Solid forms of promoter of spinogenesis

Abstract

To provide solid forms of promoter of spinogenesis.SOLUTION: There are provided herein crystalline forms of 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Compound I). There are also provided processes of manufacturing the crystalline forms and methods of using the crystalline forms. The present disclosure provides forms of Compound I and salts, co-crystals, hydrates, and solvates thereof. There are also described herein processes for making the forms of Compound I, pharmaceutical compositions comprising crystalline forms of Compound I and methods for using such forms and pharmaceutical compositions in the treatment of diseases responsive to spinogenesis. In some embodiments, the disease is a neuronal disease.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 799,644, filed January 31, 2019, which is incorporated by reference herein in its entirety.

[0002] The present disclosure generally relates to a crystalline form of the compound 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol, designated herein as Compound I, pharmaceutical compositions thereof, their therapeutic uses, and processes for making said form. [Background technology]

[0003] Neuropathies are diseases of the brain, spinal cord, and peripheral nervous system. In terms of epidemiology and individual morbidity, the greatest social costs are caused by neurodegenerative conditions, which result in damage or loss of neurons and the synaptic connections between them. The most well-known of these are Alzheimer's disease and Parkinson's disease. Other neurodegenerative conditions include age-related conditions (e.g., Parkinson's dementia, vascular dementia, amyotrophic lateral sclerosis), genetic syndromes (e.g., Down's syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic encephalopathy), and conditions that are usually considered purely psychiatric in nature, such as schizophrenia and depression.

[0004] Researchers have classified hundreds of diseases of the nervous system, such as brain tumors, epilepsy, Alzheimer's disease, Parkinson's disease, and stroke, as well as conditions associated with old age, such as dementia. Some such conditions result from the progressive loss of synapses (the junctions between two different neurons) and ultimately the loss of neurons (neurodegeneration). Unfortunately, neurodegenerative diseases are almost completely resistant to treatment. Neurons in the brain communicate with each other by the sending neuron releasing chemicals (neurotransmitters) into the synapse, which changes the electrical potential of the receiving neuron. The part of the neuron that releases the neurotransmitter is the axon (the presynaptic side of the synapse), and the part of the synapse that is affected by the neurotransmitter is called the dendritic spine (the postsynaptic side of the synapse). Changes in the number, location, and even shape of synaptic junctions form the basis of memory, learning, thinking, and our personality. A part of the brain called the hippocampus is intimately involved in the formation of memories and suffers a noticeable loss of synapses and neurons in neurodegenerative diseases. The development of new methods to restore hippocampal spine density may have important implications for the treatment of a host of neurodegenerative and developmental cognitive disorders.

[0005] Thus, small molecules that promote spine formation have potential applications in ameliorating cognitive impairment in neuronal diseases, including neurodegenerative diseases such as Alzheimer's disease. However, there is a need for highly pure, single polymorphic forms of compounds that are effective and exhibit improved pharmacokinetic and / or pharmacodynamic profiles for the treatment of diseases that respond to the promotion of spine formation, including neuronal diseases. Summary of the Invention [Means for solving the problem]

[0006] Compound I exhibits activity in promoting spine formation and is described, for example, in International Publication No. WO2019 / 028164 (February 7, 2019), which is incorporated herein by reference in its entirety. Compound I has the following formula: [ka]

[0007] Compound I can be synthesized according to the methods described herein and in International Publication No. WO2019 / 028164 (February 7, 2019).

[0008] The present disclosure provides forms of Compound I, as well as salts, cocrystals, hydrates, and solvates thereof. Also described herein are processes for making forms of Compound I, pharmaceutical compositions comprising crystalline forms of Compound I, and methods for using such forms and pharmaceutical compositions in treating diseases that respond to spine formation. In some embodiments, the disease is a neuronal disease.

[0009] Thus, one embodiment is crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form I of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks: about 4.6, about 20.8, and about 23.7°2θ±0.2°2θ, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.

[0010] Another embodiment is crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form II of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks: about 9.2, about 13.8, and about 16.1 degrees 2θ±0.2 degrees 2θ, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.

[0011] Another embodiment is crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form III of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks: about 7.7, about 10.3, and about 15.3 degrees 2θ±0.2 degrees 2θ, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.

[0012] Another embodiment is crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form IV of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks: about 5.4, about 22.4, and about 23.3 °2θ±0.2 °2θ, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å.

[0013] Another embodiment is crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form V of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks: about 4.6, about 9.2, and about 23.1 degrees 2θ±0.2 degrees 2θ, as determined with a diffractometer using Cu-Kα radiation at 1.5406 Å.

[0014] Another embodiment is amorphous 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol.

[0015] Some embodiments provided herein relate to crystalline forms of hydrates or co-crystals of Compound I.

[0016] Some embodiments are directed to pharmaceutical compositions comprising a form of Compound I described herein and one or more pharma- ceutically acceptable carriers.

[0017] Another embodiment is directed to the use of a form of Compound I as described herein or a pharmaceutical composition as described herein for promoting spine formation in a patient in need thereof.

[0018] Another embodiment is directed to a method of treating a disease responsive to spine formation in a patient in need thereof, comprising administering a therapeutically effective amount of a form of Compound I described herein or a pharmaceutical composition described herein. In some embodiments, the disease is a neuronal disease. In some embodiments, the disease is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury.

[0019] Another embodiment is directed to a method of treating Alzheimer's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a form of Compound I described herein or a pharmaceutical composition described herein.

[0020] Another embodiment is directed to the use of a form of Compound I as described herein or a pharmaceutical composition as described herein in the treatment of a disease selected from Alzheimer's disease, Parkinson's disease, Parkinson-dementia, autism, fragile X syndrome, and traumatic brain injury. The disease may be Alzheimer's disease.

[0021] Another embodiment is directed to the use of a form of Compound I as described herein or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of a disease selected from Alzheimer's disease, Parkinson's disease, Parkinson-dementia, autism, fragile X syndrome, and traumatic brain injury. The disease may be Alzheimer's disease.

[0022] In some embodiments, a process for preparing Compound I, or a pharma- ceutically acceptable salt thereof, is provided, comprising: [ka] contacting compound A with compound B to form compound I; [ka] This is carried out under first reaction conditions which include a halide.

[0023] In some embodiments, the process for preparing compound I further comprises contacting compound C with compound D to form compound A; [ka] This is carried out under second reaction conditions which include a protic acid.

[0024] In some embodiments, the process for preparing compound I further comprises contacting compound E with p-toluenesulfonyl chloride to form compound B; [ka] This is carried out under third reaction conditions which include a silver salt. [Brief description of the drawings]

[0025] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) of Form I of Compound I. [Diagram 2] 1 shows the differential scanning calorimetry (DSC) curve and thermogravimetric analysis (TGA) of Form I of Compound I. [Diagram 3] 1 shows the X-ray powder diffraction (XRPD) of Form II of Compound I. [Figure 4] 1 shows the X-ray powder diffraction (XRPD) of Form III of Compound I. [Diagram 5] 1 shows the X-ray powder diffraction (XRPD) of Form IV of Compound I. [Figure 6] 1 shows the differential scanning calorimeter (DSC) curve and thermogravimetric analysis (TGA) of Form IV of Compound I. [Figure 7] 1 shows the X-ray powder diffraction (XRPD) of Form V of Compound I. [Figure 8] 1 shows the differential scanning calorimeter (DSC) curve and thermogravimetric analysis (TGA) of Form V of Compound I. [Figure 9] 1 shows the interconversion relationships of crystalline forms of Compound I obtained during polymorph screening. [Figure 10]1 shows the XRPD pattern of the starting material of Compound I. [Figure 11] 1 shows the TGA / DSC curve of the starting material of Compound I. [Figure 12] 1 shows a DVS plot of Compound I starting material. [Figure 13] 1 shows an XRPD overlay of Compound I starting material before and after DVS testing. [Figure 14] 1 shows an XRPD overlay of Compound I after storage under 30° C. / 65% RH / open conditions. [Figure 15] 1 shows an XRPD overlay of Compound I after storage under 30° C. / 65% RH / closed conditions. [Figure 16] 1 shows an XRPD overlay of Compound I after storage under 40° C. / 75% RH / open conditions. [Figure 17] 1 shows an XRPD overlay of Compound I after storage under 40° C. / 75% RH / closed conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The compound 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol, designated herein as Compound I, has the formula: [ka]

[0027] The present disclosure relates to various crystalline forms of Compound I, and processes for making the crystalline forms. Also described herein are forms of Compound I further labeled as "Form I of Compound I", "Form II of Compound I", "Form III of Compound I", "Form IV of Compound I", "Form V of Compound I", and "amorphous Compound I". In some embodiments, such forms of Compound I may be anhydrous. In some embodiments, such forms of Compound I may be solvates or hydrates.

[0028] Additional crystalline forms of Compound I are also further described herein. For example, in some embodiments, the crystalline form of Compound I can include a salt or co-crystal of Compound I.

[0029] definition As used herein, the following words and phrases are intended to have the meanings generally set forth below, except to the extent that the context in which they are used indicates otherwise.

[0030] The term "fascin" refers to a 54-58 kDa protein that is an actin cross-linking protein. The term "fascin" may refer to the amino acid sequence of human fascin 1. The term "fascin" includes both the wild-type nucleotide sequence or protein, and any mutants thereof. In some embodiments, "fascin" is wild-type fascin. In some embodiments, "fascin" is one or more mutant forms. In some embodiments, fascin is human fascin 1. In some embodiments, the fascin protein is encoded by a nucleotide sequence corresponding to reference number GI:347360903. In some embodiments, the fascin protein is encoded by a nucleotide sequence in RefSeq M_003088. In some embodiments, fascin corresponds to an amino acid sequence in RefSeq NP_003079.1.

[0031] Terms such as "spine formation" refer in their normal accustomed sense to the development (e.g., growth and / or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote spine formation without affecting spine morphology. Promotion is relative to the absence of administration of the compound.

[0032] As used herein, the term "dendrite" refers to the branched extension of a neuronal cell. Dendrites are usually responsible for receiving electrochemical signals transmitted from the axons of adjacent neurons. The term "dendritic spines" or "dendrite spines" refers to the protoplasmic protuberances on a neuronal cell (e.g., dendrites). In some embodiments, dendritic spines may be described as having a membranous neck that may terminate in a small head (e.g., head). Dendritic spines are classified as headless, thin, stubby, mushroom, or branched depending on their shape. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuronal cell. For example, dendritic spine density may be given as the number of dendritic spines per micron.

[0033] Terms such as "dendritic spine formation" refer in their normal, customary sense to a process that results in an increase in the number of dendritic spines or an increase in the development of dendritic spines. Terms such as "dendritic spine morphology" refer in their normal, customary sense to the physical characteristics (e.g., shape and structure) of dendritic spines. Improving dendritic spine morphology is a change in morphology (e.g., an increase in length or an increase in width) that results in improved function (e.g., an increase in the number of contacts between neurons or a decrease in the space (e.g., synaptic cleft) between adjacent neurons). As known in the art and disclosed herein, exemplary methods for such characterization include measuring the dimensions (i.e., length and width) of dendritic spines. Thus, the term "improving dendritic spine morphology" generally refers to an increase in the length, width, or both length and width of dendritic spines.

[0034] "Binding" refers to at least two different species (e.g., compounds, including biomolecules, or cells) coming into sufficient proximity to react or interact, thereby resulting in the formation of a complex. For example, binding of two different species (e.g., a protein and a compound described herein) can result in the formation of a complex in which the species interact through non-covalent or covalent bonds. In some embodiments, the resulting complex is formed when two different species (e.g., a protein and a compound described herein) interact through non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).

[0035] As defined herein, the terms "activation," "activate," "activating," and the like, in reference to protein-activator (e.g., agonist) interactions, mean a positive effect (e.g., an increase) on the activity or function of the protein compared to the activity or function in the absence of the activator (e.g., a compound described herein).

[0036] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subjects or agents are treated as in a parallel experiment, except for the omission of an experimental procedure, agent, or variable. In some cases, a control is used as a standard of comparison in evaluating the effect of an experiment.

[0037] "Contacting" is used according to its simple ordinary meaning and refers to the process of allowing at least two different species (e.g., compounds including biomolecules or cells) to come into sufficient proximity to interact. The term "contacting" can include allowing two molecular species to react or come into physical contact, where the two species can be, for example, compounds, biomolecules, proteins, or enzymes described herein. In some embodiments, contacting includes allowing a compound described herein to interact with a protein (e.g., phasin) or enzyme.

[0038] As defined herein, the terms "inhibit", "inhibit", "inhibiting" and the like should be given their usual meaning to one of ordinary skill in the art. The terms "inhibit", "inhibit", "inhibiting" in the context of protein-inhibitor (e.g., antagonist) interactions refer to a negative effect (e.g., a decrease) on the functional activity of the protein compared to the functional activity of the protein in the absence of the inhibitor.

[0039] As used herein, the term "about" used in the context of quantitative measurements means the amount stated ±10%, or alternatively, the amount stated ±5% or ±1%.

[0040] The term "complex" refers to a formation that results from the interaction between compound I and another molecule.

[0041] The term "solvate" refers to a complex formed by combining Compound I with a solvent. As used herein, the term "solvate" includes hydrates (i.e., solvates where the solvent is water).

[0042] The term "cocrystal" refers to a molecular complex of ionized or non-ionized compound I (or any other form, salt or compound disclosed herein) and one or more non-ionized co-crystal formers (such as pharma- ceutically acceptable salts) bound via non-covalent interactions. In certain embodiments, the cocrystal can have improved properties compared to the free form (i.e., the free molecule, zwitterions, hydrates, solvates, etc.) or salts (including salt hydrates and solvates). In further embodiments, the improved properties are selected from the group consisting of increased solubility, increased solubility, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline forms of normally amorphous compounds, crystalline forms of compounds that are less prone to salting out or are non-salting out compounds, reduced morphological diversity, more desirable morphologies, and the like.

[0043] The term "co-crystal former" or "coformer" refers to one or more pharma- ceutically acceptable bases and / or pharma-ceutically acceptable acids, as disclosed herein, in association with compound I, or any other compound disclosed herein.

[0044] Any formula or structure described herein, including compound I, is also intended to represent unlabeled form of the compound as well as isotopically labeled form.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom with a selected atomic weight or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, but 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, such as 3 H, 13 C, and 14 They may be prepared incorporating radioactive isotopes, such as C. Such isotopically labeled compounds may be useful in detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0045] The present disclosure also includes compounds I in which one to "n" hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and may be useful for increasing the half-life of any compound I when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0046] The deuterium-labeled or substituted compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties in relation to distribution, metabolism, and excretion (ADME). The isotopically labeled compounds of the present disclosure and their prodrugs may generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting non-isotopically labeled reagents for readily available isotopically labeled reagents. In addition, it is particularly possible to prepare isotopically labeled compounds that are not deuterium-labeled (i.e., 2 Substitution with heavier isotopes, such as H or D, may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. Isotopic labeling for diagnostic purposes is also contemplated.

[0047] The concentration of such an isotope, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium at greater than natural abundance.

[0048] As used herein, " pharmaceutically acceptable carrier " includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, which are not harmful to the compound of the present invention or its use.The use of such carriers and agents for preparing compositions of pharmaceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0049] The term "therapeutically effective amount" refers to an amount of a compound described herein sufficient to effect treatment as defined below when administered in one or more doses to a patient (particularly a human) in need of such treatment. The therapeutically effective amount will vary depending on the patient, the disease being treated, the patient's weight and / or age, the severity of the disease, or the method of administration as determined by a qualified prescriber or caregiver.

[0050] The term "treatment" or "treating" refers to any of the following purposes: (I) delaying the onset of the disease, i.e., not developing or delaying the onset of clinical symptoms or markers of the disease; (II) inhibiting the disease, i.e., slowing or preventing the onset of clinical symptoms or markers thereof, or the spread of the disease; and / or (III) Relieving the disease, ie, meaning administering a compound described herein to cause regression of clinical symptoms or markers of their severity.

[0051] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds, in some embodiments, may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0052] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. When the subject is a human, the subject may be referred to as a "patient."

[0053] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine optimal schedules and / or dosages of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used to set up in vivo treatment protocols, either for experimental purposes or in the clinic. Other ex vivo applications for which the compounds and compositions described herein may be suitable are described below and will be apparent to those skilled in the art. Selected compounds may be further characterized to determine safety or tolerated dosage in human or non-human subjects. Such properties may be determined using methods commonly known to those of skill in the art.

[0054] In addition, the abbreviations used herein have the following respective meanings: [Table 7]

[0055] Form of Compound I As generally described above, the present disclosure provides crystalline forms of Compound I, and co-crystals thereof. Additional forms are also discussed further herein.

[0056] Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form I of Compound I) is characterized by an X-ray powder diffractogram containing the following peaks: about 4.6, about 20.8, and about 23.7 °2θ ± 0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. The diffractogram contains additional peaks at about 9.2, about 16.3, about 18.6, and about 19.6 °2θ ± 0.2 °2θ. Form I of Compound I is also characterized by its complete X-ray powder diffractogram, as shown in FIG. 1. Form I of Compound I may be characterized by one or more, for example, 1, 2, 3, 4, 5, or 6, of the following XRPD peaks: [Table 8]

[0057] In some embodiments, Form I of Compound I is characterized by a differential scanning calorimetry (DSC) curve that includes an endothermic peak at about 70° C.±2° C. Form I of Compound I is also characterized by its substantially complete DSC curve, as shown in FIG.

[0058] Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form II of Compound I) is characterized by an X-ray powder diffractogram containing the following peaks: about 9.2, about 13.8, and about 16.1 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. The diffractogram contains additional peaks at about 6.9, about 11.5, and about 18.4 °2θ±0.2 °2θ. Form II of Compound I is also characterized by its substantially complete X-ray powder diffractogram, as shown in FIG. 3. In some embodiments, Form II of Compound I exists as a wet material. Form II of Compound I may be characterized by one or more, e.g., 1, 2, 3, 4, 5, or 6, of the following XRPD peaks: [Table 9]

[0059] Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form III of Compound I) is characterized by an X-ray powder diffractogram containing the following peaks: about 7.7, about 10.3, and about 15.3 °2θ ± 0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. The diffractogram contains additional peaks at about 5.1, about 12.8, and about 18.0 °2θ ± 0.2 °2θ. Form III of Compound I is also characterized by its substantially complete X-ray powder diffractogram, as shown in FIG. 4. In some embodiments, Form III of Compound I exists as a wet material. Form I of Compound I may be characterized by one or more, e.g., 1, 2, 3, 4, 5, or 6, of the following XRPD peaks: [Table 10]

[0060] Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form IV of Compound I) is characterized by an X-ray powder diffractogram containing the following peaks: about 5.4, about 22.4, and about 23.3°2θ±0.2°2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. The diffractogram contains additional peaks at about 10.8, about 18.9, about 23.9, and about 26.8θ±0.2°2θ. Form IV of Compound I is also characterized by its substantially complete X-ray powder diffractogram, as shown in FIG. 5. Form IV of Compound I may be characterized by one or more, for example, 1, 2, 3, 4, 5, or 6, of the following XRPD peaks: [Table 11]

[0061] In some embodiments, Form IV of Compound I is characterized by a differential scanning calorimetry (DSC) curve that includes an endothermic peak at about 48±2° C. and an endothermic peak at about 59° C.±2° C. Form IV of Compound I is also characterized by its substantially complete DSC curve, as shown in FIG.

[0062] Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form V of Compound I) is characterized by an X-ray powder diffractogram containing the following peaks: about 4.6, about 9.2, and about 23.1 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. The diffractogram contains additional peaks at about 13.8 and about 18.6 °2θ±0.2 °2θ. Form V of Compound I is also characterized by its substantially complete X-ray powder diffractogram, as shown in FIG. 7. Form IV of Compound I may be characterized by one or more, e.g., 1, 2, 3, 4, 5, or 6, of the following XRPD peaks: [Table 12]

[0063] In some embodiments, Form V of Compound I is characterized by a differential scanning calorimetry (DSC) curve that includes an endothermic peak at about 70° C.±2° C. Form V of Compound I is also characterized by its substantially complete DSC curve, as shown in FIG.

[0064] Some embodiments are directed to compositions that include a form of Compound I described herein that is free of any other forms of Compound I. In some embodiments, the composition includes greater than 95% of a form of Compound I described herein, as compared to other forms of Compound I. In some embodiments, the composition includes greater than 97% of a form of Compound I described herein, as compared to other forms of Compound I. In some embodiments, the composition includes greater than 99% of a form of Compound I described herein, as compared to other forms of Compound I.

[0065] Some embodiments are directed to compositions comprising Form I of crystalline Compound I as described herein, as compared to other forms of Compound I. In some embodiments, the compositions comprise greater than 95% of Form I of crystalline Compound I as described herein, as compared to other forms of Compound I. In some embodiments, the compositions comprise greater than 97% of Form I of crystalline Compound I as described herein, as compared to other forms of Compound I. In some embodiments, the compositions comprise greater than 99% of Form I of crystalline Compound I as described herein, as compared to other forms of Compound I.

[0066] In some embodiments, the composition comprises Form I of crystalline Compound I in a purity of greater than 95%. In some embodiments, the composition comprises Form I of crystalline Compound I in a purity of greater than 97%. In some embodiments, the composition comprises Form I of crystalline Compound I in a purity of greater than 99%.

[0067] Some embodiments are directed to a process for making a form of Compound I described herein. In some embodiments, the process is as described in the Examples provided herein.

[0068] In some embodiments, the process for preparing Form I of Compound I is selected from solid vapor diffusion, anti-solvent addition, liquid vapor diffusion, slow cooling, slurry conversion, temperature cycling, and slow evaporation. Solid vapor diffusion is carried out using acetone, THF, EtOH, H 2The anti-solvent addition can be performed at room temperature with a solvent selected from 0, EtOAc, dioxane, toluene, DCM, and acetonitrile. The anti-solvent addition can be performed by adding an anti-solvent selected from IPA, MTBE, CPME, and heptane to a solution of compound I in a solvent selected from THF, MeOH, DCM, and EtOAc. The slow cooling can be performed by cooling a solution of compound I with a solvent or solvent system selected from MEK, dioxane:toluene (optionally in a ratio of about 1:1 v / v), EtOAc:acetonitrile (optionally in a ratio of 1:1 v / v), DCM:IPA (optionally in a ratio of about 4:1 v / v), and THF:heptane (optionally in a ratio of about 4:1 v / v). The slow evaporation can be performed by cooling a solution of compound I with a solvent or solvent system selected from THF, EtOAc, MEK, acetonitrile, and dioxane:H 2 O (optionally in a ratio of about 9:1 v / v).

[0069] In some embodiments, Form I of Compound I is stable for at least 4 weeks under conditions of 30° C. / 65% RH (closed or open) and 40° C. / 75% RH (closed or open). In some embodiments, Form I of Compound I retains at least 99% purity after storage for at least 4 weeks under conditions of, optionally, 30° C. / 65% RH (closed or open) or 40° C. / 75% RH (closed or open).

[0070] Pharmaceutical Compositions and Dosages The forms of Compound I described herein may be administered in the form of a pharmaceutical composition. Thus, provided herein are pharmaceutical compositions that include one or more of the forms of Compound I described herein and one or more pharma- ceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharma-ceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.). The pharmaceutical composition may be administered alone or in combination with other therapeutic agents.

[0071] The pharmaceutical composition can be administered in a single dose or multiple doses.The pharmaceutical composition can be administered by various methods, including, for example, rectal, buccal, intranasal and transdermal routes.In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalant.

[0072] One mode of administration is parenterally, for example, by injection.The forms that the pharmaceutical compositions described herein can be incorporated into for administration by injection include, for example, aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0073] Oral administration may be another route for administering one or more of the forms of Compound I described herein. Administration may be via, for example, capsules or enteric coated tablets. In making pharmaceutical compositions containing one or more of the forms of Compound I described herein, the active ingredient is usually diluted by an excipient and / or enclosed within a carrier, such as may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it serves as a vehicle, carrier or medium for the active ingredient and may be in the form of a solid, semi-solid or liquid material. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or liquid medium), for example, ointment containing up to 10% by weight of the active ingredient, soft and hard gelatin capsules, sterile injection solution, and sterile packaged powder.

[0074] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents.

[0075] Compositions comprising one or more of the forms of Compound I described herein can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems comprising polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the forms of Compound I described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches include those constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0076] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the form of Compound I described herein. These preformulation compositions are referred to as homogenous because the active ingredient is evenly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, capsules, etc.

[0077] Tablets or pills in the form of Compound I described herein can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0078] Compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In some embodiments, compositions are administered by oral or nasal respiratory routes for local or systemic effect. In other embodiments, compositions in pharma- ceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0079] The forms of Compound I described herein may be administered in a pharma- ceutically effective amount. For oral administration, each dosage unit may contain 1 mg to 2 grams, 1 mg to 1 gram, or 1 mg to 500 mg of Compound I. In some embodiments, the dose is 1 mg to 250 mg of Compound I. In some embodiments, the dose of Compound I ranges from about 20 mg twice daily to about 50 mg twice daily. In some embodiments, the dose is 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 25 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 200 mg, or 500 mg of Compound I. However, it will be understood that the amount of compound actually administered will normally be determined by a physician taking into account the condition to be treated, the selected route of administration, and any co-administered compounds, as well as the relevant circumstances, including, where applicable, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

[0080] The compound I forms of the present application or compositions thereof can be administered once, twice, three times, or four times a day using any suitable mode described above. The compound I forms of the present application or compositions thereof can also be administered once or twice a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, the compound I forms of the present application or compositions thereof can be administered once a day for 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 weeks, or longer as needed.

[0081] The specific dosage level for any particular subject of an active agent of the present application, e.g., a form of Compound I described herein, or a pharmaceutical composition thereof, will depend on a variety of factors, including the activity of the particular compound used, the age, weight, general health, sex, diet, time of administration, route of administration, as well as the excretion rate, drug combination, and severity of the particular disease in the subject undergoing therapy. For example, dosages can be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, between about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, as occurs when using a drug in both children and adults, or when translating an effective dosage for a non-human subject, such as a dog, to a dosage appropriate for a human subject.

[0082] A daily dose may also be described as the total amount of a compound described herein administered per dose or per day. The daily dose of a compound described herein or a salt thereof may be between about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0083] When administered intranasally, the total daily dosage for a human subject can be 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In various embodiments, the daily dosage is about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range of values ​​therebetween.

[0084] The forms of Compound I described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered once, twice, three times, or four times a day, using any suitable mode described above. Administration or treatment can also continue for several days. For example, treatment usually continues for at least 7 days, 14 days, or 28 days in one cycle of treatment. Treatment cycles are well known and often alternate with rest periods of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. In other embodiments, treatment cycles can also be continuous. Administration or treatment can be continued indefinitely.

[0085] In certain embodiments, the method includes administering to the subject an initial daily dose of about 1-800 mg of a form of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, and gradually increasing the dose until a clinical response is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0086] The forms of Compound I described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered under fed conditions. The term "fed conditions" or variations thereof refer to the consumption or ingestion of food, in solid or liquid form, or calories, in any suitable form, prior to or simultaneously with administration of the active ingredient. For example, the forms of Compound I described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered to a subject (e.g., a patient) within minutes or hours of consuming calories (e.g., a meal). In some embodiments, the forms of Compound I described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered to a subject (e.g., a patient) within 5 to 10 minutes, within about 30 minutes, or within about 60 minutes of consuming calories.

[0087] Treatment Methods and Uses Fashin Described herein are methods for regenerating spine synapses lost in neurodegenerative conditions by targeting cytoskeletal proteins by administering to a subject a form of Compound I described herein. Unexpectedly, it has been observed that inhibition of the cytoskeletal protein Fascin 1 (FSCN1) rapidly upregulates dendritic spines in vivo and in vitro. Dendritic spines contain filamentous actin (F-actin), a cytoskeletal polymer that provides structure to cells and their subcellular specialization. Without wishing to be limited by theory, it is believed that dendritic spines require the formation of highly branched assemblies of F-actin, and that the formation of such assemblies may be prevented or greatly reduced by bundling into parallel arrays by Fascin 1.

[0088] In some embodiments, a method of binding fascin protein is provided, the method comprising contacting the fascin protein with an effective amount of Compound I, as described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the method inhibits fascin. It is believed that a form of Compound I, or a pharma- ceutically acceptable salt thereof, may promote dendritic spine formation by inhibiting fascin.

[0089] Fascin is an important actin cross-linker that has no amino acid sequence homology with other actin-binding proteins. Three forms of fascin are found in vertebrates: fascin 1 in the nervous system and elsewhere, fascin 2 in retinal photoreceptor cells, and fascin 3 only in the testis. In some embodiments, the fascin is human fascin 1. Fascin has a molecular weight of 55 kDa and functions as a monomer, cross-linking actin filaments into straight, compact, and rigid bundles, providing mechanical rigidity to actin bundles. Fascin is thought to hold parallel actin filaments together to form filopodia with diameters of approximately 60-200 nm.

[0090] During neuronal development, long bundles of f-actin are believed to extrude the neuronal membrane to form structures such as axons, dendrites, filopodia, and lamellipodia. Fascin is thought to be involved in cytoskeletal rearrangements in nascent dendrite protrusions. Thus, it is generally believed that actin bundling by fascin is required for the formation and elongation of axons and dendrites. Surprisingly, it was found that inhibiting the activity of fascin in the formation of actin bundles promoted the formation of dendritic spines, protrusions of the cytoplasmic membrane of dendrites.

[0091] Neuronal diseases and conditions and treatments thereof A unifying feature of neurodegenerative conditions associated with a cognitive component is the loss of synapses that utilize the amino acid glutamate as a neurotransmitter ("glutamatergic" synapses), which are thought to be the most abundant type of synapse in humans and other mammals. Importantly, approximately 90% of glutamatergic synapses involve postsynaptic dendritic spines. The majority of synapses lost in neurodegenerative conditions are synapses where an axon contacts a dendritic spine, so-called "axon-spine synapses." Under normal conditions, changes in the density, shape, and protein composition of dendritic spines affect the strength of synaptic communication and underlie several forms of synaptic change (i.e., "plasticity") involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes. These changes in axon-spine synapses are thought to be important for the memory encoding function of structures such as the hippocampus. Thus, early and progressive loss of dendritic spines in the hippocampus and other regions is thought to be a driving force behind memory loss and cognitive decline in Alzheimer's disease and other dementias. The development of new methods to regenerate spine density may have important implications for the treatment of a host of neurodegenerative and developmental cognitive disorders.

[0092] Dendritic spines are specialized protrusions involved in receiving synaptic inputs and provide important functions in communication between neurons. The morphology of dendritic spines and their overall density are correlated with synaptic function and are strongly implicated in memory and learning. Cellular changes in brain cells may contribute to the pathogenesis of neuronal diseases. For example, abnormal levels (e.g., reductions) of dendritic spine density in the brain may contribute to the pathogenesis of neuronal diseases. As a result, alterations or misregulation of dendritic spines affect synaptic function and are thought to play a major role in various neurological and psychiatric disorders, such as autism, fragile X syndrome, Parkinson's disease (PD), and Alzheimer's disease (AD). For example, in AD, increasing evidence suggests that loss begins with alterations in hippocampal synaptic function caused by amyloid-β (Aβ) protein, prior to neuronal loss. Thus, therapeutic strategies targeting early synapse loss rather than later disease interventions may offer better prognosis for the treatment of AD. Moreover, because most cognitive disorders induce abnormalities in dendritic spine morphology and function, it would be desirable to directly target them using small molecules to alter or mitigate these spine changes. For example, fragile X syndrome is characterized by an excess of immature spines.

[0093] Provided herein are methods useful for promoting spine formation. In some embodiments, the methods include administering to a subject an effective amount of a form of Compound I as described herein, or a pharmaceutical composition thereof, as described herein, including embodiments. Spine formation may be observed as an increase in the average number of spines per neuron, or an increase in unit length of a neuron, which may be referred to as an increase in dendritic spine density. Spine formation may be observed as an improvement in dendritic spine morphology. For example, an improvement in dendritic spine morphology may be observed as an increase in the average size of the spine head. Spine formation may be observed as an improvement in dendritic spine size, spine plasticity, spine motility, spine density, and / or synaptic function. Spine formation may be observed as an increase in the local spatial average of membrane potential. Spine formation may be observed as an increase in Ca 2+ The spine formation may be observed as an increase in the postsynaptic concentration (e.g., volume average) of . Spine formation may be observed as an increase in the average ratio of mature to immature spines. In some embodiments, a form of Compound I described herein, or a pharmaceutical composition thereof, increases dendritic spine density compared to a control. In some embodiments, a form of Compound I described herein, or a pharmaceutical composition thereof, increases dendritic spine density compared to that observed when treatment is initiated. In some embodiments, the increase in dendritic spine density results in a reduction in symptoms of a neuronal disease or disorder in a subject or patient. In some embodiments, the increase in dendritic spine density is explained by anatomical observations. In some embodiments, the increase in dendritic spine density is observed in primary hippocampal neurons.

[0094] In some embodiments, the average receptor spine density is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two numbers (including the endpoints), compared to the time treatment with a form of Compound I or a pharmaceutical composition thereof described herein is initiated. In some embodiments, the dendritic spine density is increased by about 50% to about 500% compared to the time treatment with a form of Compound I or a pharmaceutical composition thereof described herein is initiated. In some embodiments, the dendritic spine density is increased by about 100% to about 300% compared to the time treatment with a form of Compound I or a pharmaceutical composition thereof described herein is initiated. In some embodiments, dendritic spine density is increased by about 200% to about 300% as compared to the time treatment with a form of Compound I or a pharmaceutical composition thereof described herein is initiated. In some embodiments, the duration of treatment with a form of Compound I or a pharmaceutical composition thereof described herein is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0095] In some embodiments, the method increases spine density by promoting the formation of new spines. In some embodiments, the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two numbers (including the endpoints), compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases the average spine density by about 50% to about 500% compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 100% to about 300% as compared to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases spine density by about 200% to about 300% as compared to a control (e.g., spine density in the absence of the compound).

[0096] In some embodiments, the method increases spine density by increasing neuronal length. In some embodiments, the method increases the average neuronal length by about 100 nm, 300 nm, 500 nm, 700 nm, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 7 microns, 10 microns, 15 microns, 20 microns, 25 microns, or any range between any two numerical values ​​(including endpoints) compared to the time treatment with a form of Compound I described herein or a pharmaceutical composition thereof is initiated. In some embodiments, the method increases the average neuronal length by about 500 nm to about 25 microns compared to a control (e.g., neuronal length in the absence of the compound). In some embodiments, the method increases the neuronal length by about 10% to about 300% compared to a control (e.g., neuronal length in the absence of the compound). In some embodiments, the method increases the neuronal length by about 200% to about 300% compared to a control (e.g., neuronal length in the absence of the compound).

[0097] In some embodiments, the method increases the average number of spines per neuron compared to the time treatment with a form of Compound I described herein, or a pharmaceutical composition thereof, is initiated. In some embodiments, the average number of spines per unit length of a neuron is increased by at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 or more, or any range between any two numbers (including the endpoints). In some embodiments, the time is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0098] In some embodiments, the form of compound I described herein or its pharmaceutical composition is useful for treating neurological disease and neurological disorder. Neurological disease is a disease or condition that impairs the function of the nervous system of a subject. Neurological disease or disorder can be a neurological disease or disorder. Neurological disease or disorder can be related to neurodegenerative disease or disorder.

[0099] In one aspect, a method of treating a neurological disease in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a form of Compound I described herein, or a pharmaceutical composition thereof. In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is fragile X syndrome. In some embodiments, the disease or disorder is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the neuronal disease is traumatic brain injury. In some embodiments, a patient with a neuronal disease suffers from traumatic brain injury before, during, or after the onset of the neuronal disease. In some embodiments, the neuronal disease comprises neuronal dysfunction. Neuronal dysfunction can comprise atrophy or other reduction in effective function of the neuron. For example, Alzheimer's disease is known to exhibit neuronal dysfunction, particularly in cortical neurons, such as hippocampal neurons and neurons proximal to the hippocampus. Synapse loss may correlate with dendritic spine loss and neurodegeneration.

[0100] In some embodiments, the neuronal disease is associated with abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density, and / or abnormal synaptic function. In some embodiments, the neuronal disease is associated with abnormal (e.g., reduced) levels of dendritic spine density.

[0101] In some embodiments, the neuronal disease is Alzheimer's disease. In some embodiments, the neuronal disease is Parkinson's disease. In some embodiments, the neuronal disease is Parkinson's disease with dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is stroke. In some embodiments, the neuronal disease is post-traumatic stress disorder (PTSD). In some embodiments, the neuronal disease is traumatic brain disorder (TBD). In some embodiments, the neuronal disease is chronic traumatic encephalopathy (CTE). In some embodiments, the neuronal disease is schizophrenia. In some embodiments, the neuronal disease is dementia (e.g., general dementia). In some embodiments, the neuronal disease is attention deficit / hyperactivity disorder (ADHD). In some embodiments, the neuronal disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neuronal disease is frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS). In some embodiments, the neuronal disease is memory loss. In some embodiments, the neuronal disease comprises memory loss. In some embodiments, the neuronal disease is age-associated memory loss. In some embodiments, the neuronal disease comprises age-associated memory loss. In some embodiments, the neuronal disease is hypertensive encephalopathy. In some embodiments, the neuronal disease is chronic stress. In some embodiments, the neuronal disease comprises chronic stress. In some embodiments, the neuronal disease is FTLD-TDP form I. In some embodiments, the neuronal disease is FTLD-TDP form II. In some embodiments, the neuronal disease is FTLD-TDP form III. In some embodiments, the neuronal disease is FTLD-TDP form IV.

[0102] Examples of neuronal diseases that may be treated with the forms of Compound I described herein, or pharmaceutical compositions thereof, include Alexander disease, Alper's disease, Alzheimer's disease, depression, perinatal asphyxia, Parkinson's disease dementia ("PD dementia"), amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voght-Sjogren-Batten disease), spongiform encephalopathies (e.g., bovine spongiform encephalopathy (mad cow disease), kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, and the like). dementia, Canavan disease, Cockayne syndrome, corticobasal degeneration, fragile X syndrome, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease , subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with variable features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, fistula, drug-induced parkinsonism, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial, type 1 (PARK1), Parkinson's disease 3, autosomal dominant with Lewy bodies (PARK3), Parkinson's disease 4, autosomal dominant with Lewy bodies (PARK4), Parkinson's disease 5 (PARK5), Parkinson's disease 6, autosomal recessive early-onset (PARK6), Parkinson's disease 2, autosomal recessive juvenile (PARK2), Parkinson's disease 7, autosomal recessive early-onset (PARK7), Parkinson's disease 8 (PARK8), Parkinson's disease 9 (PARK9), Parkinson's disease 10 (PARK10), Parkinson's disease 11 (PARK11), Parkinson's disease 12 (PARK12), Parkinson's disease 13 (PARK13), or mitochondrial Parkinson's disease.In some embodiments, the neuronal disease includes Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, stroke, post-traumatic stress disorder (PTSD), traumatic brain injury (TBD), chronic traumatic encephalopathy (CTE), schizophrenia, dementia (e.g., general dementia), attention-deficit / hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP, or FTLD-FUS), memory loss (e.g., age-associated memory loss), hypertensive encephalopathy, or chronic stress.

[0103] In some embodiments, the neuronal disease is Alzheimer's disease (AD). Alzheimer's disease is characterized by symptoms of memory loss in the early stages of the disease. Apoε4 carriers are at increased risk of developing AD. APOε4 is believed to be less efficient than other isoforms in removing Aε, and thus may correlate with increased amyloid burden, tau phosphorylation, synaptic toxicity, and reduced synaptic density. Experiencing traumatic brain injury (TBI) is another risk factor for developing AD, and studies have shown that those who have experienced TBI have a significantly increased risk of AD. Cognitive decline is correlated with progressive synaptic loss. As the disease progresses, symptoms include confusion, loss of long-term memory, paraphasia, loss of vocabulary, aggression, irritability, and / or mood swings. In more advanced stages of the disease, there is loss of physical function. Patients with Alzheimer's disease (AD) exhibit many characteristic neurological disorders, including increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. Without wishing to be bound by theory, it is believed that both the cause and the consequence of these neurological disorders is the accumulation of harmful forms of aggregated amyloid beta (Aβ) peptides in the brain. AD-related disorders include senile dementia of the AD type (SDAT), frontotemporal dementia (FTD), vascular dementia, mild cognitive impairment (MCI), and age-associated memory impairment (AAMI). In some embodiments, a method of treating or preventing Alzheimer's disease is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a form of Compound I as described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the patient is an Apoε2 or Apoε3 carrier. In some embodiments, the patient has suffered from TBI. In some embodiments, the patient is an Apoε4 carrier. In some embodiments, the patient is an Apoε4 carrier who has suffered a TBI.

[0104] In some embodiments, the neuronal disease is fragile X syndrome (FXS). As known in the art, FXS is a genetic syndrome that is associated with various disorders (e.g., autism and hereditary intellectual disability). Physical disability can range from mild to severe. It has been observed that men with FXS, usually from age 40 onwards, begin to develop gradually more severe problems in performing tasks that require working memory. This is especially observed with respect to verbal working memory. In some embodiments, the neuronal disease is autism. As known in the art, autism is a neurodevelopmental disorder. Without wishing to be bound by theory, it is believed that autism affects information processing in the brain by changing how nerves and synapses connect and organize.

[0105] In further embodiments, compositions and methods are provided for alleviating, reducing, or reversing the symptoms of a neuronal disease or disorder. The symptoms may be any of those described herein.

[0106] Terms such as "memory" refer in their normal and customary sense to the process by which information is encoded, stored, and retrieved by a subject. Terms such as "encode" and "register" in the context of memory refer in their normal and customary sense to the reception, processing, and combination of information that affects the senses as chemical or physical stimuli. Terms such as "stored" in this context refer in their normal and customary sense to the creation of a record of encoded information. Terms such as "retrieve" and "recall" in this context refer in their normal and customary sense to the recall of stored information. As known in the art, retrieval can be in response to a cue. In some embodiments, memory loss refers to a reduced ability to encode, store, or retrieve information. In some embodiments, memory can be recognition memory or recall memory. In this context, "recognition memory" refers to the recollection of a previously encountered stimulus. The stimulus can be, for example, a word, a scene, a sound, a smell, etc., as known in the art. A broader class of memory is "recall memory," which involves the retrieval of previously learned information, such as a sequence of actions, a list of words or numbers that the subject previously encountered. Methods for evaluating the level of memory encoding, storage and retrieval performed by a subject are well known in the art, including the methods disclosed herein.For example, in some embodiments, the method improves memory in a subject suffering from a neuronal disease, in a subject in need of memory improvement.In some embodiments, the method improves memory in a subject.In some embodiments, the method treats neuronal or cognitive dysfunction in a subject.In some embodiments, the method treats neuronal dysfunction in a subject.In some embodiments, the method treats cognitive dysfunction in a subject.

[0107] In addition to any aspect disclosed herein, in some embodiments, the subject suffers from brain injury. Types of brain injury include brain damage (i.e., destruction or degeneration of brain cells), traumatic brain injury (i.e., damage resulting from external force to the brain), stroke (i.e., vascular injury, e.g., anoxia, that temporarily or permanently damages the brain), and acquired brain injury (i.e., brain damage not present at birth). In some embodiments, the method improves memory in the subject. In some embodiments, the method improves learning in the subject. In some embodiments, the method treats neuronal or cognitive dysfunction in the subject. In some embodiments, the method treats neuronal dysfunction in the subject. In some embodiments, the method treats cognitive dysfunction in the subject.

[0108] In some embodiments, a method is provided for promoting spine formation in a patient in need thereof, comprising administering to the patient a form of Compound I as described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, a method is provided for treating or preventing a neuronal disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a form of Compound I as described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, a form of Compound I, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a neuronal disease or disorder is provided. In some embodiments, a form of Compound I, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a neuronal disease or disorder is provided. In some embodiments, the neuronal disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or disorder is Alzheimer's disease. In some embodiments, a form of Compound I as described herein, or a pharmaceutical composition thereof, inhibits cross-linking of f-actin. In some embodiments, a form of Compound I as described herein, or a pharmaceutical composition thereof, is anti-metastatic.

[0109] Combination therapy In one embodiment, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents that are being used and / or developed to treat a neuronal disease or disorder.

[0110] When used in the treatment or prevention of the above diseases and disorders, the forms of Compound I described herein, or pharmaceutical compositions thereof, can be administered together with one or more additional therapeutic agents, such as additional therapeutic agents approved for use in the treatment or prevention of a particular disease or disorder, and more specifically, agents that are considered to form the current standard of care. When combination therapy is envisioned, the active agents can be administered simultaneously, separately, or sequentially in one or more pharmaceutical compositions.

[0111] Thus, recent strategies for the treatment of AD include controlling the production or aggregation state of specific isoforms of Aβ peptides. Additional strategies include the prevention, reduction, or elimination of toxic forms of phosphorylated tau. Other strategies include small molecule targeting of enzymes that play a role in the production of Aβ peptides through the processing of amyloid precursor proteins to lower the abundance of Aβ peptides in the brain. In addition, information is accumulating regarding the role of nonamyloid neuropathy, such as tauopathies or sporadic inheritance of specific mutations in the apolipoprotein E gene, which encourages additional strategies to combat neurodegeneration.

[0112] The one or more additional therapeutic agents may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, lisuride, rasagiline, tolcapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, rivastigmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omigapil, CEP-1347, isradipine, DOPA, lithium, riluzole, levetiracetam, ezogabine, pregabalin, rufinamide, felbamate, carbamazepine The agent may be valproic acid, sodium valproate, lamotrigine, phenytoin, oxcarbazepine, ethosuximide, gabapentin, tiagabine, topiramate, vigabatrin, phenobarbital, pyrimidone, clonazepam, interferon beta-la, interferon beta-lb, mitoxantrone, natalizumab, fingolimod, natalizumab, teriflunomide, dimethyl fumarate, glatiramer, ATOH1 gene therapy, ozanezumab, arimoclomol, tiracemtib, dexpramipexole, pridopidine, or galantamine, or phosphoglycerate kinase (PGK) as described in US2018 / 0147263. In some embodiments, the one or more additional therapeutic agents can be an acetylcholinesterase inhibitor (AChEI), such as acotiamide, alpha pinene, ambenonium, demecarium, DFP (diisopropylfluorophosphate), donepezil, edrophonium, galantamine, huperzine A, lactucopicrin, ladostigil, neostigmine, physostigmine, pyridostigmine, diflo, echothiopate, rivastigmine, rosmarinic acid, tacrine, ungeremine, zanapezil, ganstigmine, phenserine, phenethylnorcymserine (PENC), cymserine, thiacymserine, SPH1371 (galantamine plus), ER127528, RS1259, or F3796.In some embodiments, the one or more additional therapeutic agents may be an amyloid-clearing antibody, such as bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, BAN2401, or aducanumab.

[0113] The one or more additional therapeutic agents may be chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, or zolpidem tartrate, or other hypnotic-sedatives, acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximide, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobarbital, Anticonvulsants such as nobarbital sodium, phenytoin, phenytoin sodium, pyrimidones, tiagabine hydrochloride, topiramate, sodium valproate, or valproic acid, amitriptyline hydrochloride, amitriptyline pamoate, amoxapine, bupropion hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine hydrochloride, imipramine hydrochloride, imipramine pamoate, mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phenelzine sulfate, and sertra antidepressants such as thiamine hydrochloride, tranylcypromine sulfate, trimipramine maleate, or venlafaxine hydrochloride; anxiolytics such as alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, meprobamate, midazolam hydrochloride, or oxazepam; chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluphenazine enanthate , fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, or antipsychotics such as trifluoperazine hydrochloride, amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride,Central nervous system stimulants such as modafinil, pemoline, or phentermine hydrochloride; antiparkinsonian drugs such as amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, or trihexyphenidyl hydrochloride; bupropion hydrochloride, donepezil hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naphthalene hydrochloride ... central nervous system agents such as latriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan; cholinergic agents (e.g., parasympathomimetics) such as bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, or pyridostigmine bromide; atropine sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine, sulfate; Anticholinergics such as hyoscyamine, propantheline bromide, scopolamine, butylscopolamine bromide, or scopolamine hydrobromide; adrenergic agonists (sympathomimetics) such as dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, or pseudoephedrine sulfate; adrenergic blockers (sympatholytics) such as dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, or propranolol hydrochloride; baclofen a skeletal muscle relaxant such as cyclobenzaprine hydrochloride, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, or tizanidine hydrochloride; a neuromuscular blocker such as atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, or vecuronium bromide; or betamethasone, betamethasone acetate, or betamethasone sodium phosphate,It may be a corticosteroid such as betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, or triamcinolone acetate.

[0114] kit Also provided herein is a kit comprising a form of Compound I as described herein or a pharmaceutical composition thereof, optionally a second active agent, and suitable packaging.In one embodiment, the kit further comprises instructions for use.In one aspect, the kit comprises a form of Compound I as described herein or a pharmaceutical composition thereof, and a label and / or instructions for use of the pharmaceutical composition in the treatment of an indication, including a disease or condition as described herein.

[0115] Also provided herein is an article of manufacture comprising a form of Compound I as described herein, or a pharmaceutical composition thereof, in a suitable container, which may be a vial, jar, ampoule, prefilled syringe, nebulizer, aerosol dispensing device, dropper, or intravenous bag.

[0116] synthesis In some embodiments, the present disclosure provides a process for synthesizing compound I.

[0117] This process can be carried out using the methods disclosed herein and their routine variations that are obvious in light of the disclosure herein, as well as methods known in the art.In addition to the teachings herein, conventional and well-known synthetic methods can be used.The synthesis of the exemplary compounds described herein, such as Compound I, Compound A, etc., or other formulas or compounds disclosed herein, can be accomplished as described in the following examples.When available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0118] Exemplary embodiments of compounds according to the present disclosure can be synthesized using the general reaction schemes set forth below. A given reagent may be defined as a general class or category (e.g., functional or structural), which should be construed to include any reagent that matches a given descriptor.

[0119] The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0120] Additionally, conventional protecting groups may be described herein, as would be apparent to one skilled in the art. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis,3rd Edition,Wiley,New York and the references cited therein.

[0121] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others are described in detail in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals(Elsevier Science Publishers,1989)organic Reactions,Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 th Organic synthesis may be prepared by procedures described in standard reference texts, such as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0122] The term "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the conditions of the reaction described in connection therewith (e.g., benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, acetic acid, and the like). Unless otherwise specified, the reaction is carried out under an inert gas such as nitrogen or argon. A "solvent" need not be inert.

[0123] In each of the exemplary schemes, it may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or sequence of steps are separated and / or purified (hereinafter separated) to a desired degree of homogeneity by techniques common in the art. Usually, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve a variety of methods, including, for example, reversed and normal phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and devices; small-scale analysis; simulated moving bed (SMB) and preparative thin-layer or thick-layer chromatography, and small-scale thin-layer and flash chromatography.

[0124] Another class of separation methods involves treating the mixture with a medium selected to bind or otherwise render separable the desired product, unreacted starting materials, reactions with the product, etc. Such media include adsorbents or absorbents such as activated charcoal, molecular sieves, ion exchange media, or acids (for basic substances) or bases (for acidic substances), binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction reagents (LIX), etc.

[0125] The selection of an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the materials in acidic and basic media in multiphase extraction, etc. The skilled artisan will apply the technique most likely to achieve the desired separation.

[0126] Starting materials and reagents were purchased from Energy Chemical Shanghai Titan Scientific Co.,Ltd. These materials were used without further purification. Oxygen- and moisture-sensitive reactions were carried out under a nitrogen atmosphere. Reactions were monitored by thin-layer chromatography (TLC) and thin-layer chromatography plates were visualized by exposure to ultraviolet light. Elution was monitored at 254 nm. Flash column chromatography was typically performed on silica gel (300-400 mesh). Yields refer to isolated chromatographically and spectroscopically homogeneous material unless otherwise stated.

[0127] Scheme 1 represents an exemplary synthesis of compound I, which can be carried out according to the embodiments described herein. It is contemplated that the exemplary synthesis shown in Scheme 1 can be particularly advantageous. For example, this synthesis avoids toxic reagents. This synthesis can also utilize milder reaction conditions and require fewer purification steps (e.g., avoids column chromatography). The synthesis can also provide higher yields. The specific reaction conditions and reagents used in Scheme 1 are described below.

[0128] Compound I can be synthesized according to the general scheme, Scheme 1. [ka]

[0129] In some embodiments, a process for preparing Compound I, or a pharma- ceutically acceptable salt thereof, is provided, comprising: [ka] contacting compound A with compound B to form compound I; [ka] This is carried out under first reaction conditions which include a halide.

[0130] In some embodiments of the process for preparing compound I, the halide is an alkali metal halide. In some embodiments of the process for preparing compound I, the alkali metal halide is an alkali metal iodide. In some embodiments of the process for preparing compound I, the alkali metal iodide is potassium iodide. In some embodiments of the process for preparing compound I, the first reaction conditions further comprise an inorganic base. In some embodiments of the process for preparing compound I, the inorganic base is potassium carbonate. In some embodiments of the process for preparing compound I, the first reaction conditions comprise a temperature of 65 to 120°C.

[0131] In some embodiments, the process for preparing compound A, and optionally for preparing compound I, further comprises contacting compound C with compound D to form compound A; [ka] This is carried out under second reaction conditions which include a protic acid.

[0132] In some embodiments of the process for preparing compound I, the protic acid is an organic acid. In some embodiments of the process for preparing compound I, the organic acid is acetic acid. In some embodiments of the process for preparing compound I, the protic acid is present in greater than stoichiometric molar ratio to both compound C and compound D. In some embodiments of the process for preparing compound I, the protic acid dissolves compound C and compound D. In some embodiments of the process for preparing compound I, acetic acid is a non-inert solvent.

[0133] In some embodiments, the process for preparing compound B, and optionally compound I, comprises contacting compound E with p-toluenesulfonyl chloride to form compound B; [ka] This is carried out under third reaction conditions which include a silver salt.

[0134] In some embodiments of the process for preparing compound I, the silver salt is Ag 2 In some embodiments of the process for preparing compound I, the third reaction condition further comprises an alkali metal iodide. In some embodiments of the process for preparing compound I, the alkali metal iodide is potassium iodide. EXAMPLES

[0135] Example 1 Experimental procedure Compound I was subjected to various crystallization conditions including solid vapor diffusion, antisolvent addition, liquid vapor diffusion, slow cooling, slurry conversion at various temperatures, temperature cycling, and slow evaporation. The crystalline forms of compound I were analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), while the metastable forms were analyzed by XRPD. XRPD was performed using a Panalytical X'Pert3 Powder XRPD equipped with a Si zero background holder. 2θ positions were determined using a Panalytical The instrument parameters used are listed in Table 1-1. [Table 1-1]

[0136] TGA data was collected using a TA Q500 and Q550 from TA Instruments. DSC was performed using a TA Q2000 from TA Instruments. The DSC was calibrated using an indium reference standard and the TGA was calibrated using a nickel reference standard. The detailed parameters used in the TGA and DSC tests are shown in Table 1-2. [Table 1-2]

[0137] PLM images were captured using a Zeiss Axio Scope.A1 microscope. PLM images of samples obtained in single crystal growth experiments were captured using a Shanghai Cewei PXS9-T stereo microscope at RT.

[0138] DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25 °C was measured using LiCl, Mg(NO 3 ) 2 and calibrated against the deliquescence point of KCl. The actual parameters of the DVS test are listed in Tables 1-3. [Table 1-3]

[0139] An Agilent 1260 HPLC equipped with a VWD detector was used, and the detailed chromatographic conditions for the purity analysis are shown in Tables 1-4. [Table 1-4]

[0140] A total of five crystalline forms were observed for compound I, including one anhydrous form (form I), one hydrate / solvate (form IV), and three metastable forms (forms II, III, and V). Forms II and III existed only in the wet state, and no solids were isolated by thermal analysis. A solid of form V was obtained, but upon drying in a vacuum oven, form V transformed to form I at approximately 50° C. A summary of the isolated forms and conditions is shown in Tables 1-5 and 1-6. [Table 1-5] [Table 1-6]

[0141] Example 2 Form of Compound I Form I of Compound I Form I of Compound I is an anhydrous form of Compound I and is believed to be the most thermodynamically stable polymorph of the compound. To date, Form I is the only stable anhydrous form of Compound I that has been identified.

[0142] Compound I Form I was obtained by various methods. The XRPD results in Figure 1 showed that Form I was crystalline. The TGA / DSC curves (Figures 2 and 3) showed negligible weight loss and one endothermic peak at 70.3°C. Based on these characterization data, Form I was considered to be anhydrous.

[0143] Form I of Compound I was isolated using the methods provided herein.

[0144] Form II of Compound I Form II was obtained by various methods. XRPD results showed that Form II was crystalline. It existed only as a wet cake and changed to a mixture of Form II and Form C or Form III and Form V on storage. To further investigate Form II, several attempts at reconstitution resulted in the formation of Form III, IV, V, or an amorphous form, indicating that Form II is a metastable form. Therefore, DSC and TGA data for Form II were not obtained.

[0145] Form III of Compound I Form III was obtained by various methods. XRPD results showed that Form III was crystalline. Form III solid obtained by slow evaporation in MEOH quickly converted to Form I upon exposure to air during XRPD analysis. To further investigate Form III, several attempts at reconstitution resulted in the formation of Form I or an amorphous form, indicating that Form III is a metastable form. Therefore, DSC and TGA data for Form III were not obtained.

[0146] Form IV of Compound I Form IV is dissolved in MEK stock solution. 2The IV form was obtained by adding an anti-solvent of 0. The XRPD results showed that Form IV was crystalline. The TGA / DSC curve showed a weight loss of 4.4% up to 150° C. and two endothermic peaks at 48.0 and 58.9° C. Form IV was considered to be a hydrate or solvate based on these characterization data.

[0147] Form V of Compound I Form V was obtained by various methods. XRPD results showed that Form V is crystalline. TGA / DSC curve showed 6.6% weight loss up to 150° C., and two thermal events at 45.7° C. (transition, onset) and 70.2° C. (melting, peak). XRPD data also showed that Form V solids converted to Form I upon vacuum drying at about 50° C. Compound I Form V undergoes dehydration / desolvation at about 50° C. and is converted to Compound I Form I. These results indicate that Form V is a metastable hydrate / solvate that converts to Form I upon dehydration / desolvation.

[0148] Amorphous Compound I Amorphous Compound I was observed under the conditions described herein.

[0149] Example 3 Process for the Formation of Compound I solubility The approximate solubility of compound I was measured in 20 single solvents at RT. Approximately 2 mg of powder sample was added to a 3 mL glass vial. The corresponding solvent was added stepwise (50 μL → 100 μL → 300 μL → 1000 μL) to each vial until the powder solids were visually completely dissolved or a total volume of 1 mL of solvent was added. Approximate solubility values ​​were calculated based on the sample mass, the amount of solvent, and experimental observations. The results, summarized in Table 3-1, were used to guide subsequent solvent selection in the design of polymorph screening experiments. [Table 3-1]

[0150] Solid Vapor Diffusion Solid vapor diffusion experiments were carried out using nine different solvents. Approximately 15 mg of starting material was weighed into a 4 mL vial and placed in a 20 mL vial containing 3 mL of a volatile solvent. The 20 mL vial was then sealed with a cap and kept at RT for 7 days to allow the solvent vapor to interact with the sample. When the solid was completely dissolved in the solvent, it was allowed to slowly evaporate at RT. The resulting solid was analyzed by XRPD. The results summarized in Table 3-2 showed that Form I and Form V were observed. [Table 3-2]

[0151] Antisolvent addition Antisolvent addition experiments were performed under 12 conditions. Approximately 20 mg of starting material was dissolved in 0.5 or 1.0 mL of solvent to obtain a clear solution. The solution was then filtered and magnetically stirred with antisolvent added at a rate of 0.2 mL per step. Antisolvent was added until no solid precipitated or the total volume of solvent reached 5.0 mL. If the solution remained clear, the sample was stirred at 5 °C to induce precipitation. If no precipitation occurred at 5 °C, it was slowly evaporated at RT to obtain a solid. The solid precipitate was isolated by centrifugation for subsequent XRPD analysis. The results in Table 3-3 show that Forms I, II, III, IV, V, and the amorphous form were observed. [Table 3-3]

[0152] Liquid Vapor Diffusion Liquid vapor diffusion experiments were performed under six conditions. Briefly, approximately 20 mg of starting material was dissolved in 1 mL of solvent and filtered into a 5 mL vial using a 0.45 μm pore size PTFE syringe filter. This solution was then placed in a 20 mL vial containing 3 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at RT to allow the organic solvent vapors to interact with the solution for at least 14 days. The precipitate was then isolated for XRPD analysis. The results, summarized in Tables 3-4, indicate that Form I and Form II were observed. [Table 3-4]

[0153] Slow cooling Slow cooling experiments were performed with seven solvents or solvent combinations. Briefly, approximately 20 mg of starting material was dissolved in 0.5 or 1 mL of solvent at 50°C and filtered into a new vial using a PTFE syringe filter with a pore size of 0.45 μm. The filtrate was slowly cooled from 50°C to 5°C at a rate of 0.1°C / min. The resulting solid was kept isothermal at 5°C before centrifugation and XRPD analysis. If the solution remained clear, it was slowly evaporated to obtain the solid for XRPD analysis. The results are summarized in Tables 3-5. The results showed that Forms I, III, V, and the amorphous form were observed. [Table 3-5]

[0154] Slurry Conversion Slurry conversion experiments were performed at RT or 60°C in 17 solvent systems. Approximately 20 mg of starting material was suspended in 0.35 mL of solvent for 7 days at the target temperature. The remaining solid was isolated for XRPD analysis. If the sample was completely dissolved, additional solid was added until a total of approximately 100 mg of powdered solid had been added. The solid was then isolated by centrifugation and analyzed by XRPD. The results, summarized in Tables 3-6, indicated that Form I and Form V were observed. [Table 3-6]

[0155] Temperature Cycling Temperature cycling experiments were performed under six conditions. Briefly, approximately 20 mg of starting material was dissolved in 0.35 mL of solvent and magnetically stirred. The suspension was held at 50°C for 2 hours, cooled to 5°C at a rate of 0.05°C / min, held at 5°C for 2 hours, then ramped to 50°C at a rate of 3°C / min, isothermal for 2 hours, and then cooled to 5°C at a rate of 0.05°C / min. Samples were kept at 5°C before centrifugation. The results are summarized in Tables 3-7. Form A and Form B were formed. [Table 3-7]

[0156] Slow Evaporation Slow evaporation experiments were carried out under seven conditions. Approximately 20 mg of starting material was dissolved in 0.5 or 1.0 mL of solvent and filtered using a PTFE syringe filter with a pore size of 0.45 μm. The filtrate was then filtered through three pinholes in Parafilm. (登録商標) The mixture was covered with a paper towel and stored at RT. The resulting solid was collected for XRPD analysis. The results are summarized in Tables 3-8. It is shown that Form I and Form III crystalline forms were observed. [Table 3-8]

[0157] Example 4 Solid-state stability of compound I The solid state stability of Compound I was evaluated under the conditions of 30°C / 65%RH (open dish and closed container) and 40°C / 75%RH (open dish and closed container) for 4 weeks. The detailed procedures used for the stability evaluation are listed below: 1) Approximately 10 mg of Compound I starting material was weighed into a 3 mL glass vial; 2) In the open dish condition, the vial was covered with Parafilm® and 6 holes were drilled. In the closed condition, the vial was sealed with a cap and the vial was kept in the corresponding condition. In the 40°C / 75%RH condition, the vial was placed in a 40°C / 75%RH stability chamber; in the 30°C / 65%RH condition, the vial was placed in an airtight atmosphere generated by a saturated aqueous potassium iodide solution in biochemicals at 30°C; 4) Samples were taken for XRPD, PLM, and HPLC purity after 3 days, 1 week, 2 weeks, and 4 weeks.

[0158] Based on the XRPD results, no change in shape was observed after storage under all the above conditions. The PLM characterization results showed that the compound I sample was still irregular thin plate-like crystals with some precipitation. HPLC analysis showed that no significant decrease in HPLC purity was observed after 4 weeks under 30°C / 65% RH (open and closed) and 40°C / 75% RH (open and closed) conditions.

[0159] Solid-state stability evaluation of Compound I Form I starting material was performed under conditions of 30°C / 65% RH (closed and open) and 40°C / 75% RH (closed and open). X-ray powder diffraction (XRPD), polarized light microscopy (PLM), and HPLC purity were characterized at four sampling points (3 days, 1 week, 2 weeks, and 4 weeks). No changes were observed for Compound I Form I and no significant decrease in HPLC purity was observed over 4 weeks under both 30°C / 65% RH and 40°C / 75% RH conditions. The solid-state stability evaluation results are summarized in Table 4-1.

[0160] For the determination of single crystal structures, 83 single crystal growth experiments were performed by various methods including slow evaporation, liquid vapor diffusion, slow cooling, heating-cooling, and solvent-thermal synthesis. Stability evaluation experiments at 40°C / 75%RH conditions were performed using a stability chamber, and 30°C / 65%RH conditions were set by saturated potassium iodide aqueous solution in a 30°C biochemical incubator. [Table 4-1]

[0161] The starting material for Compound I was the sample as received. The starting material was characterized by XRPD, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), PLM, and dynamic vapor sorption (DVS).

[0162] The TGA / DSC results of the Compound I starting material showed a weight loss of 0.45% up to 150 °C and a sharp endotherm at 68.2 °C (onset temperature), likely due to melting. The PLM results showed that the starting material presented irregular morphology with aggregation. The DVS plot (Figure 12) showed a water absorption of 0.64% at 25 °C / 80% RH and 21.43% at 25 °C / 95% RH. No change in morphology was observed after the DVS test, as shown in Figure 13. Sample information and characterization results are summarized in Table 4-2. [Table 4-2]

[0163] Example 5 Single crystal growth A total of 83 single crystal growth experiments were performed for compound I with various methods, including slow evaporation, liquid vapor diffusion, slow cooling, heating-cooling, and solvent-thermal synthesis. However, only thin plate-like overlaid crystal samples were obtained, and these samples were too thin to perform SCXRD characterization. Typical experimental procedures and detailed information are described.

[0164] Slow Evaporation A total of 40 slow evaporation experiments were performed to obtain several single crystal samples with thin plate-like morphology. Typical experimental procedure: Compound I starting material was weighed into a 3 mL glass vial, and the selected solvent was added to the vial to dissolve the solid (accelerate dissolution with a vortex oscillator or ultrasonic device). The solution was filtered into a 4 mL shell vial (44.6 mm × 14.65 mm) with a PTFE filter (0.45 μm) and a disposable syringe. In some of the experiments, a small amount of Compound I starting material was added as a crystal seed. Subsequently, the shell vial was covered with a PE plug with one pinhole and placed at the corresponding temperature for slow evaporation. After several days, the samples were observed via PLM. Detailed experimental information is listed in Table 5-1, Table 5-2, Table 5-3, and Table 5-4. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0165] Slow Evaporation A total of 22 liquid-vapor diffusion experiments were performed, and several single crystal samples with thin plate-like morphology were obtained.

[0166] Typical experimental procedure: Compound I starting material was weighed into a 3 mL glass vial, and the selected solvent was added to the vial to dissolve the solid (dissolution can be accelerated with a vortex oscillator or ultrasonic device). The solution was filtered into a 4 mL shell vial (44.6 mm × 14.65 mm) with a PTFE filter (0.45 μm) and a disposable syringe. In some of the experiments, a small amount of Compound I starting material was added as a crystal seed to induce crystallization. The shell vial was subsequently covered with a PE plug with one pinhole. The 4 mL shell vial was then placed into a 20 mL glass vial containing 3.0 mL of antisolvent, sealed, and stored at the corresponding temperature for liquid vapor diffusion. After several days, the sample was observed via PLM. Detailed experimental information is listed in Table 5-5, Table 5-6, and Table 5-7. [Table 5-5] [Table 5-6] [Table 5-7]

[0167] Slow cooling A total of six slow cooling experiments were performed, and several single crystal samples with plate-like morphology were obtained.

[0168] Typical experimental procedure: Compound I starting material was weighed into a 3 mL glass vial with 0.5 mL of the selected solvent. After accelerating the dissolution process via a vortex oscillator or ultrasonic device, the suspension was kept in an oven at 50 °C for about 0.5 h. The hot solution was then filtered through a PTFE filter (0.45 μm) and a 2.0 mL disposable syringe (PTFE filter, disposable syringe, 3 mL glass vial preheated to 50 °C) for another 3 h. The solution was filtered into a 1 mL glass vial and a small amount of starting material was added to the vial as a crystal seed. The vial was then sealed and placed in a biochemical incubator and cooled slowly (cooling program: 50°C → 5°C, 0.01°C / min). [Table 5-8]

[0169] heating-cooling A total of nine heating-cooling experiments were carried out, and several single crystal samples with plate-like morphology were obtained.

[0170] Typical experimental procedure: Compound I starting material was weighed into a 3 mL glass vial with 0.5 mL of the selected solvent. After accelerating the dissolution process via a vortex oscillator or ultrasonic device, the suspension was kept in an oven at 50 °C for about 0.5 h. The hot solution was then filtered with a PTFE filter (0.45 μm) and a 2.0 mL disposable syringe into another 3 mL glass vial (PTFE filter, disposable syringe, 3 mL glass vial preheated to 50 °C). A small amount of starting material was added to the vial as a crystal seed. The vial was then sealed and placed in a biochemical incubator to slowly cool (cooling program: 50 °C → 5 °C, 0.05 °C / min, 5 cycles). [Table 5-9]

[0171] Solvent-Heat A total of six solvent-thermal experiments were performed, yielding several single crystal samples with needle-like morphology. Typical experimental procedure: Compound I starting material was weighed into a 3 mL glass vial with 0.4 mL of the selected solvent. The vial was then placed in a hydrothermal reactor, sealed, and placed in an oven for the solvent-thermal experiment (temperature program: 25°C → 80°C → 25°C). [Table 5-10]

[0172] Example 6 synthesis Tosylation of compound E to form compound B [ka] Compound E (99.8 g) was dissolved in dry DCM (2.0 L) and stirred at room temperature. After 5 minutes, potassium iodide (18.1 g), Ag 2 O (179.8 g) and p-toluenesulfonyl chloride (108.5 g) were added successively to the solution. The reaction mixture was cooled to 37° C. 2 The mixture was stirred vigorously under reduced pressure overnight. After filtering through Celite to remove the solids, the filtrate was concentrated and purified by column chromatography (PE:EA=1:1 to PE:EA=1:2 to DCM:MeOH=25:1) to give compound B (110.0 g, 61.4% yield) as a colorless oil. 1 H NMR (FIG. 18) (400 MHz, CDCl 3 )δ7.75(d, J=8.0Hz, 2H), 7.34(d, J=8.0Hz, 2H), 4.18-4.15(m, 2H), 3.72-3.59 (m, 14H).

[0173] Condensation of Compound C with Compound D to form Compound A [ka] In a 3 L flask, compound C (160.3 g) and compound D (172.0 g) were dissolved in AcOH (1.5 L). The mixture was refluxed at 105° C. for 3.5 h. After cooling to room temperature, the solution was poured into ice water and then filtered. The filtrate was concentrated and purified by recrystallization using EtOH (about 1.4 L) to produce compound A (105.7 g, 36.3% yield) as a dark gray solid. Recrystallization procedure: The crude product was dissolved in 1.4 L of EtOH to form a solution at 80° C. The solution was refluxed for a few minutes and then slowly cooled to room temperature. The solid was collected and washed with EtOH. The solid was dried under vacuum at 50° C. for about 8 h. 1 H NMR (Figure 19) (400 MHz, CD 3 OD) δ7.95-7.91(m, 4H), 7.51-7.47(m, 1H), 7.40-7.36(m, 1H), 6.93-6.91(m, 2H).

[0174] Nucleophilic addition of compound B to compound A to form compound I [ka] Compound I was synthesized by condensation of compound A and compound B. First, the condensation of compound A and compound B was attempted on a small scale. A flask was charged with compound B (5.0 g), compound A (3.3 g), K 2 CO 3 (4.0 g), KI (0.2 g) and dry DMF (60 mL). The resulting mixture was heated under reduced pressure in a 250-mL flask. 2 The mixture was heated at 80° C. under reduced pressure overnight. After cooling to room temperature, the product was extracted into EA by washing the aqueous layer with EA. The EA solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE:EA=3:1) to obtain a white powder (4.3 g, yield 74.0%). The preparation of compound I was then scaled up to several hundred grams. A flask was charged with compound B (105.0 g), compound A (68.5 g), K 2 CO 3 (83.4 g), KI (5.0 g) and dry DMF (1.1 L). The resulting mixture was heated to 100° C. for 24 hours. 2 The mixture was heated at 80° C. overnight under reduced pressure. After cooling to room temperature, the aqueous layer (approximately 5 L of H 2 The product was extracted into EA by washing the PE:EA (about 7 L) with EA. The solvent of EA was removed under reduced pressure, and the residue was purified twice by column chromatography (PE:EA=3:1) to obtain a white powder (about 110.0 g). The two batches of compound I were mixed in DCM to form a solution. The solvent of DCM was evaporated under reduced pressure to obtain pure compound I (103.0 g, 80.8% yield). The structure of compound I is 1 1H NMR (Figure 20) and MS (Figure 21). MS (m / z): [M+H]+=404.1. 1 H NMR (400 MHz, CDCl 3) δ 8.18 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 4.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.38-7.34 (m, 1H), 7.01-6.98 (m, 2H), 4.18-4.15 (m, 2H), 3.84-3.81 (m, 2H), 3.67-3.61 (m, 10H), 3.55-3.53 (m, 2H). The HPLC purity of compound I was also tested (HPLC, UV 230 nm and 254 nm). The HPLC purity of compound I was determined to be 99.8 area % when detected at 230 nm and 99.7 area % by HPLC at 254 nm (Tables 6-1 and 6-2, respectively). The XRPD pattern of the prepared compound I was consistent with Form I. [Table 6-1] [Table 6-2]

[0175] Materials were procured in accordance with Table 6-3. [Table 6-3]

[0176] Example 7 In vitro spine formation using benzothiazole compounds To demonstrate the efficacy of the compounds for promoting spine formation, the effects of the compounds described herein on synaptic puncta and synapses of mouse cortical neurons are investigated.

[0177] Primary mouse cortical neurons are treated with 5 μM of test compound at DIV 15. As a control, primary mouse cortical neurons are treated with vehicle only (10% DMSO, 90% phosphate-buffered saline (PBS)). After 24 h, DIV 16 neurons are fixed, immunostained using the presynaptic vesicle protein synaptophysin (P38), counterstained with the nuclear dye DAPI (4'6-diamidino-2-phenylindole), and counted. Immunolabeled neurons were imaged with a Leica confocal microscope. The number of P38 immunopositive puncta was analyzed using FIJI with the Squash plugin.

[0178] In a similar experiment, primary mouse cortical neurons are treated with 1 μM test compound at DIV 15, using the same DMSO / PBS buffer as above as a control vehicle. 24 hours later, DIV 16 neurons are fixed, immunolabeled with synaptophysin, stained with DAPI, and counted as above.

[0179] Example 8 In silicofascin binding To assess the ability of the compounds described herein to bind to fascin and thereby inhibit its ability to bundle actin fibrils, in silico studies are performed using test compounds and available crystal structures of human fascin 1. Binding sites are identified on the surface of each fascin crystal structure, followed by virtual docking of test compounds into each pocket to determine preferred binding conformations. See International Publication No. WO2019 / 028164 (February 7, 2019).

[0180] Analysis and preparation of phasin crystal structure All available phasin crystal structures were downloaded from the PDB and prepared for structure analysis (see Sedeh, RS et al. J. Mol. Biol. 400, 589-604 (2010); Chen, L. et al. Nature 464, 1062-1066 (2010); Jansen, S. et al. J. Biol. Chem. 286, 30087-30096 (2011); Yang, S. et al. J. Biol. Chem. 288, 274-284 (2013)). Structures were solved by eye and by standard automated protocols built into MolSoft's ICM-Pro software. Hydrogen atoms were added to the structures and consideration was given to crystallographic quality flags such as correct orientation of Asn and Gln side chains, ligand and protein charges, histidine orientation and protonation state, and high b-factor or low occupancy.

[0181] Pocket identification MolSoft's ICMPocketFinder algorithm was used to identify potential ligand-binding pockets and cavities in all available fascin crystal structures (see An, J., et al. Genome Inform. Int. Conf. Genome Inform. 15, 31-41 (2004); Kufareva, I., et al. Nucleic Acids Res. 40, D535-540 (2012)). First, pockets in active chain A of the crystal structure 3LLP were searched, since this structure was found to have the highest resolution (1.8 Å). Four "drug-like" pockets were identified as possessing suitable properties for small molecule binding.

[0182] Ligand docking and scoring The headgroup and head+tail of the test compound are docked into each of the four pockets using MolSoft's ICM-Docking software, version 3.8-6a (Abagyan, R. & Totrov, MJ Mol. Biol. 235, 983-1002 (1994)). A docking score into each pocket is determined. The lower the docking score, the better the "compound-fascin binding pocket" interaction.

[0183] Pocket B, located in actin-binding site 1, is contemplated to yield the lowest docking score. Binding pocket B will be further explored in other fascin crystal structures. The docked head group is then used as an anchor point to dock the tail group to generate an energetically favorable final compound pose.

[0184] The present disclosure should not be limited in scope by the specific embodiments disclosed in the examples, which are intended to be illustrative of some embodiments of the present disclosure, nor should the disclosure be limited by any embodiments that are functionally equivalent within the scope of the present disclosure. Indeed, various modifications of the present disclosure in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. To this end, it should be noted that one or more hydrogen atoms or methyl groups may be omitted from the structures depicted in accordance with accepted shorthand notations for such organic compounds, and that those skilled in the art of organic chemistry will readily recognize their presence. The present invention provides, for example, the following items. (Item 1) Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form I of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks (°2θ±0.2°2θ): about 4.6, about 20.8, and about 23.7, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. (Item 2) Item 1, wherein the diffractogram further comprises peaks at about 9.2, about 16.3, about 18.6, and about 19.6 (°2θ±0.2°2θ). (Item 3) Form I of compound I according to item 1, characterized by a differential scanning calorimetry (DSC) curve containing an endotherm at about 70°C. (Item 4) Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form II of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks (°2θ±0.2°2θ): about 9.2, about 13.8, and about 16.1, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. (Item 5) 5. Form II of compound I according to item 4, wherein the diffractogram further comprises peaks at about 6.9, about 11.5, and about 18.4 (°2θ±0.2°2θ). (Item 6) Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form III of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks (°2θ±0.2°2θ): about 7.7, about 10.3, and about 15.3, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. (Item 7) 7. Form III of compound I according to item 6, wherein the diffractogram further comprises peaks at about 5.1, about 12.8, and about 18.0 (°2θ±0.2°2θ). (Item 8) Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form IV of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks (°2θ±0.2°2θ): about 5.4, about 22.4, and about 23.3, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. (Item 9) 9. Form IV of compound I according to item 8, wherein the diffractogram further comprises peaks at about 10.8, about 18.9, about 23.9, and about 26.8 (°2θ±0.2°2θ). (Item 10) Form IV of compound I according to item 8, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 48°C and an endotherm at about 59°C. (Item 11) Crystalline 2-(2-(2-(2-(4-(benzo[d]thiazol-2-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (Form V of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks (°2θ±0.2°2θ): about 4.6, about 9.2, and 23.1, as determined with a diffractometer using Cu-Kα radiation at a wavelength of 1.5406 Å. (Item 12) 12. Form V of compound I according to item 11, wherein the diffractogram further comprises peaks at about 13.8 and about 18.6 (°2θ±0.2°2θ). (Item 13) Item 12. Form V of compound I according to item 11, characterized by a differential scanning calorimetry (DSC) curve containing an endotherm at about 70° C. (Item 14) 14. A pharmaceutical composition comprising one or more crystalline forms according to any one of items 1 to 13 and one or more pharma- ceutically acceptable carriers. (Item 15) A method for promoting spine formation in a patient, comprising administering a therapeutically effective amount of a form of compound I according to any one of items 1 to 13 or a pharmaceutical composition according to item 14. (Item 16) 16. The method of claim 15, wherein the patient is suffering from a neuronal disease. (Item 17) 17. The method of claim 16, wherein the neuronal disease is selected from Alzheimer's disease, Parkinson's disease, Parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. (Item 18) 18. The method of claim 17, wherein the neuronal disease is Alzheimer's disease. (Item 19) A process for preparing Compound I, or a pharma- ceutically acceptable salt thereof, comprising: [ka] contacting compound A with compound B to form compound I; [ka] This is carried out under first reaction conditions which include a halide. (Item 20) 20. The process of claim 19, wherein the halide is an alkali metal halide. (Item 21) 21. The process according to item 20, wherein the alkali metal halide is an alkali metal iodide. (Item 22) 22. The process according to claim 21, wherein the alkali metal iodide is potassium iodide. (Item 23) 20. The process of claim 19, wherein the first reaction conditions further comprise an inorganic base. (Item 24) 24. The process according to claim 23, wherein the inorganic base is potassium carbonate. (Item 25) 20. The process of claim 19, wherein the first reaction conditions comprise a temperature of 65 to 120°C. (Item 26) further comprising contacting compound C with compound D to form compound A; [ka] 20. The process of claim 19, wherein this is carried out under second reaction conditions which include a protic acid. (Item 27) 27. The process of claim 26, wherein the protic acid is an organic acid. (Item 28) 28. The process according to claim 27, wherein the organic acid is acetic acid. (Item 29) 27. The process of claim 26, wherein the protic acid is present in greater than stoichiometric molar ratio to both compound C and compound D. (Item 30) 30. The process according to item 29, wherein the protic acid dissolves compound C and compound D. (Item 31) further comprising contacting compound E with p-toluenesulfonyl chloride to form compound B; [ka] 27. The process of claim 26, wherein this is carried out under third reaction conditions that include a silver salt. (Item 32) The silver salt is Ag 2 32. The process according to item 31, wherein the compound is O. (Item 33) 32. The process of claim 31, wherein the third reaction conditions further comprise an alkali metal iodide.

Claims

[Claim 1] The invention described in the present specification.

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