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

Abstract

The present invention relates to a salt of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine useful for the treatment of CNS disorders, a crystalline form thereof, and a method for preparing the same.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 818,256 filed on March 14, 2019, the full text of which is incorporated herein by reference.

[0003] Technology field

[0004] The present invention relates to a salt of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1), and a crystalline form thereof, a method of preparation, a therapeutic use, and a pharmaceutical composition. Background Technology

[0005] Central nervous system diseases and disorders affect a wide range of populations with varying degrees of severity. Neurological and psychiatric diseases and disorders include, in particular, major depressive disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD). These diseases and disorders affect an individual's thoughts, mood, behavior, and social interactions, and can significantly impair daily functioning. For example, refer to the following literature: Diagnostic and Statistical Manual of Mental Disorders , 4 th Ed., American Psychiatric Association (2000) (“DSM-IV-TR”); Diagnostic and Statistical Manual of Mental Disorders , 5 th Ed., American Psychiatric Association (2013) ("DSM-5"). In addition, neuropsychiatric symptoms, such as apathy, depression, anxiety, cognitive decline, psychosis, aggression, agitation, impulse control, and sleep disorders, are currently recognized as core functional declines in neurological diseases and disorders such as Alzheimer's disease and Parkinson's disease.

[0006] Recently, various drugs for treating CNS disorders have been developed. For example, (R)-1-(8-fluoroisocroman-1-yl)-N-methylmethaneamine reported in U.S. Patent No. 10,196,403 is useful for the treatment of CNS disorders, the full text of which is incorporated herein by reference. There is a need for a new form of (R)-1-(8-fluoroisocroman-1-yl)-N-methylmethaneamine to facilitate the manufacture of safe, effective, and high-quality drug products.

[0007] The present invention provides a salt of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine and a crystalline form thereof. Compound (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (Compound 1) has the chemical formula of the following structure:

[0008]

[0009] (Compound 1)

[0010] In some embodiments, a method for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1) or a salt or crystalline form thereof is provided.

[0011] In some embodiments, a method of using (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1) or its salt or crystalline form in the treatment of CNS disorders is provided.

[0012] In some embodiments, a pharmaceutical composition is provided comprising (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (Compound 1) or a salt or crystalline form thereof and one or more pharmaceutically acceptable excipients. Brief explanation of the drawing

[0013] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of the hydrochloride form HA of compound 1. Figure 2 shows a differential scanning calorimetry (DSC) thermogram of the hydrochloride form HA of compound 1. Figure 3 shows the thermogravimetric analysis (TGA) thermogram of the hydrochloride form HA of compound 1. Figure 4 shows the dynamic vapor adsorption (DVS) isotherm of the hydrochloride form HA of compound 1. Figure 5 shows the XRPD pattern of the hydrochloride form HB of compound 1. Figure 6 shows the XRPD pattern of the phosphate of compound 1. Figure 7 shows the DSC thermogram of the phosphate of compound 1. Figure 8 shows the TGA thermogram of the phosphate of compound 1. Figure 9 shows the DVS isotherm of the phosphate of compound 1. Figure 10 shows the XRPD pattern of the L-tartrate form LA of compound 1. Figure 11 shows the DSC thermogram of the L-tartrate form LA of compound 1. Figure 12 shows the TGA thermogram of the L-tartrate form LA of compound 1. Figure 13 shows the DVS isotherm of the L-tartrate form LA of compound 1. Figure 14 shows the XRPD pattern of the L-tartrate form LB of compound 1. Figure 15 shows the DVS isotherm of the L-tartrate form LB of compound 1. Figure 16 shows the XRPD pattern of the L-tartrate form LC of compound 1. Figure 17 shows the DSC thermogram of the L-tartrate form LC of compound 1. Figure 18 shows the TGA thermogram of the L-tartrate form LC of compound 1. Figure 19 shows the DVS isotherm of the L-tartrate form LC of compound 1. Figure 20 shows the XRPD pattern of the D-tartrate of compound 1. Figure 21 shows the DVS isotherm of the D-tartrate of compound 1. Figure 22 shows the XRPD pattern of the fumarate form FA of compound 1. Figure 23 shows the DSC thermogram of the fumarate form FA of compound 1. Figure 24 shows the TGA thermogram of the fumarate form FA of compound 1. Figure 25 shows the DVS isotherm of the fumarate form FA of compound 1. Figure 26 shows the XRPD pattern of the fumarate form FB of compound 1. Figure 27 shows the DSC thermogram of the fumarate form FB of compound 1. Figure 28 shows the TGA thermogram of the fumarate form FB of compound 1. Figure 29 shows the DVS isotherm of the fumarate form FB of compound 1. Figure 30 shows the XRPD pattern of the citrate of compound 1. Figure 31 shows the DSC thermogram of the citrate of compound 1. Figure 32 shows the TGA thermogram of the citrate of compound 1. Figure 33 shows the DVS isotherm of the citrate of compound 1. Figure 34 shows the XRPD pattern of the succinate of compound 1. Figure 35 shows the DSC thermogram of the succinate of compound 1. Figure 36 shows the TGA thermogram of the succinate of compound 1. Figure 37 shows the DVS isotherm of the succinate of compound 1. Figure 38 shows the XRPD pattern of glutarate of compound 1. Figure 39 shows the DVS isotherm of glutarate of compound 1. Figure 40 shows the XRPD pattern of the L-male of compound 1. Figure 41 shows the DSC thermogram of the L-maleate of compound 1. Figure 42 shows the TGA thermogram of the L-male of compound 1. Figure 43 shows the DVS isotherm of the L-maleate of compound 1. Figure 44 shows the XRPD pattern of the besylate of compound 1. Figure 45 shows the DSC thermogram of the besylate of compound 1. Figure 46 shows the TGA thermogram of the besylate of compound 1. Figure 47 shows the DVS isotherm of the besylate of compound 1. Specific details for implementing the invention

[0014] The method of the present invention relates to the use of the compounds and compositions disclosed herein for treating neurological or psychiatric diseases and disorders or functional decline. In some embodiments, the neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, psychostimulation, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, Alzheimer's disease, Parkinson's disease, or cognitive decline. 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 some embodiments, functional decline in neurological diseases or disorders such as Alzheimer's disease and Parkinson's disease includes neuropsychiatric symptoms, e.g., apathy, depression, anxiety, cognitive decline, psychosis, aggression, agitation, impulse control disorder, and / or sleep disorder.

[0015] The description herein provides details to facilitate an understanding of various embodiments of the invention, and it is understood that the provided specification is not intended to limit the claims to specific embodiments but is an example of the subject matter claimed. Accordingly, specific embodiments disclosed herein may be combined with other specific embodiments disclosed herein, including specific embodiments under various headings, and said specific embodiments are provided for convenience and organization but should not be interpreted as limiting the claims in any way.

[0016] All public literature cited herein is incorporated herein in its entirety by reference.

[0017] definition

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art.

[0019] The singular forms "a," "an," and "the" used herein are intended to include their plural forms unless the context clearly indicates otherwise.

[0020] As used herein, and unless otherwise specified, the term “about” refers to a numerical value or range of values ​​provided to describe a particular solid form (e.g., a particular temperature or temperature range, such as indicating melting, dehydration, or glass transition; a change in mass, such as a change in mass as a function of temperature or humidity; a solvent or moisture content, such as expressed in mass or percentage; or, for example, 13When used in conjunction with peak positions in analyses by 3C NMR, DSC, TGA, and XRPD, it indicates that the value or range of values ​​may deviate to an extent reasonably considered by those skilled in the art while representing a specific solid form. Specifically, when the term "about" is used in this context, it indicates that the numerical value or range of 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 cited value or range of values ​​while representing a specific solid form. In some embodiments, the value may vary by about 5%. When the term "about" is used in relation to degree 2-theta values, it indicates ±0.3 degree 2-theta or ±0.2 degree 2-theta. In some embodiments, "about" indicates a 2-theta degree value of ±0.2 2-theta degrees. In some embodiments, "about" indicates a temperature of ±3℃.

[0021] The phrase “alkali metal bicarbonate” used herein alone or in combination with other terms refers to a base having the chemical formula M(HCO3), where M represents an alkali metal (e.g., lithium, sodium, or potassium). Examples of alkali metal bicarbonates include, but are not limited to, lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate.

[0022] The phrase “alkali metal alkoxide” used herein alone or in combination with other terms refers to a base having the chemical formula M(O-alkyl), where M represents an alkali metal (e.g., lithium, sodium, or potassium). Examples of alkali metal alkoxides include, but are not limited to, lithium alkoxide, sodium alkoxide, and potassium alkoxide.

[0023] The phrase “metal hydroxide base” used herein alone or in combination with other terms refers to a base having the chemical formula MOH, where M represents a metal, e.g., an alkali metal (e.g., lithium, sodium, or potassium). Examples of alkali metal hydroxide bases include, but are not limited to, lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0024] The terms "comprising" and "including" as used herein, or their grammatical variations, shall be deemed to specify the characteristic construction, integer, step, or component mentioned, but are not prohibited from adding one or more additional characteristic constructions, integers, steps, components, or groups thereof. The above terms include the term "comprising."

[0025] The expressions "ambient temperature" and "room temperature" as used herein refer to a reaction temperature, which is understood in the art and is generally the approximate temperature of the room where the reaction is carried out, such as a temperature of about 20 to about 30°C.

[0026] As used herein, the terms “amorphous” or “amorphous form” are intended to mean that the material, component, or product is not crystalline when measured, for example, by XRPD, or that the material, component, or product is not birefringent when viewed under a microscope. For example, amorphous implies the absence of a regularly repeating molecular arrangement or the lack of a long range of orders of crystals; that is, the amorphous form is non-crystalline. The amorphous form does not exhibit an X-ray diffraction pattern defined by sharp maxima. In certain embodiments, a sample containing a material in an amorphous form may substantially lack other amorphous and / or crystalline forms. For example, an amorphous material can be identified by an XRPD spectrum that is free of easily distinguishable reflections.

[0027] As used herein, the terms “chemical purity” or “purity” refer to the measurement of the purity of a compound. In some embodiments, the compounds described herein may be isolated to a 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 may be isolated to a remnant-isomer purity of more than about 90%. In some embodiments, the compounds described herein may be isolated to a remnant-isomer purity of more than about 95%. In some embodiments, the compounds described herein may be isolated to a remnant-isomer purity of more than about 99%. Measurements may be performed by methods widely known in the art, such as elemental analysis, column chromatography, NMR spectroscopy, etc.

[0028] As used herein, the terms “crystallization” or “crystallization form” refer to the crystalline solid form of a chemical compound, including but not limited to single-component or multi-component crystalline forms, such as solvates, hydrates, inclusions, and co-crystals. For example, crystallinity implies having a regular repeating and / or ordered arrangement of molecules and possessing a distinguishable crystal lattice. The term “crystallization form” is intended to indicate a specific lattice position configuration of a crystalline material. Different crystalline forms of the same material generally possess different crystalline lattices (e.g., unit cells), generally have different physical properties due to their different crystalline lattices, and in some cases, have different water or solvent contents. Different crystalline lattices can be identified by solid-state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor deposition (DVS), help not only to identify crystalline forms but also to measure stability and solvent / water content.

[0029] As used herein, the terms “% crystallinity” or “crystallinity” mean the percentage of the crystalline form in a formulation or sample, said formulation or sample may contain other forms such as amorphous forms of the same compound, at least one other crystalline form of the compound, or a mixture thereof. In some embodiments, the crystalline form may be isolated to a 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 crystalline form may be isolated to a purity greater than about 90%. In some embodiments, the crystalline form may be isolated to a purity greater than about 95%. In some embodiments, the crystalline form may be isolated to a purity greater than about 99%.

[0030] As used herein, "delay" in the development of a disorder refers to slowing, hindering, slowing, stabilizing, and / or postponing the development of the disorder. The duration of the delay may vary depending on the history of the disorder and / or the individual being treated.

[0031] As used herein, the term "disorder" or any specifically identified disorder disclosed herein (e.g., CNS disorder) refers to a disorder defined in the Diagnostic and Statistical Manual of Psychiatric Disorders, Fifth Edition (DSM-5).

[0032] As used herein, the term "enantiomer purity" refers to the measurement of purity for chiral compounds. In some embodiments, the compounds described herein may be isolated to an enantiomer 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 may be isolated to an enantiomer purity greater than about 99%. In some embodiments, the compounds described herein may be isolated to an enantiomer purity greater than about 90%. In some embodiments, the compounds described herein may be isolated to an enantiomer purity greater than about 95%. The measurement may be performed by methods widely known in the art, such as specific optical rotation, chiral column chromatography, NMR spectroscopy, etc.

[0033] As used herein, the term “hydrate” is intended to refer to the solid form (e.g., crystalline form) of compound 1 containing water and its salt. The water in the hydrate may be present in stoichiometric amounts relative to the amount of salt in the solid, or in varying amounts, as may be found in relation to channel hydrates.

[0034] The reaction of the method described herein may be carried out in a suitable solvent that can be easily selected by a person skilled in organic synthesis. The suitable solvent may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, in the range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in a single solvent or in a mixture of one or more solvents. Depending on a specific reaction step, a solvent suitable for that specific reaction step may be selected. In some embodiments, the reaction may be carried out in the absence of a solvent, for example, 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., containing carbon in its structure) used to dissolve or disperse one or more of the compounds described herein.

[0035] Suitable solvents may include halogenated solvents, for example, 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, mixtures thereof, etc.

[0036] Suitable solvents may 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 (diglaim), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, mixtures thereof, etc.

[0037] Suitable solvents may include protic solvents (e.g., polar protic solvents), which may include, in the manner of examples and without limitation, 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-pentanol, 2-pentanol or 3-pentanol, neo-pentyl alcohol, tert-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol or glycerol.

[0038] Suitable solvents may include aprotic solvents and may include, in an exemplary manner and without limitation, 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.

[0039] Suitable solvents may include hydrocarbon solvents and include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene or p-xylene, octane, indane, nonane or naphthalene.

[0040] The terms “peak” or “characteristic peak” as used herein refer to a reflection having a relative height / intensity of at least about 3% of the maximum peak height / intensity.

[0041] As used herein, "pharmaceuticalally acceptable" or "physiologically acceptable" refers to compounds (e.g., solid form), compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0042] The term “pharmaceuticalally acceptable excipients” refers 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, flavoring agents, drying agents, plasticizers, vehicles, disintegrants, or lubricants that do not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients that can be used in the composition of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0043] As used herein, “prevention” or “preventing” refers to a regimen that protects against the onset of a disorder so as not to manifest clinical symptoms of the disorder. Accordingly, “prevention” refers to the administration of a regimen comprising the administration of a compound disclosed herein to a subject before signs of the disease become detectable in the subject (e.g., administration of a compound described herein to a subject in the absence of a detectable syndrome of the disorder). The subject may be at risk of developing the disorder. As used herein, a “at-risk” subject is a subject at risk of developing the disorder being treated. This may be indicated, for example, by one or more risk factors, which are measurable parameters known in the art that correlate with the development of the disorder.

[0044] The preparation of compounds may involve the protection and deprotection of various chemical groups. The necessity of protection and deprotection, and the selection of an appropriate protection group (PG), can be easily determined by those skilled in the art. The chemistry of the protection group is, for example, [Wuts and Greene, Greene's Protective Groups in Organic Synthesis , 4 th This can be found in Ed., John Wiley & Sons: New York, 2006, the full text of which is incorporated herein by reference. The preparation of the compound may also include a leaving group (LG), which is a molecular fragment that leaves upon bond cleavage. The leaving group may be an anionic or neutral fragment and may stabilize the additional electron density resulting from bond cleavage. Typical leaving groups are halides, e.g., Cl, Br, and I, and sulfonate esters, e.g., tosylate (TsO), triflate (TfO), mesylate (MsO), etc.

[0045] When describing a specific method, the terms “reacting,” “contacting,” or “processing” as used herein are used as known in the art and generally indicate the use of chemical reagents together in a manner that allows for interactions at the molecular level to achieve chemical or physical modification. In some embodiments, the reacting comprises two reagents, wherein a second reagent that is one or more equivalents to the first reagent is used. The reaction step of the method described herein may be carried out for a certain period of time and under conditions suitable for producing the identified product.

[0046] As used herein, the term “salt” refers to a substance produced from a combination of a compound and an acid or a base. For example, a free base compound 1 may be combined with a desired acid as a solvent or melt to produce a salt of compound 1. In some embodiments, the acid addition salt of compound 1 may be converted to a different acid addition salt by anion exchange. Salts produced in a solvent system may be isolated by precipitation from the solvent. Precipitation and / or crystallization may be induced, for example, by evaporation, temperature reduction, reverse solvent addition, or a combination thereof.

[0047] As used herein, the term “solid form” refers to a compound in an amorphous state or a crystalline state (e.g., a crystalline form) provided by the present invention, wherein the compound provided by the present invention in a crystalline state may optionally contain a solvent or water within the crystal lattice to form, for example, a solvated or hydrated crystalline form. In some embodiments, the compound provided by the present invention is in the crystalline state described herein.

[0048] The "solvent" used herein is formed by the interaction between a solvent and a compound.

[0049] The term “subject” as used herein, to which administration is being considered, 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, or elderly adults) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially related mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or commercially related birds, including chickens, ducks, geese, quail and / or turkeys. The “subject” may independently be diagnosed with a disorder defined herein, may currently be experiencing symptoms related to the disorder, may have experienced symptoms in the past, may be at risk of developing the disorder, or may report one or more symptoms of the disorder even if a diagnosis has not been made. In some embodiments, the subject may independently be diagnosed with a disorder defined herein, may currently be experiencing symptoms related to the disorder, may have experienced symptoms in the past, or may be at risk of developing the disorder It is a human being who has, or can report one or more symptoms of a disorder even if a diagnosis has not been made.

[0050] In cases where characteristic features of a crystal form, such as XRPD patterns, DSC thermograms, and TGA thermograms, are described, the term "substantially" as used herein means that the subject feature is not identical to the references described herein, but falls within the range of experimental error and can be determined by a person skilled in the art to be derived from the same crystal form disclosed herein. For example, the term "substantially" as used herein in relation to XRPD means that it includes variations disclosed herein (e.g., instrumentation variation, measurement variation, etc.).

[0051] As used herein, the term “substantially amorphous” means that most of the weight of a sample or formulation (e.g., a salt of compound 1) is amorphous and the remainder of said sample is a crystalline form of the same compound. In some embodiments, the 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% (e.g., about 96% of the amorphous form of the same compound), more preferably less than about 3% (e.g., about 97% of the amorphous form of the same compound), much more preferably less than about 2% (e.g., about 98% of the amorphous form of the same compound), even more preferably less than about 1% (e.g., about 99% of the amorphous form of the same compound), and most preferably about 0% (e.g., about 100% of the amorphous form of the same compound). In some embodiments, the term "completely noncrystalline" means a degree of crystallinity of less than about 99% or about 0%.

[0052] As used herein, the term “substantially crystalline” means that most of the weight of a sample or formulation (e.g., a salt of compound 1) is crystalline and the remainder of said sample is an amorphous form of the same compound (e.g., amorphous). In some embodiments, the 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% (e.g., about 4% of the amorphous form of the same compound), more preferably at least about 97% (e.g., about 3% of the amorphous form of the same compound), much more preferably at least about 98% (e.g., about 2% of the amorphous form of the same compound), even more preferably at least about 99% (e.g., about 1% of the amorphous form of the same compound), and most preferably about 100% (e.g., about 0% of the amorphous form of the same compound). In some embodiments, the term "perfect crystallinity" means at least about 99% or about 100% crystallinity.

[0053] The term “substantially isolated” means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition rich in the compound, salt, hydrate, solvate, or solid form provided by the present invention. Substantial separation may include a composition containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compound, salt, hydrate, solvate, or solid form provided by the present invention.

[0054] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to an amount effective in inducing a desired biological or medical response, comprising an amount of compound sufficient to influence the treatment of said disorder when administered to a subject to treat said disorder. The effective dose will vary depending on the compound, the disorder and its severity, and the age, weight, etc., of the subject being treated. The effective dose may be one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective dose may be considered provided as an effective dose if a desirable or beneficial result can or is achieved in combination with one or more other agents. The appropriate dose of any co-administered compound may be lowered at any time due to the combined, adductive, or synergistic effects of said compounds.

[0055] As used herein, the terms “treatment,” “to treat,” and “treating” refer to an approach to obtain a beneficial or desired outcome, including but not limited to therapeutic benefits. Therapeutic benefits include the eradication and / or improvement of the underlying disorder being treated; and also include the eradication and / or improvement of one or more symptoms associated with the underlying disorder that cause improvement to be observed in said subject, even though said subject may still be suffering from the underlying disorder. In some embodiments, “treatment” or “treating” includes one or more of the following: (a) suppression of the disorder (e.g., reduction of one or more symptoms of the disorder and / or reduction in the degree of the disorder); (b) slowing or stopping the development of one or more symptoms associated with the disorder (e.g., stabilization of the disorder and / or delay of the worsening or progression of the disorder); and / or (c) alleviation of the disorder (e.g., inducing regression of clinical symptoms, improvement of the disorder, delay of the progression of the disorder and / or improvement of the quality of life). In some embodiments, treatment may be administered after one or more symptoms have occurred. In another embodiment, treatment may be administered in the absence of symptoms. For example, treatment may be administered to individuals who are susceptible before the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other susceptibility factors). For example, treatment may be continued even after symptoms have resolved to prevent or delay the recurrence of symptoms.

[0056] The term “treatment-resistant depression,” as used herein and also known as “treatment-refractory depression,” refers to a Major Depressive Disorder (MDD) situation in which a subject exhibits an inadequate response to treatment with at least two antidepressants (e.g., commercially available standard antidepressants). An inadequate response cannot be considered a response. An inadequate response may also be when the subject does not demonstrate complete remission of symptoms, or when a physician or clinician does not consider the subject’s response to be adequate. Symptoms of treatment-resistant depression may range from mild to severe. Factors that may contribute to an inadequate response include, but are not limited to, premature discontinuation of treatment, insufficient dosage of medication, patient non-adherence, misdiagnosis, and concomitant psychiatric disorders.

[0057] EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HCl (hydrochloric acid); M (mol); MeCN (acetonitrile); MeOH (methanol); mg (milligram(s)); min. (min(s)); mL (milliliter(s)); mmol (millimolar(s)); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); nM (nanomolar); Ph (phenyl); μg (microgram(s)); μL (microliter(s)); μM (micromolar); wt% (weight%).

[0058] Salts and their crystalline forms

[0059] The present invention provides a salt of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (Compound 1) and a crystalline form thereof. Compound (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (Compound 1) has the chemical formula of the following structure:

[0060]

[0061] Compound 1

[0062] Compound 1 is described in U.S. Patent Application No. 15 / 663,688 (granted), the full text of which is incorporated herein by reference.

[0063] Compound 1 (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine is named or identified using other generally recognized naming systems. For example, the compound may be named or identified by a generic name, a systematic name, or a non-systematic name. Naming systems generally recognized in the field of chemistry include, but are not limited to, the Chemical Abstract Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). The IUPAC name provided by ChemDraw Professional 15.0 has been used herein for Compound 1.

[0064] Compound 1 can be prepared as a salt. In some embodiments, compound 1 can be prepared as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include maleate, tartrate, citrate, phosphate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, monohydrogen-phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Includes methoxybenzoate, phthalates, sulfonates, methylsulfonate, propylsulfonate, besylate, tosylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, lactate, gamma-hydroxybutyrate, glycolate, and maleate. A list of other suitable pharmaceutically acceptable salts can be found in the literature [Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006].

[0065] In some embodiments, the salt of the present invention is a hydrochloric acid salt of Compound 1. The hydrochloric acid salt form of Compound 1 is denoted herein as "hydrochloride of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride salt.

[0066] In some embodiments, the salt of the present invention is a phosphate salt of compound 1. The phosphate salt form of compound 1 is denoted herein as "phosphate of compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate salt.

[0067] In some embodiments, the salt of the present invention is the L-tartrate salt of Compound 1. The form of the L-tartrate salt of Compound 1 is denoted herein as "L-tartrate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate salt.

[0068] In some embodiments, the salt of the present invention is the D-tartrate salt of Compound 1. The form of the D-tartrate salt of Compound 1 is denoted herein as "D-tartrate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate salt.

[0069] In some embodiments, the salt of the present invention is a fumarate salt of Compound 1. The fumarate salt form of Compound 1 is denoted herein as "fumarate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate salt.

[0070] In some embodiments, the salt of the present invention is a citrate salt of Compound 1. The citrate salt form of Compound 1 is denoted herein as "citrate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate salt.

[0071] In some embodiments, the salt of the present invention is a succinate salt of compound 1. The succinate salt form of compound 1 is denoted herein as "succinate of compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate salt.

[0072] In some embodiments, the salt of the present invention is the glutarate salt of Compound 1. The citric acid salt form of Compound 1 is denoted herein as "glutarate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate salt.

[0073] In some embodiments, the salt of the present invention is the L-malate salt of Compound 1. The form of the L-malate salt of Compound 1 is denoted herein as "L-malate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-malate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-malate salt.

[0074] In some embodiments, the salt of the present invention is a benzenesulfonate salt of Compound 1. The form of the benzenesulfonate salt of Compound 1 is denoted herein as "besylate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine besylate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine benzenesulfonate salt.

[0075] In some embodiments, the salt of the present invention is the p-toluenesulfonate salt of Compound 1. The form of the p-toluenesulfonate salt of Compound 1 is denoted herein as "tosylate of Compound 1". Other names for the salt are (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine tosylate or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine p-toluenesulfonate salt.

[0076] The salt described herein may have an acid of about half equivalent, about 1 equivalent, about 2 equivalents, about 3 equivalents, etc., with respect to Compound 1. In some embodiments, the salt described herein contains about half equivalent of acid with respect to Compound 1. In some embodiments, the salt described herein contains about 1 equivalent of acid with respect to Compound 1. In some embodiments, the salt described herein contains about 2 equivalents of acid with respect to Compound 1. In some embodiments, the salt described herein contains about 3 equivalents of acid with respect to Compound 1. Those skilled in the art will recognize that there is an equilibrium between the acid and Compound 1, and that protons may be present depending on conditions (e.g., solvent, temperature, etc.) and the strength of the acid. For example, under some conditions, the acid becomes a counter-anion by losing one or more protons with respect to Compound 1, and Compound 1 becomes a counter-cation. Under some conditions, the proton of the acid can form a weak interaction with the basic site of compound 1, so the proton is shared between the acid and compound 1.

[0077] The salt described herein may have less than about 1 equivalent, less than about 2 equivalents, less than about 3 equivalents, less than about 4 equivalents, less than about 5 equivalents, or less than about 6 equivalents of a solvent or hydrate with respect to the salt. In some embodiments, the salt described herein has less than about 1 equivalent of a solvent or hydrate with respect to the salt. In some embodiments, the salt described herein has less than about 1 equivalent of a hydrate with respect to the salt. In some embodiments, the salt described herein has about 2 equivalents of a solvent or hydrate with respect to the salt. In some embodiments, the salt described herein has about 2 equivalents of a hydrate with respect to the salt. In some embodiments, the salt described herein has about 3 equivalents of a solvent or hydrate with respect to the salt. In some embodiments, the salt described herein has about 3 equivalents of a hydrate with respect to the salt.

[0078] In some embodiments, the salts described herein are anhydrous.

[0079] The salt of Compound 1 may be isolated into one or more crystalline forms. Different crystalline forms of the same substance may have different bulk properties, for example, with respect to hygroscopicity, solubility, stability, etc. A crystalline form with a high melting point may have excellent thermodynamic stability, which may be advantageous for extending the shelf life of drug formulations containing said crystalline form. A crystalline form with a low melting point may be less thermodynamically stable but may be advantageous for having increased water solubility, which can translate into increased drug bioavailability. A crystalline form with low hygroscopicity may be desirable for stability against heat or humidity and may be resistant to degradation during long-term storage. The crystalline forms described herein have many advantages and, for example, desirable properties. Furthermore, the crystalline forms disclosed herein may be useful for improving performance characteristics of pharmaceutical products, such as solubility profiles, shelf life, and bioavailability.

[0080] Different crystalline forms of a specific material described herein, such as Compound 1, may include both an anhydrous form of the material and a solvated / hydrated form of the material, wherein the anhydrous form and the solvated / hydrated form are each distinguished by different XRPD patterns or other solid-state characterization methods and exhibit different crystal lattices. In some examples, a single crystalline form (e.g., identified by a unique XRPD pattern) may have varying water or solvent contents, wherein the lattice remains substantially unchanged (as with the XRPD pattern) despite changes in composition with respect to water and / or solvent.

[0081] The XRPD pattern of reflections (peaks) is generally considered to be a fingerprint of a specific crystallographic form. It is widely known that the relative intensity of XRPD peaks can vary widely, particularly depending on the sample preparation technique, crystal size distribution, the filter used, the sample mounting procedure, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the instrument type or setting (e.g., whether a Ni filter is used). Additionally, instrument variation and other factors may affect the 2-theta (2θ) value. Thus, for example, the peak assignments reported herein may vary by plus or minus (±) about 0.2° (2-theta) or about 0.3° (2-theta).

[0082] In the same way, temperature readings associated with DSC, TGA, or other thermal experiments may vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Accordingly, it is understood that the crystalline form reported herein, having a DSC thermogram as "substantially" illustrated in any drawing, accommodates such variation.

[0083] A crystalline form of a material can be obtained by a number of methods known in the art. These methods include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as on polymers, recrystallization in the presence of additives such as co-crystallized conjugate molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, exposure to moisture, grinding, and solvent-dropping grinding.

[0084] Compound 1 and its salts may be prepared in batches represented as batches, samples, or formulations. A batch, sample, or formulation may comprise Compound 1 and a salt of Compound 1 in any crystalline or amorphous form described herein, including hydrated and non-hydrated forms and mixtures thereof.

[0085] The compounds provided by the present invention (e.g., salts of Compound 1) may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds provided by the present invention may be replaced or substituted with isotopes of atoms in their natural or non-natural abundance. In some embodiments, the compounds of the present invention include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present invention may be replaced or substituted with deuterium. In some embodiments, the compounds of the present invention include two or more deuterium atoms. In some embodiments, the compounds of the present invention include 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art. Examples of isotopes that may 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) is included.

[0086] In some embodiments, compound 1 or its salt and its crystalline form are substantially isolated.

[0087] Compound 1 can be observed and / or isolated as various salt forms and polymorphs of compound 1, including, for example, hydrochloride salt (form HA and form HB), phosphate salt, L-tartrate salt (form LA, form LB and form LC), D-tartrate salt, fumarate (form FA and form FB), citrate, succinate, glutarate, L-maleate, besylate and tosylate.

[0088] Hydrochloride of Compound 1

[0089] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride (hydrochloride of compound 1) is provided. In some embodiments, the hydrochloride of compound 1 is crystalline.

[0090] The hydrochloride of Compound 1 can be prepared according to the procedure provided in U.S. Patent No. 10,196,403. In some embodiments, the hydrochloride of Compound 1 is provided, prepared by isolating the hydrochloride form HA of Compound 1 from a mixture of Compound 1, HCl, and S1, wherein 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 methanol. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0091] Hydrochloride form of Compound 1, HA

[0092] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride form HA (hydrochloride form HA of Compound 1) is provided. In some embodiments, the hydrochloride form HA of Compound 1 is crystalline.

[0093] In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 9.4°±0.2°. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 11.4°±0.2°. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 15.1°±0.2°.

[0094] In some embodiments, the hydrochloride form HA of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, 15.1°±0.2°, 17.2°±0.2°, and 17.6°±0.2°.

[0095] In some embodiments, the hydrochloride form HA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0096] In some embodiments, the hydrochloride form HA of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0097] In some embodiments, the hydrochloride form HA of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0098] In some embodiments, the hydrochloride form HA of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 1.

[0099] In some embodiments, the hydrochloride form HA of Compound 1 has endothermic peaks at temperatures of about 99°C and about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 has an endothermic peak at a temperature of about 99°C. In some embodiments, the hydrochloride form HA of Compound 1 has an endothermic peak at a temperature of about 187°C. In some embodiments, the hydrochloride form HA of Compound 1 has a DSC thermogram substantially as shown in FIG. 2. In some embodiments, the hydrochloride form HA of Compound 1 has a TGA thermogram substantially as shown in FIG. 3. In some embodiments, the hydrochloride form HA of Compound 1 has a DVS isotherm substantially as shown in FIG. 4.

[0100] In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, and 15.1°±0.2°; and has an endothermic peak at temperatures of about 99° and about 187°. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, and 15.1°±0.2°; and has an endothermic peak at a temperature of about 99°. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, and 15.1°±0.2°; It has an endothermic peak at a temperature of approximately 187°C. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, and 15.1°±0.2°; and has a DSC thermogram substantially as shown in FIG. 2. In some embodiments, the hydrochloride form HA of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, and 15.1°±0.2°; and has a DVS isotherm substantially as shown in FIG. 4.

[0101] In some embodiments, the hydrochloride form HA of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the hydrochloride form HA of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0102] In some embodiments, a hydrochloride form HA of Compound 1 is provided, prepared by isolating the hydrochloride form HA of Compound 1 from a mixture of Compound 1, HCl, and S1, wherein 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 It is an alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0103] Hydrochloride form of Compound 1, HB

[0104] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride form HB (hydrochloride form HB of Compound 1) is provided. In some embodiments, the hydrochloride HB of Compound 1 is crystalline.

[0105] In some embodiments, the hydrochloride form HB of Compound 1 has a characteristic XRPD peak in the 2θ side 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 has a characteristic XRPD peak in the 2θ side at 8.6°±0.2°. In some embodiments, the hydrochloride form HB of Compound 1 has a characteristic XRPD peak in the 2θ side at 9.6°±0.2°. In some embodiments, the hydrochloride HB of Compound 1 has a characteristic XRPD peak in the 2θ side at 10.3°±0.2°.

[0106] In some embodiments, the hydrochloride form HB of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 8.6°±0.2°, 9.6°±0.2°, 10.3°±0.2°, and 17.3°±0.2°.

[0107] In some embodiments, the hydrochloride form HB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0108] In some embodiments, the hydrochloride form HB of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0109] In some embodiments, the hydrochloride form HB of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0110] In some embodiments, the hydrochloride form HB of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 5.

[0111] 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 greater than about 99%. In some embodiments, the hydrochloride form HB of Compound 1 can be isolated with a crystalline purity greater than about 99.9%.

[0112] In some embodiments, a hydrochloride form of compound 1, HB, is provided, which is prepared by isolating the hydrochloride form of compound 1, HA, from a mixture of compound 1, HCl, and S1, wherein S1 is a solvent. In some embodiments, S1 comprises water. In some embodiments, the form HB is prepared by exposing the form HA to high humidity. In some embodiments, the form HB is prepared by exposing the form HA to about 75% relative humidity.

[0113] Phosphate of Compound 1

[0114] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate is provided. In some embodiments, the phosphate of compound 1 is crystalline.

[0115] In some embodiments, the phosphate of compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2°, and 18.2°±0.2°. In some embodiments, the phosphate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 4.6°±0.2°. In some embodiments, the phosphate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 9.1°±0.2°. In some embodiments, the phosphate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 18.2°±0.2°.

[0116] In some embodiments, the phosphate of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2°, 18.2°±0.2°, and 22.8°±0.2°.

[0117] In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0118] In some embodiments, the phosphate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0119] In some embodiments, the phosphate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0120] In some embodiments, the phosphate of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 6.

[0121] In some embodiments, the phosphate of compound 1 has an endothermic peak at a temperature of about 213°C. In some embodiments, the phosphate of compound 1 has a DSC thermogram substantially as shown in FIG. 7. In some embodiments, the phosphate of compound 1 has a TGA thermogram substantially as shown in FIG. 8. In some embodiments, the phosphate of compound 1 has a DVS isotherm substantially as shown in FIG. 9.

[0122] In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2°, 18.2°±0.2°, and 22.8°±0.2°; and has an endothermic peak at a temperature of about 213°. In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2°, 18.2°±0.2°, and 22.8°±0.2°; and has a DSC thermogram substantially as shown in FIG. 7. In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2°, 18.2°±0.2° and 22.8°±0.2°; and substantially has a DVS isotherm as shown in FIG. 9.

[0123] 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 more than about 99%. In some embodiments, the phosphate of compound 1 can be isolated with a crystalline purity of more than about 99.9%.

[0124] In some embodiments, a phosphate of compound 1 is provided, prepared by isolating the phosphate of compound 1 from a mixture of compound 1, phosphoric acid, and S1, wherein 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 a mixture of organic solvents. In some embodiments, S1 is C 1-6 Alkyl alcohols and C 1-6It is a mixture of alkyl acetates. 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.

[0125] L-tartrate of Compound 1

[0126] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate (L-tartrate of Compound 1) is provided. In some embodiments, the L-tartrate of Compound 1 is crystalline.

[0127] In some embodiments, the L-tartrate of Compound 1 is provided, prepared by isolating the L-tartrate of Compound 1 from a mixture of Compound 1, tartaric acid, and S1, wherein 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 C 1-6 Alkyl alcohols and C 1-6 It is a mixture of alkyl ketones. In some embodiments, S1 is C 1-6 Alkyl alcohols and C 1-6 It is a mixture of alkyl acetates. 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.

[0128] L-tartrate form of Compound 1 LA

[0129] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate form LA (L-tartrate form LA of Compound 1) is provided. In some embodiments, the L-tartrate form LA of Compound 1 is crystalline.

[0130] In some embodiments, the L-tartrate form LA of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 12.1°±0.2°. In some embodiments, the L-tartrate form LA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 18.1°±0.2°. In some embodiments, the L-tartrate form LA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 24.2°±0.2°.

[0131] In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0132] In some embodiments, the L-tartrate form LA of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0133] In some embodiments, the L-tartrate form LA of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0134] In some embodiments, the L-tartrate form LA of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 10.

[0135] In some embodiments, the L-tartrate form LA of Compound 1 has endothermic peaks at temperatures of about 89°C and about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 has an endothermic peak at a temperature of about 89°C. In some embodiments, the L-tartrate form LA of Compound 1 has an endothermic peak at a temperature of about 138°C. In some embodiments, the L-tartrate form LA of Compound 1 has a DSC thermogram substantially as shown in FIG. 11. In some embodiments, the L-tartrate form LA of Compound 1 has a TGA thermogram substantially as shown in FIG. 12. In some embodiments, the L-tartrate form LA of Compound 1 has a DVS isotherm substantially as shown in FIG. 13.

[0136] In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2°, and 24.2°±0.2°; and has endothermic peaks at temperatures of about 89°C and about 138°C. In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2°, and 24.2°±0.2°; and has an endothermic peak at a temperature of about 89°C. In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2°, and 24.2°±0.2°; and has an endothermic peak at a temperature of about 138°. In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2°, and 24.2°±0.2°; and has a DSC thermogram substantially as shown in FIG. 11. In some embodiments, the L-tartrate form LA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2° and 24.2°±0.2°; and substantially has a DVS isotherm as shown in FIG. 13.

[0137] In some embodiments, the L-tartrate form LA of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the L-tartrate form LA of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0138] In some embodiments, an L-tartrate form LA of Compound 1 is provided, prepared by isolating the L-tartrate form LA of Compound 1 from a mixture of Compound 1, L-tartaric acid, and S1, wherein 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 It is an alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0139] L-tartrate form of Compound 1 LB

[0140] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate form LB (L-tartrate form LB of Compound 1) is provided. In some embodiments, the L-tartrate form LB of Compound 1 is crystalline.

[0141] In some embodiments, the L-tartrate form LB of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 18.7°±0.2°. In some embodiments, the L-tartrate form LB of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 25.0°±0.2°. In some embodiments, the L-tartrate form LB of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 31.4°±0.2°.

[0142] In some embodiments, the L-tartrate form LB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0143] In some embodiments, the L-tartrate form LB of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0144] In some embodiments, the L-tartrate form LB of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0145] In some embodiments, the L-tartrate form LB of compound 1 has an XRPD pattern with characteristic peaks as shown in FIG. 14. In some embodiments, the L-tartrate form LB of compound has a DVS isotherm as shown in FIG. 15.

[0146] In some embodiments, the L-tartrate form LB of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the L-tartrate form LB of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0147] In some embodiments, an L-tartrate form LB of Compound 1 is provided, prepared by isolating the L-tartrate form LB of Compound 1 from a mixture of Compound 1, L-tartaric acid, and S1, wherein 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 C 1-6It is an alkyl ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is C 1-6 Alkyl alcohols and C 1-6 It is a mixture of alkyl ketones. In some embodiments, S1 is a mixture of methanol and acetone.

[0148] L-tartrate form of Compound 1 LC

[0149] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate form LC (L-tartrate form LC of Compound 1) is provided. In some embodiments, the L-tartrate form LC of Compound 1 is crystalline.

[0150] In some embodiments, the L-tartrate form LC of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 12.2°±0.2°. In some embodiments, the L-tartrate form LC of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 16.5°±0.2°. In some embodiments, the L-tartrate form LC of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 24.8°±0.2°.

[0151] In some embodiments, the L-tartrate form LC of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0152] In some embodiments, the L-tartrate form LC of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0153] In some embodiments, the L-tartrate form LC of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0154] In some embodiments, the L-tartrate form LC of compound 1 has an XRPD pattern with characteristic peaks as shown in FIG. 16.

[0155] In some embodiments, the L-tartrate form LC of Compound 1 has an endothermic peak at a temperature of about 137°C. In some embodiments, the L-tartrate form LC of Compound 1 has a DSC thermogram substantially as shown in FIG. 17. In some embodiments, the L-tartrate form LC of Compound 1 has a TGA thermogram substantially as shown in FIG. 18. In some embodiments, the L-tartrate form LC of Compound 1 has a DVS isotherm substantially as shown in FIG. 19.

[0156] In some embodiments, the L-tartrate form LC of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.2°±0.2°, 16.5°±0.2°, and 24.8°±0.2°; and has an endothermic peak at a temperature of about 137°. In some embodiments, the L-tartrate form LC of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.2°±0.2°, 16.5°±0.2°, and 24.8°±0.2°; and has a DSC thermogram substantially as shown in FIG. 17. In some embodiments, the L-tartrate form LC of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.2°±0.2°, 16.5°±0.2° and 24.8°±0.2°; and substantially has a DVS isotherm as shown in FIG. 19.

[0157] In some embodiments, the L-tartrate form LC of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the L-tartrate form LC of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0158] In some embodiments, an L-tartrate form LB of Compound 1 is provided, prepared by isolating the L-tartrate form LB of Compound 1 from a mixture of Compound 1, L-tartaric acid, and S1, wherein 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 C 1-6 It is an alkyl acetate. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is C 1-6 Alkyl alcohols and C 1-6It is a mixture of alkyl acetates. In some embodiments, S1 is a mixture of methanol and ethyl acetate.

[0159] D-tartrate of Compound 1

[0160] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate (D-tartrate of Compound 1) is provided. In some embodiments, the D-tartrate of Compound 1 is crystalline.

[0161] In some embodiments, the D-tartrate of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, and 17.9°±0.2°. In some embodiments, the D-tartrate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 11.9°±0.2°. In some embodiments, the D-tartrate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 16.9°±0.2°. In some embodiments, the D-tartrate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 17.9°±0.2°.

[0162] In some embodiments, the D-tartrate of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, 17.9°±0.2°, and 23.9°±0.2°.

[0163] In some embodiments, the D-tartrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0164] In some embodiments, the D-tartrate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0165] In some embodiments, the D-tartrate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0166] In some embodiments, the D-tartrate of compound 1 has an XRPD pattern having a characteristic peak as shown in FIG. 20.

[0167] In some embodiments, the D-tartrate of Compound 1 has endothermic peaks at temperatures of about 76°C and about 153°C. In some embodiments, the D-tartrate of Compound 1 has an endothermic peak at a temperature of about 76°C. In some embodiments, the D-tartrate of Compound 1 has an endothermic peak at a temperature of about 153°C. In some embodiments, the D-tartrate of Compound 1 substantially has a DVS isotherm as shown in FIG. 21.

[0168] In some embodiments, the D-tartrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, 17.9°±0.2°, and 23.9°±0.2°; and has an endothermic peak at temperatures of about 76° and about 153°. In some embodiments, the D-tartrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, 17.9°±0.2°, and 23.9°±0.2°; and has an endothermic peak at a temperature of about 76°. In some embodiments, the D-tartrate of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, 17.9°±0.2° and 23.9°±0.2°; and has an endothermic peak at a temperature of about 153°. In some embodiments, the D-tartrate of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2°, 17.9°±0.2° and 23.9°±0.2°; and has a DVS isotherm substantially as shown in FIG. 21.

[0169] In some embodiments, the D-tartrate of compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the compound D-tartrate can be isolated with a crystallization purity greater than about 99.9%.

[0170] In some embodiments, a D-tartrate of Compound 1 is provided, prepared by isolating the D-tartrate of Compound 1 from a mixture of Compound 1, D-tartaric acid, and S1, wherein 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 It is an alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0171] Fumarate of Compound 1

[0172] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate (fumarate of compound 1) is provided. In some embodiments, the fumarate of compound 1 is crystalline.

[0173] In some embodiments, a fumarate of compound 1 is provided, prepared by isolating the fumarate of compound 1 from a mixture of compound 1, fumaric acid, and S1, wherein 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 Alkyl alcohols and C 1-6 It 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.

[0174] Fumarate form of Compound 1 FA

[0175] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate form FA (fumarate form FA of Compound 1) is provided. In some embodiments, the fumarate form FA of Compound 1 is crystalline.

[0176] In some embodiments, the fumarate form FA of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 7.7°±0.2°. In some embodiments, the fumarate form FA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 14.2°±0.2°. In some embodiments, the fumarate form FA of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 15.2°±0.2°.

[0177] In some embodiments, the fumarate form FA of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 7.7°±0.2°, 15.2°±0.2°, 22.9°±0.2°, and 30.7°±0.2°.

[0178] In some embodiments, the fumarate form FA of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0179] In some embodiments, the fumarate form FA of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0180] In some embodiments, the fumarate form FA of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0181] In some embodiments, the fumarate form FA of compound 1 has an XRPD pattern having a characteristic peak as shown in FIG. 22.

[0182] In some embodiments, the fumarate form FA of Compound 1 has an endothermic peak at a temperature of about 138°C. In some embodiments, the fumarate form FA of Compound 1 has a DSC thermogram substantially as shown in FIG. 23. In some embodiments, the L-fumarate form FA of Compound 1 has a TGA thermogram substantially as shown in FIG. 24. In some embodiments, the fumarate form FA of Compound 1 has a DVS isotherm substantially as shown in FIG. 25.

[0183] In some embodiments, the fumarate form FA of Compound 1 has characteristic XRPD peaks in the 2θ aspect selected from 7.7°±0.2°, 14.2°±0.2°, and 15.2°±0.2°; and has an endothermic peak at a temperature of about 147°. In some embodiments, the fumarate form FA of Compound 1 has characteristic XRPD peaks in the 2θ aspect selected from 7.7°±0.2°, 14.2°±0.2°, and 15.2°±0.2°; and has a DSC thermogram substantially as shown in FIG. 23. In some embodiments, the fumarate form FA of Compound 1 has characteristic XRPD peaks in the 2θ aspect selected from 7.7°±0.2°, 14.2°±0.2°, and 15.2°±0.2°; and has a DVS isotherm substantially as shown in FIG. 25.

[0184] In some embodiments, the fumarate form FA of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the fumarate form FA of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0185] In some embodiments, a fumarate form FA of Compound 1 is provided, prepared by isolating the fumarate form FA of Compound 1 from a mixture of Compound 1, fumaric acid, and S1, wherein 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 ketone. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is C 1-6 Alkyl alcohols and 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 a mixture of methanol and acetone.

[0186] Fumarate FB of Compound 1

[0187] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate form FB (fumarate form FB of Compound 1) is provided. In some embodiments, the fumarate form FB of Compound 1 is crystalline.

[0188] In some embodiments, the fumarate form FB of Compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has a characteristic XRPD peak in the 2θ aspect at 6.7°±0.2°. In some embodiments, the fumarate form FB of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 13.8°±0.2°. In some embodiments, the fumarate form FB of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 20.2°±0.2°. In some embodiments, the fumarate form FB of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 27.0°±0.2°.

[0189] In some embodiments, the fumarate form FB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0190] In some embodiments, the fumarate form FB of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0191] In some embodiments, the fumarate form FB of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0192] In some embodiments, the fumarate form FB of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 26.

[0193] In some embodiments, the fumarate form FB of Compound 1 has 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 has an endothermic peak at a temperature of about 96°C. In some embodiments, the fumarate form FB of Compound 1 has an endothermic peak at a temperature of about 139°C. In some embodiments, the fumarate form FB of Compound 1 has an endothermic peak at a temperature of about 146°C. In some embodiments, the fumarate form FB of Compound 1 has a DSC thermogram substantially as shown in FIG. 27. In some embodiments, the fumarate form FB of Compound 1 has a TGA thermogram substantially as shown in FIG. 28. In some embodiments, the fumarate form FB of Compound 1 has a DVS isotherm substantially as shown in FIG. 29.

[0194] In some embodiments, the fumarate form FB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; and has an endothermic peak at temperatures of about 96°, about 139°, and about 146°. In some embodiments, the fumarate form FB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; and has an endothermic peak at a temperature of about 96°. In some embodiments, the fumarate form FB of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; and has an endothermic peak at a temperature of about 139°C. In some embodiments, the fumarate form FB of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; and has an endothermic peak at a temperature of about 146°C. In some embodiments, the fumarate form FB of Compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; It substantially has a DSC thermogram as shown in FIG. 27. In some embodiments, the fumarate form FB of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2° and 20.2°±0.2°; and substantially has a DVS isotherm as shown in FIG. 29.

[0195] In some embodiments, the fumarate form FB of Compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the fumarate form FB of Compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0196] In some embodiments, a fumarate form FB of Compound 1 is provided, prepared by isolating the fumarate form FB of Compound 1 from a mixture of Compound 1, fumaric acid, and S1, wherein S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is C 1-6 It is an alkyl acetate. In some embodiments, S1 is ethyl acetate.

[0197] Citrate of Compound 1

[0198] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate is provided. In some embodiments, the citrate of compound 1 is crystalline.

[0199] In some embodiments, the citrate of compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2°, and 20.4°±0.2°. In some embodiments, the citrate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 6.5°±0.2°. In some embodiments, the citrate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 15.5°±0.2°. In some embodiments, the citrate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 20.4°±0.2°.

[0200] In some embodiments, the citrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0201] In some embodiments, the citrate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0202] In some embodiments, the citrate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0203] In some embodiments, the citrate of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 30.

[0204] In some embodiments, the citrate of compound 1 has an endothermic peak at a temperature of about 142°C. In some embodiments, the citrate of compound 1 has a DSC thermogram substantially as shown in FIG. 31. In some embodiments, the citrate of compound 1 has a TGA thermogram substantially as shown in FIG. 32. In some embodiments, the citrate of compound 1 has a DVS isotherm substantially as shown in FIG. 33.

[0205] In some embodiments, the citrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2°, and 20.4°±0.2°; and has an endothermic peak at a temperature of about 142°. In some embodiments, the citrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2°, and 20.4°±0.2°; and has a DSC thermogram substantially as shown in FIG. 31. In some embodiments, the citrate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2°, and 20.4°±0.2°; It substantially has a DVS isotherm as shown in Fig. 33.

[0206] In some embodiments, the citrate of compound 1 can be isolated with a crystallization 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 crystallization purity greater than about 99%. In some embodiments, the citrate of compound 1 can be isolated with a crystallization purity greater than about 99.9%.

[0207] In some embodiments, a citrate of compound 1 is provided, prepared by isolating the citrate of compound 1 from a mixture of compound 1, citric acid, and S1, wherein 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 Alkyl alcohols and C 1-6It is a mixture of alkyl ketones. In some embodiments, S1 is C 1-6 Alkyl alcohols and C 1-6 It is a mixture of alkyl acetates. 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.

[0208] Succinate of Compound 1

[0209] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate is provided. In some embodiments, the succinate of compound 1 is crystalline.

[0210] In some embodiments, the succinate of compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 6.6°±0.2°, 12.8°±0.2°, and 13.9°±0.2°. In some embodiments, the succinate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 6.6°±0.2°. In some embodiments, the succinate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 12.8°±0.2°. In some embodiments, the succinate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 13.9°±0.2°.

[0211] In some embodiments, the succinate of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.8°±0.2°, 13.9°±0.2°, 19.8°±0.2°, and 26.5°±0.2°.

[0212] In some embodiments, the succinate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0213] In some embodiments, the succinate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0214] In some embodiments, the succinate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0215] In some embodiments, the succinate of compound 1 substantially has an XRPD pattern with characteristic peaks as shown in FIG. 34.

[0216] In some embodiments, the succinate of compound 1 has an endothermic peak at a temperature of about 153°C. In some embodiments, the succinate of compound 1 has a DSC thermogram substantially as shown in FIG. 35. In some embodiments, the succinate of compound 1 has a TGA thermogram substantially as shown in FIG. 36. In some embodiments, the succinate of compound 1 has a DVS isotherm substantially as shown in FIG. 37.

[0217] In some embodiments, the succinate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.8°±0.2°, 13.9°±0.2°, 19.8°±0.2° and 26.5°±0.2°; and has an endothermic peak at a temperature of about 153°. In some embodiments, the succinate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.8°±0.2°, 13.9°±0.2°, 19.8°±0.2° and 26.5°±0.2°; and has a DSC thermogram substantially as shown in FIG. 35. In some embodiments, the succinate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 12.8°±0.2°, 13.9°±0.2°, 19.8°±0.2° and 26.5°±0.2°; and substantially has a DVS isotherm as shown in FIG. 37.

[0218] 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 greater than about 99%. In some embodiments, the succinate of compound 1 can be isolated with a crystalline purity greater than about 99.9%.

[0219] In some embodiments, a succinate of compound 1 is provided, prepared by isolating the succinate of compound 1 from a mixture of compound 1, succinic acid, and S1, wherein 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 It is an alkyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0220] Glutarate of Compound 1

[0221] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate is provided. In some embodiments, the glutarate of compound 1 is crystalline.

[0222] In some embodiments, the glutarate of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 9.1°±0.2°, 10.6°±0.2°, and 18.2°±0.2°. In some embodiments, the glutarate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 9.1°±0.2°. In some embodiments, the glutarate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 10.6°±0.2°. In some embodiments, the glutarate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 18.2°±0.2°.

[0223] In some embodiments, the glutarate of compound 1 has a characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect selected from 9.1°±0.2°, 10.6°±0.2°, 18.2°±0.2°, and 19.0°±0.2°.

[0224] In some embodiments, the glutarate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0225] In some embodiments, the glutarate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0226] In some embodiments, the glutarate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0227] In some embodiments, the glutarate of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 38. In some embodiments, the glutarate of compound 1 has a DVS isotherm as shown in FIG. 39.

[0228] 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 more than about 99%. In some embodiments, the glutarate of compound 1 can be isolated with a crystalline purity of more than about 99.9%.

[0229] In some embodiments, a glutarate of compound 1 is provided, prepared by isolating the glutarate of compound 1 from a mixture of compound 1, glutaric acid, and S1, wherein 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 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 Alkyl alcohols and C 1-6 It is a mixture of alkyl ketones. In some embodiments, S1 is a mixture of methanol and acetone. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0230] L-male of Compound 1

[0231] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-maleate is provided. In some embodiments, the L-maleate of compound 1 is crystalline.

[0232] In some embodiments, the L-maleate of Compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 13.5°±0.2°, 18.8°±0.2°, and 25.2°±0.2°. In some embodiments, the L-maleate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 13.5°±0.2°. In some embodiments, the L-maleate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 18.8°±0.2°. In some embodiments, the L-maleate of Compound 1 has a characteristic XRPD peak in the 2θ aspect at 25.2°±0.2°.

[0233] In some embodiments, the L-male of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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-male of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0234] In some embodiments, the L-male of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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-male of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0235] In some embodiments, the L-male of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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-male of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0236] In some embodiments, the L-maleate of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 40.

[0237] In some embodiments, the L-maleate of Compound 1 has an endothermic peak at a temperature of about 82°C. In some embodiments, the L-maleate of Compound 1 has a DSC thermogram substantially as shown in FIG. 41. In some embodiments, the L-maleate of Compound 1 has a TGA thermogram substantially as shown in FIG. 42. In some embodiments, the L-maleate of Compound 1 has a DVS isotherm substantially as shown in FIG. 43.

[0238] In some embodiments, the L-maleate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 13.5°±0.2°, 18.8°±0.2°, and 25.2°±0.2°; and has an endothermic peak at a temperature of about 82°. In some embodiments, the L-maleate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 13.5°±0.2°, 18.8°±0.2°, and 25.2°±0.2°; and has a DSC thermogram substantially as shown in FIG. 41. In some embodiments, the L-maleate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 13.5°±0.2°, 18.8°±0.2°, and 25.2°±0.2°; It substantially has a DVS isotherm as shown in Fig. 43.

[0239] In some embodiments, the L-maleate of compound 1 can be isolated with a crystallization 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-maleate of compound 1 can be isolated with a crystallization purity of more than about 99%. In some embodiments, the L-maleate of compound 1 can be isolated with a crystallization purity of more than about 99.9%.

[0240] In some embodiments, the L-maleate of compound 1 is provided, which is prepared by isolating the L-maleate of compound 1 from a mixture of compound 1, L-malic acid, and S1, wherein 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 methanol. In some embodiments, S1 is THF. In some embodiments, S1 is ethyl acetate.

[0241] Besylate of Compound 1

[0242] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine besylate is provided. In some embodiments, the besylate of compound 1 is crystalline.

[0243] In some embodiments, the besylate of compound 1 has a characteristic XRPD peak in the 2θ aspect selected from 6.0°±0.2°, 12.0°±0.2°, and 24.1°±0.2°. In some embodiments, the besylate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 6.0°±0.2°. In some embodiments, the besylate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 12.0°±0.2°. In some embodiments, the besylate of compound 1 has a characteristic XRPD peak in the 2θ aspect at 24.1°±0.2°.

[0244] In some embodiments, the besylate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect 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 has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0245] In some embodiments, the besylate of compound 1 has at least two characteristic XRPD peaks in the 2θ aspect 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 has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0246] In some embodiments, the besylate of compound 1 has at least three characteristic XRPD peaks in the 2θ aspect 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 has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0247] In some embodiments, the besylate of compound 1 has an XRPD pattern having characteristic peaks as shown in FIG. 44.

[0248] In some embodiments, the besylate of compound 1 has an endothermic peak at a temperature of about 136°C. In some embodiments, the besylate of compound 1 has a DSC thermogram substantially as shown in FIG. 45. In some embodiments, the besylate of compound 1 has a TGA thermogram substantially as shown in FIG. 46. In some embodiments, the besylate of compound 1 has a DVS isotherm substantially as shown in FIG. 47.

[0249] In some embodiments, the besylate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.0°±0.2°, 12.0°±0.2°, and 24.1°±0.2°; and has an endothermic peak at a temperature of about 136°. In some embodiments, the besylate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.0°±0.2°, 12.0°±0.2°, and 24.1°±0.2°; and has a DSC thermogram substantially as shown in FIG. 45. In some embodiments, the besylate of compound 1 has at least one characteristic XRPD peak in the 2θ aspect selected from 6.0°±0.2°, 12.0°±0.2°, and 24.1°±0.2°; It substantially has a DVS isotherm as shown in Fig. 47.

[0250] In some embodiments, the besylate of compound 1 can be isolated with a crystallization purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 98%. In some embodiments, the besylate of compound 1 can be isolated with a crystallization purity of more than about 99%. In some embodiments, the besylate of compound 1 can be isolated with a crystallization purity of more than about 99.9%.

[0251] In some embodiments, a besylate of compound 1 is provided, prepared by isolating the besylate of compound 1 from a mixture of compound 1, benzenesulfonic acid and S1, wherein 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 Alkyl alcohols and C 1-6It is a mixture of alkyl ketones. In some embodiments, S1 is ethyl acetate. In some embodiments, S1 is THF. In some embodiments, S1 is a mixture of methanol and acetone.

[0252] Tosylate of Compound 1

[0253] In some embodiments, (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine tosylate (tosylate of compound 1) is provided.

[0254] In some embodiments, a tosylate of compound 1 is provided, prepared by isolating the tosylate of compound 1 from a mixture of compound 1, p-toluenesulfonic acid, and S1, wherein 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 Alkyl alcohols and C 1-6 It 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.

[0255] Compound 1 and method for preparing the phosphate of Compound 1

[0256] The present invention also provides a method for preparing Compound 1 or a salt thereof. A method for preparing Compound 1 is described in U.S. Patent No. 10,196,403, the full text of which is incorporated herein by reference. The method for preparing Compound 1 or a salt thereof provided by the present invention has specific advantages over methods currently disclosed in the art. For example, the method described herein exhibits excellent scalability, yield, and stereochemical selectivity. The method described herein involves chiral decomposition by crystallization, which avoids chiral separation by HPLC and is therefore more suitable for production on a scale of several kilograms.

[0257] The present invention has a chemical formula of the following structure:

[0258] Phosphate of Compound 1

[0259] A method for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (phosphate of Compound 1) having,

[0260] (a) Chemical formula of the following structure in the presence of A1 (where A1 is an acid):

[0261] Chemical Formula III

[0262] A compound of formula III having (where X is a halo) or a salt thereof having the following chemical formula:

[0263] Compound 4

[0264] By reacting with N-methylaminoacetaldehyde dimethylacetal (compound 4) having:

[0265] Chemical Formula II

[0266] A step of providing a compound of formula II having (where X is a halo) or a salt thereof;

[0267] (b) hydrogenating a compound of Formula II or a salt thereof in the presence of a metal catalyst to form a formula of the following structure:

[0268] Racemic compound 1

[0269] A step of providing 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) having;

[0270] (c) Racemic compound 1 is reacted with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is the solvent) to obtain the chemical formula of the following structure:

[0271] Dibenzoyl-L-tartrate of Compound 1

[0272] A step of providing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) having;

[0273] (d) Dibenzoyl-L-tartrate of compound 1 is reacted with B1 (where B1 is a base) to obtain the chemical formula of the following structure:

[0274] Compound 1

[0275] Step of providing compound 1 having and

[0276] (e) A method comprising the step of reacting compound 1 with phosphoric acid to provide the phosphate of compound 1.

[0277] The present invention has a chemical formula of the following structure:

[0278] Compound 1

[0279] A method for preparing compound 1 having,

[0280] (a) Chemical formula of the following structure in the presence of A1 (where A1 is an acid):

[0281] Chemical Formula III

[0282] A compound of formula III having (where X is a halo) or a salt thereof having the following chemical formula:

[0283] Compound 4

[0284] React with N-methylaminoacetaldehyde dimethylacetal (compound 4) having the following chemical formula:

[0285] Chemical Formula II

[0286] A step of providing a compound of formula II having (where X is a halo) or a salt thereof;

[0287] (b) hydrogenating a compound of Formula II or a salt thereof in the presence of a metal catalyst to form a formula of the following structure:

[0288] Racemic compound 1

[0289] A step of providing 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) having;

[0290] (c) Racemic compound 1 is reacted with dibenzoyl-L-tartaric acid in the presence of S3 (where S3 is the solvent) to obtain the chemical formula of the following structure:

[0291] Dibenzoyl-L-tartrate of Compound 1

[0292] A step of providing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) having and

[0293] (d) A method comprising the step of reacting dibenzoyl-L-tartrate of compound 1 with B1 (wherein B1 is a base) to provide compound 1.

[0294] In some embodiments, the present invention is a method for preparing compound 1, wherein

[0295] (a) a step of hydrogenating a compound of Formula II or a salt thereof in the presence of a metal catalyst to provide a racemic compound 1;

[0296] (b) a step of reacting racemic compound 1 with dibenzoyl-L-tartrate in the presence of S3 (where S3 is a solvent) to provide dibenzoyl-L-tartrate of compound 1, and

[0297] (c) A method comprising the step of reacting dibenzoyl-L-tartrate of compound 1 with B1 (wherein B1 is a base) to provide compound 1.

[0298] In some embodiments, as a method for preparing compound 1,

[0299] (a) reacting racemic compound 1 with dibenzoyl-L-tartaric acid in the presence of S3 (wherein S3 is a solvent) to provide dibenzoyl-L-tartrate of compound 1, and

[0300] (c) A method is provided comprising the step of reacting dibenzoyl-L-tartrate of compound 1 with B1 (wherein B1 is a base) to provide compound 1.

[0301] The present invention has a chemical formula of the following structure:

[0302] Compound 1

[0303] A method comprising the step of reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1) having with phosphoric acid,

[0304] Chemical formula of the following structure:

[0305] Phosphate of Compound 1

[0306] A method for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (phosphate of Compound 1) having [the following text is a misreading of the product description] is provided.

[0307] In some embodiments, the phosphate of compound 1 is crystalline.

[0308] In some embodiments, the phosphoric acid of the present invention is an aqueous phosphoric acid solution. In some embodiments, the aqueous phosphoric acid solution of the present invention is an aqueous phosphoric acid solution of about 80 to about 95% by weight. In some embodiments, the aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 87% by weight.

[0309] In some embodiments, the reaction between compound 1 and phosphoric acid is carried out in the presence of S1a, said S1a is a solvent. In some embodiments, S1a is a polar aprotic solvent, water, or a mixture thereof. In some embodiments, S1, which is a polar aprotic solvent, is acetonitrile. In some embodiments, S1a is a mixture of acetonitrile and water.

[0310] In some embodiments, the reaction between compound 1 and phosphoric acid is carried out at a temperature of about 15 to about 25°C. In some embodiments, the reaction between compound 1 and 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. In some embodiments, about 1 molar equivalent of phosphoric acid is used per molar equivalent of compound 1.

[0311] Compound 1 has the chemical formula of the following structure:

[0312] Dibenzoyl-L-tartrate of Compound 1

[0313] It can be prepared by a method comprising the step of reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) having with B1 (where B1 is a base).

[0314] In some embodiments, B1 is an alkali hydroxide base. In some embodiments, B1 is potassium hydroxide. In some embodiments, B1 is an aqueous solution of potassium hydroxide. In some embodiments, the aqueous solution of potassium hydroxide is an aqueous solution of potassium hydroxide in an amount of about 10 to about 20% by weight. In some embodiments, the aqueous solution of potassium hydroxide is an aqueous solution of potassium hydroxide in an amount of about 14% by weight.

[0315] In some embodiments, the reaction of dibenzoyl-L-tartrate of compound 1 with a base is carried out in the presence of S2, said 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-butylmethyl ether.

[0316] In some embodiments, the reaction of dibenzoyl-L-tartrate of compound 1 with B1 is carried out at a temperature of about 20 to about 30°C. In some embodiments, the reaction of dibenzoyl-L-tartrate of compound 1 with a 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.

[0317] 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.

[0318] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) has the chemical formula of the following structure in the presence of S3 (where S3 is a solvent):

[0319]

[0320] It can be prepared by a method comprising the step of reacting 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) having with dibenzoyl-L-tartaric acid.

[0321] In some embodiments, S3 is a polar protic solvent. In some embodiments, S3 is C 1-6 It is an 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 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. In some embodiments, about 1 molar equivalent of dibenzoyl-L-tartaric acid is used per molar equivalent of racemic compound 1.

[0322] A method for preparing dibenzoyl L-tartrate of compound 1 may further include the step of precipitating dibenzoyl-L-tartrate of compound 1 from a mixture comprising 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.

[0323] A method for preparing dibenzoyl L-tartrate of compound 1 may further include the step of isolating dibenzoyl-L-tartrate of compound 1 from S3a, said S3a is a solvent. In some embodiments, S3a is a polar protic solvent. In some embodiments, S3a is C 1-6 It is an alkyl-OH. In some embodiments, S3a is methanol. In some embodiments, the isolation of dibenzoyl-L-tartrate of compound 1 is carried out at a temperature of about 10 to about 65°C.

[0324] 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) has the chemical formula of the following structure in the presence of a metal catalyst:

[0325]

[0326] It can be prepared by a method comprising the step of hydrogenating a compound of formula II having (where X is a halo) or a salt thereof.

[0327] In some embodiments, the compound of formula II is compound 2, which has the following formula:

[0328]

[0329] It is 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethaneamine trifluoromethanesulfonate (compound 2) having

[0330] In some embodiments, the metal catalyst is palladium on 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.

[0331] In some embodiments, the hydrogenation of the compound of Formula II is carried out at a temperature of about 20 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.

[0332] In some embodiments, the hydrogenation of the compound of Formula II is carried out in the presence of S4, said S4 is a solvent. In some embodiments, S4 is a polar protic solvent, and in some embodiments, S4 is C 1-6 It is an alkyl-OH. In some embodiments, S4 is methanol.

[0333] In some embodiments, the hydrogenation of the compound of Formula II is carried out in the presence of B2, said 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% potassium carbonate by weight.

[0334] The compound of chemical formula II, in the presence of A1 (where A1 is an acid), has the chemical formula of the following structure:

[0335] Chemical Formula III

[0336] A compound of formula III having (where X is a halo) or a salt thereof having the following chemical formula:

[0337] Compound 4

[0338] It can be prepared by reacting with N-methylaminoacetaldehyde dimethylacetal (compound 4) having [it].

[0339] In some embodiments, the compound of formula III has the following chemical formula:

[0340] Compound 3

[0341] It is 2-(2-bromo-5-fluorophenyl)ethanol-1-ol (compound 3) having

[0342] In some embodiments, A1 is trifluoromethanesulfonic acid. In some embodiments, the reaction of compound of formula III and compound 4 is carried out in the presence of S5, said S5 is a solvent. In some embodiments, S5 is a halogenated solvent. In some embodiments, S5 is dichloromethane.

[0343] In some embodiments, the reaction between the compound of Formula III and Compound 4 is carried out at a temperature of about 0 to about 35°C. In some embodiments, the reaction between 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.

[0344] For clarity, it is understood that specific characteristic features of the invention described in relation to separate embodiments may be provided in combination in a single embodiment (the embodiments are conceived as being combined as written in a multiple dependent form). Conversely, for brevity, various characteristic features of the invention described in the context of a single embodiment may be provided individually or in any suitable sub-combination.

[0345] The reactions of the methods described herein may be carried out in air or under an inert atmosphere. Generally, reactions involving reagents or products that are substantially reactive with air may be carried out using air-sensitive synthesis techniques widely known to those skilled in the art.

[0346] The method described herein may be monitored according to any suitable method known in the art. For example, the formation of the product may be monitored by spectroscopic means, for example, nuclear magnetic resonance spectroscopy (for example, 1 H or 13 C), it may be monitored by infrared spectroscopy, spectrophotometry (e.g., UV-visible light) or mass spectrometry; or it may be performed by chromatography, e.g., high-performance liquid chromatography (HPLC) or thin-layer chromatography. The compound obtained by the reaction may be purified by any suitable method known in the art. For example, chromatography (medium pressure), HPLC, or thin-layer chromatography on a suitable adsorbent (e.g., silica gel, alumina, etc.); distillation; sublimation, grinding, or recrystallization. The purity of the compound is generally measured by physical methods, e.g., measuring the melting point (in the case of a solid), obtaining an NMR spectrum, or performing HPLC separation. If the melting point is lowered, unwanted signals in the NMR spectrum are reduced, or external peaks of HPLC traces are removed, it can be said that the compound has been purified. In some embodiments, the compound of the present invention is substantially purified.

[0347] How to use

[0348] In some embodiments, the present invention provides a method for treating a neurological or psychiatric disorder or disorder in a subject, comprising administering to the subject an effective amount of a compound of the present invention (or a pharmaceutically acceptable salt thereof) or a composition comprising a compound of the present invention (or a pharmaceutically acceptable salt thereof). Neurological and / or psychiatric disorders and disorders may manifest various psychiatric and behavioral symptoms, including apathy, depression, anxiety, cognitive decline, psychosis, aggression, agitation, poor impulse control, and sleep disorders.

[0349] In one aspect, the neurological or psychiatric disease or disorder is bipolar disorder, Alzheimer's disease accompanied by anxiety, depression, agitation, Alzheimer's disease accompanied by aggression, Alzheimer's disease with agitation, or Alzheimer's disease accompanied by agitation and aggression.

[0350] In one aspect, neurological or psychiatric diseases or disorders are bipolar disorder, anxiety, depression, dementia, Alzheimer's disease, Alzheimer's disease with agitation, Alzheimer's disease with aggression, Alzheimer's disease with agitation or agitation with aggression, neurocognitive disorders, and neurocognitive disorders with behavioral and psychological symptoms.

[0351] In one modality, neurological or psychiatric diseases or disorders are behavioral and psychological symptoms of neurocognitive disorders, including dementia and Alzheimer's disease. Behavioral and psychological symptoms include disturbances in perception, thought content, or mood, or delusions (distressing beliefs), hallucinations, psychosis, agitation (easily angered, repeating questions, arguing or complaining, hoarding, pacing, inappropriate screaming, crying, disjointed sounds, refusal of home care), aggression (physical or verbal), depression or dysphoria, anxiety (worry, shadowing), apathy or indifference, disinhibition (socially inappropriate behavior, sexually inappropriate behavior, irritability or instability), motor disturbances (repetitive aimless activity, wandering, rummaging), nocturnal behavior (waking up at night), impulsivity, attention deficit, and executive dysfunction.

[0352] Tests to identify representative candidate therapies were used at this institution. Examples of candidate therapies include, without limitation, treatments for Alzheimer's disease with agitation, Alzheimer's disease with agitation, and Alzheimer's disease with agitation and agitation with agitation. Aggression and agitation are common symptoms of neurological and psychiatric diseases and disorders. Aggression and agitation are associated with hyperactivity in subcortical brain regions that can be modeled in animals using psychostimulants (e.g., PCP, amphetamines). For example, psychostimulants induce hyperkinetic activity (HLA) in animals. Antipsychotics (e.g., haloperidol, clozapine, and risperidone) have been shown to reduce psychostimulant-induced HLA and have been shown to be effective against agitation in Alzheimer's disease. Other drugs used off-label or currently being studied in clinical trials for agitation in Alzheimer's disease include mood stabilizers such as lithium (which also reduces amphetamine-induced HLA) and antidepressants (e.g., citalopram). Antidepressants demonstrate activity in assays such as forced swim and tail suspension tests. Therefore, the aforementioned assays have helped identify candidate treatments for agitation in Alzheimer's disease and agitation / aggression in other neurological and psychiatric diseases and disorders.

[0353] In one embodiment, a method for treating bipolar disorder in a subject requiring treatment for bipolar disorder is provided, comprising administering an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof to said subject.

[0354] In one embodiment, a method for treating anxiety in a subject requiring treatment for anxiety is provided, comprising administering an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof to said subject.

[0355] In some modalities, neurological or psychiatric diseases or disorders include schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizotypal disorder, schizoaffective disorder, delusional disorder, brief psychiatric disorder, shared psychiatric disorder, general medical pathology and psychiatric disorders caused by substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants and cocaine), psychosis, psychiatric disorders, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders, e.g., schizophrenic or schizotypal personality disorder, or psychosis associated with diseases including all positive, negative, and cognitive symptoms of schizophrenia and other psychoses (e.g., major depressive disorder, or manic-bipolar disorder, Alzheimer's disease and post-traumatic stress disorder); Cognitive impairments including dementia (semantic dementia, frontotemporal dementia, dementia with depressive features, persistent, subcortical dementia, Lewy body dementia, Parkinsonism-ALS dementia complex, and Alzheimer's disease-related dementia, ischemia, multi-infarct dementia, trauma, vascular problems, stroke, HIV disease, Parkinson's disease, Huntington's disease, Down syndrome, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, or substance abuse), delirium, memory impairment, or senile cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, substance-induced anxiety disorder, and disorders due to general medical conditions; Substance-related disorders and addictive behaviors (substance-induced delirium, persistent dementia, persistent memory impairment, psychiatric disorders, or anxiety disorders; including tolerance, dependence, or withdrawal symptoms to substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidines, sedatives, hypnotics, or anxiolytics); eating disorders such as obesity, bulimia nervosa, and feed and compulsive eating disorders;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 specific bipolar disorders and related disorders, and non-specific bipolar disorders and related disorders, unipolar depression, seasonal depression and postpartum depression, atypical depression, catatonic depression, geriatric depression, endogenous depression, depressive depression, perinatal depression, situational depression, chronic depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to general medical conditions, and bipolar disorder including depressive disorders including substance-induced mood disorders; Attention, learning, and developmental disorders, e.g., pervasive developmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and attention disorders including behavioral disorders, e.g., disorders such as autism and autism spectrum disorder (including Asperger syndrome, pervasive developmental disorder, Rett syndrome, and Fragile X syndrome), depression, benign amnesia, childhood learning disabilities, specific learning disabilities, intellectual developmental disorders, and closed head injury; movement disorders and symptoms including tremor, dyskinesia, dystonia, tics, dysphonia, ataxia, myoclonus, essential tremor, tardive dyskinesia, restless legs syndrome, Tourette syndrome, multiple system atrophy, multiple sclerosis, Huntington's disease, Parkinson's disease, and atypical Parkinson's disease; epilepsy; urinary incontinence; neurological damage including ocular injury, retinopathy of the eye or macular degeneration, tinnitus, hearing impairment and loss, and cerebral edema; vomiting; and is selected from sleep disorders including insomnia, disturbed sleep, flight jet lag, hypersomnia, cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep stage disorder, sleepwalking, nocturnal terrors, nocturnal enuresis, rapid eye movement sleep behavior disorder, shift sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.;

[0356] In some modalities, the neurological or psychiatric disease or disorder is Alzheimer's disease, Parkinson's disease, depression, cognitive decline, stroke, schizophrenia, Down syndrome, or fetal alcohol syndrome. In some modalities, the neurological or psychiatric disorder is Alzheimer's disease. In some modalities, the neurological or psychiatric disorder is Parkinson's disease. In some modalities, the neurological or psychiatric disorder is depression. In some modalities, the neurological or psychiatric disorder is cognitive decline. In some modalities, cognitive decline is cognitive dysfunction associated with depression, for example, major depressive disorder. In some modalities, the neurological or psychiatric disorder is stroke. In some modalities, the neurological or psychiatric disorder is schizophrenia. In some modalities, the neurological or psychiatric disorder is Down syndrome. In some modalities, the neurological or psychiatric disorder is fetal alcohol syndrome.

[0357] In some forms, neurological or psychiatric diseases or disorders are bipolar disorders. Bipolar disorder (including both Bipolar I and Bipolar II) is a serious psychiatric disorder with a prevalence of approximately 2% of the population and affects all genders. It is a relapsing-remitting condition characterized by a cycle between elevated mood (i.e., mania) and depressed mood, distinguishing it from other disorders, such as major depressive disorder and schizophrenia. Bipolar I is defined by the occurrence of a full manic episode, but most individuals experience significant depression. Symptoms of mania include elevated or irritable mood, hyperactivity, curiosity, reduced sleepiness, racing thoughts, and, in some cases, psychosis. Depressive episodes are characterized by anhedonia, sad mood, despair, low self-esteem, poor concentration, and drowsiness. Bipolar II is defined by the occurrence of major depressive episodes and hypomanic (less severe manic) episodes, but the individual spends a significant amount of time in a depressive state. Other related conditions include cyclothymic disorder.

[0358] In some forms, a neurological or psychiatric disease or disorder is schizophrenia. Schizophrenia is a disorder of unknown origin that generally first appears in early adulthood and is characterized by features such as psychiatric symptoms, phase progression and development, and / or decline in social behavior and professional competence. Characteristic psychiatric symptoms include thought content (e.g., multiple, fragmentary, inconsistent, irrational or simple delusional content, or perplexing thoughts) and mental state (e.g., loss of association, flights of fancy, contradictions to the point of being incomprehensible), disturbances of perception (e.g., hallucinations), emotions (e.g., surface or inappropriate emotions), self-awareness, intentions, impulses and / or interpersonal relationships, and psychomotor disorders (e.g., catatonia). Other symptoms are also associated with the aforementioned disorder. Schizophrenia is classified into subgroups: the paranoid type, characterized by the absence of delusions, hallucinations, and thought disorders, disorganized behavior, and affective blunting; the disorganized type, also known as "disorganized schizophrenia," characterized by the presence of thought disorders and affective blunting; A catatonic type characterized by distinct psychomotor disturbances, with symptoms potentially including catatonic stupor and waxy flexibility; and an undifferentiated type where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types are not met. Symptoms of schizophrenia generally appear in three broad categories: positive, negative, and cognitive symptoms. Positive symptoms are those indicating an "excess" of normal experience, such as hallucinations and delusions. Negative symptoms involve a lack of normal experience, such as anhedonia and a lack of social interaction. Cognitive symptoms relate to cognitive decline in schizophrenia, such as a sustained lack of attention and deficits in decision-making.

[0359] In some forms, neurological or psychiatric disorders or conditions are anxiety disorders. Anxiety disorders are characterized by fear, worry, and anxiety, which are generally generalized and distracting, such as an overreaction to a situation. Anxiety disorders differ in the types of situations or objects that trigger fear, anxiety, or avoidance behaviors, as well as in the associated cognitive concepts. Anxiety and fear differ in that anxiety is an emotional response to a perceived future threat, whereas fear is associated with a perceived or actual direct threat. Additionally, they differ in the content of the associated thoughts or beliefs. Examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attack specifier, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, anxiety disorders due to other medical conditions, and non-specific anxiety disorders; and stressor-related disorders including reactive attachment disorder, disinhibited social entry disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and coordination disorder.

[0360] Cognitive decline includes a decrease in cognitive functions or cognitive domains, e.g., working memory, attention and alertness, language learning and memory, visual learning and memory, reasoning and problem-solving (e.g., executive function, processing speed, and / or social cognition). In particular, cognitive decline may include attention deficit, disorganized thinking, slow thinking, difficulty understanding, lack of concentration, impaired problem-solving ability, memory loss, difficulty expressing thoughts and / or difficulty integrating thoughts, emotions, and behaviors, or difficulty dispelling meaningless thoughts.

[0361] In some modalities, neurological or psychiatric disorders or conditions involve cognitive deficits (cognitive domains defined by the DSM-5 are complex attention, executive function, learning and memory, language, perceptual-motor, and social cognition). In some modalities, neurological or psychiatric disorders are associated with a deficiency in dopamine signaling. In some modalities, neurological or psychiatric disorders are associated with basal ganglion dysfunction. In some modalities, neurological or psychiatric disorders are associated with dyscoordinating motor activity. In some modalities, neurological or psychiatric disorders are associated with a decline in frontal cortex function.

[0362] In some embodiments, the present invention provides a method for treating one or more symptoms of a neurological and / or psychiatric disease or disorder provided herein. Such disease or disorder is a mood disorder including bipolar I disorder, bipolar II disorder, mania, cyclothymic disorder, substance / drug-induced bipolar disorder and related disorder, bipolar disorder and related disorder due to another medical condition, other specific bipolar disorder and related disorder, and non-specific bipolar disorder and related disorder; Schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophrenic personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychiatric disorder, brief psychiatric disorder, shared psychiatric disorder, psychiatric disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), schizoaffective disorder, agitation, aggression, delirium, catatonia, dissociative identity disorder, paranoid personality disorder, psychotic depression, schizophrenic personality disorder, childhood disintegrative disorder (Heller syndrome), disintegrative psychosis, dissociative amnesia, somatic symptom disorder, Parkinsonian psychosis, peptic psychosis, Tourette syndrome, and psychiatric disorders including organic or NOS psychosis; Depressive disorders including breakdown mood dysregulation disorder, major depressive disorder (MDD) (including major depressive episode), hypothymia, persistent depressive disorder (hypothymia), treatment-resistant depression, premenstrual dysphoric disorder, substance / drug-induced depressive disorder, depressive disorder due to another medical condition, other specific depressive disorders and non-specific depressive disorders; anxiety disorders;and substance abuse or dependence (e.g., nicotine, alcohol, cocaine), addiction, internet gaming disorder, eating disorders, behavioral disorders, seizures, vertigo, epilepsy, agitation, aggression, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesia, Huntington's disease, dementia, premenstrual dysphoria, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), hyperactivity syndrome, autism, autism spectrum disorder, obsessive-compulsive disorder, pain, fibromyalgia, migraine, cognitive decline, movement disorders, restless legs syndrome (RLS), multiple sclerosis, primary progressive multiple sclerosis, Parkinson's disease, Huntington's disease, dyskinesia multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effects of medications, insomnia, sexual dysfunction, hypertension, vomiting, Lesy-Nyhann disease, Wilson's disease, Rett syndrome, and other conditions including Huntington's chorea Disorders include. In some forms, neurological and / or psychiatric disorders include agitation and aggression.

[0363] In some forms, agitation and aggression are associated with Alzheimer's disease, Parkinson's disease, and / or autism.

[0364] In some forms, agitation is associated with psychiatric disorders such as depression and schizophrenia.

[0365] In some modalities, neurological and / or psychiatric disorders or disorders are obsessive-compulsive disorders and related disorders (e.g., body dysmorphic disorder, accumulation disorder, trichotillomania, hair-scratching disorder).

[0366] In some modalities, neurological and / or psychiatric disorders or disorders are disruptive, impulse-controlling, oppositional defiant disorder, intermittent explosive disorder, behavioral disorders, antisocial personality disorder, behavioral disorders including firewalls, kleptomania, and other specific disruptive, impulse-controlling behavioral disorders, and non-specific disruptive, impulse-controlling behavioral disorders.

[0367] Depressive disorders include major depressive disorder and hypothymia, and are associated with a depressed mood (sadness), difficulty concentrating, insomnia, fatigue, appetite disorders, excessive guilt, and suicidal thoughts.

[0368] In some embodiments, the present invention relates to depression (e.g., major depressive disorder or hypothymia); bipolar disorder, seasonal affective disorder; cognitive deficits; sleep-related disorders including sleep disorders caused by mental states (e.g., sleep apnea, insomnia, narcolepsy, cataplexy); chronic fatigue syndrome; anxiety (e.g., generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; postmenopausal vasomotor symptoms (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 oculomotor (atrophic) palsy, pseudoparalytic spinal muscular atrophy diseases (e.g., SMA type I, also known as Werdnig-Hoffmann disease; SMA type II, also known as Kugelberg-Welander disease; and Kennedy disease, also known as progressive spinomedullary muscular atrophy), Hallervorden-Spatz disease, Seitelberger disease (infant axonal degenerative atrophy), adrenoleukodystrophy, Alexander disease, autosomal dominant cerebellar ataxia (ADCA), pure autonomic insufficiency (Bradbury-Eggleston syndrome) The present invention provides a method for treating one or more symptoms including (syndrome), CADASIL syndrome and neuroceroid lipophenophobia disorders, e.g., Batten disease (Spielmeyer-Vogt-Sjoegren); manic disorder; dysthymia; and obesity.

[0369] In some embodiments, depressive disorders are associated with acute suicidal tendencies or suicidal ideation. The U.S. Food and Drug Administration has adopted a “black box” label warning indicating that antidepressants may increase the risk of suicidal thoughts and behaviors in some children, adolescents, and young adults (24 years of age or younger) with depressive disorders, e.g., MDD. In some embodiments, the provided compound does not increase the risk of suicidal thoughts and / or behaviors in children, adolescents, and / or young adults with depressive disorders, e.g., MDD. In some embodiments, the present invention provides a method for treating one or more of the symptoms of a depressive disorder (e.g., MDD) in children, adolescents, and / or young adults without increasing the risk of suicidal thoughts and / or behaviors.

[0370] In some embodiments, the present invention provides a method for treating one or more of the symptoms including senile dementia, early-onset Alzheimer's disease, Alzheimer's-type dementia, cognitive impairment, memory loss, amnesia / amnesia syndrome, impaired consciousness, coma, reduced attention, speech disorder, agnosia, aphasia, apraxia, mild cognitive decline (MCI), benign amnesia, mild neurocognitive disorder, major neurocognitive disorder, neurocognitive disorder due to disease (e.g., Huntington's disease, Parkinson's disease, prion disease, traumatic brain injury, HIV or AIDS), Binswanger's disease (subcortical white brain disease), and Capgras syndrome.

[0371] In some embodiments, the present invention provides a method for treating one or more of the symptoms of pain, e.g., neuropathic pain, neuropathic pain accompanied by sensitization, or inflammatory pain. In some embodiments, the pain is neuropathic pain including post-herpetic neuralgia (or post-herpetic neuralgia), reflex sympathetic degeneration atrophy / burning pain or nerve trauma, ring limb pain, carpal tunnel syndrome, and peripheral neuropathy (e.g., diabetic neuropathy or neuropathy resulting from chronic alcohol use). In some modalities, pain is acute pain, nociceptive pain, arthritis pain, rheumatoid arthritis, osteoarthritis, joint pain, musculoskeletal pain, lower back pain, back pain, herniated disc, hip pain, visceral pain, headache, tension headache, acute tension headache, chronic tension headache, chronic cluster headache, chronic migraine, typical migraine, cluster headache, mixed headache, post-traumatic headache, ocular tension headache, transient short-lasting unilateral neuralgiform (SUNCT) headache, SUNCT syndrome, herpes zoster, acute herpes zoster, herpes zoster, post-herpetic neuralgia (herpes zoster), burning pain, central pain, central pain syndrome, chronic back pain, neuralgia, neuropathic pain syndrome, neuropathy, diabetic neuropathy, diabetes-related neuropathy, diabetes-related nerve pain, fibroitis, chemotherapy-induced peripheral neuropathy, peripheral nerve disease, peripheral neuropathy, nerve pain, nerve trauma, accompanied by sensitization Neuropathic pain, Complex Regional Pain Syndrome, Compression Neuropathy, Craniofacial Pain, Chronic Joint Pain, Chronic Knee Pain, Chronic Pain Syndrome, Cancer Pain, Trigeminal Neuralgia, Painful Tic (tic doloreaux), Reflex Sympathetic Burning Pain, Painful Peripheral Neuropathy, Spinal Nerve Injury, Arachnitis, Spinal Cord Pain, Bernhardt-Roth Syndrome (Femoral Paresthesia), Carpal Tunnel Syndrome, Cerebrospinal Fluid Syndrome, Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathy, Calf Muscle Atrophy, Cluster Tic Syndrome,Coccygeal pain syndrome, compartment syndrome, degenerative disc disease, failed back surgery syndrome, genital-pelvic pain / insertion dysfunction, gout, inflammatory pain, lumbar radiculopathy, neuroma (painful scar), multiple sclerosis-related pain, pelvic floor disorder, ring limb pain, piriformis syndrome, psychogenic pain, slow-twitch muscle pain syndrome, Raeder's syndrome, referred pain, reflex sympathetic atrophy syndrome, sciatica, sciatic pain, scoliosis, disc herniation, body pain, spinal stenosis, stiff-person syndrome / stiff-man syndrome, amputation pain, persistent sympathetic pain, Tolosa-Hunt syndrome, whiplash or Lyme disease-related pain.

[0372] In some embodiments, the present invention provides a method for treating one or more of the symptoms including: obesity; migraine or migraine headache; and sexual dysfunction of a man or woman caused by psychological and / or physiological factors, including, but not limited to, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual arousal, and inability to obtain orgasm; and psychosexual dysfunction and atypical psychosexual dysfunction, including, but not limited to, suppressed libido, suppressed sexual arousal, suppressed female orgasm, suppressed male orgasm, functional dyspareunia, and functional vaginismus.

[0373] In some embodiments, the present invention provides a method for suppressing rapid eye movements (REM) during both sleep and daytime.

[0374] In some embodiments, the present invention provides a method for suppressing or eliminating pathological or excessive REM during both equivalent night and daytime.

[0375] In some embodiments, the present invention provides a method for treating one or more of the following symptoms: cataplexy (sudden, involuntary, transient muscle weakness or paralysis while awake); nocturnal sleep disorder / sleep fragmentation associated with narcolepsy or other pathological conditions; sleep paralysis associated with narcolepsy or other pathological conditions; hypnagogic and hypnagogic hallucinations associated with narcolepsy or other pathological conditions; and excessive daytime sleepiness associated with narcolepsy, sleep apnea or shift work disorder and other medical conditions, e.g., cancer, chronic fatigue syndrome and fibromyalgia.

[0376] In some embodiments, the present invention provides a method for treating one or more symptoms of a movement disorder or disorder, including inability to move, inability-muscle rigidity syndrome, dyskinesia and dystonia. Examples of akinesia and akinesia-muscular rigidity syndromes include Parkinson's disease, drug-induced parkinsonism, post-meningitisal parkinsonism, secondary parkinsonism, Parkinson plus syndrome, atypical parkinsonism, idiopathic parkinsonism, progressive supranuclear palsy, multiple system atrophy, cerebral cortical degeneration, parkinsonism-ALS dementia complex and basal ganglion calcification, drug-induced parkinsonism (e.g., neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute ataxia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, muscle spasms, and disorders associated with muscle rigidity or weakness including tremor. Examples of dyskinesia include drug-induced (e.g., L-DOPA) dyskinesia tremors (e.g., resting tremor, postural tremor, action tremor), chorea (e.g., Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacrocytosis, symptom-associated chorea, drug-induced chorea and hemichorea), myoclonus (including generalized myoclonus and focal myoclonus), and tics (including simple tics, complex tics and symptom-associated tics). Examples of dystonia include generalized dystonia, idiopathic dystonia, drug-induced dystonia, symptom-related dystonia, paroxysmal dystonia, focal dystonia, blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writing spasm, and hemiplegic dystonia.Other examples of movement disorders or conditions include stereotyped movement disorders, persistent (chronic) movement disorders, drug-induced movement disorders, psychogenic movement disorders, substance / drug-induced movement disorders, extrapyramidal movement disorders, hyperkinetic disorder, hypokinetic disorder, alternating hemiplegia, Angelman syndrome, Hallervorden-Spats disease, ataxia, dentate-cerebellar ataxia, ataxic telangiectasia (Louis-Bar syndrome), Friedreich's ataxia, hereditary spinal cord ataxia, hereditary spinal sclerosis, Machado-Joseph disease, spinocerebellar ataxia, progressive myoclonus, ataxia, chorea, blepharospasm (eye spasm), cerebral palsy, tardive dystonia, tardive dyskinesia, idiopathic torticollis, torticollis It includes dystonia, focal dystonia, idiopathic familial dystonia, idiopathic nonfamilial dystonia, cervical dystonia (spasmodic torticollis), primary dystonia, Bell's finger dystonia, developmental coordination disorder, medullary spinal muscular atrophy (Kennedy's disease), Shy-Drager syndrome, and Stiff-person (Stiff-Man) syndrome.

[0377] In some embodiments, the present invention relates to celiac epilepsy, absence seizures, acquired epilepsy, acquired epileptic aphasia, Aicardi syndrome, Alpers' disease, Alpers-Huttenlocher syndrome, Angelman syndrome, benign focal epilepsy, childhood benign focal epilepsy, benign intracranial hypertension, benign Roland epilepsy (BRE), CDKL5 disorder, childhood absence epilepsy, dentate cerebellar ataxia, Doose syndrome, Dravet syndrome, cognitively impaired focal seizures, epilepsy with grand mal seizures, epilepsy with myoclonic-absence, epileptic hemiparesis, febrile seizures, focal seizures, frontal lobe epilepsy, generalized tonic-clonic seizures, hereditary epilepsy, Glut1 deficiency syndrome, hypothalamic hamartoma, idiopathic epilepsy, idiopathic generalized epilepsy, idiopathic localization-related Epilepsy, idiopathic partial epilepsy, idiopathic seizures, pediatric absence epilepsy, pediatric myoclonic epilepsy, Lafora disease, Lafora progressive myoclonic epilepsy, Landau-Kleffner syndrome, Lassueur-Graham-Little syndrome, Lennox syndrome, Lennox-Gastaut syndrome, medically refractory epilepsy, pan-temporal lobe sclerosis, myoclonic seizures, neonatal epilepsy, occipital lobe epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, parietal lobe epilepsy, PCDH19 epilepsy, photosensitive epilepsy, progressive myoclonic epilepsy, Rasmussen's encephalitis, Rasmussen syndrome, refractory Epilepsy, seizure disorder, status epilepticus, Sturge-Weber syndrome, symptom-related generalized epilepsy, symptom-related partial epilepsy, TBCK-related ID syndrome,Provides a method for treating one or more of the symptoms of epilepsy and / or seizures, including temporal lobe epilepsy, temporal lobe seizures, tonic-clonic seizures, West syndrome, tremor, cerebellar tremor, cerebellar outflow tremor, action tremor, essential tremor, benign essential tremor, Parkinsonian tremor, and drug-induced postural tremor.

[0378] Pharmaceutical composition

[0379] According to one embodiment, the present invention provides a composition comprising compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound 1 in the composition of the present invention is an amount effective for treating, preventing, and / or managing various neurological and / or psychiatric disorders, disorders, and / or symptoms in a subject. In some embodiments, the composition of the present invention is formulated for administration to a subject who requires such composition. In some embodiments, the composition of the present invention is formulated for oral administration to a subject.

[0380] The term “subject” as used herein, for which administration is being considered, 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, or elderly adults) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals including commercially related mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds including commercially related birds such as chickens, ducks, geese, quail and / or turkeys.

[0381] In certain embodiments, the present invention provides a composition (e.g., a pharmaceutical composition) comprising compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) and a pharmaceutically acceptable excipient or carrier. In some embodiments, the present invention provides a method for treating a neurological or psychiatric disorder in a subject requiring treatment for a neurological or psychiatric disorder, comprising administering an effective amount of compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) or the pharmaceutical composition described herein. Examples of carriers and excipients are widely known to those skilled in the art, for example [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: Lippincott, Williams & Wilkins, 2000; [and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005] is described in detail. The formulations of the present invention may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, lubricants, processing aids, coloring agents, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide excellent presentation of a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to assist in the preparation of a pharmaceutical product (i.e., a medicine).

[0382] The compositions of the present invention may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, sublingually, vaginally, or via an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intravertebral, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions of the present invention are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oil-based suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally usable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oils are typically used as solvents or suspension media. Pharmaceutically acceptable compositions of the present invention may be administered orally in any orally available dosage form comprising capsules, tablets, aqueous suspensions, or solutions.

[0383] The amount of Compound 1 or its salt (or its crystalline form, hydrate, or solvate) that may be combined with a carrier material to prepare a composition in a single-dose form will vary depending on various factors, including the host being treated and the specific mode of administration. It should be understood that the specific dosage and therapeutic regimen for any specific subject may vary depending on various factors, including the activity of the specific form of Compound 1 used, age, body weight, general health, gender, diet, time of administration, elimination rate, concomitant medications, the judgment of the treating physician, and the severity of the specific disease being treated.

[0384] Combination therapy

[0385] In some embodiments, the present invention provides a method for treating neurological and / or psychiatric diseases or disorders described herein, comprising administering a compound of the present invention together with one or more pharmaceutical preparations. Suitable pharmaceutical preparations that may be used in combination with compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) include anti-Parkinson's drugs, anti-Alzheimer's drugs, antidepressants, antipsychotics, anti-ischemic agents, CNS depressants, anticholinergics, antipsychotics, epilepsy drugs, attention (e.g., ADD / ADHD) drugs, sleep-promoting drugs, wakefulness-promoting drugs, and pain drugs. In some embodiments, suitable pharmaceutical preparations are anxiolytics.

[0386] Suitable anti-Parkinson's drugs include dopamine replacement therapies (e.g., L-DOPA, carbidopa, COMT inhibitors, e.g., entacapone or tolcapone), dopamine agonists (e.g., D1 agonists, D2 agonists, mixed D1 / D2 agonists, bromocriptine, pergolide, cabergoline, ropinirol, pramipexole, pyrivedil, or apomorphine in combination with domeridone), histamine H2 antagonists, monoamine oxidase inhibitors (e.g., selegiline, rasagiline, safinamide, and tranylcypromine), certain atypical antipsychotics, e.g., pimavanserin (a non-dopaminergic atypical antipsychotic and a antagonist of the serotonin 5-HT2A receptor) and amantadine.

[0387] In some embodiments, compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) may be used in combination with levodopa (a selective extracerebral decarboxylase inhibitor, e.g., carbidopa or benserazide), anticholinergics, e.g., biperiden (optional hydrochloride or lactate salt thereof) and trihexyphenidyl (benzhexyl) hydrochloride, COMT inhibitors, e.g., entacapone or tolcapone, MAO A / B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergics, MDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists, e.g., alentemol, bromocriptine, phenoldopam, risulide, naxagolide, pergolide, and pramipexol. It will be understood that dopamine agonists may be in pharmaceutically acceptable salt forms, e.g., alentemol hydrobromide, bromocriptine mesylate, phenoldopham mesylate, naxagolide hydrochloride, and pergolide mesylate. Risulide and pramipexole are generally used in non-salt forms.

[0388] Suitable anti-Alzheimer's drugs include beta-secretase inhibitors, gamma-secretase inhibitors, cholinesterase inhibitors, e.g., donepazil, galantamine, or rivastigmine, HMG-CoA reductase inhibitors, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In some embodiments, the anti-Alzheimer's drug is memantine.

[0389] Suitable antidepressants and anxiolytics include norepinephrine reuptake inhibitors (including tertiary amine tricyclic and secondary amine tricyclic), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI), inverse monoamine oxidase inhibitors (RIMA), serotonin and noradrenaline reuptake inhibitors (SNRI), corticotropin-releasing factor (CRF) antagonists, α-adreno receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, in particular 5-HT1A partial agonists and corticotropin-releasing factor (CRF) antagonists.

[0390] Specific suitable antidepressants and anxiolytics are amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertaline; isocarboxazide, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine; desvenlafaxine, duloxetine; aprepitant; bupropion, vilazodone, mirtazapine, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazefate, diazepam, harazepam, lorazepam, oxazepam, and prazepam; Includes buspirone, plesinoxane, zepyron and sappyron, lovexetine, bortioxetine, chlorazefate and ketamine, and pharmaceutically acceptable salts thereof. In some embodiments, suitable antidepressants and anxiolytics are tianeptine or pharmaceutically acceptable salts thereof.

[0391] Suitable antipsychotics and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, and anticonvulsants.

[0392] Specific suitable antipsychotics and mood stabilizers include chlorpromazine, fluphenazine, haloperidol, amisulpride, perphenazine, thioridazine, trifluoperazine, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, brexpiprazole, paliperidone, cariprazine, pimavanserin, iloperidone, lumateperon, MIN-101, quetiapine, risperidone, ziprasidone, lurasidone, flupentixol, levomepromazine, periciazine, perphenazine, pimozide, prochlorperazine, zuclopentixol, olanzapine, and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid, iloperidone, thiothixene, gabapentin, thiagabine, and pharmaceutically acceptable salts thereof.

[0393] Suitable antiepileptic drugs include levetiracetam, oxcarbazepine, clobazam, retigabine, zonisamide, felbamate, esclicarbazepine acetate, lacosamide, carbamazepine, thiagabine, metsuccinamide, progabide, valproic acid, lamotrigine, brivaracetam, rufinamide, topiramate, and perampanel.

[0394] Suitable cautionary drugs include methylphenidate, atomoxetine, guanfacine, D-amphetamine, lisdexamphetamine, methylamphetamine, and clonidine.

[0395] Suitable sleep-promoting drugs include ramelteon, triazolam, zopiclone, eszopiclone, zolpidem, temazepam, and trazodone.

[0396] Suitable stimulant drugs include modafinil, D-amphetamine, caffeine, and armodafinil.

[0397] Suitable pain medications include dextromethorphan, tapentadol, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine, naloxegol, oxycodone, tramadol, gabapentyl, difluprednate, pregabalin, acetylsalicylic acid, bromafenac, diclofenac, diflunisal, indomethacin, ketorolac, meoxycan, and naproxen.

[0398] In some embodiments, the compounds and compositions of the present invention may be used in combination with other therapies. Suitable therapies include psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, and cardiac stimulation.

[0399] The exact amount required will vary for each subject depending on the subject's species, age and general condition, severity of the condition, specific formulation, and method of administration. The compounds and compositions of the present invention are preferably formulated in dosing unit forms for ease of administration and uniformity of dosage. As used herein, the term "dosing unit form" refers to a physically distinct unit formulation suitable for the subject being treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment.

[0400] The pharmaceutically acceptable compositions of the present invention may be administered to humans or other animals orally, rectally, parenterally, intracolonically, vaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally, or sublingually, depending on the severity of the infection being treated, or as oral or nasal sprays, etc. In some embodiments, compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) may be administered orally or parenterally at least once a day at a dosage level of about 0.01 to about 50 mg / kg subject body weight per day, preferably about 1 to about 25 mg / kg subject body weight per day, to obtain the desired therapeutic effect.

[0401] In some embodiments, a combination of two or more therapeutic agents may be administered together with compound 1 or its salt (or its crystalline form, hydrate, or solvate). In some embodiments, a combination of three or more therapeutic agents may be administered together with compound 1 or its salt (or its crystalline form, hydrate, or solvate).

[0402] Other examples of formulations in which the compounds and compositions of the present invention may be used in combination include: vitamins and nutritional supplements; antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, K1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergics); multiple sclerosis (MS) treatments, e.g., beta interferons (e.g., Avonex® and Rebif®, dalfampridine, alemtuzumab), Copaxone® and mitoxatron; Huntington's disease treatments, e.g., tetrabenazine; asthma treatments, e.g., albuterol and Singulair®; anti-inflammatory agents, e.g., corticosteroids, TF blockers, IL-1RAs, azathioprine and sulfasalazine; Immunomodulators and immunosuppressants, e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole; cardiovascular disease treatments, e.g., beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins, fibrates, cholesterol resorption inhibitors, bile acid sequestrants, and niacin; liver disease treatments, e.g., corticosteroids, cholestyramine, interferon, and antivirals; blood disorder treatments, e.g., corticosteroids, anti-leukemic agents, and growth factors; immunodeficiency disorder treatments, e.g., gamma globulin;Antidiabetic agents, e.g., viagulinides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetohexaamide, tollazamide, chlorpropamide, glipizide, gliburide, glimepiride, gliclazide), meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbocese), incretin analogs (exanatide, liraglutide, taspoglutide), gastric suppression peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide), and insulin and insulin analogs.;

[0403] In some embodiments, compound 1 or its salt (or its crystalline form, hydrate, or solvate) is administered in combination with an antisense agent, a monoclonal or polyclonal antibody, or a siRNA therapeutic agent.

[0404] The additional agent mentioned above may be administered separately from the compound-containing composition of the present invention as part of a multiple-dose regimen. Alternatively, the agent may be part of a single-dose form mixed with the compound of the present invention as a single composition. When administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or from each other within a certain period of time, typically within 5 hours from each other.

[0405] As used herein, the terms “concurrent,” “concurrently used,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, Compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate) may be administered simultaneously or sequentially with another therapeutic agent in an individual unit dosage form, or may be administered together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising Compound 1 or a salt thereof (or its crystalline form, hydrate, or solvate), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0406] The amounts of both the compound of the present invention and the additional therapeutic agent (including the additional therapeutic agent as described above in the composition) that can be combined with a carrier material to produce a single-dose form will vary depending on the host being treated and the specific method of administration. Preferably, the composition of the present invention should be formulated so that a dose of 0.01 to 100 mg / kg body weight / day of the present invention can be administered.

[0407] In a composition comprising an additional therapeutic agent, said additional therapeutic agent and compound 1 or its salt (or its crystalline form, hydrate, or solvate) may act synergistically. Accordingly, the amount of the additional therapeutic agent in such a composition will be less than the amount required in a single therapy using only said therapeutic agent. In such a composition, an additional therapeutic agent may be administered in a dosage of 0.01 to 100 mg / kg body weight / day.

[0408] The amount of additional therapeutic agent present in the composition of the present invention will not exceed the amount typically administered in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition of the present invention will be in the range of about 50 to 100% of the amount typically present in a composition containing said formulation as the sole therapeutic active agent.

[0409] In some embodiments, the present invention provides a medicine comprising compound 1 or a salt thereof (or its crystalline form, hydrate or solvate) and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0410] 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 medicines for treating neurological and / or psychiatric diseases or disorders.

[0411] Examples

[0412] Example 1: Preparation of a salt of Compound 1

[0413] The free base (500 mg) of Compound 1 was dissolved in MeOH (34 mL). The solution was divided into 33 vials (resulting in Compound 1 on a 15 mg scale). An appropriate counterion (0.95 equivalents) was added to each vial and dissolved in the screening solvents listed in Table 1. The solution was heated at 60°C for 1 hour and then cooled undisturbed to room temperature. Each vial was opened and left to stand at room temperature (slow evaporation). In several cases, acetone or EtOAc additives were added to the vials and left to stand at room temperature for slow evaporation. The results of the solvent screening are shown in Table 1 below. Additionally, specific experiments were performed on a larger scale as shown in Table 1.

[0414]

[0415]

[0416]

[0417] Example 2. Synthesis of free bases

[0418] Saturated sodium bicarbonate solution (15 ml) and water (5 ml) were added to the hydrochloride (600 mg) of Compound 1. The solution was extracted with chloroform (15 ml, three times). The organic extract was washed with brine (20 ml) and evaporated. The free base of Compound 1 was isolated as oil (about 500 mg).

[0419] Example 3. Hydrochloride form of Compound 1, HA

[0420] The XRPD spectrum for the hydrochloride HA of compound 1 is provided in Fig. 1, and the corresponding peak data is provided in Table 2 below.

[0421]

[0422]

[0423] The DSC thermogram for form HA is shown in Fig. 2. The thermogram features endothermic peaks at temperatures of approximately 99°C and approximately 187°C. Fig. 3 shows the thermogravimetric analysis (TGA) thermogram of form HA. Fig. 4 shows the dynamic vapor adsorption (DVS) isotherm of form HA.

[0424] Example 4. Hydrochloride form of Compound 1 HB

[0425] The XRPD spectrum for the hydrochloride HB of compound 1 is provided in FIG. 5, and the corresponding peak data is provided in Table 3 below.

[0426]

[0427] Figure 6 shows the dynamic vapor adsorption (DVS) isotherm of the HB type.

[0428] Example 5. Phosphate of Compound 1

[0429] The XRPD spectrum for the phosphate of compound 1 is provided in FIG. 7, and the corresponding peak data is provided in Table 4 below.

[0430]

[0431]

[0432] A DSC thermogram for the phosphate of Compound 1 is shown in Fig. 8. The thermogram is characterized by an endothermic peak at a temperature of approximately 213°C. Fig. 9 shows a thermogravimetric analysis (TGA) thermogram of the phosphate of Compound 1. Fig. 10 shows the dynamic vapor adsorption (DVS) isotherm of the phosphate of Compound 1.

[0433] Example 6. L-Tartrate form of Compound 1 LA

[0434] The XRPD spectrum for the LA form of compound 1 is provided in Fig. 11, and the corresponding peak data is provided in Table 5 below.

[0435]

[0436]

[0437] The DSC thermogram for form LA is shown in Fig. 12. The thermogram is characterized by endothermic peaks at temperatures of approximately 89°C and approximately 138°C. Fig. 13 shows the thermogravimetric analysis (TGA) thermogram of the L-tartrate form LA of Compound 1. Fig. 14 shows the dynamic vapor adsorption (DVS) isotherm of form LA.

[0438] Example 7. L-Tartrate Form of Compound 1 LB

[0439] The XRPD spectrum for the L-tartrate form LB of compound 1 is provided in FIG. 15, and the corresponding peak data is provided in Table 6 below.

[0440]

[0441]

[0442] Figure 16 shows the dynamic vapor adsorption (DVS) isotherm of the LB type.

[0443] Example 8. L-tartrate form of Compound 1 LC

[0444] The XRPD spectrum for the L-tartrate form LC of compound 1 is provided in FIG. 17, and the corresponding peak data is provided in Table 7 below.

[0445]

[0446]

[0447] The DSC thermogram for the LC form is shown in Fig. 18. The thermogram is characterized by an endothermic peak at a temperature of approximately 137°C. Fig. 19 shows the thermogravimetric analysis (TGA) thermogram of the L-tartrate LC form of Compound 1. Fig. 20 shows the dynamic vapor adsorption (DVS) isotherm of the LC form.

[0448] Example 9. D-tartrate of Compound 1

[0449] The XRPD spectrum for the D-tartrate of compound 1 is provided in FIG. 22, and the corresponding peak data is provided in Table 8 below.

[0450]

[0451] A DSC thermogram for the D-tartrate of Compound 1 is shown in FIG. 23. The thermogram is characterized by endothermic peaks at temperatures of approximately 76°C and approximately 153°C. FIG. 23 shows a thermogravimetric analysis (TGA) thermogram of the D-tartrate of Compound 1. FIG. 24 shows the dynamic vapor adsorption (DVS) isotherm of the D-tartrate of Compound 1.

[0452] Example 10. Fumarate form of Compound 1 FA

[0453] The XRPD spectrum for the fumarate FA of compound 1 is provided in FIG. 25, and the corresponding peak data is provided in Table 9 below.

[0454]

[0455]

[0456] The DSC thermogram for the FA form is shown in Fig. 26. The thermogram is characterized by an endothermic peak at a temperature of approximately 147°C. Fig. 27 shows the thermogravimetric analysis (TGA) thermogram of the FA in the fumarate form of Compound 1. Fig. 28 shows the dynamic vapor adsorption (DVS) isotherm of the FA form.

[0457] Example 11. Fumarate form of Compound 1 FB

[0458] The XRPD spectrum for the fumarate FB of compound 1 is provided in FIG. 29, and the corresponding peak data is provided in Table 10 below.

[0459]

[0460]

[0461] A DSC thermogram for the form FB is shown in FIG. 30. The thermogram is characterized by endothermic peaks at temperatures of approximately 96°C, approximately 139°C, and approximately 146°C. FIG. 31 shows a thermogravimetric analysis (TGA) thermogram of the fumarate form FB of Compound 1. FIG. 32 shows the dynamic vapor adsorption (DVS) isotherm of the form FB.

[0462] Example 12. Citrate of Compound 1

[0463] The XRPD spectrum for the citrate of compound 1 is provided in FIG. 33, and the corresponding peak data is provided in Table 11 below.

[0464]

[0465]

[0466] A DSC thermogram for the citrate of Compound 1 is shown in Fig. 34. The thermogram is characterized by an endothermic peak at a temperature of approximately 142°C. Fig. 35 shows a thermogravimetric analysis (TGA) thermogram of the citrate of Compound 1. Fig. 36 shows the dynamic vapor adsorption (DVS) isotherm of the citrate of Compound 1.

[0467] Example 13. Succinate of Compound 1

[0468] The XRPD spectrum for the succinate of compound 1 is provided in FIG. 37, and the corresponding peak data is provided in Table 12 below.

[0469]

[0470]

[0471] A DSC thermogram for the succinate of Compound 1 is shown in Fig. 38. The thermogram is characterized by an endothermic peak at a temperature of approximately 153°C. Fig. 39 shows a thermogravimetric analysis (TGA) thermogram of the succinate of Compound 1. Fig. 40 shows the dynamic vapor adsorption (DVS) isotherm of the succinate of Compound 1.

[0472] Example 14. Glutarate of Compound 1

[0473] The XRPD spectrum for the glutarate of compound 1 is provided in FIG. 41, and the corresponding peak data is provided in Table 13 below.

[0474]

[0475]

[0476] 42 shows the dynamic vapor adsorption (DVS) isotherm of glutarate of compound 1.

[0477] Example 15. L-maleate of Compound 1

[0478] The XRPD spectrum for the L-maleate of compound 1 is provided in FIG. 43, and the corresponding peak data is provided in Table 14 below.

[0479]

[0480]

[0481] A DSC thermogram for the L-maleate of Compound 1 is shown in Fig. 44. The thermogram is characterized by an endothermic peak at a temperature of approximately 82°C. Fig. 45 shows a thermogravimetric analysis (TGA) thermogram of the L-maleate of Compound 1. Fig. 46 shows the dynamic vapor adsorption (DVS) isotherm of the L-maleate of Compound 1.

[0482] Example 16. Besylate of Compound 1

[0483] The XRPD spectrum for the besylate of compound 1 is provided in FIG. 47, and the corresponding peak data is provided in Table 15 below.

[0484]

[0485] A DSC thermogram for the besylate of Compound 1 is shown in Fig. 48. The thermogram is characterized by an endothermic peak at a temperature of approximately 136°C. Fig. 49 shows a thermogravimetric analysis (TGA) thermogram of the besylate of Compound 1. Fig. 50 shows the dynamic vapor adsorption (DVS) isotherm of the besylate of Compound 1.

[0486] Example 17. Stability Study

[0487] Each sample was stored at 60°C and 60°C at 75% RH for one month. Each sample was measured by HPLC at 20 days and one month. The HPLC conditions are described below.

[0488] column: Waters XSelect CSH C18, 4.6x150mm, 3.5μm

[0489] MPA: 50mM HClO4 in water (pH = 3)

[0490] MPB: MeOH / acetonitrile (9:1)

[0491] wavelength: 215nm

[0492] Column temperature: 40℃

[0493] Flow velocity: 1 mL / min

[0494] gradient:

[0495] 0 minutes 10% MPB

[0496] 12 minutes 24% MPB

[0497] 20 minutes 90% MPB

[0498] 20 minutes 90% MPB

[0499] 21 minutes 10% MPB

[0500] 31 minutes 10% MPB

[0501] The results of the stability are shown in Table 16 below.

[0502]

[0503] The free base (amorphous) of Compound 1 was unstable at 60°C and 75% RH. Other salts (hydrochloride, phosphate, L-tartrate, fumarate, citrate) were stable.

[0504] Example 18. Phosphate polymorph screen

[0505] The phosphate of Compound 1 was subjected to three forms of polymorph screening: solvent screening, slurry screening, and rapid cooling screening. Each screening procedure is provided below.

[0506] Solvent screening : 5 mg of the phosphate of Compound 1 was placed in a small glass vial, and solvent was added until the sample dissolved at 90°C or the boiling point. The maximum volume of solvent was 500 μL. The solution or suspension was heated for 1 hour, cooled undisturbed at room temperature overnight, and cooled at 5°C for 3 days. The non-precipitated sample was opened and left to stand at room temperature until dry (slow evaporation). The precipitated solid was filtered through a sintered filter plate and measured directly on the plate by XRPD.

[0507] Slurry screening : 10 mg of the phosphate of Compound 1 was placed in a small glass vial, and an organic solvent mixed with water was added. The sample was then suspended at room temperature or 50°C and shaken for 4 to 10 days. The suspension was filtered. The collected solid was analyzed by XRPD to determine the polymorphic form.

[0508] Rapid cooling screening : 10 mg of the phosphate of Compound 1 was dissolved at 90°C or the boiling point. The solution was rapidly cooled to 0°C. After 1 hour, the solution was cooled to -20°C for 3 days. The precipitated crystals were filtered. The recovered solid was analyzed by XRPD to determine the polymorphic form.

[0509] From screening studies (more than 75 attempts), only one polymorph (phosphate of Compound 1 described in Example 5) was identified.

[0510] Example 19. Synthesis of Compound 1 and the Phosphate of Compound 1

[0511] Step 1. Preparation of 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethaneamine trifluoromethanesulfonate.

[0512]

[0513] A solution of 2-(2-bromo-5-fluorophenyl)ethanol-1-ol (200 g, 913 mmol) and N-methylaminoacetaldehyde dimethylacetal (130 g, 1,091 mmol) in dichloromethane (300 mL) was cooled to 0°C, and while maintaining the temperature below 35°C by external cooling, trifluoromethanesulfonic acid (554 g, 3,691 mmol) was added over 1 hour. The mixture was heated to 30°C and stirred at 30°C for 23 hours. The mixture was cooled to 20°C, and methanol (33 mL), dichloromethane (1,275 mL), and tert-butylmethyl ether (1,358 mL) were added. The precipitate was collected by suction filtration. The solid was washed with a solution (1,830 mL) consisting of 1:1 (v / v) dichloromethane and tert-butyl methyl ether and dried under vacuum (>28" Hg) at 45°C for 21 hours to obtain 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethaneamine trifluoromethanesulfonate as a yellowish-brown powder (339 g, 87% yield). MS (ESI): m / z 274, 276 [M + H] + ; 1 H-NMR (400 MHz, DMSO-d6): [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); 13C-NMR (100 MHz, DMSO-d6): [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.

[0514] Step 2. Preparation of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamin(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate.

[0515]

[0516] 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethaneamine trifluoromethanesulfonate (300 g, 707 mmol), 10 wt% palladium on activated carbon (dry basis), 50% water (1.2 g), methanol (1,006 mL), and 5 wt% aqueous potassium carbonate (1,059 g) were hydrogenated for 1 hour at 25°C and a hydrogen pressure of 5 bar. After releasing the pressure, the solution was filtered through a 5-micron disposable polypropylene in-line filter cartridge and washed with a solution consisting of 1:1 (v / v) methanol and water (540 g). The solution was concentrated to a final volume of 1,200 mL under reduced pressure. Tert-butyl methyl ether (893 mL) and 20 wt% aqueous potassium hydroxide (185 mL) were added to the mixture. 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-butylmethyl ether (649 mL). The combined organic layer was concentrated under reduced pressure to a final volume of 450 mL. SDA (Special Denatured Alcohol) 3A ethanol (851 mL) was added to the solution. The solution was concentrated under reduced pressure to a final volume of 675 mL. The solution (Solution A) was set aside for further processing. Dibenzoyl-L-tartaric acid (252 g, 703 mmol), SDA 3A ethanol (2,704 mL), and deionized water (69 mL) were added to a separate container. The mixture was heated to approximately 70°C, Solution A was added over 9 minutes, and precipitation occurred. The mixture was stirred at approximately 70°C for 45 minutes, then cooled to 20°C over approximately 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 for 17 hours under vacuum (>28" Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneaminum(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (181 g, 46% yield) as a white solid.

[0517] Other dividing agents other than dibenzoyl-L-tartaric acid have been investigated, but most have been found to be unsuitable or impractical for various reasons (e.g., availability, cost, performance). These dividing agents include (R)-mandelic acid, L-tartaric acid, and L-malic acid. However, N-acetyl-D-leucine has been found to provide the desired (R)-isomer in a ratio of about 91:9 and a yield of about 17%.

[0518] The optical purity of the intermediate (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamin(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate was enriched to 96.4% by performing a subsequent recrystallization procedure.

[0519] Methanol (3,578 mL) was added to (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamin(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (177 g, 320 mmol), and the solution was concentrated to a final volume of 1,326 mL at atmospheric pressure, which was then crystallized. The temperature of the slurry was adjusted to approximately 62°C and stirred continuously 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 overnight at 45°C under vacuum (>28" Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamin(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (136 g, 77% yield) as a white solid. MS (ESI): m / z 196 [M + H] + ; 1H-NMR (400 MHz, DMSO-d6): [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 C-NMR (100 MHz, DMSO-d6): [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.

[0520] Step 3. Preparation of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate.

[0521]

[0522] A solution consisting of 14 wt% aqueous potassium hydroxide (120 mL) and sodium chloride (15 g) was added to a mixture of compound (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamin(2R,3R)-2,3-bis(benzoyloxy)-3-carboxypropanoate (75 g, 135.5 mmol) and tert-butylmethyl ether (223 mL). The mixture was stirred at 23 to 25°C for 10 minutes. Stirring was stopped, and the phases were separated. The aqueous phase was extracted with tert-butylmethyl ether (2 x 78 mL). The combined organic layer was concentrated to a final volume of 90 mL under reduced pressure. The solution was cooled to approximately 48°C, and acetonitrile (288 mL) was added. The solution was concentrated to a final volume of approximately 210 mL at atmospheric pressure. The mixture was cooled to 20°C, and acetonitrile (97 mL) and DI water (23 mL) were added. To this, a solution consisting of 87 wt% aq. H3PO4 (16.9 g) and acetonitrile (81 mL) at 20°C was added. The product precipitated during the addition. The slurry was stirred at 20°C for 3 hours, and the solid was collected by suction filtration. The solid was washed with a solution consisting of acetonitrile (135 mL) and DI water (8 mL) and dried overnight at 55°C under vacuum (>28" Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (36 g, 89% yield) as a white crystalline solid, which is the phosphate of Compound 1 characterized in Example 5. MS (ESI): m / z 196 [M + H] + ; 1H-NMR (400 MHz, D2O): [ppm 7.27 (td, J=7.83, 5.87 Hz, 1 H), 7.03 (d, J=7.25 Hz, 1 H), 6.97 (dd, J=10.37, 8.80 Hz, 1 H), 5.25 (t, J=5.87 Hz, 1 H), 4.04 (dt, J=11.74, 5.87 Hz, 1 H), 3.91 - 3.80 (m, 1 H), 3.47 (d, J=5.87 Hz, 2H); 2.83 (t, J=5.48 Hz, 2H), 2.75 (s, 3H); 13 C-NMR (100 MHz, D2O-d4 with 5% methanol): [ppm 161.09, 158.67, 138.10, 138.07, 130.51, 130.42, 126.19, 126.16, 120.28, 120.13, 114.37, 114.17, 68.33, 62.15, 51.39, 51.34, 34.05, 28.38, 28.35.

[0523] Step 4. Recrystallization of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate using water / acetone

[0524]

[0525] 19.5 g of the (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate product from Step 3 was dissolved in 70 g of water at 20°C, and then 30 g of acetone was added into the process stream to prepare a 16.3 wt% starting solution. The solution was passed through a polish filter to remove all insoluble substances. Subsequently, 600 g of acetone was added to the solution within about 1 hour. During the addition, the product crystallized and was discharged. The slurry was stirred at 20°C for at least 30 minutes, and the solid was collected by suction filtration. The solid was washed with binary solvents acetone (54 g) and DI water (6 g) and dried overnight at 55°C under vacuum (>28" Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate as a white crystalline solid (18.1 g, 93% yield).

[0526] Step 4. Recrystallization of (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate using water / acetonitrile

[0527]

[0528] 35.0 g of the (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate product from Step 3 was dissolved in 70 g of water at 20°C, and then 30 g of acetonitrile was added into the process stream to prepare a 25.9 wt% starting solution. The solution was passed through a polish filter to remove all insoluble substances. Subsequently, 600 g of acetonitrile was added to the solution within approximately 1 hour. During the addition, the product crystallized and was discharged. The slurry was stirred at 20°C for at least 30 minutes, and the solid was collected by suction filtration. The solid was washed with binary solvents acetonitrile (90 g) and DI water (6 g) and dried overnight at 55°C under vacuum (>28" Hg) to obtain (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate as a white crystalline solid (31.2 g, 89% yield).

[0529] Various preferred embodiments [A] to [DY] of the present invention may be described below:

[0530] [Mode A] Hagi Yeom:

[0531] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (phosphate of Compound 1);

[0532] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate (L-tartrate of Compound 1);

[0533] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate (D-tartrate of Compound 1);

[0534] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate (fumarate of compound 1);

[0535] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate (citrate of compound 1);

[0536] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate (succinate of compound 1);

[0537] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate (glutarate of compound 1);

[0538] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-maleate (L-maleate of Compound 1);

[0539] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine besylate (besylate of compound 1) or

[0540] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine tosylate (tosylate of compound 1)

[0541] or their hydrates or solvates.

[0542] [Aspect B] The salt of Aspect [B] or a salt according to another aspect of the present invention, wherein the salt is in a solid form.

[0543] [Aspect C] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (phosphate of Compound 1).

[0544] [Aspect D] A salt of Aspect [C] or a salt according to another aspect of the present invention, wherein the phosphate of Compound 1 is crystalline.

[0545] [Aspect E] The salt of Aspect [D] or a salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 4.6°±0.2°, 9.1°±0.2° and 18.2°±0.2°.

[0546] [Aspect F] The salt of Aspect [D] or a salt according to another aspect of the present invention, wherein the salt has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0547] [Aspect G] The salt of Aspect [D] or a salt according to another aspect of the present invention, wherein the salt has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0548] [Aspect H] The salt of Aspect [D] or a salt according to another aspect of the present invention, wherein the salt has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0549] [Aspect I] A salt of any one of the aspects [D] to [H] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 6.

[0550] [Aspect J] A salt according to any one of Aspects [D] to [I] or another aspect of the present invention, wherein the salt has an endothermic peak at a temperature of about 213°C.

[0551] [Aspect K] A salt of any one of the aspects [D] to [J] or a salt according to another aspect of the present invention, wherein the salt has a DSC thermogram as substantially shown in FIG. 7.

[0552] [Aspect L] A salt of any one of the aspects [D] to [K] or a salt according to another aspect of the present invention, wherein the salt has a DVS isotherm as substantially shown in FIG. 9.

[0553] [Aspect M] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate (L-tartrate of Compound 1).

[0554] [Aspect N] A salt of Aspect [M] or a salt according to another aspect of the present invention, wherein the L-tartrate of Compound 1 is crystalline.

[0555] [Aspect O] A salt of the above aspect [N] having a form LA, or a salt according to another aspect of the present invention.

[0556] [Aspect P] A salt of the above aspect [O] or a salt according to another aspect of the present invention, wherein the LA of the above aspect [Aspect P] has a characteristic XRPD peak in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2° and 24.2°±0.2°.

[0557] [Aspect Q] A salt of the aspect [N] or [O] or a salt according to another aspect of the present invention, wherein the form LA has an XRPD pattern having characteristic peaks as shown in FIG. 10.

[0558] [Aspect R] A salt of the above aspect [N] having a form LB, or a salt according to another aspect of the present invention.

[0559] [Aspect S] A salt of the embodiment [R] or a salt according to another aspect of the present invention, wherein the form LB has a characteristic XRPD peak in the 2θ aspect selected from 18.7°±0.2°, 25.0°±0.2° and 31.4°±0.2°.

[0560] [Aspect T] A salt of the aspect [R] or [S] or a salt according to another aspect of the present invention, wherein the form LB has an XRPD pattern having characteristic peaks as shown in FIG. 14.

[0561] [Aspect U] A salt of the above aspect [N] having a form LC, or a salt according to another aspect of the present invention.

[0562] [Aspect V] A salt of Aspect [U] or a salt according to another aspect of the present invention, wherein the LC of the form [Aspect V] has a characteristic XRPD peak in the 2θ aspect selected from 12.2°±0.2°, 16.5°±0.2° and 24.8°±0.2°.

[0563] [Aspect W] A salt of Aspect [U] or [V] or a salt according to another aspect of the present invention, wherein the LC of the form [Aspect W] has an XRPD pattern having characteristic peaks as shown in FIG. 16.

[0564] [Aspect X] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate (D-tartrate of Compound 1).

[0565] [Aspect Y] A salt of Aspect [X] or a salt according to another aspect of the present invention, wherein the D-tartrate of Compound 1 is crystalline.

[0566] [Aspect Z] The salt of Aspect [Y] or a salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 11.9°±0.2°, 16.9°±0.2° and 17.9°±0.2°.

[0567] [Aspect AA] The salt of Aspect [Y] or [Z] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 20.

[0568] [Aspect AB] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate (L-fumarate of Compound 1).

[0569] [Aspect AC] A salt of Aspect [AB] or a salt according to another aspect of the present invention, wherein the fumarate of compound 1 is crystalline.

[0570] [Aspect AD] A salt of the above aspect [AC] having a form FA, or a salt according to another aspect of the present invention.

[0571] [Aspect AE] A salt of the embodiment [AD] or a salt according to another aspect of the present invention, wherein the FA has a characteristic XRPD peak in the 2θ aspect selected from 7.7°±0.2°, 14.2°±0.2° and 15.2°±0.2°.

[0572] [Aspect AF] A salt of the aspect [AD] or [AE] or a salt according to another aspect of the present invention, wherein the form FA has an XRPD pattern having characteristic peaks as shown in FIG. 22.

[0573] [Aspect AG] A salt of the above aspect [AC] having a form FB, or a salt according to another aspect of the present invention.

[0574] [Aspect AH] A salt of the above aspect [AG] or a salt according to another aspect of the present invention, wherein the FB of the above aspect [Aspect AH] has a characteristic XRPD peak in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2° and 20.2°±0.2°.

[0575] [Aspect AI] A salt of the aspect [AG] or [AH] or a salt according to another aspect of the present invention, wherein the form FB substantially has an XRPD pattern having characteristic peaks as shown in FIG. 26.

[0576] [Aspect AJ] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate (citrate of Compound 1).

[0577] [Aspect AK] A salt of Aspect [AJ] or a salt according to another aspect of the present invention, wherein the citrate of compound 1 is crystalline.

[0578] [Aspect AL] The salt of Aspect [AK] or a salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2° and 20.4°±0.2°.

[0579] [Aspect AM] A salt of Aspect [AK] or [AL] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 30.

[0580] [Aspect AN] The salt of Aspect [A] or [B] or a salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate (succinate of Compound 1).

[0581] [Aspect AO] A salt of Aspect [AN] or a salt according to another aspect of the present invention, wherein the succinate of compound 1 is crystalline.

[0582] [Aspect AP] The salt of the above aspect [AO] or the salt according to another aspect of the present invention, wherein the above salt has a characteristic XRPD peak in the 2θ aspect selected from 6.6°±0.2°, 12.8°±0.2° and 13.9°±0.2°.

[0583] [Aspect AQ] The salt of Aspect [AO] or [AP] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 34.

[0584] [Aspect AR] The salt of Aspect [A] or [B] or a salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate (glutarate of Compound 1).

[0585] [Aspect AS] A salt of Aspect [AR] or a salt according to another aspect of the present invention, wherein the glutarate of Compound 1 is crystalline.

[0586] [Aspect AT] The salt of the aspect [AS] or the salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 9.1°±0.2°, 10.6°±0.2° and 18.2°±0.2°.

[0587] [Aspect AU] The salt of the aspect [AS] or [AT] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 38.

[0588] [Aspect AV] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-maleate (L-maleate of Compound 1).

[0589] [Aspect AW] A salt of the above aspect [AV] or a salt according to another aspect of the present invention, wherein the L-maleate of compound 1 is crystalline.

[0590] [Aspect AX] The salt of Aspect [AW] or a salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 13.5°±0.2°, 18.8°±0.2° and 25.2°±0.2°.

[0591] [Aspect AY] The salt of the aspect [AW] or [AX] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 40.

[0592] [Aspect AZ] The salt of Aspect [A] or [B] or the salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine besylate (besylate of Compound 1).

[0593] [Aspect BA] A salt of Aspect [AZ] or a salt according to another aspect of the present invention, wherein the besylate of compound 1 is crystalline.

[0594] [Aspect BB] The salt of the aspect [BA] or a salt according to another aspect of the present invention, wherein the salt has a characteristic XRPD peak in the 2θ aspect selected from 6.0°±0.2°, 12.0°±0.2° and 24.1°±0.2°.

[0595] [Aspect BC] The salt of Aspect [BA] or [BB] or a salt according to another aspect of the present invention, wherein the salt has an XRPD pattern having characteristic peaks as shown in FIG. 44.

[0596] [Aspect BD] The salt of Aspect [A] or a salt according to another aspect of the present invention, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine tosylate (tosylate of Compound 1).

[0597] [Aspect BE] A salt that is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine hydrochloride (hydrochloride of Compound 1) or a salt that is a hydrate or solvate thereof, wherein the salt is crystalline and has a form HA or a form HB.

[0598] [Aspect BF] A salt of the above aspect [BE] having a form HA, or a salt according to another aspect of the present invention.

[0599] [Aspect BG] A salt of the above aspect [BF] or a salt according to another aspect of the present invention, wherein the HA of the above aspect [Aspect BG] has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2° and 15.1°±0.2°.

[0600] [Aspect BH] A salt of the [BF] aspect or a salt according to another aspect of the present invention, wherein the HA of the [Aspect BH] form has a characteristic XRPD peak in the 2θ aspect selected from 9.4°±0.2°, 11.4°±0.2°, 15.1°±0.2°, 17.2°±0.2° and 17.6°±0.2°.

[0601] [Aspect BI] A salt of the [BF] aspect or a salt according to another aspect of the present invention, wherein the HA of the [Aspect BI] form has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0602] [Aspect BJ] A salt of the [BF] aspect or a salt according to another aspect of the present invention, wherein the HA of the [Aspect BJ] form has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0603] [Aspect BK] A salt of the [BF] aspect or a salt according to another aspect of the present invention, wherein the HA of the [Aspect BK] form has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0604] [Aspect BL] A salt of any one of the aspects [BE] to [BK] or a salt according to another aspect of the present invention, wherein the form HA has an XRPD pattern having characteristic peaks as shown in FIG. 1.

[0605] [Aspect BM] A ​​salt of any one of the above aspects [BE] to [BL] or a salt according to another aspect of the present invention, wherein the HA of the form [Aspect BM] has an endothermic peak at temperatures of about 99°C and about 187°C.

[0606] [Aspect BN] A salt of any one of the aspects [BE] to [BM] or a salt according to another aspect of the present invention, wherein the form HA has a DSC thermogram substantially as shown in FIG. 2.

[0607] [Aspect BO] A salt of any one of the aspects [BE] to [BN] or a salt according to another aspect of the present invention, wherein the form HA substantially has a DVS isotherm as shown in FIG. 4.

[0608] [Aspect BP] A salt of the above aspect [BE] having the form HB, or a salt according to another aspect of the present invention.

[0609] [Aspect BQ] A salt of the embodiment [BP] or a salt according to another aspect of the present invention, wherein the HB form has a characteristic XRPD peak in the 2θ aspect selected from 8.6°±0.2°, 9.6°±0.2° and 10.3°±0.2°.

[0610] [Aspect BR] A salt of the embodiment [BP] or a salt according to another aspect of the present invention, wherein the HB of the form [Aspect BR] has a characteristic XRPD peak in the 2θ aspect selected from 8.6°±0.2°, 9.6°±0.2°, 10.3°±0.2° and 17.3°±0.2°.

[0611] [Aspect BS] A salt of the embodiment [BP] or a salt according to another aspect of the present invention, wherein the HB of the form [Aspect BS] has at least one characteristic XRPD peak in the 2θ aspect 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°.

[0612] [Aspect BT] A salt of the embodiment [BP] or a salt according to another aspect of the present invention, wherein the HB of the form [Aspect BT] has at least two characteristic XRPD peaks in the 2θ aspect 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°.

[0613] [Aspect BU] A salt of the embodiment [BP] or a salt according to another aspect of the present invention, wherein the HB of the embodiment [BU] has at least three characteristic XRPD peaks in the 2θ aspect 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°.

[0614] [Aspect BV] A salt of any one of the aspects [BP] to [BU] or a salt according to another aspect of the present invention, wherein the form HB has an XRPD pattern having characteristic peaks as shown in FIG. 5.

[0615] [Aspect BW] A pharmaceutical composition comprising a salt of any one of the above aspects [A] to [BV] or a salt according to another aspect of the present invention and a pharmaceutically acceptable excipient.

[0616] [Aspect BX] A method for treating a neurological or psychiatric disorder or disorder in a subject requiring treatment for such disorder or disorder, comprising administering an effective amount of any one of the above aspects [A] to [BV] or a pharmaceutical composition of the above [Aspect BW] or a salt or composition according to another aspect of the present invention to the subject.

[0617] [Aspect BY] The above neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia or other psychotic disease, obsessive-compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism or cognitive disease or disorder, the method according to the above aspect [BX] or the method according to another aspect of the present invention.

[0618] [Aspect BZ] A method according to the above aspect [BX] or a method according to another aspect of the present invention, wherein the above neurological or psychiatric disease or disorder is depression.

[0619] [Aspect CA] A method according to the aspect [BZ] or a method according to another aspect 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.

[0620] [Aspect CB] A method according to the above aspect [BX] or a method according to another aspect of the present invention, wherein the above neurological disease or disorder is selected from Alzheimer's disease and Parkinson's disease.

[0621] [Aspect CC] The method according to the above aspect [CB] or the method according to another aspect of the present invention, wherein the above Alzheimer's disease is Alzheimer's disease accompanied by agitation, Alzheimer's disease accompanied by aggression, Alzheimer's disease accompanied by agitation, or Alzheimer's disease accompanied by agitation and aggression.

[0622] [Aspect CD] A method for treating agitation in a subject requiring treatment for agitation, comprising administering an effective amount of any one of the above aspects [A] to [BV] or a pharmaceutical composition of the above [Aspect BW] or a salt or pharmaceutical composition according to another aspect of the present invention to the subject.

[0623] [Aspect CE] A method for treating agitation associated with a neurological or psychiatric disorder or disorder in a subject requiring treatment for agitation associated with a neurological or psychiatric disorder or disorder, comprising administering an effective amount of any one of the above-mentioned aspects [A] to [BV] or a pharmaceutical composition of the above-mentioned aspect [Aspect BW] or a salt or pharmaceutical composition according to another aspect of the present invention to the subject.

[0624] [Mode CF] Chemical formula of the following structure:

[0625] Compound 1

[0626] A method comprising the step of reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1) having with phosphoric acid,

[0627] Chemical formula of the following structure:

[0628] Phosphate of Compound 1

[0629] A method for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine phosphate (phosphate of Compound 1) having

[0630] [Aspect CG] The method of the above aspect [CF] or a method according to another aspect of the present invention, wherein the above phosphoric acid is an aqueous phosphoric acid solution.

[0631] [Aspect CH] The method of the above aspect [CF] or a method according to another aspect of the present invention, wherein the above aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 80 to about 95% by weight.

[0632] [Aspect CI] The method of the above aspect [CF] or a method according to another aspect of the present invention, wherein the above aqueous phosphoric acid solution is an aqueous phosphoric acid solution of about 87% by weight.

[0633] [Aspect CJ] A method according to any one of the aspects [CF] to [CI] or another aspect of the present invention, wherein the step of reacting compound 1 with phosphoric acid is performed in the presence of S1a, and said S1a is a solvent.

[0634] [Aspect CK] The method of the above aspect [CJ] or a method according to another aspect of the present invention, wherein S1a is a mixture of acetonitrile and water.

[0635] [Aspect CL] The method of the above aspect [CJ] or a method according to another aspect of the present invention, wherein S1a is a mixture of acetone and water.

[0636] [Aspect CM] The method of the above aspect [CJ] or a method according to another aspect of the present invention, wherein S1a is a polar aprotic solvent, water, or a mixture thereof.

[0637] [Aspect CN] A method according to any one of the above aspects [CF] to [CM] or another aspect of the present invention, wherein about 1 to about 5 molar equivalents of phosphoric acid are used per molar equivalent of compound 1.

[0638] [Mode CO] Compound 1 has the chemical formula of the following structure:

[0639] Dibenzoyl-L-tartrate of Compound 1

[0640] A method according to any one of the embodiments [CF] to [CN] or another embodiment of the present invention, prepared by reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) having [C] with B1, wherein B1 is a base.

[0641] [Mode CP] Chemical formula of the following structure:

[0642] Dibenzoyl-L-tartrate of Compound 1

[0643] A method for preparing (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (compound 1), comprising the step of reacting (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of compound 1) having with B1 (wherein B1 is a base).

[0644] [Aspect CQ] The method of the above-mentioned aspect [CO] or [CP], in which B1 is an alkali hydroxide base, or a method according to another aspect of the present invention.

[0645] [Aspect CR] The method of the above-mentioned aspect [CO] or [CP], in which B1 is potassium hydroxide, or a method according to another aspect of the present invention.

[0646] [Aspect CS] The method of the above-mentioned aspect [CO] or [CP] or a method according to another aspect of the present invention, wherein B1 is an aqueous potassium hydroxide solution.

[0647] [Aspect CT] The method of the above aspect [CS] or a method according to another aspect of the present invention, wherein the above potassium hydroxide aqueous solution is about 10 to about 20% potassium hydroxide aqueous solution by weight.

[0648] [Aspect CU] The method of the above aspect [CS] or a method according to another aspect of the present invention, wherein the above potassium hydroxide aqueous solution is an aqueous potassium hydroxide solution of about 14% by weight.

[0649] [Aspect CV] A method according to any one of the aspects [CO] to [CU] or another aspect of the present invention, wherein the reaction step of the dibenzoyl-L-tartrate of compound 1 and the base is carried out in the presence of S2, and said S2 is a solvent.

[0650] [Aspect CW] The method of the above aspect [CV] or a method according to another aspect of the present invention, wherein S2 is a polar aprotic solvent.

[0651] [Aspect CX] A method according to any one of the above aspects [CO] to [CW] or another aspect 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.

[0652] [Aspect CY] A method according to any one of the aspects [CO] to [CX] or another aspect of the present invention, wherein the reaction step of the dibenzoyl-L-tartrate of compound 1 and B1 is further carried out in the presence of sodium chloride.

[0653] [Aspect CZ] A method according to any one of the above aspects [CO] to [CY] or another aspect 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.

[0654] [Mode DA] Chemical formula of the following structure in the presence of S3 (where S3 is the solvent):

[0655] Racemic compound 1

[0656] A step comprising reacting 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) having with dibenzoyl-L-tartaric acid,

[0657] (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine dibenzoyl-L-tartrate (dibenzoyl-L-tartrate of Compound 1) preparation method.

[0658] [Aspect DB] The method of the above aspect [DA] or a method according to another aspect of the present invention, wherein S3 is a polar protic solvent.

[0659] [Aspect DC] The method of the above aspect [DA] or a method according to another aspect of the present invention, wherein S3 is a mixture of methanol and water.

[0660] [Aspect DD] A method according to any one of the above aspects [DA] to [DC] or another aspect 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.

[0661] [Aspect DE] A method according to any one of the aspects [DA] to [DD] or another aspect of the present invention, further comprising the step of precipitating the dibenzoyl-L-tartrate of compound 1 from a compound comprising racemic compound 1, dibenzoyl-L-tartrate and S3.

[0662] [Aspect DF] A method according to any one of aspects [DA] to [DE] or another aspect of the present invention, further comprising the step of isolating dibenzoyl-L-tartrate of compound 1 from S3a, wherein S3a is a solvent.

[0663] [Aspect DG] The method of the above aspect [DF] or a method according to another aspect of the present invention, wherein S3a is methanol.

[0664] [Mode DH] Chemical formula of the following structure in the presence of a metal catalyst:

[0665] Chemical Formula II

[0666] A method according to any one of embodiments [DA] to [DG] or another embodiment of the present invention, wherein 1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine (racemic compound 1) is prepared by a method comprising the step of hydrogenating a compound of formula II having (where X is a halo) or a salt thereof.

[0667] [Mode DI] A compound of Chemical Formula II has the following chemical formula:

[0668] Compound 2

[0669] A method according to embodiment [DH] or another embodiment of the present invention having 1-(5-bromo-8-fluoroisochroman-1-yl)-N-methylmethaneamine trifluoromethanesulfonate (compound 2).

[0670] [Aspect DJ] The method of aspect [DH] or [DI], or a method according to another aspect of the present invention, wherein the metal catalyst is palladium on activated carbon.

[0671] [Aspect DK] A method according to any one of the aspects [DH] to [DJ] or another aspect of the present invention, wherein the hydrogenation of the compound of Formula II is performed at a hydrogen pressure of about 2 to about 10 bar.

[0672] [Aspect DL] A method according to any one of the aspects [DH] to [DK] or another aspect of the present invention, wherein the hydrogenation of the compound of Formula II is performed at a hydrogen pressure of about 5 bar.

[0673] [Aspect DM] A method according to any one of the aspects [DH] to [DL] or another aspect of the present invention, wherein the hydrogenation of the compound of Formula II is carried out in the presence of S4, and said S4 is a solvent.

[0674] [Aspect DN] The method of the above aspect [DM] or a method according to another aspect of the present invention, wherein S4 is a polar protic solvent.

[0675] [Aspect DO] A method according to any one of the aspects [DH] to [DN] or another aspect of the present invention, wherein the hydrogenation of the compound of Formula II is carried out in the presence of B2, and said B2 is a base.

[0676] [Aspect DP] The method of the above aspect [DO] or a method according to another aspect of the present invention, wherein B2 is a carbonate base.

[0677] [Aspect DQ] The method of the above aspect [DO] or a method according to another aspect of the present invention, wherein B2 is potassium carbonate.

[0678] [Aspect DR] The method of the above aspect [DO] or a method according to another aspect of the present invention, wherein B2 is an aqueous solution of potassium carbonate.

[0679] [Aspect DS] The compound of Formula II above, in the presence of A1 (where A1 is an acid), has the following chemical formula:

[0680] Chemical Formula III

[0681] A compound of formula III having (where X is a halo) or a salt thereof having the following chemical formula:

[0682] Compound 4

[0683] A method according to any one of the above embodiments [DH] to [DR] or another embodiment of the present invention, prepared by reacting with N-methylaminoacetaldehyde dimethylacetal (compound 4).

[0684] [Aspect DT] The compound of Chemical Formula III above has the following chemical formula:

[0685] Compound 3

[0686] The method of the above embodiment [DS] or the method according to another embodiment of the present invention, which is 2-(2-bromo-5-fluorophenyl)ethanol-1-ol (compound 3).

[0687] [Aspect DU] The method of the above-mentioned aspect [DS] or [DT], in which A1 is trifluoromethanesulfonic acid, or a method according to another aspect of the present invention.

[0688] [Aspect DV] A method according to any one of the aspects [DS] to [DU] or another aspect of the present invention, wherein the reaction step of the compound of formula III and compound 4 is carried out in the presence of S5, said S5 is a solvent.

[0689] [Aspect DW] The method of the above aspect [DV] or a method according to another aspect of the present invention, wherein S5 is a halogenated solvent.

[0690] [Aspect DX] A method according to any one of the above aspects [DS] to [DW] or another aspect of the present invention, wherein about 1.2 molar equivalents of compound 4 are used per molar equivalent of the compound of formula III.

[0691] [Aspect DY] A phosphate of Compound 1 prepared by any one of the methods of Aspects [CF] to [CO] or by a method according to another aspect of the present invention, wherein the phosphate of Compound 1 is crystalline.

[0692] Various modifications of the present invention other than those described herein 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 mentioned in the present invention, is incorporated herein by reference in its entirety.

Claims

Claim 1 (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate (L-tartrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine D-tartrate (D-tartrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate (fumarate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate (citrate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine succinate (succinate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine glutarate (of Compound 1 A salt or hydrate or solvate thereof which is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-maleate (L-maleate of Compound 1); (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine besylate (besylate of Compound 1); or (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine tosylate (tosylate of Compound 1). Claim 2 The salt according to claim 1, wherein the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine L-tartrate (L-tartrate of Compound 1). Claim 3 In paragraph 2, the L-tartrate of compound 1 is a salt in solid form and / or crystalline. Claim 4 In paragraph 3, the salt wherein the L-tartrate of compound 1 has form LA, form LB, or form LC. Claim 5 In paragraph 4, (A) form LA is Characteristic XRPD peaks in the 2θ aspect selected from 12.1°±0.2°, 18.1°±0.2°, and 24.2°±0.2°; A substantially XRPD pattern having characteristic peaks as illustrated in FIG. 10; Endothermic peak at temperatures of approximately 89°C and / or approximately 138°C; Substantially, a DSC thermogram as shown in FIG. 11; Substantially, a TGA thermogram as shown in FIG. 12; or In substantial terms, it has a DVS isotherm as illustrated in FIG. 13, or (B) a type LB Characteristic XRPD peaks in the 2θ aspect selected from 18.7°±0.2°, 25.0°±0.2°, and 31.4°±0.2°; A substantially XRPD pattern having characteristic peaks as shown in FIG. 14; or Practically having a DVS isotherm as illustrated in FIG. 15, or (C) type LC Characteristic XRPD peaks in the 2θ aspect selected from 12.2°±0.2°, 16.5°±0.2°, and 24.8°±0.2°; A substantially XRPD pattern having characteristic peaks as shown in FIG. 16; Endothermic peak at a temperature of approximately 137°C; Substantially, a DSC thermogram as shown in FIG. 17; Substantially, a TGA thermogram as shown in FIG. 18; or A salt having a DVS isotherm as substantially shown in FIG.

19. Claim 6 In claim 1, the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine fumarate (fumarate of compound 1). Claim 7 In paragraph 6, the salt, wherein the fumarate of compound 1 is in solid form and / or crystalline. Claim 8 In claim 7, the salt wherein the fumarate of compound 1 has the form FA or the form FB. Claim 9 In paragraph 8, (A) form FA is Characteristic XRPD peaks in the 2θ aspect selected from 7.7°±0.2°, 14.2°±0.2°, and 15.2°±0.2°; A substantially XRPD pattern having characteristic peaks as shown in FIG. 22; Endothermic peak at a temperature of approximately 147°C; Substantially, a DSC thermogram as shown in FIG. 23; Substantially, a TGA thermogram as shown in FIG. 24; or In substantial terms, it has a DVS isotherm as illustrated in FIG. 25, or (B) form FB Characteristic XRPD peaks in the 2θ aspect selected from 6.7°±0.2°, 13.8°±0.2°, and 20.2°±0.2°; A substantially XRPD pattern having characteristic peaks as illustrated in FIG. 26; Endothermic peaks at temperatures of approximately 96°C, approximately 139°C, and / or approximately 146°C; Substantially, a DSC thermogram as shown in FIG. 27; Substantially, a TGA thermogram as shown in FIG. 28; or A salt having a DVS isotherm substantially as shown in FIG. 29 Claim 10 In claim 1, the salt is (R)-1-(8-fluoroisochroman-1-yl)-N-methylmethaneamine citrate (citrate of Compound 1). Claim 11 In paragraph 10, the citrate of the compound 1 is a salt in solid form and / or crystalline. Claim 12 In claim 11, the citrate of the above compound 1, Characteristic XRPD peaks in the 2θ aspect selected from 6.5°±0.2°, 15.5°±0.2°, and 20.4°±0.2°; A substantially XRPD pattern having characteristic peaks as illustrated in FIG. 30; Endothermic peak at a temperature of approximately 142°C; Substantially, a DSC thermogram as shown in FIG. 31; Substantially, a TGA thermogram as shown in FIG. 32; or A salt having a DVS isotherm as substantially illustrated in FIG.

33. Claim 13 A pharmaceutical composition for treating neurological or psychiatric diseases or disorders, comprising a salt described in any one of claims 1 to 12 and a pharmaceutically acceptable excipient. Claim 14 In paragraph 13, the above-mentioned neurological or psychiatric disease or disorder is depression, bipolar disorder, pain, schizophrenia or other psychotic disease, obsessive-compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism or cognitive disease or disorder, pharmaceutical composition. Claim 15 A pharmaceutical composition according to Clause 13, wherein the neurological or psychiatric disease or disorder is depression. Claim 16 A pharmaceutical composition according to claim 15, wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression, or depression associated with another disease or disorder. Claim 17 A pharmaceutical composition according to claim 13, wherein the neurological disease or disorder is selected from Alzheimer's disease and Parkinson's disease. Claim 18 A pharmaceutical composition according to claim 17, wherein the above-mentioned Alzheimer's disease is Alzheimer's disease accompanied by agitation, Alzheimer's disease accompanied by aggression, Alzheimer's disease accompanied by agitation, or Alzheimer's disease accompanied by agitation and aggression. Claim 19 A pharmaceutical composition for treating agitation, comprising a salt described in any one of claims 1 to 12. Claim 20 A pharmaceutical composition comprising a salt described in any one of claims 1 to 12 for treating agitation associated with neurological or psychiatric diseases or disorders.

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