein can be substituted or replaced with isotopes of natural or non-natural abundant atoms. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be substituted or replaced with deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (e.g., 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I).

[0078] In some embodiments, Compound 1 or a salt and a crystal thereof are substantially isolated.

[0079] Compound 1 can exist and / or be isolated as various salt forms and their polymorphs, such as hydrochloride (forms HA and HB), phosphate, L-tartrate (forms LA, LB, and LC), D-tartrate, fumarate (forms FA and FB), citrate, succinate, glutarate, L-malate, benzenesulfonate, and toluenesulfonate.

[0080] The hydrochloride of Compound 1 In some embodiments, provided herein is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride (the hydrochloride of Compound 1). In some embodiments, the hydrochloride of Compound 1 is crystalline.

[0081] The hydrochloride of Compound 1 can be prepared according to the procedure described in U.S. Patent No. 10,196,403. In some embodiments, provided is the hydrochloride of Compound 1 prepared by isolating the hydrochloride form HA of Compound 1 from a mixture of Compound 1, HCl, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In one embodiment, S1 is an ether. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is methanol. In one embodiment, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0082] The hydrochloride form HA of Compound 1 In some embodiments, provided is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride (the hydrochloride form HA of Compound 1). In some embodiments, the hydrochloride form HA of Compound 1 is crystalline.

[0083] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4 ± 0.2°, and 15.1° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 9.4° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 11.4° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 15.1° ± 0.2°.

[0084] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4 ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, and 17.6° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 9.4° ± 0.2°, 11.4 ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, and 17.6° ± 0.2°.

[0085] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, and 27.0° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, 18.8° ± 0.2°, 19.2° ± 0.2°, 24.3° ± 0.2°, and 27.0° ± 0.2°.

[0086] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2° and 27.0° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, 18.8° ± 0.2°, 19.2° ± 0.2°, 24.3° ± 0.2° and 27.0° ± 0.2°.

[0087] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2° and 27.0° ± 0.2°. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, 18.8° ± 0.2°, 19.2° ± 0.2°, 24.3° ± 0.2° and 27.0° ± 0.2°.

[0088] In some embodiments, the hydrochloride form HA of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 1.

[0089] In some embodiments, the hydrochloride form HA of Compound 1 exhibits endothermic peaks at temperatures of about 99°C and about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits an endothermic peak at a temperature of about 99°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits an endothermic peak at a temperature of about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 2. In some embodiments, the hydrochloride form HA of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 3. In some embodiments, the hydrochloride form HA of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 4.

[0090] In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4°±0.2°, 11.4±0.2° and 15.1°±0.2°; and exhibits endothermic peaks at temperatures of about 99°C and about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4°±0.2°, 11.4±0.2° and 15.1°±0.2°; and exhibits an endothermic peak at a temperature of about 99°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4°±0.2°, 11.4±0.2° and 15.1°±0.2°; and exhibits an endothermic peak at a temperature of about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4°±0.2°, 11.4±0.2° and 15.1°±0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 2. In some embodiments, the hydrochloride form HA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.4°±0.2°, 11.4±0.2° and 15.1°±0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 4.

[0091] In some embodiments, the hydrochloride form HA of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the hydrochloride form HA of Compound 1 can be isolated with a crystalline purity of greater than about 99%. In some embodiments, the hydrochloride form HA of Compound 1 can be isolated with a crystalline purity of greater than about 99.9%.

[0092] In some embodiments, the hydrochloride form HA of Compound 1 is produced by isolating the hydrochloride form HA of Compound 1 from a mixture of Compound 1, HCl and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0093] The hydrochloride form HB of Compound 1 In some embodiments, the (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride form HB (the hydrochloride form HB of Compound 1) is provided. In some embodiments, the hydrochloride HB of Compound 1 is crystalline.

[0094] In some embodiments, the hydrochloride form HB of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2° and 10.3° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits an XRPD peak characteristic of 2θ of 8.6° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits an XRPD peak characteristic of 2θ at 9.6° ± 0.2°. In some embodiments, the hydrochloride HB of Compound 1 exhibits an XRPD peak characteristic of 2θ at 10.3° ± 0.2°.

[0095] In some embodiments, the hydrochloride form HB of Compound 1 exhibits characteristic XRPD peaks with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, and 17.3° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, and 17.3° ± 0.2°.

[0096] In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 16.5° ± 0.2°, 17.3° ± 0.2°, 18.3° ± 0.2°, 23.8° ± 0.2°, 24.4° ± 0.2°, 26.9° ± 0.2°, and 27.1° ± 0.2°.

[0097] In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 16.5° ± 0.2°, 17.3° ± 0.2°, 18.3° ± 0.2°, 23.8° ± 0.2°, 24.4° ± 0.2°, 26.9° ± 0.2°, and 27.1° ± 0.2°.

[0098] In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2°, and 23.8° ± 0.2°. In some embodiments, the hydrochloride form HB of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 16.5° ± 0.2°, 17.3° ± 0.2°, 18.3° ± 0.2°, 23.8° ± 0.2°, 24.4° ± 0.2°, 26.9° ± 0.2°, and 27.1° ± 0.2°.

[0099] In some embodiments, the hydrochloride form HB of Compound 1 exhibits an XRPD pattern substantially as represented in FIG. 5.

[0100] In some embodiments, the hydrochloride form HB of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the hydrochloride form HB of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the hydrochloride form HB of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0101] In some embodiments, the hydrochloride form HB of Compound 1 is obtained by isolating the hydrochloride form HB of Compound 1 from a mixture of Compound 1, HCl, and S1, where S1 is a solvent. In some embodiments, S1 contains water. In some embodiments, Form HB is produced by exposing Form HA to high humidity. In some embodiments, Form HB is produced by exposing Form HA to a relative humidity of about 75%.

[0102] The phosphate of Compound 1 Provided in some embodiments is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate. In some embodiments, the phosphate of Compound 1 is crystalline.

[0103] In some embodiments, the phosphate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, and 18.2° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 4.6° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 9.1° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 18.2° ± 0.2°.

[0104] In some embodiments, the phosphate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 18.2° ± 0.2°, and 22.8° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 18.2° ± 0.2°, and 22.8° ± 0.2°.

[0105] In some embodiments, the phosphate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2°, and 24.8° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 19.1° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2°, 24.8° ± 0.2°, 26.0° ± 0.2°, 27.4° ± 0.2°, and 30.1° ± 0.2°.

[0106] In some embodiments, the phosphate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 19.1° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2°, 24.8° ± 0.2°, 26.0° ± 0.2°, 27.4° ± 0.2° and 30.1° ± 0.2°.

[0107] In some embodiments, the phosphate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°. In some embodiments, the phosphate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 19.1° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2°, 24.8° ± 0.2°, 26.0° ± 0.2°, 27.4° ± 0.2° and 30.1° ± 0.2°.

[0108] In some embodiments, the phosphate of Compound 1 exhibits an XRPD pattern of characteristic peaks substantially as represented in FIG. 6 (FIG. 6).

[0109] In some embodiments, the phosphate of Compound 1 exhibits an endothermic peak at a temperature of about 213°C. In some embodiments, the phosphate of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 7. In some embodiments, the phosphate of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 8. In some embodiments, the phosphate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 9.

[0110] In some embodiments, the phosphate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 18.2° ± 0.2° and 22.8° ± 0.2°; and exhibits an endothermic peak at a temperature of about 213°C. In some embodiments, the phosphate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 18.2° ± 0.2° and 22.8° ± 0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 7. In some embodiments, the phosphate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 18.2° ± 0.2° and 22.8° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 9.

[0111] In some embodiments, the phosphate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the phosphate of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the phosphate of Compound 1 can be isolated with a high crystalline purity of about 99.9% or more.

[0112] In some embodiments, provided is a phosphate of Compound 1 produced by isolating the phosphate of Compound 1 from a mixture of Compound 1, phosphoric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl acetate. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is C 1-6 alkyl alcohol and C 1-6 alkyl acetate mixture. In one embodiment, S1 is THF. In some embodiments, S1 is ethyl acetate. In one embodiment, S1 is a mixture of methanol and acetone. In one embodiment, S1 is a mixture of methanol and ethyl acetate.

[0113] L-tartrate of Compound 1 Provided in some embodiments is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate (L-tartrate of Compound 1). In some embodiments, the L-tartrate of Compound 1 is crystalline.

[0114] Provided is a tartrate of Compound 1 produced by isolating the tartrate of Compound 1 from a mixture of Compound 1, L-tartaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl acetate. In some embodiments, S1 is C 1-6 alkyl ketone. In some embodiments, S1 is C 1-6 alkyl alcohol and C 1-6It is a mixture of alkyl ketones. In some embodiments, S1 is C 1-6 a mixture of alkyl alcohol and C 1-6 a mixture of alkyl acetate. In some embodiments, S1 is methanol. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is a mixture of methanol and acetone. In some embodiments, S1 is a mixture of methanol and ethyl acetate.

[0115] The L-tartrate form LA of Compound 1 Provided in some embodiments is the L-tartrate form LA of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (the L-tartrate form LA of Compound 1). In some embodiments, the L-tartrate form LA of Compound 1 is crystalline.

[0116] In some embodiments, the L-tartrate form LA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2° and 24.2° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 12.1° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 18.1° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits an XRPD peak characteristic of 2θ at 24.2° ± 0.2°.

[0117] In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 23.9° ± 0.2° and 24.2° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 19.3° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 24.8° ± 0.2° and 27.2° ± 0.2°.

[0118] In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 23.9° ± 0.2° and 24.2° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 19.3° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 24.8° ± 0.2° and 27.2° ± 0.2°.

[0119] In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 23.9° ± 0.2° and 24.2° ± 0.2°. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 12.1° ± 0.2°, 15.0° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 17.1° ± 0.2°, 18.1° ± 0.2°, 19.3° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 24.8° ± 0.2° and 27.2° ± 0.2°.

[0120] In some embodiments, the L-tartrate form LA of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially shown in FIG. 10.

[0121] In some embodiments, the L-tartrate form LA of Compound 1 exhibits endothermic peaks at temperatures of about 89°C and about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits an endothermic peak at a temperature of about 89°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits an endothermic peak at a temperature of about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits a DSC thermogram substantially as shown in FIG. 11. In some embodiments, the L-tartrate form LA of Compound 1 exhibits a TGA thermogram substantially as shown in FIG. 12. In some embodiments, the L-tartrate form LA of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 13.

[0122] In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°; and exhibits endothermic peaks at temperatures of about 89°C and about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 89°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°; and exhibits a DSC thermogram substantially as shown in FIG. 11. In some embodiments, the L-tartrate form LA of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 13.

[0123] In some embodiments, the L-tartrate form LA of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the L-tartrate form LA of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the L-tartrate form LA of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0124] In some embodiments, provided is the L-tartrate form LA of compound 1, which is produced by isolating the L-tartrate form LA of compound 1 from a mixture of compound 1, L-tartaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0125] The L-tartrate form LB of compound 1 In some embodiments, provided is the (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate form LB (the L-tartrate form LB of compound 1). In some embodiments, the L-tartrate form LB of compound 1 is crystalline.

[0126] In some embodiments, the L-tartrate form LB of compound 1 exhibits XRPD peaks characteristic of 2θ selected from 18.7° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°. In some embodiments, the L-tartrate form LB of compound 1 exhibits an XRPD peak characteristic of 2θ at 18.7° ± 0.2°. In some embodiments, the L-tartrate form LB of compound 1 exhibits an XRPD peak characteristic of 2θ at 25.0° ± 0.2°. In some embodiments, the L-tartrate form LB of compound 1 exhibits an XRPD peak characteristic of 2θ at 31.4° ± 0.2°.

[0127] In some embodiments, the L-tartrate form LB of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 23.9° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°. In some embodiments, the L-tartrate form LB of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 20.0° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°.

[0128] In some embodiments, the L-tartrate form LB of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 23.9° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°. In some embodiments, the L-tartrate form LB of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 20.0° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°.

[0129] In some embodiments, the L-tartrate form LB of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 23.9° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°. In some embodiments, it exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.3° ± 0.2°, 12.5° ± 0.2°, 18.1° ± 0.2°, 18.7° ± 0.2°, 20.0° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°.

[0130] In some embodiments, the L-tartrate form LB of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as depicted in FIG. 14. In some embodiments, the L-tartrate form LB of Compound 1 exhibits a DVS isotherm substantially as depicted in FIG. 15.

[0131] In some embodiments, the L-tartrate form LB of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the L-tartrate form LB of Compound 1 can be isolated with a crystalline purity of about 99% or higher. In some embodiments, the L-tartrate form LB of Compound 1 can be isolated with a crystalline purity of about 99.9% or higher.

[0132] In some embodiments, provided is the L-tartrate form LB of Compound 1 produced by isolating the L-tartrate form LB of Compound 1 from a mixture of Compound 1, L-tartaric acid and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a 1-6 alkyl alcohol. In some embodiments, S1 is a 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of a 1-6 alkyl alcohol and a 1-6 alkyl ketone. In some embodiments, S1 is a mixture of methanol and acetone.

[0133] The L-tartrate form LC of Compound 1 In some embodiments, provided is the (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate form LC (the L-tartrate form LC of Compound 1). In some embodiments, the L-tartrate form LC of Compound 1 is crystalline.

[0134] In some embodiments, the L-tartrate form LC of Compound 1 exhibits characteristic XRPD peaks for 2θ selected from 12.2° ± 0.2°, 16.5° ± 0.2°, and 24.8° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a characteristic XRPD peak for 2θ at 12.2° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a characteristic XRPD peak for 2θ at 16.5° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a characteristic XRPD peak for 2θ at 24.8° ± 0.2°.

[0135] In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 12.2° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, and 25.5° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 12.2° ± 0.2°, 12.8° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 20.0° ± 0.2°, 22.4° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, 25.0° ± 0.2°, 25.5° ± 0.2°, and 27.1° ± 0.2°.

[0136] In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least two characteristic XRPD peaks for 2θ selected from 12.2° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, and 25.5° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least two characteristic XRPD peaks for 2θ selected from 12.2° ± 0.2°, 12.8° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 20.0° ± 0.2°, 22.4° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, 25.0° ± 0.2°, 25.5° ± 0.2°, and 27.1° ± 0.2°.

[0137] In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 12.2° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, and 25.5° ± 0.2°. In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 12.2° ± 0.2°, 12.8° ± 0.2°, 15.4° ± 0.2°, 16.5° ± 0.2°, 18.7° ± 0.2°, 19.8° ± 0.2°, 20.0° ± 0.2°, 22.4° ± 0.2°, 22.6° ± 0.2°, 24.8° ± 0.2°, 25.0° ± 0.2°, 25.5° ± 0.2°, and 27.1° ± 0.2°.

[0138] In some embodiments, the L-tartrate form LC of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 16.

[0139] In some embodiments, the L-tartrate form LC of Compound 1 exhibits an endothermic peak at a temperature of about 137°C. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 17. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 18. In some embodiments, the L-tartrate form LC of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 19.

[0140] In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.2° ± 0.2°, 16.5° ± 0.2° and 24.8° ± 0.2°; and exhibits an endothermic peak at a temperature of about 137°C. In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.2° ± 0.2°, 16.5° ± 0.2° and 24.8° ± 0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 17. In some embodiments, the L-tartrate form LC of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.2° ± 0.2°, 16.5° ± 0.2° and 24.8° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 19.

[0141] In some embodiments, the L-tartrate form LC of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the L-tartrate form LC of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the L-tartrate form LC of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0142] In some embodiments, the L-tartrate form LB of Compound 1 is provided by isolating the L-tartrate form LB of Compound 1 from a mixture of Compound 1, L-tartaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 an alkyl alcohol. In some embodiments, S1 is C 1-6 an alkyl acetate. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of C 1-6 an alkyl alcohol and C 1-6 an alkyl acetate. In some embodiments, S1 is a mixture of methanol and ethyl acetate.

[0143] The D-tartrate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate (the D-tartrate of Compound 1) is provided. In some embodiments, the D-tartrate of Compound 1 is crystalline.

[0144] In some embodiments, the D-tartrate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, and 17.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 11.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 16.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 17.9° ± 0.2°.

[0145] In some embodiments, the D-tartrate of Compound 1 exhibits characteristic XRPD peaks with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits characteristic XRPD peaks with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°.

[0146] In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 11.9° ± 0.2°, 12.3° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2°, and 23.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.0° ± 0.2°, 11.9° ± 0.2°, 12.3° ± 0.2°, 13.4° ± 0.2°, 14.9° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2°, 21.6° ± 0.2°, 23.9° ± 0.2°, and 24.6° ± 0.2°.

[0147] In some embodiments, the D-tartrate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 11.9° ± 0.2°, 12.3° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2°, and 23.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 6.0° ± 0.2°, 11.9° ± 0.2°, 12.3° ± 0.2°, 13.4° ± 0.2°, 14.9° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2°, 21.6° ± 0.2°, 23.9° ± 0.2°, and 24.6° ± 0.2°.

[0148] In some embodiments, the D-tartrate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 11.9° ± 0.2°, 12.3° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2° and 23.9° ± 0.2°. In some embodiments, the D-tartrate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.0° ± 0.2°, 11.9° ± 0.2°, 12.3° ± 0.2°, 13.4° ± 0.2°, 14.9° ± 0.2°, 16.1° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, 19.1° ± 0.2°, 21.6° ± 0.2°, 23.9° ± 0.2° and 24.6° ± 0.2°.

[0149] In some embodiments, the D-tartrate of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 20.

[0150] In some embodiments, the D-tartrate of Compound 1 exhibits endothermic peaks at temperatures of about 76°C and about 153°C. In some embodiments, the D-tartrate of Compound 1 exhibits an endothermic peak at a temperature of about 76°C. In some embodiments, the D-tartrate of Compound 1 exhibits an endothermic peak at a temperature of about 153°C. In some embodiments, the D-tartrate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 21.

[0151] In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°; and exhibits endothermic peaks at temperatures of about 76°C and about 153°C. In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°; and exhibits an endothermic peak at a temperature of about 76°C. In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°; and exhibits an endothermic peak at a temperature of about 153°C. In some embodiments, the D-tartrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2°, 17.9° ± 0.2°, and 23.9° ± 0.2°; and exhibits a DVS isotherm substantially as shown in FIG. 21.

[0152] In some embodiments, the D-tartrate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the D-tartrate of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the D-tartrate of the compound can be isolated with a crystalline purity of about 99.9% or more.

[0153] In some embodiments, there is provided a D-tartrate form LB of Compound 1 produced by isolating the D-tartrate of Compound 1 from a mixture of Compound 1, D-tartaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6It is an alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0154] Fumarate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate (fumarate of Compound 1) is provided. In some embodiments, the fumarate of Compound 1 is crystalline.

[0155] In some embodiments, there is provided a fumarate of Compound 1 produced by isolating the fumarate of Compound 1 from a mixture of Compound 1, fumaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 It is an alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 It is an alkyl acetate. In some embodiments, S1 is C 1-6 It is an alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is C 1-6 A mixture of an alkyl alcohol and C 1-6 It is a mixture with an alkyl ketone. In some embodiments, S1 is methanol. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is a mixture of methanol and acetone.

[0156] Fumarate form FA of Compound 1 In some embodiments, there is provided a fumarate form FA of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (fumarate form FA of Compound 1). In some embodiments, the fumarate form FA of Compound 1 is crystalline.

[0157] In some embodiments, the fumarate form FA of Compound 1 exhibits characteristic XRPD peaks for 2θ selected from 7.7° ± 0.2°, 14.2° ± 0.2° and 15.2° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits a characteristic XRPD peak for 2θ at 7.7° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits a characteristic XRPD peak for 2θ at 14.2° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits a characteristic XRPD peak for 2θ at 15.2° ± 0.2°.

[0158] In some embodiments, the fumarate form FA of Compound 1 exhibits characteristic XRPD peaks for 2θ selected from 7.7° ± 0.2°, 15.2° ± 0.2°, 22.9° ± 0.2° and 30.7° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 7.7° ± 0.2°, 15.2° ± 0.2°, 22.9° ± 0.2° and 30.7° ± 0.2°.

[0159] In some embodiments, the fumarate form FA of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 7.7° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 15.2° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2° and 30.7° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 7.7° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 14.6° ± 0.2°, 15.2° ± 0.2°, 18.1° ± 0.2°, 18.8° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2° and 30.7° ± 0.2°.

[0160] In some embodiments, the fumarate form FA of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 7.7° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 15.2° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2°, and 30.7° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 7.7° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 14.6° ± 0.2°, 15.2° ± 0.2°, 18.1° ± 0.2°, 18.8° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2°, and 30.7° ± 0.2°.

[0161] In some embodiments, the fumarate form FA of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 7.7° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 15.2° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2°, and 30.7° ± 0.2°. In some embodiments, the fumarate form FA of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 7.7° ± 0.2°, 12.1° ± 0.2°, 13.0° ± 0.2°, 14.2° ± 0.2°, 14.6° ± 0.2°, 15.2° ± 0.2°, 18.1° ± 0.2°, 18.8° ± 0.2°, 22.9° ± 0.2°, 24.6° ± 0.2°, 26.0° ± 0.2°, and 30.7° ± 0.2°.

[0162] In some embodiments, the fumarate form FA of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 22.

[0163] In some embodiments, the fumarate form FA of Compound 1 exhibits an endothermic peak at a temperature of about 138°C. In some embodiments, the fumarate form FA of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 23. In some embodiments, the L-fumarate form FA of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 24. In some embodiments, the fumarate form FA of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 25.

[0164] In some embodiments, the fumarate form FA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 7.7° ± 0.2°, 14.2° ± 0.2°, and 15.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 147°C. In some embodiments, the fumarate form FA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 7.7° ± 0.2°, 14.2° ± 0.2°, and 15.2° ± 0.2°; and exhibits a DSC thermogram substantially as shown in FIG. 23. In some embodiments, the fumarate form FA of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 7.7° ± 0.2°, 14.2° ± 0.2°, and 15.2° ± 0.2°; and exhibits a DVS isotherm substantially as shown in FIG. 25.

[0165] In some embodiments, the fumarate form FA of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the fumarate form FA of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the fumarate form FA of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0166] In some embodiments, there is provided the fumarate form FA of Compound 1, which is produced by isolating the fumarate form FA of Compound 1 from a mixture of Compound 1, fumaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of C 1-6 alkyl alcohol and C 1-6 alkyl ketone. In some embodiments, S1 is methanol. In some embodiments, S1 is THF. In some embodiments, S1 is a mixture of methanol and acetone.

[0167] Fumarate FB of Compound 1 In some embodiments, there is provided the form FB of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate (the fumarate form FB of Compound 1). In some embodiments, the fumarate form FB of Compound 1 is crystalline.

[0168] In some embodiments, the fumarate form FB of Compound 1 exhibits characteristic XRPD peaks with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 6.7° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 13.8° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 20.2° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 27.0° ± 0.2°.

[0169] In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.5° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, 24.2° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°.

[0170] In some embodiments, the fumarate form FB of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.5° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, 24.2° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°.

[0171] In some embodiments, the fumarate form FB of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.5° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°. In some embodiments, the fumarate form FB of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 6.7° ± 0.2°, 13.4° ± 0.2°, 13.8° ± 0.2°, 20.2° ± 0.2°, 23.1° ± 0.2°, 23.5° ± 0.2°, 24.2° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2° and 29.6° ± 0.2°.

[0172] In some embodiments, the fumarate form FB of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 26.

[0173] In some embodiments, the fumarate form FB of Compound 1 exhibits endothermic peaks at temperatures of about 96°C, about 139°C and about 146°C. In some embodiments, the fumarate form FB of Compound 1 exhibits an endothermic peak at a temperature of about 96°C. In some embodiments, the fumarate form FB of Compound 1 exhibits an endothermic peak at a temperature of about 139°C. In some embodiments, the fumarate form FB of Compound 1 exhibits an endothermic peak at a temperature of about 146°C. In some embodiments, the fumarate form FB of Compound 1 exhibits a DSC thermogram substantially as shown in FIG. 27. In some embodiments, the fumarate form FB of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 28. In some embodiments, the fumarate form FB of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 29.

[0174] In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits endothermic peaks at temperatures of about 96°C, about 139°C, and about 146°C. In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 96°C. In some embodiments, in some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 139°C. In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 146°C. In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 27 (FIG. 27). In some embodiments, the fumarate form FB of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2°, and 20.2° ± 0.2°; and exhibits a DVS isotherm substantially as shown in FIG. 29 (FIG. 29).

[0175] In some embodiments, the fumarate form FB of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the fumarate form FB of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the fumarate form FB of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0176] In some embodiments, there is provided a fumarate form FB of Compound 1 produced by isolating the fumarate form FB of Compound 1 from a mixture of Compound 1, fumaric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is ethyl acetate.

[0177] Citrate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate is provided. In some embodiments, the citrate of Compound 1 is crystalline.

[0178] In some embodiments, the citrate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 6.5° ± 0.2°, 15.5° ± 0.2°, and 20.4° ± 0.2°. In some embodiments, the citrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 6.5° ± 0.2°. In some embodiments, the citrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 15.5° ± 0.2°. In some embodiments, the citrate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 20.4° ± 0.2°.

[0179] In some embodiments, the citrate of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 14.5° ± 0.2°, 15.5° ± 0.2°, 17.8° ± 0.2°, 19.4° ± 0.2°, and 20.4° ± 0.2°. In some embodiments, the citrate of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 14.5° ± 0.2°, 15.5° ± 0.2°, 16.5° ± 0.2°, 17.3° ± 0.2°, 17.8° ± 0.2°, 19.4° ± 0.2°, 20.4° ± 0.2°, 20.8° ± 0.2°, 21.2° ± 0.2°, 21.5° ± 0.2°, 22.0° ± 0.2°, 23.1° ± 0.2°, and 26.0° ± 0.2°.

[0180] In some embodiments, the citrate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 14.5° ± 0.2°, 15.5° ± 0.2°, 17.8° ± 0.2°, 19.4° ± 0.2°, and 20.4° ± 0.2°. In some embodiments, the citrate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.5° ± 0.2°, 10.2° ± 0.2°, 13.0° ± 0.2°, 14.5° ± 0.2°, 15.5° ± 0.2°, 16.5° ± 0.2°, 17.3° ± 0.2°, 17.8° ± 0.2°, 19.4° ± 0.2°, 20.4° ± 0.2°, 20.8° ± 0.2°, 21.2° ± 0.2°, 21.5° ± 0.2°, 22.0° ± 0.2°, 23.1° ± 0.2°, and 26.0° ± 0.2°.

[0181] In some embodiments, the citrate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.5°±0.2°, 10.2°±0.2°, 13.0°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 17.8°±0.2°, 19.4°±0.2° and 20.4°±0.2°. In some embodiments, the citrate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.5°±0.2°, 10.2°±0.2°, 13.0°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.3°±0.2°, 17.8°±0.2°, 19.4°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 21.5°±0.2°, 22.0°±0.2°, 23.1°±0.2° and 26.0°±0.2°.

[0182] In some embodiments, the citrate of Compound 1 exhibits characteristic XRPD peaks substantially as represented in FIG. 30.

[0183] In some embodiments, the citrate of Compound 1 exhibits an endothermic peak at a temperature of about 142°C. In some embodiments, the citrate of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 31. In some embodiments, the citrate of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 32. In some embodiments, the citrate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 33.

[0184] In some embodiments, the citrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.5° ± 0.2°, 15.5° ± 0.2°, and 20.4° ± 0.2°; and exhibits an endothermic peak at a temperature of about 142°C. In some embodiments, the citrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.5° ± 0.2°, 15.5° ± 0.2°, and 20.4° ± 0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 31. In some embodiments, the citrate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.5° ± 0.2°, 15.5° ± 0.2°, and 20.4° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 33.

[0185] In some embodiments, the citrate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the citrate of Compound 1 can be isolated with a crystalline purity greater than about 99%. In some embodiments, the citrate of Compound 1 can be isolated with a crystalline purity higher than about 99.9%.

[0186] In some embodiments, provided is the citrate of Compound 1 produced by isolating the citrate of Compound 1 from a mixture of Compound 1, citric acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is a C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a C 1-6 alkyl alcohol and C 1-6It is a mixture with an alkyl ketone. In some embodiments, S1 is C 1-6 a mixture of an alkyl alcohol and C 1-6 an alkyl acetate. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is a mixture of methanol and acetone. In some embodiments, S1 is THF. In some embodiments, S1 is a mixture of methanol and ethyl acetate.

[0187] The succinate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate is provided. In some embodiments, the succinate of Compound 1 is crystalline.

[0188] In some embodiments, the succinate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 6.6° ± 0.2°, 12.8° ± 0.2° and 13.9° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 6.6° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 12.8° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 13.9° ± 0.2°.

[0189] In some embodiments, the succinate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 19.8° ± 0.2° and 26.5° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 19.8° ± 0.2° and 26.5° ± 0.2°.

[0190] In some embodiments, the succinate of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits at least one characteristic XRPD peak related to 2θ selected from 6.6° ± 0.2°, 9.0° ± 0.2°, 11.5° ± 0.2°, 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.2° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°.

[0191] In some embodiments, the succinate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 6.6° ± 0.2°, 9.0° ± 0.2°, 11.5° ± 0.2°, 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.2° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°.

[0192] In some embodiments, the succinate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°. In some embodiments, the succinate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 6.6° ± 0.2°, 9.0° ± 0.2°, 11.5° ± 0.2°, 12.8° ± 0.2°, 13.9° ± 0.2°, 16.0° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.9° ± 0.2°, 23.3° ± 0.2°, 25.2° ± 0.2°, 25.4° ± 0.2° and 26.5° ± 0.2°.

[0193] In some embodiments, the succinate of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 34.

[0194] In some embodiments, the succinate of Compound 1 exhibits an endothermic peak at a temperature of about 153°C. In some embodiments, the succinate of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 35. In some embodiments, the succinate of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 36. In some embodiments, the succinate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 37.

[0195] In some embodiments, the succinate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 19.8° ± 0.2° and 26.5° ± 0.2°; and exhibits an endothermic peak at a temperature of about 153 °C. In some embodiments, the succinate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 19.8° ± 0.2° and 26.5° ± 0.2°; and exhibits a DSC thermogram substantially as shown in FIG. 35. In some embodiments, the succinate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 12.8° ± 0.2°, 13.9° ± 0.2°, 19.8° ± 0.2° and 26.5° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 37.

[0196] In some embodiments, the succinate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the succinate of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the succinate of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0197] In some embodiments, provided is the succinate of Compound 1 produced by isolating the succinate of Compound 1 from a mixture of Compound 1, succinic acid and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is an ether. In some embodiments, S1 is C 1-6 alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0198] The glutarate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate is provided. In some embodiments, the glutarate of Compound 1 is crystalline.

[0199] In some embodiments, the glutarate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2° and 18.2° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 9.1° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 10.6° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 18.2° ± 0.2°.

[0200] In some embodiments, the glutarate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2° and 19.0° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2° and 19.0° ± 0.2°.

[0201] In some embodiments, the glutarate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 22.5° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits at least one XRPD peak characteristic of 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 21.8° ± 0.2°, 21.9° ± 0.2°, 22.5° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°.

[0202] In some embodiments, the glutarate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 22.5° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits at least two characteristic XRPD peaks related to 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 21.8° ± 0.2°, 21.9° ± 0.2°, 22.5° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°.

[0203] In some embodiments, the glutarate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 22.5° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°. In some embodiments, the glutarate of Compound 1 exhibits at least three characteristic XRPD peaks related to 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, 18.2° ± 0.2°, 19.0° ± 0.2°, 21.8° ± 0.2°, 21.9° ± 0.2°, 22.5° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2° and 28.0° ± 0.2°.

[0204] In some embodiments, the glutarate of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 38. In some embodiments, the glutarate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 39.

[0205] In some embodiments, the glutarate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the glutarate of Compound 1 can be isolated with a crystalline purity of about 99% or higher. In some embodiments, the glutarate of Compound 1 can be isolated with a crystalline purity of about 99.9% or higher.

[0206] In some embodiments, provided is a glutarate of Compound 1 produced by isolating the glutarate of Compound 1 from a mixture of Compound 1, glutaric acid and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is a C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of a C 1-6 alkyl alcohol and a C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of methanol and acetone. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0207] L-malate of Compound 1 In some embodiments, provided is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate. In some embodiments, the L-malate of Compound 1 is crystalline.

[0208] In some embodiments, the L-malate of Compound 1 exhibits characteristic XRPD peaks with respect to 2θ selected from 13.5° ± 0.2°, 18.8° ± 0.2°, and 25.2° ± 0.2°. In some embodiments, the L-malate of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 13.5° ± 0.2°. In some embodiments, the malate of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 18.8° ± 0.2°. In some embodiments, the L-malate of Compound 1 exhibits a characteristic XRPD peak with respect to 2θ at 25.2° ± 0.2°.

[0209] In some embodiments, the L-malate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 18.8° ± 0.2°, 23.8° ± 0.2°, 24.8° ± 0.2°, and 25.2° ± 0.2°. In some embodiments, the L-malate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 17.7° ± 0.2°, 18.8° ± 0.2°, 22.4° ± 0.2°, 23.8° ± 0.2°, 24.6° ± 0.2°, 24.8° ± 0.2°, and 25.2° ± 0.2°.

[0210] In some embodiments, the L-malate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 18.8° ± 0.2°, 23.8° ± 0.2°, 24.8° ± 0.2°, and 25.2° ± 0.2°. In some embodiments, the malate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 17.7° ± 0.2°, 18.8° ± 0.2°, 22.4° ± 0.2°, 23.8° ± 0.2°, 24.6° ± 0.2°, 24.8° ± 0.2°, and 25.2° ± 0.2°.

[0211] In some embodiments, the L-malate of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 18.8° ± 0.2°, 23.8° ± 0.2°, 24.8° ± 0.2° and 25.2° ± 0.2°. In some embodiments, the L-malate of Compound 1 exhibits at least three characteristic XRPD peaks for 2θ selected from 13.5° ± 0.2°, 14.4° ± 0.2°, 15.2° ± 0.2°, 17.7° ± 0.2°, 18.8° ± 0.2°, 22.4° ± 0.2°, 23.8° ± 0.2°, 24.6° ± 0.2°, 24.8° ± 0.2° and 25.2° ± 0.2°.

[0212] In some embodiments, the L-malate of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in FIG. 40.

[0213] In some embodiments, the L-malate of Compound 1 exhibits an endothermic peak at a temperature of about 82°C. In some embodiments, the L-malate of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 41. In some embodiments, the L-malate of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 42. In some embodiments, the L-malate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 43.

[0214] In some embodiments, the L-malate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 13.5° ± 0.2°, 18.8° ± 0.2°, and 25.2° ± 0.2°; and exhibits an endothermic peak at a temperature of about 82°C. In some embodiments, the L-malate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 13.5° ± 0.2°, 18.8° ± 0.2°, and 25.2° ± 0.2°; and exhibits a DSC thermogram substantially as shown in FIG. 41. In some embodiments, the L-malate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 13.5° ± 0.2°, 18.8° ± 0.2°, and 25.2° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 43.

[0215] In some embodiments, the L-malate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the L-malate of Compound 1 can be isolated with a crystalline purity of about 99% or higher. In some embodiments, the L-malate of Compound 1 can be isolated with a crystalline purity higher than about 99.9%.

[0216] In some embodiments, provided is the L-malate of Compound 1 produced by isolating the L-malate of Compound 1 from a mixture of Compound 1, L-malic acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is methanol. In some embodiments, SⅠ is THF. In some embodiments, S1 is ethyl acetate.

[0217] Besylate of Compound 1 In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine besylate is provided. In some embodiments, the besylate of Compound 1 is crystalline. In some embodiments, the besylate of Compound 1 exhibits XRPD peaks characteristic of 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, and 24.1° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 6.0° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 12.0° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits an XRPD peak characteristic of 2θ at 24.1° ± 0.2°.

[0218] In some embodiments, the besylate of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.6° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits at least one characteristic XRPD peak for 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.4° ± 0.2°, 16.6° ± 0.2°, 19.0° ± 0.2°, 21.2° ± 0.2°, 22.2° ± 0.2°, 23.2° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°.

[0219] In some embodiments, the besylate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.6° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.4° ± 0.2°, 16.6° ± 0.2°, 19.0° ± 0.2°, 21.2° ± 0.2°, 22.2° ± 0.2°, 23.2° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°.

[0220] In some embodiments, the besylate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.6° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°. In some embodiments, the besylate of Compound 1 exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2°, 16.4° ± 0.2°, 16.6° ± 0.2°, 19.0° ± 0.2°, 21.2° ± 0.2°, 22.2° ± 0.2°, 23.2° ± 0.2°, 24.1° ± 0.2°, 26.8° ± 0.2°, and 30.3° ± 0.2°.

[0221] In some embodiments, the besylate of Compound 1 exhibits an XRPD pattern having characteristic peaks substantially as represented in Figure 44 (FIG. 44).

[0222] In some embodiments, the besylate of Compound 1 exhibits an endothermic peak at a temperature of about 136°C. In some embodiments, the besylate of Compound 1 exhibits a DSC thermogram substantially as represented in FIG. 45. In some embodiments, the besylate of Compound 1 exhibits a TGA thermogram substantially as represented in FIG. 46. In some embodiments, the besylate of Compound 1 exhibits a DVS isotherm substantially as represented in FIG. 47.

[0223] In some embodiments, the besylate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2° and 24.1° ± 0.2°; and exhibits an endothermic peak at a temperature of about 136°C. In some embodiments, the besylate of Compound 1 exhibits at least one characteristic XRPD peak with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2° and 24.1° ± 0.2°; and exhibits a DSC thermogram substantially as represented in FIG. 45. In some embodiments, the besylate of Compound 1 has at least one characteristic XRPD peak with respect to 2θ selected from 6.0° ± 0.2°, 12.0° ± 0.2° and 24.1° ± 0.2°; and exhibits a DVS isotherm substantially as represented in FIG. 47.

[0224] In some embodiments, the besylate of Compound 1 can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99%. In some embodiments, the besylate of Compound 1 can be isolated with a crystalline purity of about 99% or more. In some embodiments, the besylate of Compound 1 can be isolated with a crystalline purity of about 99.9% or more.

[0225] In some embodiments, provided is a besylate of Compound 1 produced by isolating the besylate of Compound 1 from a mixture of Compound 1, benzenesulfonic acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is a C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of a C 1-6 alkyl alcohol and a C 1-6 alkyl ketone. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is a mixture of methanol and acetone.

[0226] Tosylate of Compound 1 In some embodiments, provided is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate (tosylate of Compound 1).

[0227] In some embodiments, provided is a tosylate of Compound 1 produced by isolating the tosylate of Compound 1 from a mixture of Compound 1, p-toluenesulfonic acid, and S1, where S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is a C 1-6 alkyl alcohol. In some embodiments, S1 is an ether. In some embodiments, S1 is a C 1-6 alkyl acetate. In some embodiments, S1 is a C 1-6 alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of a C 1-6 alkyl alcohol and a C 1-6It is a mixture of alkyl ketones. In some embodiments, S1 is methanol. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is a mixture of methanol and acetone.

[0228] Method for producing Compound 1 and phosphate of Compound 1 Also provided herein is a method for producing Compound 1 or a salt thereof. The method for producing Compound 1 is described in U.S. Patent No. 10,196,403, which is hereby incorporated by reference in its entirety. The method for producing Compound 1 or a salt thereof provided herein has certain advantages compared to the methods currently disclosed in the art. For example, the method described herein exhibits good scalability, yield, and stereochemical selectivity. The method described herein can avoid chiral resolution by HPLC and perform chiral resolution by crystallization, so it is more suitable for production on a scale of several kilograms.

[0229] Provided herein is the following structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0230] This specification provides a method for producing compound 1 having the following structure:

Chemical formula

[0231] In some embodiments, a method for producing Compound 1 is provided, the method comprising the following steps: (a) Hydrogenating the compound of formula II or a salt thereof in the presence of a metal catalyst to obtain racemic compound 1; (b) reacting the racemic compound 1 with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is a solvent) to obtain the dibenzoyl-L-tartrate of compound 1; and (c) reacting the dibenzoyl-L-tartrate of compound 1 with B1 (where B1 is a base) to obtain compound 1, is included.

[0232] In some embodiments, a method for producing compound 1 is provided, the method comprising the following steps: (a) reacting the racemic compound 1 with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is a solvent) to obtain the dibenzoyl-L-tartrate of compound 1; and (c) reacting the dibenzoyl-L-tartrate of compound 1 with B1 (where B1 is a base) to obtain compound 1, is included.

[0233] As used herein, the following structure:

Chemical formula

Chemical formula

[0234] In some embodiments, the phosphoric acid is an aqueous phosphoric acid solution. In some embodiments, the aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 80 wt% to about 95 wt%. In some embodiments, the aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 87 wt%.

[0235] In some embodiments, the reaction of compound 1 with phosphoric acid is carried out in the presence of S1a (where S1a is a solvent). In some embodiments, S1a is a polar protic solvent, water or a mixture thereof. In some embodiments, the polar aprotic solvent of S1 is acetonitrile. In some embodiments, S1a is a mixture of acetonitrile and water.

[0236] In some embodiments, the reaction of compound 1 with phosphoric acid is carried out at a temperature between about 15 °C and about 25 °C. In some embodiments, the reaction of compound 1 with phosphoric acid is carried out at about 20 °C. In some embodiments, about 1 to about 5 molar equivalents of phosphoric acid are used per molar equivalent of compound 1.

[0237] Compound 1 has the following structure:

Chemical formula

[0238] In some embodiments, B1 is an alkali hydroxide base. In some embodiments, B1 is potassium hydroxide. In some embodiments, B1 is an aqueous potassium hydroxide solution. In some embodiments, the aqueous potassium hydroxide solution is an aqueous solution of potassium hydroxide of about 10 wt% to about 20 wt%. In some embodiments, the aqueous potassium hydroxide solution is an aqueous potassium hydroxide solution of about 14 wt%.

[0239] In some embodiments, the reaction of dibenzoyl-L-tartrate of Compound 1 with a base is carried out in the presence of S2, where S2 is a solvent. In some embodiments, S2 is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is an ether. In some embodiments, S2 is tert-butyl methyl ether.

[0240] In some embodiments, the reaction of dibenzoyl-L-tartrate of Compound 1 with B1 is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the reaction of dibenzoyl-L-tartrate of Compound 1 with the base is carried out at a temperature of about 23 °C. In some embodiments, about 0.5 to about 5 molar equivalents of B1 are used per molar equivalent of dibenzoyl-L-tartrate of Compound 1. In some embodiments, about 1 to about 3 molar equivalents of B1 are used per molar equivalent of dibenzoyl-L-tartrate of Compound 1. In some embodiments, about 1 to about 2 molar equivalents of B1 are used per molar equivalent of dibenzoyl-L-tartrate of Compound 1. In some embodiments, about 1 molar equivalent of B1 is used per molar equivalent of dibenzoyl-L-tartrate of Compound 1.

[0241] In some embodiments, the reaction of dibenzoyl-L-tartrate of Compound 1 with B1 is further carried out in the presence of sodium chloride. In some embodiments, about 1 to about 10 molar equivalents of sodium chloride are used per molar equivalent of dibenzoyl-L-tartrate of Compound 1. In some embodiments, about 5 molar equivalents of sodium chloride are used per molar equivalent of dibenzoyl-L-tartrate of Compound 1.

[0242] (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) has the following structure:

Chemical formula

[0243] In some embodiments, S3 is a polar protic solvent. In some embodiments, S3 is C 1-6 alkyl-OH. In some embodiments, S3 is methanol. In some embodiments, S3 is a mixture of methanol and water. In some embodiments, the reaction is carried out at a temperature of about 20°C to about 70°C. In some embodiments, precipitation is carried out at a temperature of about 20°C. In some embodiments, about 1 to about 5 molar equivalents of dibenzoyl-L-tartaric acid are used per molar equivalent of racemic compound 1.

[0244] The method for producing the dibenzoyl-L-tartrate of compound 1 can further include precipitating the dibenzoyl-L-tartrate of compound 1 from a mixture containing racemic compound 1, dibenzoyl-L-tartaric acid and S3. In some embodiments, S3 is methanol. In some embodiments, S3 is a mixture of methanol and water.

[0245] The method for producing the dibenzoyl-L-tartrate of compound 1 can further include a step of isolating the dibenzoyl-L-tartrate of compound 1 from S3a (where S3a is a solvent). In some embodiments, S3a is a polar protic solvent. In some embodiments, S3a is C 1-6 alkyl-OH. In some embodiments, S3a is methanol. In some embodiments, the isolation step of the dibenzoyl-L-tartrate of compound 1 is carried out at a temperature of about 10°C to about 65°C.

[0246] 1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine (racemic compound 1) has the following structure:

Chemical formula

[0247] In some embodiments, the compound of formula II is compound 2, which has the following structure: [Chemical formula] 1-(5-Bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine trifluoromethanesulfonate (compound 2) represented by

[0248] In some embodiments, the metal catalyst is palladium / activated carbon. In some embodiments, the hydrogenation of the compound of formula II is carried out at a hydrogen pressure of about 2 to about 10 bar. In some embodiments, the hydrogenation of the compound of formula II is carried out at a hydrogen pressure of about 5 bar.

[0249] In some embodiments, the hydrogenation of the compound of formula II is carried out at a temperature of about 20°C to about 30°C. In some embodiments, the hydrogenation of the compound of formula II is carried out at a temperature of about 25°C.

[0250] In some embodiments, the hydrogenation of the compound of formula II is carried out in the presence of S4 (where S4 is a solvent). In some embodiments, S4 is a polar protic solvent. In some embodiments, S4 is C 1-6 alkyl-OH. In some embodiments, S4 is methanol.

[0251] In some embodiments, the hydrogenation of the compound of formula II is carried out in the presence of B2 (where B2 is a base). In some embodiments, B2 is a carbonate base. In some embodiments, B2 is potassium carbonate. In some embodiments, B2 is an aqueous solution of potassium carbonate. In some embodiments, the aqueous solution of potassium carbonate is about 5 wt% potassium carbonate.

[0252] The compound of formula II has the following structure: [Chemical formula] (wherein X is halo) A compound of formula III having the following structure: [Chemical formula] or a salt thereof can be produced by reacting with N-methylaminoacetaldehyde dimethyl acetal (Compound 4) having the following structure:

[0253] In some embodiments, the compound of formula III has the following structure: [Chemical formula] which is 2-(2-bromo-5-fluorophenyl)ethan-1-ol (Compound 3).

[0254] In some embodiments, A1 is trifluoromethanesulfonic acid. In some embodiments, the reaction of the compound of formula III and Compound 4 is carried out in the presence of S5 (where S5 is a solvent). In some embodiments, S5 is a halogenated solvent. In some embodiments, S5 is dichloromethane.

[0255] In some embodiments, the reaction of the compound of formula III and Compound 4 is carried out at a temperature of about 0 °C to about 35 °C. In some embodiments, the reaction of the compound of formula III and Compound 4 is carried out at a temperature of about 30 °C. In some embodiments, about 1.2 molar equivalents of Compound 4 are used per molar equivalent of the compound of formula III. In some embodiments, about 4 molar equivalents of A1 are used per molar equivalent of the compound of formula III.

[0256] It will be understood that features of the invention described in the context of separate embodiments may also be provided in combination in one embodiment (whereas, when the embodiments are written in multi - claim form, combinations are intended). Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub - combination.

[0257] The reactions of the methods described herein can be carried out under air or an inert atmosphere. Usually, reactions involving reagents or products that substantially react with air can be carried out using air - sensitive synthetic techniques well known to those skilled in the art.

[0258] The methods described herein can be monitored according to any suitable method known in the art. For example, the formation of products can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV - visible) or mass spectrometry; or by chromatography such as high - performance liquid chromatography (HPLC) or thin - layer chromatography. Compounds obtained by the reaction can be purified by any suitable method known in the art, such as chromatography (medium - pressure) using a suitable adsorbent (e.g., silica gel, alumina, etc.), HPLC or preparative thin - layer chromatography; distillation; sublimation, trituration or recrystallization. The purity of the compound is generally determined by physical methods such as measurement of the melting point (in the case of solids), acquisition of an NMR spectrum or performance of an HPLC separation. If the melting point decreases, if the unwanted signals in the NMR spectrum decrease, or if the unwanted peaks in the HPLC trace are removed, it can be said that the compound is purified. In some embodiments, the compound is substantially purified.

[0259] Method of Use In some embodiments, the present specification provides a method for treating a neurological or psychiatric disease or disorder in a subject, characterized by administering to the subject an effective amount of the compound of the present application (or a pharmaceutically acceptable salt thereof) or a composition comprising the compound of the present application (or a pharmaceutically acceptable salt thereof). Neurological and / or psychiatric diseases and disorders can exhibit various psychiatric and behavioral symptoms, including anhedonia, depression, anxiety, cognitive impairment, psychosis, aggressive behavior, agitated excitement, reduced impulse control, and sleep disorders.

[0260] In one embodiment, the neurological or psychiatric disease or disorder is bipolar disorder, anxiety, depression, Alzheimer's disease with agitated excitement, Alzheimer's disease with aggressive behavior, Alzheimer's disease-related agitated excitement, or Alzheimer's disease with agitated excitement / aggressive behavior.

[0261] In one embodiment, the neurological or psychiatric disease or disorder is bipolar disorder, anxiety, depression, dementia, Alzheimer's disease, Alzheimer's disease with agitated excitement, Alzheimer's disease with aggressive behavior, Alzheimer's disease-related agitated excitement, or Alzheimer's disease with agitated excitement / aggressive behavior, neurocognitive disorder, or neurocognitive disorder with behavioral and psychological symptoms.

[0262] In one embodiment, the neurological or psychiatric disease or disorder is the behavioral and psychological symptoms of neurocognitive disorder, such as dementia and Alzheimer's disease. Behavioral and psychological symptoms include disorders in behavior including cognition, thought content, mood or delusions (beliefs accompanied by distress), hallucinations, psychosis, agitated excitement (lability, repetitive questioning, arguing or complaining, hoarding, pacing, inappropriate vocalizations, crying out, destructive sounds, rejection of care leaving home), aggressive behavior (physical or verbal), depression or emotional lability, anxiety disorder (worrying, shadowing), apathy or indifference, disinhibition (socially inappropriate behavior, sexually inappropriate behavior, irritability or instability), movement disorders (purposeless repetitive behaviors), wandering, searching, nocturnal behavior (waking or arising at night), impulsivity, attention deficit, and executive dysfunction.

[0263] In this specification, assays were used to identify representative treatment candidates. Examples of treatment candidates include, but are not limited to, the treatment of Alzheimer's disease with agitation, Alzheimer's disease with aggressive behavior, Alzheimer's disease-related agitation, and Alzheimer's disease with agitation / aggressive behavior. Aggressive behavior and agitation are symptoms common to neurological and psychiatric diseases or disorders. Aggressive behavior and agitation are associated with hyperactivity in subcortical brain regions, which can be modeled in animals using psychostimulants (e.g., PCP, amphetamine). For example, psychostimulants induce excessive locomotor activity (HLA) in animals. Antipsychotics (e.g., haloperidol, clozapine, and risperidone) have been demonstrated to reduce HLA induced by psychostimulants and are effective against agitation in Alzheimer's disease. Other drugs used off-label for Alzheimer's disease, or drugs currently in clinical trials, include mood stabilizers such as lithium (which reduces HLA induced by amphetamine) and antidepressants (such as citalopram). Antidepressants have been demonstrated to be active in assays such as the forced swim test and the tail suspension test. Thus, the assays are useful for identifying candidates for treatments for Alzheimer's disease-related agitation or agitation / aggressive behavior in other neurological and psychiatric diseases.

[0264] In one embodiment, there is provided a method of treating bipolar disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, there is provided a method of treating anxiety in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, the neurological or psychiatric disease or disorder is, for example, schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general medical conditions and substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other stimulants and cocaine) psychosis, psychotic disorder, psychosis associated with mood disorder, brief reactive psychosis, schizoaffective disorder, "schizophrenia spectrum" disorders (e.g., schizophrenia or schizotypal personality disorder, etc.) or diseases associated with psychosis (e.g., major depressive disorder, bipolar (manic-depressive) disorder, Alzheimer's disease, post-traumatic stress disorder, etc.) (which includes both positive, negative and cognitive symptoms associated with schizophrenia and other psychoses); cognitive impairment including dementia (semantic dementia, frontotemporal dementia, dementia with depressive features, persistent dementia, subcortical dementia, Lewy body dementia, Parkinson-ALS dementia complex, dementia associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular disorder, stroke, HIV disease, Parkinson's disease, Huntington's disease, Down syndrome, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia or substance abuse), delirium, amnesia or age-related cognitive decline; anxiety disorders, e.g., acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety disorder due to general medical conditions; substance-related disorders and addictive behaviors (e.g., substance-induced delirium, persistent dementia, persistent amnesia, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); eating disorders, e.g., obesity, bulimia nervosa, pica and binge eating disorder;Bipolar disorders (such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to other medical conditions, other specified bipolar disorder and related disorders, and unspecified bipolar disorder and related disorders), depressive disorders (such as unipolar depression, seasonal depression, and postpartum depression), atypical depression, catatonic depression, geriatric depression, endogenous depression, melancholic depression, perinatal depression, situational depression, chronic depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to general medical conditions, and substance-induced mood disorders; attention disorders, learning disorders, and developmental disorders, such as pervasive developmental disorders including autism, attention deficit hyperactivity disorder (ADHD), and attention disorders including conduct disorder, autism and autism spectrum disorders (including Asperger syndrome, pervasive developmental disorder, Rett syndrome, and fragile X syndrome), etc.; depression, benign forgetfulness, childhood learning disorder, circumscribed learning disorder, intellectual developmental disorder, and closed head injury; movement disorders and symptoms, such as tremor, dyskinesia, dystonia, tic disorder, vocal disorder, ataxia, myoclonus, essential tremor, tardive dyskinesia, restless legs syndrome, Tourette syndrome, multiple system atrophy, multiple sclerosis, Huntington's disease, Parkinson's disease, and atypical parkinsonism; epileptic seizures; urinary incontinence; nerve cell disorders, such as eye disorders, retinal diseases of the eye, or macular degeneration, tinnitus, hearing disorders, deafness, and cerebral edema; vomiting; and sleep disorders, such as insomnia, sleep disorder, middle awakening, jet lag, hypersomnia, cataplexy, sleep apnea syndrome, obstructive sleep apnea syndrome, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, sleep phase delay disorder, somnambulism, night terrors, nocturia, rapid eye movement sleep behavior disorder, shift work sleep disorder, excessive sleepiness, non-24-hour sleep-wake syndrome, sleep paralysis, and narcolepsy, selected from psychoses including;

[0267] In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer's disease, Parkinson's disease, depression, cognitive impairment, stroke, schizophrenia, Down syndrome, or fetal alcohol syndrome. In some embodiments, the neurological or psychiatric disorder is Alzheimer's disease. In some embodiments, the neurological or psychiatric disorder is Parkinson's disease. In some embodiments, the neurological or psychiatric disorder is depression. In some embodiments, the neurological or psychiatric disorder is cognitive impairment. In some embodiments, the cognitive impairment is cognitive dysfunction associated with depression, such as major depression. In some embodiments, the neurological or psychiatric disorder is stroke. In some embodiments, the neurological or psychiatric disorder is schizophrenia. In some embodiments, the neurological or psychiatric disorder is Down syndrome. In some embodiments, the neurological or psychiatric disorder is fetal alcohol syndrome.

[0268] In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder. Bipolar disorder (including both bipolar I disorder and bipolar II disorder, for example) is a serious mental illness with a prevalence of about 2% of the population and affects both genders equally. Bipolar disorder is a recurrent and remitting disorder characterized by alternating episodes of elevated mood (i.e., manic state) and depressive state, and is different from other diseases such as major depression and schizophrenia. Bipolar I disorder is defined by the occurrence of a full manic episode, although most people experience significant depression. Symptoms of mania include elevated or irritable mood, hyperactivity, grandiosity, decreased need for sleep, flight of ideas, etc., and in some cases may develop into psychosis. Depressive episodes include anhedonia, feelings of sadness, despair, low self-esteem, decreased concentration, and fatigue. Bipolar II disorder is defined by the occurrence of major depressive episodes and hypomanic (not severe manic state) episodes, but the subject spends a relatively long time in a depressive state. Other related symptoms include cyclothymic disorder.

[0269] In some embodiments, the neurological or psychiatric disorder or condition is schizophrenia. Schizophrenia is a disorder of unknown cause that typically first appears in adulthood and has characteristics such as a gradual progression of psychotic symptoms and onset and / or a decline in social behavior and work ability. Characteristic psychotic symptoms include disorders of thought content (e.g., multiple, fragmented, disjointed, unrealistic or simply delusional content or ideas of persecution) and mental disorders (e.g., loss of associative power, lack of imagination, disjointedness to the point of incomprehensibility), as well as disorders of perception (e.g., hallucinations), disorders of affect (e.g., superficial or inappropriate affect), disorders of self-awareness, intention, impulse and / or interpersonal relationships and psychomotor disorders (e.g., catatonia). In addition, other symptoms are associated with this disorder. Schizophrenia is classified into the following subgroups: paranoid type characterized by delusions and hallucinations, without thought disorder, disorganized behavior, and flattening of affect; disorganized type (also called hebephrenic schizophrenia) in which thought disorder and flattening of affect appear simultaneously; catatonic type in which prominent psychomotor disorders are evident and the symptoms may include catatonic stupor and waxy flexibility; and undifferentiated type in which psychotic symptoms are present but do not meet the criteria for the paranoid, disorganized, and catatonic types. The symptoms of schizophrenia typically appear in three broad categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms indicate an "excess" of normal experiences such as hallucinations and delusions. Negative symptoms are signs that the patient is suffering from a lack of normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms are related to the impairment of the cognitive function of schizophrenia patients and include lack of sustained attention and lack of decision-making.

[0270] In some embodiments, the neurological or psychiatric disease or disorder is an anxiety disorder. Anxiety disorders are characterized by fear, worry, and unease, and are typically general and indefinite as an excessive reaction to situations. Anxiety disorders vary in the situations and types of objects that induce fear, anxiety, or avoidance behaviors and the associated cognitive beliefs. Anxiety differs from fear in that anxiety is an emotional reaction to the recognition of a future threat, whereas fear is related to the recognition of an immediate threat or reality. Also, anxiety and fear differ in the content of the associated thoughts or beliefs. Examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specifier, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, anxiety disorder due to other medical conditions, illness anxiety disorder, social (pragmatic) communication disorder, other specified anxiety disorder, and unspecified anxiety disorder; stress-related disorders (e.g., reactive attachment disorder, inhibited social participation disorder, posttraumatic stress disorder (PTSD), acute stress disorder, and adjustment disorder).

[0271] Cognitive dysfunction includes a decline in cognitive function or cognitive domains, such as working memory, attention and vigilance, language learning and memory, visual learning and memory, reasoning and problem-solving ability (e.g., executive function, processing speed, and / or social cognition). In particular, cognitive impairment can manifest as attentional impairment, disorganized thinking, slow thinking, difficulty in understanding, reduced concentration, problem-solving impairment, memory impairment, difficulty in expressing thoughts, and / or difficulty in integrating thinking, emotions, and behaviors or difficulty in eliminating irrelevant thoughts.

[0272] In some embodiments, the neurological or psychiatric disease or disorder is associated with a cognitive deficit (the cognitive domains defined in the DSM-5 are complex attention, executive function, learning and memory, language, perceptual-motor, social cognition). In some embodiments, the neurological or psychiatric disorder is associated with a lack of dopamine signaling. In some embodiments, the neurological or psychiatric disorder is associated with basal ganglia dysfunction. In some embodiments, the neurological or psychiatric disorder is associated with dysregulation of spontaneous movement. In some embodiments, the neurological or psychiatric disorder is associated with prefrontal cortex dysfunction.

[0273] In some embodiments, the present invention provides a method of treating one or more symptoms of a neurological and / or psychiatric disease or disorder provided herein.Such diseases or disorders include the following: mood disorders, such as bipolar I disorder, bipolar II disorder, mania, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to other medical conditions, and unspecified bipolar disorder and related disorders; psychotic disorders, such as schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general medical conditions, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), schizoaffective disorder, agitated excitement, aggressive behavior, delirium, catalepsy, catatonia, dissociative identity disorder, paranoid personality disorder, psychotic depression, schizotypal personality disorder, childhood disintegrative disorder (Heller syndrome), disintegrative psychosis, dissociative amnesia, somatic symptom disorder, Parkinson's disease psychosis, excitatory psychosis, Tourette syndrome, and organic psychosis or psychosis NOS; depressive disorders, such as disruptive mood dysregulation disorder, major depressive disorder (MDD) (e.g., major depressive episode), dysthymia, persistent depressive disorder (dysthymia), treatment-resistant depression, premenstrual dysphoric disorder, substance / drug-induced depressive disorder, depressive disorder due to other medical conditions, other specified depressive disorder, and unspecified depressive disorder; anxiety disorders; and other disorders, such as substance abuse or dependence (e.g., nicotine, alcohol, cocaine), intoxication, internet gaming disorder, eating disorders, conduct disorders, seizures, dizziness, epilepsy, agitated excitement, aggressive behavior, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesia, Huntington's disease, dementia, premenstrual dysphoria, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), hyperkinesis, autism, autism spectrum disorder, obsessive-compulsive disorder, pain, fibromyalgia, migraine, cognitive impairment, movement disorders, restless leg syndrome (RLS), multiple sclerosis, primary progressive multiple sclerosis, Parkinson's disease, Huntington's disease, dyskinesia multiple sclerosis, sleep disorders, sleep apnea syndrome, narcolepsy, excessive daytime sleepiness, jet lag, side effects of drug-induced sleepiness, insomnia, sexual dysfunction, hypertension, vomiting, Lesch-Nyhan disease, Wilson's disease, Rett syndrome, and Huntington's chorea.In some embodiments, the neurological and / or psychiatric disorder includes anxious arousal and aggressive behavior.

[0274] In some embodiments, anxious arousal and aggressive behavior are associated with Alzheimer's disease, Parkinson's disease, and / or autism.

[0275] In some embodiments, anxious arousal is associated with mental disorders such as depression and schizophrenia.

[0276] In some embodiments, the neurological and / or psychiatric disease or disorder is an obsessive-compulsive disorder and related disorders (e.g., body dysmorphic disorder, hoarding disorder, trichotillomania, elimination disorders).

[0277] In some embodiments, the neurological and / or psychiatric disease or disorder is a disruptive, impulse-control, and conduct disorder, e.g., oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, other specified disruptive, impulse-control, and conduct disorders, unspecified disruptive, impulse-control, and conduct disorders.

[0278] Depressive disorders include major depressive disorder and bipolar disorder and are associated with symptoms such as depressive mood (sadness), decreased concentration, insomnia, fatigue, loss of appetite, excessive guilt, and suicidal thoughts.

[0279] In some embodiments, the present specification provides a method for treating one or more of the following conditions: depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive deficits; sleep-related disorders including sleep disorders caused by symptoms of mental disorders (e.g., sleep apnea syndrome, insomnia, narcolepsy, cataplexy); chronic fatigue syndrome; anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; vasomotor symptoms after menopause (e.g., hot flashes, night sweats); neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar (atrophy) paralysis, pseudobulbar palsy, spinal muscular atrophy (e.g., SMA type I (also called Werdnig-Hoffmann disease), SMA type II, SMA type III (also called Kugelberg-Welander disease), Kennedy disease (also called progressive spinal muscular atrophy), Hallervorden-Spatz disease, Zellweger disease (infantile neuroaxonal dystrophy), adrenoleukodystrophy, Alexander disease, autosomal dominant cerebellar ataxia (ADCA), pure autonomic failure (Bradbury-Eggleston syndrome), CADASIL syndrome, Batten disease, etc., neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease)); manic disorder; dysthymia; and obesity.

[0280] In some embodiments, depressive disorders are associated with acute suicidal tendency or suicidal ideation. The US Food and Drug Administration has adopted a "black box" label warning indicating that antidepressants may increase the risk of suicidal ideation and suicidal behavior in some children, adolescents, and young adults (up to 24 years old) suffering from depressive disorders such as MDD. In some embodiments, the compounds of the present application provided do not increase the risk of suicidal ideation and / or suicidal behavior in children, adolescents, and / or young adults suffering from depressive disorders such as MDD. In some embodiments, the present invention provides a method for treating the symptoms of one or more depressive disorders (e.g., MDD) in children, adolescents, and / or young adults without increasing the risk of suicidal ideation and / or suicidal behavior.

[0281] In some embodiments, the present invention provides a method for treating one or more symptoms including senile dementia, early-onset Alzheimer's disease, Alzheimer's type dementia, dementia, memory loss, amnesia / amnesia syndrome, disturbance of consciousness, coma, decreased attention, language disorder, auditory agnosia, aphasia, apraxia, mild cognitive impairment (MCI), benign amnesia, mild neurocognitive disorder, severe neurocognitive disorder, disease-induced neurocognitive disorder (e.g., Huntington's disease, Parkinson's disease, prion disease, traumatic brain injury, HIV or AIDS), Binswanger's disease (subcortical leukoencephalopathy), and Capgras syndrome.

[0282] In some embodiments, the present invention provides a method of treating one or more symptoms of pain, such as neuropathic pain, sensitization associated with neuropathic pain or inflammatory pain. In some embodiments, the pain is neuropathic pain including post-herpetic (or post-zoster) neuralgia, reflex sympathetic dystrophy / causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome and peripheral neuropathy (e.g., diabetic neuropathy or neuropathy caused by chronic alcohol use).In some embodiments, pain includes acute pain, nociceptive pain, arthritic pain, rheumatoid arthritis, osteoarthritis, joint pain, musculoskeletal pain, low back pain, spinal pain, lumbar disc herniation pain, hip pain, visceral pain, headache, tension headache, acute tension headache, chronic tension-type headache, chronic cluster headache, common migraine, classical migraine, cluster headache, mixed headache, post-traumatic headache, eye strain headache, short-lasting unilateral neuralgiform (SUNCT) headache, SUNCT syndrome, herpes zoster, acute herpes zoster, herpes simplex, post-herpetic (post-herpetic) neuralgia, causalgia, central pain, central pain syndrome, chronic low back pain, neuralgia, neuropathic pain syndrome, neuropathy, diabetic neuropathy, diabetes-related neuropathy, diabetes-related neuralgia, fibrosis, chemotherapy-induced peripheral neuropathy, peripheral nerve disease, peripheral neuropathy, neuralgia, nerve injury, sensitization with neuropathic pain, complex regional pain syndrome, compressive neuropathy, craniofacial pain, chronic joint pain, chronic knee pain, chronic pain syndrome, cancer pain, trigeminal neuralgia, painful tic, reflex sympathetic dystrophy, painful peripheral neuropathy, spinal cord nerve injury, arachnoiditis, spinal cord pain, Ross-Bernhardt syndrome (hemiplegic pain), carpal tunnel syndrome, cerebrospinal fluid syndrome, Charcot-Marie-Tooth disease, hereditary motor and sensory neuropathy, peroneal muscular atrophy, cluster syndrome, coccydynia syndrome, compartment syndrome, intervertebral disc degeneration, failed back surgery syndrome, vulvodynia / pelvic pain / insertion disorder, gout, inflammatory pain, lumbar nerve root disorder, neuroma (painful scar), pain associated with multiple sclerosis, pelvic floor disorder, phantom limb pain, piriformis syndrome, psychogenic pain, radicular pain syndrome, Rader syndrome, referred pain, reflex sympathetic dystrophy syndrome, sciatica, pain of sciatica, scoliosis, intervertebral disc herniation, somatic pain, spinal stenosis, stiff-person / stiff-man syndrome, stump pain, sympathetically maintained pain, Troxel-Hunt syndrome, pain associated with whiplash or Lyme disease.

[0283] In some embodiments, the present invention provides a method for treating one or more symptoms of obesity; migraine or migraine headache; and sexual dysfunction in males or females (including, but not limited to, sexual dysfunction due to psychological and / or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual excitement, and inability to achieve orgasm), and psychological sexual dysfunction (including, but not limited to, inhibition of sexual desire, inhibition of sexual excitement, inhibition of female orgasm, inhibition of male orgasm, functional dyspareunia, functional vaginitis, and atypical psychological sexual dysfunction).

[0284] In some embodiments, the present invention provides a method for suppressing rapid eye movement (REM) during both sleep and corresponding daytime periods.

[0285] In some embodiments, the present invention provides a method for suppressing or eliminating pathological or excessive REM during the night or corresponding daytime periods.

[0286] In some embodiments, the present invention provides a method for treating one or more symptoms including cataplexy (an attack of sudden involuntary transient muscle weakness or paralysis during wakefulness); nocturnal sleep disorder / sleep fragmentation associated with narcolepsy or other symptoms; sleep paralysis associated with narcolepsy or other symptoms; hypnagogic and hypnopompic hallucinations associated with narcolepsy or other symptoms; and excessive daytime sleepiness associated with narcolepsy, sleep apnea syndrome, or shift work disorder and other medical conditions (such as cancer, chronic fatigue syndrome, fibromyalgia).

[0287] In some embodiments, the present specification provides a method for treating one or more symptoms of movement disorders or impairments, including akinesia, akinetic-rigid syndrome, dyskinesia and dystonia. Examples of akinesia and akinetic-rigid syndrome include Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, secondary parkinsonism, parkinsonism-plus syndromes, atypical parkinsonism, idiopathic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification, drug-induced parkinsonism (e.g., neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremor), Gilles de la Tourette syndrome, epilepsy, myoclonic disorders or disorders associated with muscle weakness including myoclonus and tremor. Examples of dyskinesia include drug (e.g., L-DOPA)-induced dyskinesia tremors (e.g., resting tremor, postural tremor, intention tremor), chorea (e.g., Sydenham chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballismus), myoclonus (e.g., generalized myoclonus and focal myoclonus), tic (e.g., simple tic, complex tic and symptomatic tic), etc. Examples of dystonia include generalized dystonia, idiopathic dystonia, drug-induced dystonia, symptomatic dystonia, paroxysmal dystonia, focal dystonia, blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia, etc.Other examples of movement disorders or impairments include stereotyped movement disorder, persistent (chronic) movement disorder, drug-induced movement disorder, psychogenic movement disorder, substance / drug-induced movement disorder, extrapyramidal movement disorder, hyperkinetic movement disorder, hypokinetic movement disorder, alternating hemiplegia, Angelman syndrome, Hallervorden-Spatz syndrome, ataxia, dentatorubral-pallidoluysian atrophy, ataxia-telangiectasia (Louis-Bar syndrome), Friedreich's ataxia, hereditary spastic ataxia, hereditary spinal sclerosis, Machado-Joseph disease, spinocerebellar ataxia, progressive myoclonic epilepsy, athetoid, ballismus, blepharospasm (spasm of the eyes), cerebral palsy, tardive dystonia, tardive dyskinesia, idiopathic torsion dystonia, torsion dystonia, focal dystonia, idiopathic familial dystonia, idiopathic nonfamilial dystonia, cervical dystonia (spasmodic torticollis), primary dystonia, oromandibular dystonia, developmental coordination disorder, spinal bulbar muscular atrophy (Kennedy disease), Shy-Drager syndrome, and stiff-person (stiff-man) syndrome.

[0288] In some embodiments, the present invention provides methods for treating one or more symptoms of epilepsy and / or seizures, including abdominal epilepsy, absence seizures, acquired epilepsy, acquired epileptiform aphasia, Aicardi syndrome, Alpers disease, Alpers-Huttenlocher syndrome, Angelman syndrome, benign focal epilepsy, benign focal epilepsy of childhood, benign intracranial hypertension, benign rolandic epilepsy (BRE), CDKL5 Disability, childhood absence epilepsy, dentate cerebellar ataxia, Douce syndrome, Dravet syndrome, cognitive impairment focal seizures, grand mal epileptic disorders, myoclonic absence epilepsy, epileptic hemiplegia, febrile seizures, focal seizures, frontal lobe epilepsy, generalized tonic-clonic seizures, diathesis epilepsy, glucose transporter 1 deficiency syndrome, hypothalamic hamartoma, idiopathic epilepsy, idiopathic generalized epilepsy, idiopathic focal-related epilepsy, idiopathic partial epilepsy, idiopathic convulsions, juvenile absence seizures epilepsy, juvenile myoclonic epilepsy, Lafora disease, Lafora progressive myoclonic epilepsy, Landau-Kleffner syndrome, Rathcoole-Graham-Little syndrome, Lennox syndrome, Lennox-Gastaut syndrome, medically refractory epilepsy, mesotemporal-temporal sclerosis, myoclonic seizures, neonatal epilepsy, occipital lobe epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, parietal lobe epilepsy, PCDH19 epilepsy, photosensitive epilepsy, progressive These conditions include: myoclonic epilepsy, Rasmussen's encephalitis, Rasmussen's syndrome, refractory epilepsy, epileptic disorder, status epilepticus, Sturge-Weber syndrome, symptomatic generalized epilepsy, symptomatic partial epilepsy, TBCK-related ID syndrome, temporal lobe epilepsy, temporal lobe seizures, tonic-clonic seizures, West syndrome, tremor, cerebellar tremor, cerebellar outflow tremor, intention tremor, essential tremor, benign essential tremor, parkinsonian tremor and drug-induced positional tremor.

[0289] Pharmaceutical Composition According to one embodiment, the present invention provides a composition comprising compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle. In some embodiments, the amount of compound 1 in the compositions herein is an amount effective to treat, prevent and / or manage various neurological and / or psychiatric diseases, disorders and / or symptoms in a subject. In some embodiments, the compositions of the present invention are formulated for administration to a subject in need thereof. In some embodiments, the compositions of the present invention are formulated for oral administration to a subject.

[0290] As used herein, the term "subject" to which administration is intended includes humans, i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or the elderly) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys, etc.); commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats and / or dogs; and / or mammals such as commercially relevant birds such as chickens, ducks, geese, quails and / or turkeys.

[0291] In certain embodiments, provided herein is a composition (e.g., a pharmaceutical composition) comprising Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) and a pharmaceutically acceptable excipient or carrier. In some embodiments, provided herein is a method of treating neurological or psychiatric diseases and disorders in a subject in need of treatment, comprising administering an effective amount of Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) or a pharmaceutical composition described herein. Examples of carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation can also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, lubricants, processing aids, coloring agents, sweeteners, flavors, diluents and other known additives to provide an elegant appearance of the dosage form (i.e., the compound of the invention or its pharmaceutical composition) or to assist in the manufacture of the pharmaceutical product (i.e., the medicine).

[0292] The composition of the present invention can be administered via oral, parenteral, inhalation, topical, rectal, nasal, buccal, sublingual, vaginal or implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intraliver, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition herein may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. One acceptable vehicle and solvent that may be used is a solution of water, Ringer's solution and physiological saline solution. Further, sterile fixed oils are conventionally used as a solvent or suspending medium. The pharmaceutically acceptable composition of the present invention may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.

[0293] The amount of Compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) that can be combined with a carrier material to produce a composition of a single dosage form will vary depending on various factors including the host being treated and the particular mode of administration. It should also be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors including the activity of the particular form of Compound 1 being used, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs and the judgment of the physician administering the treatment and the severity of the particular disease being treated.

[0294] Combination therapy In some embodiments, the present invention provides a method of treating a neurological and / or psychiatric disease and / or disorder described herein, the method comprising administering the compound of the present application in combination with one or more pharmaceutical agents. Suitable pharmaceutical agents that can be used in combination with Compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) include anti-Parkinson's disease drugs, anti-Alzheimer's disease drugs, antidepressants, antipsychotics, anti-ischemic drugs, CNS depressants, anticholinergics, psychotropics, antiepileptic drugs, attention deficit treatment drugs (e.g., ADD / ADHD), sleep aids, wakefulness-promoting agents and pain medications. In some embodiments, the suitable pharmaceutical formulation is an antianxiety drug.

[0295] Suitable anti-Parkinson's disease drugs include dopamine replacement therapy (e.g., L-DOPA, carbidopa, COMT inhibitors (e.g., entacapone or tolcapone)), dopamine agonists (e.g., D1 agonists, D2 agonists, D1 / D2 mixed agonists, bromocriptine, pergolide, cabergoline, ropinirole, pramipexole, piribedil or a combination of apomorphine and domperidone), histamine H2 antagonists, monoamine oxidase inhibitors (e.g., selegiline, rasagiline, safinamide and tranylcypromine), certain atypical antipsychotics, such as pimavanserin (an a dopamine-acting atypical antipsychotic and an inverse agonist of the serotonin 5-HT2A receptor), and amantadine.

[0296] In some embodiments, compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) can be used in combination with or without levodopa (in combination with a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), an anticholinergic agent such as biperiden (as any of its hydrochloride or lactate salts) and trihexyphenidyl (benzhexyl) hydrochloride, a COMT inhibitor such as entacapone or tolcapone, an MAO A / B inhibitor, an antioxidant, an A2a adenosine receptor antagonist, a cholinergic agonist, an MDA receptor antagonist, a serotonin receptor antagonist and a dopamine receptor agonist (e.g., alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole). It will be understood that the dopamine agonist can be in the form of a pharmaceutically acceptable salt such as, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexole are generally used in non-salt form.

[0297] Suitable anti-Alzheimer's drugs include β-secretase inhibitors, γ-secretase inhibitors, cholinesterase inhibitors (e.g., donepezil, galantamine or rivastigmine), HMG-CoA reductase inhibitors, NSAIDs including ibuprofen, vitamin E and anti-amyloid antibodies. In some embodiments, the anti-Alzheimer's disease drug is memantine.

[0298] Suitable antidepressants and anxiolytics include norepinephrine reuptake inhibitors (e.g., tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI), reversible inhibitors of monoamine oxidase (RIMA), serotonin-norepinephrine reuptake inhibitors (SNRI), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists and corticotropin-releasing factor (CRF) antagonists, etc.

[0299] Particularly suitable antidepressants and anxiolytics include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine, desvenlafaxine, duloxetine, aprepitant, bupropion, vilazodone, mirtazapine, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlordiazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam; buspirone, flesinoxan, gepirone, and ipsapirone, reboxetine, voltioxetine, chlordiazepate, and ketamine, and their pharmaceutically acceptable salts. In some embodiments, the suitable antidepressants and anxiolytics are tianeptine or its pharmaceutically acceptable salt.

[0300] Suitable antipsychotics and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, and anticonvulsants.

[0301] Particularly suitable antipsychotics and mood stabilizers include chlorpromazine, fluphenazine, haloperidol, amisulpride, perphenazine, thioridazine, trifluoperazine, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, brexpiprazole, paliperidone, cariprazine, pimavanserin, iloperidone, lumateperone, MIN-101, quetiapine, risperidone, diprasidone, lurasidone, flupentixol, levomepromazine, periciazine, perphenazine, pimozide, prochlorperazine, zuclopenthixol, olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid, iloperidone, thiothixene, gabapentin, tiagabine and their pharmaceutically acceptable salts.

[0302] Suitable antiepileptic drugs include levetiracetam, oxcarbazepine, clobazam, retigabine, zonisamide, felbamate, eslicarbazepine acetate, lacosamide, carbamazepine, tiagabine, mesuximide, progabide, valproic acid, lamotrigine, brivaracetam, rufinamide, topiramate and perampanel.

[0303] Suitable wakefulness-promoting drugs include methylphenidate, atomoxetine, guanfacine, D-amphetamine, lisdexamfetamine, methamphetamine and clonidine.

[0304] Suitable sleep-promoting drugs include ramelteon, triazolam, zopiclone, eszopiclone, zolpidem, temazepam and trazodone.

[0305] Suitable wakefulness-promoting drugs include modafinil, D-amphetamine, caffeine and armodafinil.

[0306] Suitable analgesics include dextromethorphan, tapentadol, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine, naloxegol, oxycodone, tramadol, gabapentin, difluprednate, pregabalin, acetylsalicylic acid, bromfenac, diclofenac, diflunisal, indomethacin, ketorolac, meoxicam and naproxen.

[0307] In some embodiments, the compounds and compositions of the present invention can be used in combination with other therapies. Suitable therapies include psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation and deep brain stimulation.

[0308] The exact required amount varies for each subject depending on the subject's race, age and general condition, the severity of the symptoms, the particular drug, its mode of administration, etc. The compounds and compositions of the present application are preferably formulated in unit dosage forms for ease of administration and dosage uniformity. As used herein, the expression "unit dosage form" means a physically discrete unit of the drug suitable for the subject to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present application is determined by the attending physician within the scope of sound medical judgment.

[0309] The pharmaceutically acceptable compositions herein can be administered to humans and other animals orally, rectally, parenterally, intragastrically, intraperitoneally, topically (as a powder, ointment or droplet), as an oral or oral or nasal spray, etc., depending on the severity of the infectious disease being treated. In some embodiments, Compound 1 or its salt (or its crystalline form, hydrate or solvate) can be administered orally or parenterally once or multiple times a day at a dosage of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, per day per subject's body weight to obtain the desired therapeutic effect.

[0310] In some embodiments, a combination of two or more therapeutic agents may be administered together with Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof). In some embodiments, a combination of three or more therapeutic agents may be administered together with Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof).

[0311] Examples of other agents that may be used in combination with the compounds and compositions of the present invention include vitamins and dietary supplements; antiemetics such as 5-HT3 receptor antagonists, dopamine antagonists, K1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines or anticholinergics; agents for treating multiple sclerosis (MS) such as beta interferon, e.g., Avonex® and Rebif®, dalfampridine, alemtuzumab, Copaxone® and mitoxantrone; agents for treating Huntington's disease such as tetrabenazine; agents for treating asthma such as albuterol and Singulair®; anti-inflammatory agents such as corticosteroids, TF blockers, IL-1 RA, azathioprine and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole; agents for treating cardiovascular diseases such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and niacin; agents for treating liver diseases such as corticosteroids, cholestyramine, interferon and antiviral agents; agents for treating blood diseases such as corticosteroids, antileukemic agents and growth factors; agents for treating immunodeficiency diseases such as gamma globulin;and antidiabetic agents such as biguanide agents (metformin, phenformin, buformin), thiazolidine agents (rosiglitazone, pioglitazone, troglitazone), sulfonylurea agents (tolbutamide, acetohexamide, tolazamide, chlorpropamide, glibide, glibenclamide, glimepiride, gliclazide), meglitinide agents (repaglinide, nateglinide), α-glucosidase inhibitors (miglitol, acarbose), incretin mimetics (exenatide, liraglutide, taspoglutide), gastric inhibitory polypeptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide) and insulin and insulin analogs. ;

[0312] In some embodiments, Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) is administered in combination with an antisense pharmaceutical, a monoclonal antibody or a polyclonal antibody or an siRNA therapeutic agent.

[0313] Those additional agents may be administered separately from the composition containing the compound of the present application as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form admixed in a single composition together with the compound of the present application. When administered as part of a multiple dosing regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of time with respect to each other (usually within 5 hours with respect to each other).

[0314] As used herein, the terms "in combination", "combined" and related terms mean the simultaneous or sequential administration of therapeutic agents according to this specification. For example, Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof) may be administered simultaneously with or sequentially to another therapeutic agent, separately in unit dosage forms, or together in a single unit dosage form. Accordingly, this specification provides a single unit dosage form comprising Compound 1 or a salt thereof (or a crystalline form, hydrate or solvate thereof), an additional therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0315] The amounts at which both the compound of the present application and the additional therapeutic agent (in the case of a composition containing the additional therapeutic agent as described above) can be combined with a carrier material into one dosage form vary depending on the host to be treated and the specific method of administration. Preferably, the composition of the present invention should be formulated so that a dosage of the compound of the present application of 0.01 to 100 mg / kg body weight / day can be administered.

[0316] In a composition containing an additional therapeutic agent, the additional therapeutic agent as well as compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) may act synergistically. Therefore, the amount of the additional therapeutic agent in such a composition will be less than the amount required in a monotherapy using only that therapeutic agent. In such a composition, an additional therapeutic agent can be administered in an amount of 0.01 to 100 mg / kg body weight / day.

[0317] The amount of the additional therapeutic agent present in the composition herein is less than the amount usually administered as a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the composition disclosed herein ranges from about 50% to 100% of the amount normally present in a composition containing that therapeutic agent as the sole therapeutic active agent.

[0318] In some embodiments, the present invention provides a pharmaceutical product comprising compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0319] In some embodiments, the present invention provides the use of compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) in the manufacture of a pharmaceutical product for treating neurological and / or psychiatric diseases or disorders.

Example

[0320] [[ID=2,6]]Example 1: Preparation of a salt of compound 1 The free base of Compound 1 (500 mg) was dissolved in MeOH (34 mL). This solution was divided into 33 vials (at a scale of 15 mg of Compound 1). To each vial, an appropriate counter ion (0.95 equivalents) was added and dissolved in the screening solvents listed in Table 1. The solution was heated at 60 °C for 1 hour, then allowed to stand at room temperature and cooled. Each vial was opened and allowed to stand at room temperature (evaporate slowly). In some cases, additives of acetone or EtOAc were added to the vials, allowed to stand at room temperature, and evaporated slowly. The results of the solvent screening are shown in Table 1 below. Furthermore, specific experiments as shown in Table 1 were conducted on a larger scale.

Table 1

Table 2

[0321] Example 2. Synthesis of the free base To hydrochloride of Compound 1 (600 mg), saturated aqueous sodium hydrogen carbonate (15 mL) and water (5 mL) were added. This solution was extracted with chloroform (15 mL, 3 times). The organic extract was washed with brine (20 mL) and evaporated. The free base of Compound 1 was isolated as an oil (about 500 mg).

[0322] Example 3. Hydrochloride form HA of Compound 1 The XRPD spectrum of hydrochloride HA of Compound 1 is shown in Figure 1 (FIG.1), and the corresponding peak data are shown in Table 2 below.

Table 3

Table 4

[0323] The DSC thermogram of Form HA is shown in FIG. 2. This thermogram is characterized by endothermic peaks at temperatures of about 99 °C and about 187 °C. FIG. 3 shows the thermogravimetric analysis (TGA) thermogram of Form HA. FIG. 4 shows the dynamic vapor sorption (DVS) isotherm of Form HA.

[0324] Example 4. Hydrochloride Form HB of Compound 1 The XRPD spectrum of Hydrochloride HB of Compound 1 is shown in FIG. 5, and the corresponding peak data are shown in Table 3 below. [Table 5]

[0325] FIG. 6 shows the dynamic vapor sorption (DVS) isotherm of Form HB.

[0326] Example 5. Phosphate of Compound 1 The XRPD spectrum of the phosphate of Compound 1 is shown in FIG. 7, and the corresponding peak data are shown in Table 4 below. Table 4. XRPD Peak Data for Phosphate of Compound 1 [Table 6] [Table 7]

[0327] The DSC thermogram of the phosphate of Compound 1 is shown in FIG. 8. This thermogram is characterized by an endothermic peak at a temperature of about 213 °C. FIG. 9 shows the thermogravimetric analysis (TGA) thermogram of the phosphate of Compound 1. FIG. 10 shows the dynamic vapor sorption (DVS) isotherm of the phosphate of Compound 1.

[0328] Example 6. L-Tartrate Form LA of Compound 1 The XRPD spectrum of Form LA of Compound 1 is shown in Figure 11 (FIG. 11), and the corresponding peak data are shown in Table 5 below. Table 5. XRPD Peak Data for L-Tartrate Form LA of Compound 1

Table 8

Table 9

[0329] The DSC thermogram of Form LA is shown in Figure 12 (FIG. 12). This thermogram is characterized by endothermic peaks at temperatures of approximately 89 °C and approximately 138 °C. Figure 13 (FIG. 13) shows the thermogravimetric analysis (TGA) thermogram of L-tartrate Form LA of Compound 1. Figure 14 (FIG. 14) shows the dynamic vapor sorption (DVS) isotherm of Form LA.

[0330] Example 7. L-Tartrate Form LB of Compound 1 The XRPD spectrum of L-tartrate Form LB of Compound 1 is shown in Figure 15 (FIG. 15), and the corresponding peak data are shown in Table 6 below. Table 6. XRPD Peak Data for L-Tartrate Form LB of Compound 1

Table 10

Table 11

[0331] Figure 16 (FIG. 16) shows the dynamic vapor sorption (DVS) isotherm of Form LB.

[0332] Example 8. L-Tartrate Form LC of Compound 1 The XRPD spectrum of L-tartrate Form LC of Compound 1 is shown in Figure 17 (FIG. 17), and the corresponding peak data are shown in Table 7 below. Table 7. XRPD Peak Data for L-Tartrate Form LC of Compound

Table 12

Table 13

[0333] The DSC thermogram of Form LC is shown in Figure 18 (FIG. 18). This thermogram is characterized by an endothermic peak at a temperature of about 137 °C. Figure 19 (Figure 19) shows the thermogravimetric analysis (TGA) thermogram of the L-tartrate Form LC of Compound 1. Figure 20 (FIG. 20) shows the dynamic vapor sorption (DVS) isotherm of Form LC.

[0334] Example 9. D-Tartrate of Compound 1 The XRPD spectrum of the D-tartrate of Compound 1 is shown in Figure 22 (FIG. 22), and the corresponding peak data are shown in Table 8 below. Table 8. XRPD Peak Data of D-Tartrate of Compound 1

Table 14

[0335] The DSC thermogram of the D-tartrate of Compound 1 is shown in Figure 23 (FIG. 23). This thermogram is characterized by endothermic peaks at temperatures of about 76 °C and about 153 °C. Figure 23 (FIG. 23) shows the thermogravimetric analysis (TGA) thermogram of the D-tartrate of Compound 1. Figure 24 (FIG. 24) shows the dynamic vapor sorption (DVS) isotherm of the D-tartrate of Compound 1.

[0336] Example 10. Fumarate Form FA of Compound 1 The XRPD spectrum of the fumarate FA of Compound 1 is shown in Figure 25 (FIG. 25), and the corresponding peak data are shown in Table 9 below. Table 9. XRPD Peak Data of Fumarate Form FA of Compound 1

Table 15

Table 16

[0337] The DSC thermogram of Form FA is shown in FIG. 26 (FIG. 26). This thermogram is characterized by an endothermic peak at a temperature of about 147 °C. FIG. 27 (FIG. 27) shows the thermogravimetric analysis (TGA) thermogram of the fumarate Form FA of Compound 1. FIG. 28 (FIG. 28) shows the dynamic vapor sorption (DVS) isotherm of Form FA.

[0338] Example 11. Fumarate Form FB of Compound 1 The XRPD spectrum of fumarate FB of Compound 1 is shown in FIG. 29 (FIG. 29), and the corresponding peak data are shown in Table 10 below. Table 10. XRPD Peak Data of Fumarate Form FB of Compound 1

Table 17

Table 18

[0339] The DSC thermogram of Form FB is shown in FIG. 30 (FIG. 30). This thermogram is characterized by endothermic peaks at temperatures of about 96 °C, about 139 °C and about 146 °C. FIG. 31 (FIG. 31) shows the thermogravimetric analysis (TGA) thermogram of the fumarate Form FB of Compound 1. FIG. 32 (FIG. 32) shows the dynamic vapor sorption (DVS) isotherm of Form FB.

[0340] Example 12. Citrate of Compound 1 The XRPD spectrum of citrate of Compound 1 is shown in FIG. 33 (FIG. 33), and the corresponding peak data are shown in Table 11 below. Table 11. XRPD Peak Data of Citrate of Compound 1

Table 19

Table 20

[0341] The DSC thermogram of the citrate of Compound 1 is shown in FIG. 34 (FIG. 34). This thermogram is characterized by an endothermic peak at a temperature of about 142 °C. FIG. 35 (FIG. 35) shows the thermogravimetric analysis (TGA) thermogram of the citrate of Compound 1. FIG. 36 (FIG. 36) shows the dynamic vapor sorption (DVS) isotherm of the citrate of Compound 1.

[0342] Example 13. Succinate of Compound 1 The XRPD spectrum of the succinate of Compound 1 is shown in FIG. 37 (FIG. 37), and the corresponding peak data are shown in Table 12 below. Table 12. XRPD Peak Data of the Succinate of Compound 1

Table 21

Table 22

[0343] The DSC thermogram of the succinate of Compound 1 is shown in FIG. 38 (FIG. 38). This thermogram is characterized by an endothermic peak at a temperature of about 153 °C. FIG. 39 (FIG. 39) shows the thermogravimetric analysis (TGA) thermogram of the succinate of Compound 1. FIG. 40 (FIG. 40) shows the dynamic vapor sorption (DVS) isotherm of the succinate of Compound 1.

[0344] Example 14. Glutarate of Compound 1 The XRPD spectrum of the glutarate of Compound 1 is shown in FIG. 41 (FIG. 41), and the corresponding peak data are shown in Table 13 below. Table 13. XRPD Peak Data of the Glutarate of Compound 1

Table 23

Table 24

[0345] Figure 42 shows the dynamic vapor sorption (DVS) isotherm of the glutarate of Compound 1.

[0346] Example 15. L-Malate of Compound 1 The XRPD spectrum of the L-malate of Compound 1 is shown in Figure 43 (FIG. 43), and the corresponding peak data are shown in Table 14 below. Table 14. XRPD Peak Data of L-Malate of Compound 1

Table 25

Table 26

[0347] The DSC thermogram of the L-malate of Compound 1 is shown in Figure 44 (FIG. 44). This thermogram is characterized by an endothermic peak at a temperature of about 82 °C. Figure 45 (FIG. 45) shows the thermogravimetric analysis (TGA) thermogram of the malate of Compound 1. Figure 46 (FIG. 46) shows the dynamic vapor sorption (DVS) isotherm of the malate of Compound 1.

[0348] Example 16. Besylate of Compound 1 The XRPD spectrum of the besylate of Compound 1 is shown in Figure 47 (FIG. 47), and the corresponding peak data are shown in Table 15 below. Table 15. XRPD Peak Data of Besylate of Compound 1

Table 27

[0349] The DSC thermogram of besylate of Compound 1 is shown in FIG. 48. This thermogram is characterized by an endothermic peak at a temperature of about 136°C. FIG. 49 shows the thermogravimetric analysis (TGA) thermogram of besylate of Compound 1. FIG. 50 shows the dynamic vapor sorption (DVS) isotherm of besylate of Compound 1.

[0350] Example 17. Stability Test Each sample was stored at 60°C and 75% RH for 1 month at 60°C. Each sample was measured by HPLC after 20 days and 1 month. The conditions of HPLC are described below. [Table 28]

[0351] The results of the stability are shown in Table 16 below. [Table 29]

[0352] The free base (amorphous) of Compound 1 was unstable at 60°C and 75% RH at 60°C. The other salts (hydrochloride, phosphate, L-tartrate, fumarate, citrate) were stable.

[0353] Example 18. Polymorph Screening of Phosphate The phosphate of Compound 1 was subjected to three types of polymorph screening: solvent screening, slurry screening, and rapid cooling screening. The procedures for each screening are shown below.

[0354] Solvent Screening: Phosphate of Compound 1 (5 mg) was placed in a small glass vial, and a solvent was added until the sample dissolved at 90 °C or the boiling point. The maximum volume of the solvent was 500 μL. The solution or suspension was heated for 1 hour, then allowed to cool at room temperature overnight and cooled at 5 °C for 3 days. The non-precipitated samples were opened and left standing at room temperature until dry (evaporated slowly). The precipitated solid was filtered through a sintered filter plate and measured directly on the plate by XRPD.

[0355] Slurry Screening: Phosphate of Compound 1 (10 mg) was placed in a small glass vial, and an organic solvent mixed with water was added. Then, the sample was shaken at room temperature or 50 °C for 4 - 10 days to form a suspension. The suspension was filtered. The recovered solid was analyzed by XRPD to determine the polymorph.

[0356] Rapid Cooling Screening: Phosphate of Compound 1 (10 mg) was dissolved at 90 °C or the boiling point. This solution was rapidly cooled to 0 °C. After 1 hour, the solution was cooled at -20 °C for 3 days. The precipitated crystals were filtered. The recovered solid was analyzed by XRPD to determine the polymorph.

[0357] From screening tests (more than 75 tests), only one polymorph (the phosphate of Compound 1 described in Example 5) was identified.

[0358] Example 19. Synthesis of Compound 1 and Phosphate of Compound 1 Step 1. Preparation of 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine trifluoromethanesulfonate

Chemical Structure

[0359] A solution of 2-(2-bromo-5-fluorophenyl)ethan-1-ol (200 g, 913 mmol) and N-methylaminoacetaldehyde dimethyl acetal (130 g, 1091 mmol) in dichloromethane (300 mL) was cooled to 0 °C, and trifluoromethanesulfonic acid (554 g, 3691 mmol) was added over 1 hour while maintaining the temperature below 35 °C by external cooling. The mixture was warmed to 30 °C and stirred at 30 °C for 23 hours. The mixture was cooled to 20 °C, and methanol (33 mL), dichloromethane (1275 mL) and tert-butyl methyl ether (1358 mL) were added. The precipitate was collected by suction filtration. The solid was washed with a solution consisting of 1:1 (v / v) dichloromethane and tert-butyl methyl ether (1830 mL) and dried under vacuum (>28”Hg) at 45 °C for 21 hours to give 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine trifluoromethanesulfonate (339 g, 87% yield) as a brown powder. MS (ESI): m / z 274, 276 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.65 (br s, 1 H), 8.54 (br s, 1 H), 7.67 (dd, J=8.80, 5.28 Hz, 1 H), 7.15 (dd, J=9.98, 8.80 Hz, 1 H), 5.21 (dd, J=9.78, 2.35 Hz, 1 H), 4.06 (dt, J=12.03, 5.92 Hz, 1 H), 3.89 (dt, J=11.93, 5.18 Hz, 1 H), 3.50 - 3.38 (m, 1 H), 3.31 (br s, 1 H), 2.73 (t, J=5.67 Hz, 2 H), 2.64 (br s, 3 H); 1313C-NMR (100 MHz, DMSO-d6): δ ppm 158.91, 156.48, 136.20, 136.16, 132.57, 132.48, 123.37, 123.20, 119.20, 119.17, 115.34, 115.10, 66.59, 59.63, 49.09, 49.04, 33.01, 28.75, 28.73.

[0360] Step 2. Preparation of (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanaminium (2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate [Chemical Structure] 1-(5-Bromo-8-fluoroisochroman-1-yl)-N-methylmethanamine trifluoromethanesulfonate (300 g, 707 mmol), 10 wt% (dry basis) palladium on activated carbon, 50% water (1.2 g), an aqueous solution containing methanol (1006 mL) and 5 wt% aqueous potassium carbonate solution (1059 g) was hydrogenated at 25 °C under a hydrogen pressure of 5 bar for 1 hour. The pressure was released and the solution was filtered through a 5 micron disposable polypropylene in-line filter cartridge and rinsed with a solution containing 1:1 (v / v) methanol and water (540 g). The solution was concentrated under reduced pressure to a final volume of 1200 mL. To this mixed solution, tert-butyl methyl ether (893 mL) and 20 wt% potassium hydroxide (185 mL) were added. The mixture was stirred at 20 °C for 10 minutes. Stirring was stopped and the phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (649 mL). The combined organic layers were concentrated under reduced pressure to a final volume of 450 mL. To this solution, SDA (specially denatured alcohol) 3A ethanol (851 mL) was added. The solution was concentrated under reduced pressure to a final volume of 675 mL. The solution (Solution A) was retained for the next treatment. In a separate container, dibenzoyl-L-tartaric acid (252 g, 703 mmol), SDA 3A ethanol (2704 mL) and deionized water (69 mL) were added. The mixture was heated to about 70 °C and when Solution A was added over 9 minutes, a precipitate formed. The mixture was stirred at about 70 °C for 45 minutes and then cooled to 20 °C over about 2.5 hours. The precipitate was collected by suction filtration. The solid was washed with SDA 3A ethanol (960 mL) and dried at 45 °C under vacuum (>28''Hg) for 17 hours to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium (2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (181 g, 46% yield) as a white solid.

[0361] Other solvents other than dibenzoyl-L-tartaric acid were also considered, but many of them were found to be unsuitable or impractical for various reasons (e.g., availability, cost, performance). Such solvents include (R)-mandelic acid, L-tartaric acid, and L-malic acid. However, when N-acetyl-D-leucine was used, the desired (R) isomer could be obtained at a ratio of about 91:9 and a yield of about 17%.

[0362] The optical purity of the intermediate (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium (2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate was concentrated to 96.4% de by performing the following recrystallization method.

[0363] (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanaminium (2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (177 g, 320 mmol) was added to methanol (3578 mL), and the solution was concentrated to a final volume of 1326 mL at atmospheric pressure, resulting in crystallization. The temperature of the slurry was adjusted to about 62 °C, and stirring was continued for 20 minutes. The slurry was cooled to 10 °C over 2 hours, and the solid was collected by suction filtration. The solid was washed with cold (10 °C) methanol (675 mL) and dried under vacuum ( > 28''Hg) at 45 °C overnight to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanaminium (2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (136 g, yield 77%) as a white solid. MS (ESI): m / z 196 [M+H] + ; 11H-NMR (400 MHz, DMSO-d6): δ ppm 8.03 - 7.85 (m, 4 H), 7.70 - 7.55 (m, 2 H), 7.54 - 7.43 (m, 4 H), 7.27 (td, J=7.92, 6.06 Hz, 1 H), 7.11 - 6.89 (m, 2H), 5.67 (s, 2 H), 5.15 (dd, J=9.98, 2.93 Hz, 1 H), 3.92 (ddd, J=11.84, 7.34, 4.70 Hz, 1 H), 3.69 (dt, J=11.54, 4.99 Hz, 1 H), 3.36 - 3.24 (m, 1 H), 3.22 - 3.04 (m, 1 H), 2.80 - 2.61 (m, 2 H), 2.54 (s, 3 H); 13 13C-NMR (100 MHz, DMSO-d6): δ ppm 168.21, 164.89, 159.56, 157.13, 136.87, 136.82, 133.37, 129.60, 129.23, 128.88, 128.80, 128.65, 125.10, 125.07, 120.58, 120.43, 114.57, 113.07, 112.87, 72.47, 66.71, 59.65, 49.22, 49.17, 32.62, 27.28, 27.26.

[0364] Step 3. Preparation of (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine phosphate

Chemical Structure

[0365] Step 4. Recrystallization of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate using water / acetone [Chemical formula] From Step 3, the product of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (19.5 g) was dissolved in 70 g of water at 20 °C, and then 30 g of acetone was added during this step to make a starting solution of 16.3 wt%. This solution was passed through a polish filter to remove insoluble substances. Thereafter, 600 g of acetone was added to the solution within about 1 hour. The product crystallized during the addition. The slurry was stirred at 20 °C for at least 30 minutes, and the solid was recovered by suction filtration. The solid was washed with a binary mixed solvent of acetone (54 g) and deionized water (6 g), and dried at 55 °C overnight under vacuum (>28''Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (18.1 g, yield 93%) as a white crystalline solid.

[0366] Step 4. Recrystallization of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate using water / acetone [Chemical formula]

[0367] The product of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (35.0 g) from Step 3 was dissolved in water (70 g) at 20 °C, and then acetonitrile (30 g) was added during this step to prepare a starting solution of 25.9 wt%. This solution was passed through a polish filter to remove all unwanted substances. Thereafter, within about 1 hour, 600 g of acetonitrile was added to this solution. The product crystallized during the addition. The slurry was stirred at 20 °C for at least 30 minutes, and the solid was recovered by suction filtration. The solid was washed with a binary mixed solvent of acetonitrile (90 g) and deionized water (10 g), and dried under vacuum (>28''Hg) at 55 °C overnight to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (31.2 g, yield 89%) as a white crystalline solid.

[0368] Various preferred embodiments [A] to [DY] of the present invention can be described in the following text: [Embodiment A] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate (L-tartrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate (D-tartrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate (fumarate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate (citrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate (succinate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate (glutarate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine L-malate (L-malate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine besylate (besylate of Compound 1); or (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine tosylate (tosylate of Compound 1), a salt thereof, or a hydrate or solvate thereof. [Embodiment B] The salt according to Embodiment [A] above, or a salt according to other embodiments of the present invention, wherein the salt is in solid form. [Embodiment C] The salt according to Embodiment [A] or [B] above, or a salt according to other embodiments of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (methylmethanamine phosphate of Compound 1). [Embodiment D] The salt according to Embodiment [C] above, or a salt according to other embodiments of the present invention, wherein the phosphate of Compound 1 is crystalline. [Embodiment E] The salt according to Embodiment [D] above, or a salt according to other embodiments of the present invention, wherein the salt exhibits characteristic XRPD peaks with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2° and 18.2° ± 0.2°. [Embodiment F] The salt according to Embodiment [D] above, or a salt according to other embodiments of the present invention, wherein the salt exhibits at least one characteristic XRPD peak with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°. [Embodiment G] The salt of the above embodiment [D], or a salt according to other embodiments of the present invention, shows at least two characteristic XRPD peaks with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°. [Embodiment H] The salt of the above embodiment [D], or a salt according to other embodiments of the present invention, shows at least three characteristic XRPD peaks with respect to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°. [Embodiment I] The salt of any one of the above embodiments [D] to [H], or a salt according to other embodiments of the present invention, shows an XRPD pattern of characteristic peaks substantially as represented in FIG. 6 (FIG. 6). [Embodiment J] The salt of any one of the above embodiments [D] to [I], or a salt according to other embodiments of the present invention, shows an endothermic peak at a temperature of about 213°C. [Embodiment K] The salt of any one of the above embodiments [D] to [J], or a salt according to other embodiments of the present invention, shows a DSC thermogram substantially as represented in FIG. 7 (FIG. 7). [Embodiment L] The salt of any one of the above embodiments [D] to [K], or a salt according to other embodiments of the present invention, shows a DVS isotherm substantially as represented in FIG. 9 (FIG. 9). [Embodiment M] The salt of any one of embodiments [A] or [B], or a salt according to other embodiments of the present invention, is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate (L-tartrate of Compound 1). [Embodiment N] The L-tartrate of Compound 1 of the above embodiment [M], or a salt according to other embodiments of the present invention, is crystalline. [Embodiment O] A salt of the above-described Embodiment [N] in Form LA or a salt related to other embodiments of the present invention. [Embodiment P] A salt of the above-described Embodiment [O] or a salt related to other embodiments of the present invention, wherein Form LA shows characteristic XRPD peaks with respect to 2θ selected from 12.1° ± 0.2°, 18.1° ± 0.2°, and 24.2° ± 0.2°. [Embodiment Q] A salt of the above-described Embodiment [N] or [O] or a salt related to other embodiments of the present invention, wherein Form LA shows an XRPD pattern of characteristic peaks substantially as represented in FIG. 10 (FIG. 10). [Embodiment R] A salt of the above-described Embodiment [N] in Form LB or a salt related to other embodiments of the present invention. [Embodiment S] A salt of the above-described Embodiment [R] or a salt related to other embodiments of the present invention, wherein Form LB shows characteristic XRPD peaks with respect to 2θ selected from 18.7° ± 0.2°, 25.0° ± 0.2°, and 31.4° ± 0.2°. [Embodiment T] A salt of the above-described Embodiment [R] or [S] or a salt related to other embodiments of the present invention, wherein Form LB shows an XRPD pattern of characteristic peaks substantially as represented in FIG. 14 (FIG. 14). [Embodiment U] A salt of the above-described Embodiment [N] in Form LC or a salt related to other embodiments of the present invention. [Embodiment V] A salt of the above-described Embodiment [U] or a salt related to other embodiments of the present invention, wherein Form LC shows characteristic XRPD peaks with respect to 2θ selected from 12.2° ± 0.2°, 16.5° ± 0.2°, and 24.8° ± 0.2°. [Embodiment W] A salt of the above-described Embodiment [U] or [V] or a salt related to other embodiments of the present invention, wherein Form LC shows an XRPD pattern of characteristic peaks substantially as represented in FIG. 16 (FIG. 16). [Embodiment X] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate (the D-tartrate of Compound 1), the salt of the above Embodiment [A] or [B], or the salt according to other embodiments of the present invention. [Embodiment Y] The D-tartrate of Compound 1 is a crystal, the salt of the above Embodiment [X], or the salt according to other embodiments of the present invention. [Embodiment Z] The salt shows XRPD peaks characteristic of 2θ selected from 11.9° ± 0.2°, 16.9° ± 0.2° and 17.9° ± 0.2°, the salt of the above Embodiment [Y], or the salt according to other embodiments of the present invention. [Embodiment AA] The salt shows characteristic XRPD peaks substantially as represented in FIG. 20 (FIG. 20), the salt of the above Embodiment [Y] or [Z], or the salt according to other embodiments of the present invention. [Embodiment AB] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine fumarate (the L-fumarate of Compound 1), the salt of the above Embodiment [A] or [B], or the salt according to other embodiments of the present invention. [Embodiment AC] The fumarate of Compound 1 is a crystal, the salt of the above Embodiment [AB], or the salt according to other embodiments of the present invention. [Embodiment AD] It is Form FA, the salt of the above Embodiment [AC], or the salt according to other embodiments of the present invention. [Embodiment AE] Form FA shows XRPD peaks characteristic of 2θ selected from 7.7° ± 0.2°, 14.2° ± 0.2° and 15.2° ± 0.2°, the salt of the above Embodiment [AD], or the salt according to other embodiments of the present invention. [Embodiment AF] A salt of the above embodiment [AD] or [AE], or a salt according to other embodiments of the present invention, wherein Form FA shows an XRPD pattern showing characteristic peaks substantially as represented in FIG. 22 (FIG. 22). [Embodiment AG] A salt of the above embodiment [AC], or a salt according to other embodiments of the present invention, which is Form FB. [Embodiment AH] A salt of the above embodiment [AG], or a salt according to other embodiments of the present invention, wherein Form FB shows characteristic XRPD peaks with respect to 2θ selected from 6.7° ± 0.2°, 13.8° ± 0.2° and 20.2° ± 0.2°. [Embodiment AI] A salt of the above embodiment [AG] or [AH], or a salt according to other embodiments of the present invention, wherein Form FB shows an XRPD pattern showing characteristic peaks substantially as represented in FIG. 26 (FIG. 26). [Embodiment AJ] A salt of the above embodiment [A] or [B], or a salt according to other embodiments of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine citrate (citrate of Compound 1). [Embodiment AK] A salt of the above embodiment [AJ], or a salt according to other embodiments of the present invention, wherein the citrate of Compound 1 is crystalline. [Embodiment AL] A salt of the above embodiment [AK], or a salt according to other embodiments of the present invention, wherein the salt shows characteristic XRPD peaks with respect to 2θ selected from 6.5° ± 0.2°, 15.5° ± 0.2° and 20.4° ± 0.2°. [Embodiment AM] A salt of the above embodiment [AK] or [AL], or a salt according to other embodiments of the present invention, wherein the salt shows an XRPD pattern having characteristic peaks substantially as represented in FIG. 30 (FIG. 30). [Embodiment AN] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine succinate (the succinate of Compound 1), the salt of the above-described Embodiment [A] or [B], or a salt according to another embodiment of the present invention. [Embodiment AO] The salt is the salt of the above-described Embodiment [AN], or a salt according to another embodiment of the present invention, wherein the succinate of Compound 1 is a crystal. [Embodiment AP] The salt is the salt of the above-described Embodiment [AO], or a salt according to another embodiment of the present invention, which shows characteristic XRPD peaks with respect to 2θ selected from 6.6° ± 0.2°, 12.8° ± 0.2°, and 13.9° ± 0.2°. [Embodiment AQ] The salt is the salt of the above-described Embodiment [AO] or [AP], or a salt according to another embodiment of the present invention, which shows an XRPD pattern of characteristic peaks substantially as shown in FIG. 34 (FIG. 34). [Embodiment AR] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine glutarate (the glutarate of Compound 1), the salt of the above-described Embodiment [A] or [B], or a salt according to another embodiment of the present invention. [Embodiment AS] The salt is the salt of the above-described Embodiment [AR], or a salt according to another embodiment of the present invention, wherein the glutarate of Compound 1 is a crystal. [Embodiment AT] The salt is the salt of the above-described Embodiment [AS], or a salt according to another embodiment of the present invention, which shows characteristic XRPD peaks with respect to 2θ selected from 9.1° ± 0.2°, 10.6° ± 0.2°, and 18.2° ± 0.2°. [Embodiment AU] The salt is the salt of the above-described Embodiment [AS] or [AT], or a salt according to another embodiment of the present invention, which shows an XRPD pattern of characteristic peaks substantially as shown in FIG. 38 (FIG. 38). [Embodiment AV] A salt according to embodiment [A] or [B] above, or any other embodiment of the invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine L-malate (the L-malate of Compound 1). [Implementation AW] The salt of embodiment [AV] above, or any other embodiment of the invention, wherein the L-malate of Compound 1 is crystalline. [Implementation AX] A salt according to embodiment [AW] above, or any other embodiment of the invention, wherein the salt exhibits characteristic XRPD peaks for 2θ selected from 13.5°±0.2°, 18.8°±0.2° and 25.2°±0.2°. [Embodiment AY] A salt according to embodiment [AW] or [AX] above, or any other embodiment of the invention, wherein the salt exhibits an XRPD pattern having characteristic peaks substantially as depicted in Figure 40 (FIG. 40). [Embodiment AZ] A salt according to embodiment [A] or [B] above, or any other embodiment of the invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine besylate (the besylate of Compound 1). [Embodiment BA] The salt of embodiment [AZ] above, or any other embodiment of the invention, wherein the besylate of Compound 1 is crystalline. [Embodiment BB] The salt of embodiment [BA] above, or any other embodiment of the invention, wherein the salt exhibits characteristic XRPD peaks for 2θ selected from 6.0°±0.2°, 12.0°±0.2° and 24.1°±0.2°. [Embodiment BC] A salt according to embodiment [BA] or [BB] above, or any other embodiment of the invention, wherein the salt exhibits an XRPD pattern having characteristic peaks substantially as shown in Figure 44 (FIG. 44). [Embodiment BD] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine tosylate (tosylate of Compound 1), the salt of the above Embodiment [A], or the salt of other embodiments of the present invention. [Embodiment BE] The salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine hydrochloride (hydrochloride of Compound 1), which is a crystal and in Form HA or Form HB, or a hydrate or solvate thereof. [Embodiment BF] The salt of the above Embodiment [BE], or the salt of other embodiments of the present invention, which is in Form HA. [Embodiment BG] The salt of the above Embodiment [BF], or the salt of other embodiments of the present invention, wherein Form HA shows characteristic XRPD peaks with respect to 2θ selected from 9.4° ± 0.2°, 11.4 ± 0.2° and 15.1° ± 0.2°. [Embodiment BH] The salt of the above Embodiment [BF], or the salt of other embodiments of the present invention, wherein Form HA shows characteristic XRPD peaks with respect to 2θ selected from 9.4° ± 0.2°, 11.4 ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2° and 17.6° ± 0.2°. [Embodiment BI] The salt of the above Embodiment [BF], or the salt of other embodiments of the present invention, wherein Form HA shows at least one characteristic XRPD peak with respect to 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2° and 27.0° ± 0.2°. [Embodiment BJ] The salt of the above Embodiment [BF], or the salt of other embodiments of the present invention, wherein Form HA shows at least two characteristic XRPD peaks with respect to 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2° and 27.0° ± 0.2°. [Embodiment BK] The salt of the above embodiment [BF], or the salt of other embodiments of the present invention, wherein Form HA shows at least three characteristic XRPD peaks for 2θ selected from 9.4° ± 0.2°, 11.4° ± 0.2°, 14.2° ± 0.2°, 15.1° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2° and 27.0° ± 0.2°. [Embodiment BL] The salt according to any one of the above embodiments [BE] to [BK], or the salt related to other embodiments of the present invention, wherein Form HA shows an XRPD pattern having characteristic peaks substantially as represented in FIG. 1 (FIG. 1). [Embodiment BM] The salt according to any one of the above embodiments [BE] to [BL], or the salt related to other embodiments of the present invention, wherein Form HA shows endothermic peaks at temperatures of about 99 °C and about 187 °C. [Embodiment BN] The salt according to any one of the above embodiments [BE] to [BM], or the salt related to other embodiments of the present invention, wherein Form HA shows a DSC thermogram substantially as represented in FIG. 2 (FIG. 2). [Embodiment BO] The salt according to any one of the above embodiments [BE] to [BN], or the salt related to other embodiments of the present invention, wherein Form HA shows a DVS isotherm substantially as represented in FIG. 4 (FIG. 4). [Embodiment BP] The salt of the above embodiment [BE], or the salt related to other embodiments of the present invention, which is Form HB. [Embodiment BQ] The salt of the above embodiment [BP], or the salt related to other embodiments of the present invention, wherein Form HB shows characteristic XRPD peaks for 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2° and 10.3° ± 0.2°. [Embodiment BR] The salt of the above embodiment [BP], or the salt related to other embodiments of the present invention, wherein Form HB shows characteristic XRPD peaks for 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2° and 17.3° ± 0.2°. [Embodiment BS] The salt of the above embodiment [BP], or a salt according to other embodiments of the present invention, wherein Form HB exhibits at least one characteristic XRPD peak with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2° and 23.8° ± 0.2°. [Embodiment BT] The salt of the above embodiment [BP], or a salt according to other embodiments of the present invention, wherein Form HB exhibits at least two characteristic XRPD peaks with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2° and 23.8° ± 0.2°. [Embodiment BU] The salt of the above embodiment [BP], or a salt according to other embodiments of the present invention, wherein Form HB exhibits at least three characteristic XRPD peaks with respect to 2θ selected from 8.6° ± 0.2°, 9.6° ± 0.2°, 10.3° ± 0.2°, 12.6° ± 0.2°, 14.7° ± 0.2°, 17.3° ± 0.2° and 23.8° ± 0.2°. [Embodiment BV] The salt according to any one of the above embodiments [BP] to [BU], or a salt according to other embodiments of the present invention, wherein Form HB exhibits an XRPD pattern having characteristic peaks substantially as shown in FIG. 5 (FIG. 5). [Embodiment BW] A pharmaceutical composition comprising a salt according to any one of the above embodiments [A] to [BV], or a salt according to other embodiments of the present invention, and a pharmaceutically acceptable excipient. [Embodiment BX] A method for treating a neurological or psychiatric disease or disorder in a subject in need of treatment, comprising administering an effective amount of a salt according to any one of the above embodiments [A] to [BV], or a pharmaceutical composition according to the above [Embodiment BW] or other embodiments of the present invention, to the subject. [Embodiment BY] The method according to the above embodiment [BX], or a method according to other embodiments of the present invention, wherein the neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia or other psychotic disorders, obsessive-compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism or cognitive disease or disorder. [Embodiment BZ] The method according to the above embodiment [BX], or a method according to other embodiments of the present invention, wherein the neurological or psychiatric disease or disorder is depression. [Embodiment CA] The method according to the above embodiment [BZ], or a method according to other embodiments of the present invention, wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder. [Embodiment CB] The method according to the above embodiment [BX], or a method according to other embodiments of the present invention, wherein the neurological disease or disorder is selected from Alzheimer's disease and Parkinson's disease. [Embodiment CC] The method according to the above embodiment [CB], or a method according to other embodiments of the present invention, wherein the Alzheimer's disease is characterized by Alzheimer's disease with agitation, Alzheimer's disease with aggressive behavior, Alzheimer's disease-related agitation, or Alzheimer's disease with agitation / aggression. [Embodiment CD] A method for treating agitation in a subject in need of treatment, comprising administering to the subject an effective amount of any one of the salts of the above embodiments [A] to [BV], or the pharmaceutical composition of the above [Embodiment BW], or an effective amount of a composition according to other embodiments of the present invention. [Embodiment CE] A method for treating agitation associated with a neurological or psychiatric disease or disorder in a subject in need of treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the salts of the above embodiments [A] to [BV], or the above [Embodiment BW] or other embodiments of the present invention. [Embodiment CF] Structure: [Chemical formula] A method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of Compound 1), which is Structure: [Chemical formula] characterized by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (Compound 1), which is [Embodiment CG] The method according to the above Embodiment [CF], or a method according to other embodiments of the present invention, wherein the phosphoric acid is an aqueous phosphoric acid solution. [Embodiment CH] The method according to the above Embodiment [CF], or a method according to other embodiments of the present invention, wherein the aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 80 wt% to about 95 wt%. [Embodiment CI] The method according to the above Embodiment [CF], or a method according to other embodiments of the present invention, wherein the aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 87 wt%. [Embodiment CJ] The method according to any one of the above Embodiments [CF] to [CI], or a method according to other embodiments of the present invention, wherein the reaction of Compound 1 with phosphoric acid is carried out in the presence of S1a (where S1a is a solvent). [Embodiment CK] The method according to the above Embodiment [CJ], or a method according to other embodiments of the present invention, wherein S1a is a mixture of acetonitrile and water. [Embodiment CL] The method of the above Embodiment [CJ], or a method according to other embodiments of the present invention, wherein S1a is a mixture of acetone and water. [Embodiment CM] The method of the above Embodiment [CJ], or a method according to other embodiments of the present invention, wherein S1a is a polar protic solvent, water or a mixture thereof. [Embodiment CN] The method according to any one of the above Embodiments [CF] to [CM], or a method according to other embodiments of the present invention, wherein about 1 to about 5 molar equivalents of phosphoric acid are used per molar equivalent of Compound 1. [Embodiment CO] Compound 1 has the structure: [Chemical formula] It is produced by a method characterized by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine dibenzoyl-L-tartrate (the dibenzoyl-L-tartrate of Compound 1), which has the formula: [Embodiment CP] Structure: [Chemical formula] with B1 (where B1 is a base), (R)-1-(8-fluorochroman-1-yl)-N-methylmethanamine [Embodiment CQ] The method of the above Embodiment [CO] or [CP], or a method according to other embodiments of the present invention, wherein B1 is an alkali metal hydroxide base. [Embodiment CR] The method of the above embodiment [CO] or [CP], or a method according to other embodiments of the present invention, wherein B1 is potassium hydroxide. [Embodiment CS] The method of the above embodiment [CO] or [CP], or a method according to other embodiments of the present invention, wherein B1 is an aqueous solution of potassium hydroxide. [Embodiment CT] The method of the above embodiment [CS], or a method according to other embodiments of the present invention, wherein the aqueous solution of potassium hydroxide is an aqueous solution of potassium hydroxide of about 10 wt% to about 20 wt%. [Embodiment CU] The method of the above embodiment [CS], or a method according to other embodiments of the present invention, wherein the aqueous solution of potassium hydroxide is an aqueous solution of potassium hydroxide of about 14 wt%. [Embodiment CV] The method according to any one of the above embodiments [CO] to [CU], or a method according to other embodiments of the present invention, wherein the reaction of dibenzoyl-L-tartrate of compound 1 with a base is carried out in the presence of S2 (where S2 is a solvent). [Embodiment CW] The method of the above embodiment [CV], or a method according to other embodiments of the present invention, wherein S2 is a polar aprotic solvent. [Embodiment CX] The method according to any one of the above embodiments [CO] to [CW], or a method according to other embodiments of the present invention, wherein about 0.5 to about 5 molar equivalents of B1 are used per molar equivalent of dibenzoyl-L-tartrate of compound 1. [Embodiment CY] The method according to any one of the above embodiments [CO] to [CX], or a method according to other embodiments of the present invention, wherein the reaction of dibenzoyl-L-tartrate of compound 1 with B1 is further carried out in the presence of sodium chloride. [Embodiment CZ] The method according to any one of the above embodiments [CO] to [CY], or a method according to other embodiments of the present invention, wherein about 1 to about 10 molar equivalents of sodium chloride are used per molar equivalent of dibenzoyl-L-tartrate of compound 1. [Embodiment DA] Structure: [Chemical formula] A method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1), characterized in that 1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (racemic compound 1) is reacted with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is a solvent). [Embodiment DB] A method according to the above Embodiment [DA], or a method according to other embodiments of the present invention, wherein S3 is a polar protic solvent. [Embodiment DC] A method according to the above Embodiment [DA], or a method according to other embodiments of the present invention, wherein S3 is a mixture of methanol and water. [[ID="20"]][Embodiment DD] A method according to any one of the above Embodiments [DA] to [DC], or a method according to other embodiments of the present invention, wherein about 1 to about 5 molar equivalents of dibenzoyl-L-tartaric acid are used per molar equivalent of racemic compound 1. [Embodiment DE] A method according to any one of the above Embodiments [DA] to [DD], or a method according to other embodiments of the present invention, further characterized in that the dibenzoyl-L-tartrate of Compound 1 is precipitated from a mixture containing racemic compound 1, dibenzoyl-L-tartaric acid and S3. [Embodiment DF] A method according to any one of the above Embodiments [DA] to [DE], or a method according to other embodiments of the present invention, further characterized in that the dibenzoyl-L-tartrate of Compound 1 is isolated from S3a (where S3a is a solvent). [Embodiment DG] A method according to the above Embodiment [DF], or a method according to other embodiments of the present invention, wherein S3a is methanol.<S [Embodiment DH] 1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine (racemic compound 1) has the structure:

Chemical formula

Chemical formula

[0369] In addition to the content described herein, various modifications related to the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications and publications cited in this application, is hereby incorporated by reference in its entirety into this specification.

Claims

1. (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine L-tartrate (L-tartrate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine D-tartrate (D-tartrate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine fumarate (fumarate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine citrate (citrate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine succinate (succinate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine glutarate (glutarate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine L-malate (L-malate of Compound 1); (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine besylate (besylate of Compound 1); or (R)-1-(8-Fluoroisochroman-1-yl)-N-methylmethanamine tosylate (tosylate of Compound 1); which is a salt or its hydrate or solvate.

2. The salt according to Claim 1, wherein the salt is in solid form.

3. The salt according to Claim 1 or 2, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of Compound 1).

4. The salt according to Claim 3, wherein the phosphate of Compound 1 is crystalline.

5. The salt according to Claim 4, wherein the salt exhibits XRPD peaks characteristic of 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2° and 18.2° ± 0.2°.

6. The salt according to Claim 4, wherein the salt exhibits at least one characteristic XRPD peak for 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°.

7. The salt according to claim 4, showing at least two characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°.

8. The salt according to claim 4, showing at least three characteristic XRPD peaks related to 2θ selected from 4.6° ± 0.2°, 9.1° ± 0.2°, 15.7° ± 0.2°, 18.2° ± 0.2°, 22.3° ± 0.2°, 22.8° ± 0.2° and 24.8° ± 0.2°.

9. The salt according to any one of claims 4 to 8, showing an XRPD pattern of characteristic peaks substantially as represented in FIG. 6 (FIG. 6).

10. The salt according to any one of claims 4 to 9, showing an endothermic peak at a temperature of about 213°C.

11. The salt according to any one of claims 4 to 10, showing a DSC thermogram substantially as represented in FIG. 7 (FIG. 7).

12. The salt according to any one of claims 4 to 11, showing a DVS isotherm substantially as represented in FIG. 9 (FIG. 9).

13. A pharmaceutical composition comprising the salt according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

14. A method for treating a neurological or psychiatric disease or disorder in a subject in need of treatment, comprising administering an effective amount of the salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 to the subject.

15. The method according to claim 14, wherein the neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia or other psychotic diseases, obsessive-compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism or cognitive disease or disorder.

16. The method according to claim 14, wherein the neurological or psychiatric disease or disorder is depression.

17. The method according to claim 16, wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with other diseases or disorders.

18. The method according to claim 14, wherein the neurological disease or disorder is selected from Alzheimer's disease and Parkinson's disease.

19. The method according to claim 18, wherein the Alzheimer's disease is Alzheimer's disease with agitated excitement, Alzheimer's disease with aggressive behavior, Alzheimer's disease-related agitated excitement, or Alzheimer's disease with agitated excitement / aggressive behavior.

20. A method for treating agitated excitement in a subject, comprising administering an effective amount of a salt according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 to a subject in need of treatment.

21. A method for treating agitated excitement associated with a neurological or psychiatric disease or disorder in a subject in need of treatment, comprising administering an effective amount of a salt according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 to the subject.

22. Structure: 【Chemical 1】 A method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of compound 1), characterized by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (compound 1) with phosphoric acid to obtain a structure: 【Chemical 2】 Phosphate of compound 1 (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine phosphate (phosphate of compound 1).

23. Structure: 【Chemical 3】 Dibenzoyl-L-tartrate of compound 1 A method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (compound 1), characterized by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of compound 1) with B1 (where B1 is a base).

24. Structure: 【Chemical 4】 A method for producing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethanamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of compound 1), characterized by reacting 1-(8-fluoroisochroman-1-yl)-N-methylmethanamine (racemic compound 1) with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is a solvent).

25. The phosphate of compound 1 produced by the method according to claim 22, wherein the phosphate of compound 1 is a crystal.

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