US 2016.0039810A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0039810 A1 FLYNN et al. (43) Pub. Date: Feb. 11, 2016

(54) A CRYSTALLINE FORM OF AN ANXIOLYTIC Publication Classification COMPOUND (51) Int. Cl. (71) Applicant: BIONOMICS LIMITED, Thebarton, C07D 47L/04 (2006.01) South Australia (AU) (52) U.S. Cl. (72) Inventors: Bernard Luke FLYNN, Donvale, CPC ...... C07D 471/04 (2013.01); C07B 2.200/13 Victoria (AU); Dharam PAUL, Flinders (2013.01) Park, South Australia (AU); Andrew John HARVEY, Goodwood, South Australia (AU) (57) ABSTRACT (73) Assignee: Bionomics Limited. Thebarton, South Australia (AU) A crystalline Form B of compound 1 can be used in pharma ceutically compositions. The pharmaceutical compositions (21) Appl. No.: 14/776,595 can be used in methods of treating a disease (e.g., a disease of (22) PCT Filed: May 14, 2013 the central nervous system). (86). PCT No.: PCT/AU2013AOOO497 1 S371 (c)(1), O O (2) Date: Sep. 14, 2015 H N Related U.S. Application Data 21 r (60) Provisional application No. 61/787,436, filed on Mar. S. Nul 15, 2013. N N (30) Foreign Application Priority Data N Apr. 12, 2013 (AU) ...... 2O132O4159 Patent Application Publication Feb. 11, 2016 Sheet 1 of 10 US 2016/0039810 A1

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A CRYSTALLINE FORM OF AN ANXOLYTIC therapeutics and in the preparation of pharmaceutical com COMPOUND positions and exhibit desirable characteristics for such pur poses. In general, Form B, and pharmaceutical compositions FIELD OF THE INVENTION thereof, are useful for treating or lessening the severity of a variety of diseases or disorders described herein (e.g., an 0001. The present invention relates generally to a crystal anxiety disorder). Form B is a stable crystalline hemihydrate line form of an anxiolytic compound and methods and uses of form of compound 1. Form B can be characterized using the crystalline form in therapy and to methods for preparing various techniques as described herein including, but not the crystalline form. limited to, X-ray powder diffraction, Raman spectroscopy, differential scanning calorimetry, dynamic vapor sorption, BACKGROUND OF THE INVENTION and thermogravimetric Fourier-transfor infrared thermo 0002 Polymorphism denotes the existence of more than gram. one crystal structure of a chemical entity. For any specific 0008 Also provided herein is a pharmaceutical composi chemical entity it is not readily predictable that it will exhibit tion comprising Form B of compound 1 and optionally an polymorphism. In the instance when the chemical entity is a additional ingredient selected from pharmaceutically accept drug, the ability of the chemical entity to exist in more than able carriers, diluents, and excipients. one crystal form can have a profound effect on the shelf life, 0009. Also provided herein are methods of treating vari solubility, formulation properties, and/or processing proper ous diseases, disorders, or conditions comprising administer ties of the drug. Furthermore, the biological action of the drug ing to a Subject Form B of compound 1, or a pharmaceutical can be affected by the polymorphism. Different crystalline composition thereofas described herein. forms can possess varying rates of uptake in the body, leading 0010 Also provided herein are uses of Form B of com to lower or higher biological activity than required. An undes pound 1, or a pharmaceutical composition thereof as ired polymorph may even show toxicity. Therefore the occur described herein for treating various diseases, disorders, or rence of an unknown polymorphic form during manufacture conditions. and processing of a drug can have a profound impact. 0011. Also provided herein are uses of Form B of com 0003. It is therefore important to be able to understand and pound 1, or a pharmaceutical composition thereof as control polymorphism. Predicting any possible polymorphs described herein in the manufacture of a medicament for for a drug can diminish the possibility of contamination dur treating various diseases, disorders, or conditions. ing a drugs manufacture or storage by other polymorphic forms. DEFINITIONS 0004 Also, understanding which crystal structures are 0012. The term “solvate” refers to forms of a compound possible in some cases allows researchers to maximize the (e.g., compound 1) that are associated with a solvent, usually desired properties of a compound, Such as Solubility, formu by a solvolysis reaction. This physical association may lation properties, processing properties, and shelflife. Under include hydrogen bonding. Conventional solvents include standing these factors early in the development of a new drug water, methanol, ethanol, acetic acid, DMSO, THF, diethyl may mean a more active, more stable, or more cheaply manu ether, and the like. In certain embodiments, Solvates are factured drug. formed using Class 3 solvents. Categories of solvents are defined in, for example, the International Conference on Har SUMMARY OF THE INVENTION monization of Technical Requirements for Registration of 0005 U.S. Pat. No. 8,293,737, the entirety of which is Pharmaceuticals for Human Use (ICH), "Impurities: Guide incorporated herein by reference, describes certain 18-naph lines for Residual Solvents, Q3C(R3), (November 2005). A thyridin-4(1H)-one compounds which are useful as anxi compound may be prepared, e.g., in crystalline form, and may olytic agents. Such compounds include 1-ethyl-6-(indan-2- be solvated. Suitable solvates include pharmaceutically ylamino)-3-(morpholine-4-carbonyl)-1,8-naphthyridin-4- acceptable solvates and further include both stoichiometric one (compound 1). Solvates and non-stoichiometric Solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorpo rated in the crystal lattice of a crystalline solid. “Solvate encompasses both solution-phase and isolable Solvates. Rep resentative Solvates includehydrates, ethanolates, and metha nolates. 0013 The term “hydrate.” refers to a compound (e.g., compound 1) which is associated with water. Typically, the r number of the water molecules contained in a hydrate of a compound is in a definiteratio to the number of the compound molecules in the hydrate. Hydrates include both stoichiomet croc ric hydrates and non-stoichiometric hydrates. Therefore, a hydrate of a compound may be represented, for example, by 0006 Compound 1 possesses anxiolytic activity without the general formula R.XH2O, wherein R is the compound and sedative side effects and therefore represents an attractive wherein X is a number greater than 0. A given compound may alternative to the 1,4-benzodiazepine class of anxiolytics form more than one type of hydrates, including, e.g., mono Such as diazepam. hydrates (Stoichiometric, X is 1), lower hydrates (non-sto 0007. A polymorph of compound 1 has been discovered ichiometric, X is a number greater than 0 and Smaller than 1, and named Form B, and compositions thereof, are useful as e.g., hemihydrates (R.0.5H2O)), and polyhydrates (non-sto US 2016/0039810 A1 Feb. 11, 2016

ichiometric, X is a number greater than 1, e.g., dihydrates 0019. As used herein, the terms “in combination' and (R.2H2O) and hexahydrates (R.6H2O)). “co-administration can be used interchangeably to refer to 0014. It is also to be understood that compounds that have the use of more than one therapy (e.g., one or more prophy the same molecular formula but differ in the nature or lactic and/or therapeutic agents). The use of the terms does sequence of bonding of their atoms or the arrangement of not restrict the order in which therapies (e.g., prophylactic their atoms in space are termed "isomers’. and/or therapeutic agents) are administered to a subject. 0015 The term “polymorphs' refers to a crystalline form 0020. As used herein, the terms “treatment,” “treat, and of a compound (e.g., compound 1), or a hydrate or Solvate “treating refer to reversing, alleviating, delaying the onset thereof, in a particular crystal packing arrangement. All poly of or inhibiting the progress of a "pathological condition” morphs have the same elemental composition. The term (e.g., a disease, disorder, or condition, or one or more signs or “crystalline, as used herein, refers to a solid state form which symptoms thereof). In some embodiments, treatment may be consists of orderly arrangement of structural units. Different administered after one or more signs or symptoms have devel crystalline forms of the same compound, or a hydrate, or oped or have been observed. In other embodiments, treatment solvate thereof, arise from different packing of the molecules may be administered in the absence of signs or symptoms of in the solid state, which results in different crystal symmetries the disease or condition. For example, treatment may be and/or unit cell parameter. Different crystalline forms usually administered to a susceptible individual prior to the onset of have different X-ray diffraction patterns, infrared spectra, symptoms. Treatment may also be continued after symptoms melting points, density, hardness, crystal shape, optical and have resolved, for example, to delay or prevent recurrence. electrical properties, stability, and solubility. Recrystalliza (0021. The terms “prevention.” “prevent,” and “prevent tion solvent, rate of crystallization, storage temperature, and ing.” as used herein, refer to administering a medicament other factors may cause one crystalline form to dominate. (e.g., Form B of compound 1 or a pharmaceutical composi Various polymorphs of a compound, or a hydrate or Solvate tion thereof) beforehand to avertor forestall the appearance of thereof, can be prepared by crystallization under different one or more symptoms of a disease or disorder. The person of conditions. ordinary skill in the medical art recognizes that the terms 0016. As used herein, the term "impurity” refers to extra “prevention.” “prevent,” and “preventing” are not absolute neous matter included in a compound (e.g., Form B of com terms. In the medical art these terms are understood to refer to pound 1). Extraneous matter includes one or more substances the prophylactic administration of a medicament to Substan that are different from the compound. In certain embodi tially diminish the likelihood or seriousness of a condition, or ments, the extraneous matter is undesired extraneous matter. symptom of the condition, and this is the sense intended in For example, when an anhydrous compound is desired, the this disclosure. Solvent (e.g., water) included in the compound is an impurity. 0022. As used herein, the terms “condition.” “disease.” When a crystalline compound is desired, an amorphous form and “disorder are used interchangeably. of the compound included in the compound is an impurity. 0023. An “effective amount of a compound described When certain polymorph of a compound is desired, a differ herein refers to an amount sufficient to elicit the desired ent polymorph of the compound included in the compound is biological response, e.g., treating a condition. As will be an impurity. The term “substantially free of impurities' appreciated by those of ordinary skill in this art, the effective means that a compound (e.g., Form B of compound 1), con amount of a compound described herein may vary depending tains no significant amount of extraneous matter (e.g., undes on Such factors as the desired biological endpoint, the phar ired extraneous matter). What amount of the extraneous mat macokinetics of the compound, the condition being treated, ter constitutes a significant amount depends on the Subject the mode of administration, and the age and health of the matter and is understood in the art. In certain embodiments, Subject. An effective amount encompasses therapeutic and about 1 wt %, about 2 wt %, about 3 wt %, about 5 wt %, about prophylactic treatment. For example, in treating an anxiety 7 wt %, or about 10 wt % of extraneous matter in a compound disorder, an effective amount of an inventive compound may is a significant amount of extraneous matter. provide a therapeutic and/or prophylactic benefit in the treat 0017. A “subject’ to which administration is contem ment and/or prevention of the anxiety disorder or to delay or plated includes, but is not limited to, humans (i.e., a male or minimize one or more symptoms associated with the anxiety female of any age group, e.g., a pediatric Subject (e.g., infant, disorder. child, adolescent) or adult Subject (e.g., young adult, middle 0024. A “therapeutically effective amount of a com aged adult, or senior adult)) and/or other non-human animals, pound described herein is an amount Sufficient to provide a for example, mammals (e.g., primates (e.g., cynomolgus therapeutic benefit in the treatment of a condition (e.g., an monkeys, rhesus monkeys); commercially relevant mammals anxiety disorder) or to delay or minimize one or more symp Such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) toms associated with the condition. A therapeutically effec and birds (e.g., commercially relevantbirds such as chickens, tive amount of a compound means an amount of therapeutic ducks, geese, and/or turkeys). In certain embodiments, the agent, alone or in combination with other therapies, which animal is a mammal. The animal may be a male or female at provides a therapeutic benefit in the treatment of the condi any stage of development. The animal may be a transgenic tion. The term “therapeutically effective amount can encom animal or genetically engineered animal. In certain embodi pass an amount that improves overall therapy, reduces or ments, the Subject is a non-human animal. In certain embodi avoids symptoms or causes of the condition, or enhances the ments, the animal is fish. therapeutic efficacy of another therapeutic agent. 0018. The terms “administer,” “administering,” or 0025. A “prophylactically effective amount of a com “administration, as used herein, refers to implanting, absorb pound described herein is an amount Sufficient to prevent a ing, ingesting, injecting, inhaling, or otherwise introducing a condition (e.g., an anxiety disorder), or one or more symp compound (e.g., Form B of compound 1) or pharmaceutical toms associated with the condition or prevent its recurrence. composition thereof, in or on a Subject. A prophylactically effective amount of a compound means an US 2016/0039810 A1 Feb. 11, 2016

amount of a therapeutic agent, alone or in combination with of the central nervous system (CNS), such as anxiety disor other agents, which provides a prophylactic benefit in the ders. See, e.g., U.S. Pat. No. 8,293.737. prevention of the condition. The term “prophylactically effec tive amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. 0026. The term “neurite” refers to any projection from the cell body of a neuron. This projection can be eitheran axon or a dendrite. Neurites are often packed with microtubule bundles, the growth of which is stimulated by Nerve Growth Factor (NGF), as well as tau proteins, MAP1, and MAP2. The r neural cell adhesion molecule N-CAM simultaneously com bines with another N-CAM and a fibroblast growth factor receptor to stimulate the tyrosine kinase activity of that recep croc tor to induce the growth of neurites. 0027. A disease “responsive to neurite outgrowth' is a disease, disorder, or condition which may be ameliorated by Solid Form enhancement of neurite outgrowth. Diseases responsive to 0041. In some embodiments, it would be desirable to pro neurite outgrowth include neurodegenerative diseases (e.g., vide a crystalline polymorph of compound 1 that, as com multiple Sclerosis and a Parkinsonian related disorder) and pared to the amorphous compound 1, imparts improved diseases that involve neural damage that include wound heal physical characteristics such as stability and/or ease of for ing, spinal cord injury, and peripheral nerve disorders. mulation. Accordingly, provided herein is a crystalline form 0028. The present application refers to various issued (denoted Form B) of compound 1. Form B is a hemihydrate of patent, published patent applications, journal articles, and compound 1. Form B is stable upon drying, and other Solvates other publications, all of which are incorporated herein by of compound 1 were less stable upon drying. For example, reference. Solvates of methanol, ethanol, isopropanol, tetrahydrofuran 0029. The details of one or more embodiments of the (THF), and dioxane either changed from or showed a reduc invention are set forth herein. Other features, objects, and tion in crystallinity upon drying. In some embodiments, Form advantages of the invention will be apparent from the B has a water content of about 2.0 wt %. Form B is substan Detailed Description, the Figures, the Examples, and the tially non-hygroscopic. In contrast, anhydrous forms of com Claims. pound 1 were found to show indications of hygroscopicity. Form B was also found to be more stable than an anhydrous BRIEF DESCRIPTION OF THE DRAWINGS form of compound 1. In a competitive slurry experiment there 0030 FIG. 1 depicts an X-Ray Powder Diffraction was a tendency for the anhydrous form to convert to Form B. (XRPD) pattern of Form B. 0042. In some embodiments. Form B is substantially free 0031 FIG. 2 depicts a Fourier-Transform Raman (FT-Ra of impurities. In some embodiments. Form B is 99% free of man) spectrum of Form B. impurities. In some embodiments, Form B is 97% free of 0032 FIG. 3 depicts a Differential Scanning calorimetry impurities. In some embodiments, Form B is 95% free of (DSC) thermogram of Form B. impurities. In some embodiments, Form B is 92% free of 0033 FIG. 4 depicts a Dynamic Vapor Sorption (DVS) impurities. In some embodiments, Form B is 90% free of isotherm of Form B. impurities. In certain embodiments, the impurities include extraneous matter, Such as a salt forming acid, residual Sol 0034 FIG.5 depicts a Thermogravimetric Fourier-Trans vents, or any other impurities that may result from the prepa form Infrared (TG-FTIR) thermogram of Form B. ration, and/or isolation, of compound 1. In, Some embodi 0035 FIG. 6 depicts a Proton Nuclear Magnetic Reso ments, Form B is Substantially free of amorphous compound nance (H-NMR) spectrum of Form B. 1. In some embodiments. Form B is substantially free of 0036 FIGS. 7A-B depict microscopic images of Form B another crystalline form of compound 1. In some embodi recorded without (FIG.7A) and with (FIG. 7B) crossed polar ments. Form B is substantially free of a salt of compound 1. In izers. Compound 1 appears dark in the left image and bright some embodiments. Form B is substantially free of a non in the right image. water solvate of compound 1. In some embodiments. Form B 0037 FIG. 8 depicts XRPD patterns of Form B before is obtained from mixture of methanol and water. (top) and after (bottom) drying. The patterns have been scaled 0043. Different solid forms of a compound typically differ and offset in the y-direction for purposes of comparison. in their physical and chemical properties based on the 0038 FIG. 9 depicts a TG-FTIR thermogram of a dried arrangement of the molecules in the solid form (e.g., the sample obtained from Form B. arrangement of the molecule in the crystal lattice). A given 0039 FIG. 10 depicts an infrared (IR) spectrum of Form Substance may give rise to a variety of solid forms, in particu B. lar a variety of crystalline forms, wherein each form has different and distinct physical and chemical properties. Such DETAILED DESCRIPTION OF CERTAIN as solubility profiles, thermodynamic and chemical stabili EMBODIMENTS ties, melting points, Raman spectra, and/or X-ray diffraction 0040 Compound 1 (1-ethyl-6-(indan-2-ylamino)-3-(mor peaks. pholine-4-carbonyl)-1.8-naphthyridin-4-one) has been 0044) Form B can be characterized by one or more of the reported to elicitan anxiolytic effect. Compound 1 has shown characteristics described herein including, but not limited to, significant potential for the treatment of a variety of disorders XRPD diffraction patternand/or peaks, Raman spectrum and/ US 2016/0039810 A1 Feb. 11, 2016

or peaks, DSC thermogram, DVS isotherm, TG-FTIR ther TABLE 1-continued mogram, IR spectrum and/or peaks, appearance, melting point, solubility, and stability. In certain embodiments, Form X-ray powder diffraction pattern. B is characterized by XRPD diffraction pattern and/or peaks Angle d value Intensity Intensity and Raman spectrum and/or peaks. In certain embodiments, 2-Theta Angstrom (relative) %

Form B is characterized by XRPD diffraction pattern and/or 22.32 3.98 S 60 peaks, Raman spectrum and/or peaks, and at least one other 22.77 3.90 S 50 technique as described herein (e.g., DSC thermogram, DVS 23.02 3.86 S 53 isotherm, TG-FTIR thermogram, melting point). 23.16 3.84 WS 100 23.39 3.80 l 17 0045. In some embodiments. Form B is characterized by 24.42 3.64 l 30 an X-ray powder diffraction pattern substantially similar to 25.53 3.49 l 25 25.97 3.43 W 12 the one depicted in FIG.1. In some embodiments, Form B is 26.82 3.32 l 28 characterized in that it has one or more peaks in its X-ray 27.51 3.24 W 14 powder diffraction pattern selected from those in Table 1. In 29.69 3.01 W 12 some embodiments, Form B is characterized by at least one, 30.17 2.96 W 12 31.10 2.87 W 11 at least two, at least three, at least four, at least five, at least six, 31.65 2.83 W 11 at least seven, at least eight, at least nine, at least ten, at least 34.96 2.56 W 11 eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eigh teen, at least nineteen, at least twenty, at least twenty-one, at 0046. The terms used in the tables herein have the follow least twenty-two, at least twenty-three, at least twenty-four, at ing meanings: The term “vs' stands for “very strong.” The least twenty-five, at least twenty-six, at least twenty-seven, at term “s' stands for “strong.” The term “m” stands for least twenty-eight, at least twenty-nine, at least thirty, at least “medium. The term “w” Stands for “weak. The term “vw’ thirty-one, at least thirty-two, at least thirty-three, or at least stands for “very weak.” thirty-four peaks in its X-ray powder diffraction pattern 0047. In some embodiments. Form B is characterized by selected from those in Table 1. In some embodiments, Form B one or more peaks in its X-ray powder diffraction pattern of compound 1 is characterized in that it has one or more selected from those in Table 2. In some embodiments, Form B peaks in its X-ray powder diffraction pattern selected from is characterized by at least one, at least two, at least three, at the strong and very strong peaks in Table 1. In some embodi least four, at least five, at least six, at least seven, at least eight, ments. Form B of compound 1 is characterized in that it has all at least nine, at least ten, at least eleven, at least twelve, or at the peaks in its X-ray powder diffraction pattern selected least thirteen peaks in its X-ray powder diffraction pattern from the strong and very strong peaks in Table 1. In some selected from those in Table 2. In some embodiments, the embodiments. Form B of compound 1 is characterized in that characteristic peaks include at least the two very strong peaks it has one or more peaks in its X-ray powder diffraction indicated in Table 2. In some embodiments, Form B is char pattern selected from the very strong peaks in Table 1. In some acterized by the two very strong peaks indicated in Table 2, embodiments. Form B of compound 1 is characterized in that and at least one, at least two, at least three, at least four, at least it has all the peaks in its X-ray powder diffraction pattern five, at least six, at least seven, at least eight, at least nine, at selected from the very strong peaks in Table 1. In some least ten, at least eleven, at least twelve, or at least thirteen of embodiments. Form B of compound 1 is characterized in that the other strong peaks in its X-ray powder diffraction pattern it has both very strong peaks listed in Table 1 (i.e., 19.02 and selected from those in Table 2. 23.16 angle theta-2). TABLE 2 TABLE 1. Select characteristic peaks from the X-ray powder diffraction pattern. X-ray powder diffraction pattern. Angle d value Intensity Intensity Angle d value Intensity Intensity 2-Theta Angstrom (relative) % 2-Theta Angstrom (relative) % 13.94 6.3 S 31 6.OS 14.6 l 16 14.52 6.1 S 55 6.48 13.6 W 10 16.27 5.45 S 60 8.78 10.1 W 11 16.60 S.34 S 42 9.00 9.8 l 22 17.62 S.O3 S 57 12.16 7.3 l 23 18.76 4.73 S 32 13.94 6.3 S 31 19.02 4.66 WS 79 14.25 6.2 l 25 19.29 4.6O S 43 14.52 6.1 S 55 1964 4.52 S S4 16.27 5.45 S 60 22.32 3.98 S 60 16.60 S.34 S 42 22.77 3.90 S 50 17.62 S.O.3 S 57 23.02 3.86 S 53 18.09 4.90 l 18 23.16 3.84 WS 100 18.31 4.84 l 17 18.76 4.73 S 32 19.02 4.66 WS 79 0048. For instance, in one embodiment Form B is charac 19.29 4.60 S 43 terised by the 6 peaks (from Table 2) with the Angle 2-Theta 1964 4.52 S S4 20.78 4.27 l 23 values of 13.94, 14.52, 16.27, 19.02, 22.32, and 23.16. 20.95 4.24 l 17 0049. In some embodiments, Form B is characterized by a Raman spectrum Substantially similar to the one depicted in US 2016/0039810 A1 Feb. 11, 2016

FIG. 2. In some embodiments. Form B is characterized by one TABLE 3-continued or more peaks in its Raman spectrum selected from those in Table 3. In some embodiments, Form B is characterized by at Raman spectrum. least one, at least two, at least three, at least four, at least five, Wavenumber Normalized Intensity at least six, at least seven, at least eight, at least nine, at least (cm) Absolute Intensity (%) ten, at least fifteen, at least twenty, at least thirty, at least forty, 446 O.178 35.5 at least fifty, or at least sixty peaks in its Raman spectrum 425 O.153 3O.S selected from those in Table 3. 393 O.184 36.7 0050. In some embodiments. Form B is characterized by 355 O.160 31.9 (1) a Raman spectrum Substantially similar to the one 344 O.224 44.6 319 O.O83 6.5 depicted in FIG.2 and (2) an X-ray powder diffraction pattern 3O4 O.O84 6.7 substantially similar to the one depicted in FIG. 1. In some 285 O.107 21.3 embodiments. Form B is characterized by (1) a Raman spec 271 O. 119 23.7 trum substantially similar to the one depicted in FIG.2 and (2) 243 O.O68 3.5 225 O.O85 6.9 one or more peaks in its X-ray powder diffraction pattern 208 O.096 9.1 selected from those in Table 1. In some embodiments, Form B 150 O.O61 2.2 is characterized by (1) a Raman spectrum Substantially simi 136 O.O64 2.7 lar to the one depicted in FIG. 2; and (2) one or more peaks in 112 O.OS8 1.6 O95 O.O67 3.3 its X-ray powder diffraction pattern selected from those in O64 O.078 5.5 Table 2. In some embodiments, Form B is characterized by O39 O.O86 7.1 (1) a Raman spectrum Substantially similar to the one O25 O.170 33.9 depicted in FIG. 2; and (2) the two very strong peaks indicated O10 O.O87 7.3 996 O.O87 7.3 in Table 2 and at least one, at least two, at least three, at least 957 O.O43 8.6 four, at least five, at least six, at least seven, at least eight, at 943 O.O45 9.0 least nine, at least ten, or at least eleven of the other strong 849 O.139 27.7 peaks in its X-ray powder diffraction pattern selected from 819 O.O59 1.8 810 O.O59 1.8 those in Table 2. In some embodiments, Form B is character 789 0.255 SO.8 ized by (1) at least one, at least two, at least three, at least four, 741 O.196 39.0 at least five, at least six, at least seven, at least eight, at least 713 O.091 8.1 nine, at least ten, at least fifteen, at least twenty, at least thirty, 681 O.096 9.1 603 O.O84 6.7 at least forty, at least fifty, or at least sixty peaks in its Raman 585 O.O60 2.0 spectrum selected from those in Table 3; and (2) one or more 555 O.O70 3.9 peaks in its X-ray powder diffraction pattern selected from 5O1 0.075 4.9 those in Table 2. In some embodiments, Form B is character 484 O.096 9.1 446 O.O76 S.1 ized by (1) at least one, at least two, at least three, at least four, 419 O. 104 20.7 at least five, at least six, at least seven, at least eight, at least 372 O.O8O 5.9 nine, at least ten, at least fifteen, at least twenty, at least thirty, 349 O.O76 S.1 at least forty, at least fifty, or at least sixty peaks in its Raman 316 O.O90 7.9 261 O.100 9.9 spectrum selected from those in Table 3; and (2) the two very 234 O.132 26.3 strong peaks indicated in Table 2 and at least one, at least two, 185 O.141 28.1 at least three, at least four, at least five, at least six, at least 141 O.167 33.3 seven, at least eight, at least nine, at least ten, or at least eleven of the other strong peaks in its X-ray powder diffraction 0051. In some embodiments. Form B is characterized by pattern selected from those in Table 2. one or more peaks in its Raman spectrum selected from those in Table 4. In some embodiments. Form B is characterized by TABLE 3 at least one, at least two, at least three, at least four, at least Raman spectrum. five, at least six, at least seven, at least eight, at least nine, at least ten, or at least eleven peaks in its Raman spectrum Wavenumber Normalized Intensity selected from those in Table 4. In some embodiments, Form B (cm) Absolute Intensity (%) is characterized by (1) one or more peaks in its Raman spec 3322 O.018 3.6 trum selected from those in Table 4; and (2) an X-ray powder 3070 O. 105 20.9 diffraction pattern substantially similar to the one depicted in 3007 O.097 19.3 2993 O.131 26.1 FIG.1. In some embodiments. Form B is characterized by (1) 2963 O.171 34.1 one or more peaks in its Raman spectrum selected from those 2931 O.162 32.3 in Table 4; and (2) one or more peaks in its X-ray powder 2910 O.121 24.1 2871 O.O70 13.9 diffraction pattern selected from those in Table 1. In some 2842 O.100 19.9 embodiments. Form B is characterized by (1) one or more 1636 O.SO2 1OOO peaks in its Raman spectrum selected from those in Table 4; 1611 O.432 86.1 and (2) one or more peaks in its X-ray powder diffraction 1604 O.457 91.0 1508 O. 101 20.1 pattern selected from those in Table 2. In some embodiments, 1497 O.108 21.5 Form B is characterized by (1) at least one, at least two, at 1478 0.137 27.3 least three, at least four, at least five, at least six, at least seven, 1459 O. 101 20.1 at least eight, at least nine, at least ten, or at least eleven peaks in its Raman spectrum selected from those in Table 4; and (2) US 2016/0039810 A1 Feb. 11, 2016

one or more peaks in its X-ray powder diffraction pattern TABLE 2A selected from those in Table 2. Select characteristic peaks the XRPD spectrum of Form B TABLE 4 Angle d value Intensity Intensity 2-Theta Angstrom (relative) % Select characteristic peaks from the Raman spectrum. 13.94 6.3 S 31 Wavenumber Absolute Normalized 23.16 3.84 WS 100 (cm) Intensity Intensity (%) 1636 O.SO2 1OOO 1611 O.432 86.1 1604 O.457 91.O TABLE 3A 1446 O.178 35.5 1425 O.153 3O.S Select characteristic peaks from the Raman spectrum of form B. 1393 O.184 36.7 1355 O. 160 31.9 Wavenumber Absolute Normalized 1344 O.224 44.6 (cm) Intensity Intensity (%) 1025 O.170 33.9 789 0.255 SO.8 1636 O.SO2 1OOO 741 O.196 39.0 1604 O.457 91.0 741 O.196 39.0 0.052 For instance, in some embodiments Form B is char acterised by the 8 peaks (from Table 4) with the following wavenumbers (cm) 1636, 1604, 1446, 1425, 1393, 1355, TABLE 9A 1025, and 741. Select characteristic Peaks from the IR Spectrum of form B 0053 In some embodiments. Form B is characterized by an IR spectrum Substantially similar to the one depicted in Wavenumber Cm 96 T FIG. 10. In some embodiments. Form B is characterized by 1632.45 112286 one or more peaks in its IR spectrum selected from those in 1593.88 O.2291.97 Table 9. TABLE 9 IR spectrum. No. Position Intensity No. Position Intensity No. Position Intensity

1 3389.28, 18.88O3 2 3321.78 15.2998 3 3066.26 43.31.87 4 3O33.48 S2327 5 2991.05 44.2454 6 2970.8 36.2048 7 2960.2 35.8651 8 2928.38 28.2099 9 2839.67 28.5464 10 2765.42 68.3886 11 2707.57 71.199 12 2684.43 72.4374 13 2588.97 74.7507 14 2204.24 79.2123 15 1976.68 81.6905 16 1954.5 80.4172 17 1921.72 81.2251 18 1847.47 80.7596 19 1807.94 79.7842 2O 1680.66 59.904 21 1632.45 1.12286 22 1593.88 O.229.197 23 1493.6 O.785332 24 1476.24 5.245O1 25 1458.89 16.6916 26 1431.89 12.9634 27 1390.42 25.9737 28 1379.82. 30.7322 29 1341.25 14.0312 30 1318.11 20.5376 31 1301.72 49.2933 32 1269.9 6.91712 33 1244.83 7.5622 34 1216.86 21.9545 35 1209.1S 26.O2S3 36 1128.1S SS.6498 37 1113.69 4.73713 38 109344 42.0985 39 1068.37 39.536 40 1036.55 51.1775 41 1023.OS 68.0011 42 1005.7 62.1369 43 994.12S 41-S6SS 44 955.555 72.4243 45 940.128 SS.4283 46 905415 77.3957 47 889.987 48.5083 48 848.525 48.96O4 49 808.992 37.3274 50 789.707 46.8949 51 754.995 16.0235 52 743.424 S2.7696 53 710.64 66.7717 S4 679.78S 46.5898 55 6O1.682. 34.7989 56 554.434 68.6904 57 S21.6S 76.6701 58 477.296 61.4961 59 442.583 77.4332 60 428.12 78.2972 61 410.763 75.3479

0054. In some embodiments Form B is characterised by TABLE 9A-continued the 5 peaks (from Table 9) with the following wavenumbers (cm) 1632.45, 1593.88, 1244.83, 754.995, and 601.682. Select characteristic Peaks from the IR Spectrum of form B 0055. In some embodiments. Form B is characterized by (1) an XRPD patterns having peaks shown in Table 2a, (2) Wavenumber Cm' 96 T Raman spectrum with characteristic peaks shown in the Table 1244.83 7.5622 3a, (3) IR spectrum with characteristic peaks shown Table 9a, 754.995 16.023S and (4) a DSC thermogram with an endotherm having a peak temperature (T) of about 176° C. US 2016/0039810 A1 Feb. 11, 2016

0056. In some embodiments. Form B is characterized by TABLE 9C-continued (1) an XRPD patterns having peaks shown in Table 2b, (2) Raman spectrum with characteristic peaks shown in the Table Select characteristic Peaks from the IR Spectrum of form B 3b, (3) IR spectrum with characteristic peaks shown Table 9b, Wavenumber (cm) 96 T and (4) a DSC thermogram with an endotherm having a peak 754.995 16.023S temperature (T) of about 176° C. 6O1682 34.7989 TABLE 2B 0058. In some embodiments, Form B is characterised by Select characteristic peaks the XRPD Spectrum of Form B the following: Angle d value Intensity Intensity (i) Characteristic peaks from the XRPD spectrum of Form B 2-Theta Angstrom (relative) % 13.94 6.3 S 31 Angle d value Intensity Intensity 19.02 4.66 WS 79 2-Theta Angstrom (relative) (%) 23.16 3.84 WS 100 13.94 6.3 S 31 14.52 6.1 S 55 16.27 5.45 S 60 TABLE 3B 19.02 4.66 WS 79 22.32 3.98 S 60 Select characteristic peaks from the Raman spectrum of form B. 23.16 3.84 WS 100 Wavenumber Absolute Normalized (cm) Intensity Intensity (%) and 1636 O.SO2 1OO.O (ii) Characteristic peaks from the Raman spectrum of Form B. 1604 O.457 91.0 1025 O.170 33.9 741 O.196 39.0 Wavenumber Absolute Normalized (cm) Intensity Intensity (%) 1636 OSO2 1OOO 1604 O457 91.0 TABLE 9B 1446 O.178 35.5 1425 O.153 3O.S Select characteristic Peaks from the IR Spectrum of form B 1393 O.184 36.7 1355 O-160 31.9 Wavenumber (cm) 96 T 1025 O.170 33.9 1632.45 1.12286 741 O.196 39.0 1593.88 O.2291.97 1244.83 7.5622 754.995 16.023S and 6O1682 34.7989 (iii) Characteristic Peaks from the IR Spectrum of Form B

0057. In some embodiments. Form B is characterized by Wavenumber (cm) 96 T (1) an XRPD patterns having peaks shown in Table 2c, (3) IR 1632.45 1.12286 spectrum with characteristic peaks shown Table 9c, and (3) a 1593.88 O.2291.97 DSC thermogram with an endotherm having a peak tempera 1244.83 7.5622 754.995 16.023S ture (T) of about 176° C. 6O1682 34.7989 TABLE 2C and Select characteristic peaks the XRPD spectrum of Form B (iv) a DSC thermogram with an endotherm having a peak Angle d value Intensity Intensity temperature (T) of about 176° C. 2-Theta Angstrom (relative) % 0059. In some embodiments, Form B has a DSC thermo 13.94 6.3 S 31 gram substantially similar to the one depicted in FIG. 3. In 19.02 4.66 WS 79 some embodiments, Form B is characterized in that it has a 23.16 3.84 WS 100 DSC thermogram with an endotherm having a peak tempera ture (T) of about 176°C. In some embodiments, Form B is characterized in that it has a DSC thermogram with a AH of about 105 J/g. In some embodiments. Form B is characterized TABLE 9C in that it has a glass transition (T) of about 71° C. after Select characteristic Peaks from the IR Spectrum of form B quench cooling. In some embodiments, Form B is character ized in that it has a ACp of about 0.48J/gafter quench cooling. Wavenumber (cm) 96 T 0060. In some embodiments. Form B has a DVS isotherm 1632.45 112286 substantially similar to the one depicted in FIG. 4. In some 1593.88 O.2291.97 embodiments, Form B is characterized in that it has a Am of 0.1 wt % from 50% relative humidity (rh.) to 85% rh. US 2016/0039810 A1 Feb. 11, 2016

0061. In some embodiments. Form B has a TG-FTIR ther Practice of Pharmacy, 19" edition, Mack Publishing Com mogram substantially similar to the one depicted in FIG. 5. In pany, Easton, Pa. 1995: Hoover, John E., Remington's Phar some embodiments, Form B is characterized in that it losses maceutical Sciences, Mack Publishing Company, Easton, Pa. about 2.0 wt % or 0.5 equivalent (eq.) of HO after the 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceu temperature of Form B is increased from about 100° C. to tical Dosage Forms, Marcel Decker, New York, N.Y. 1980; about 230° C. and Pharmaceutical Dosage Forms, and Drug Delivery Sys 0062. In some embodiments, Form B has a microscopic tems, 7" edition, Lippincott Williams & Wilkins, 1999, all of image substantially similar to the one depicted in FIG. 7A or which are incorporated herein by reference in their entireties. FIG. 7B. In some embodiments, Form B is granular crystals. 0068. In general, doses of provided pharmaceutical com 0063. In some embodiments. Form B has an observed positions employed for adulthuman treatment are typically in melting point of about 155-168° C. the range of about 0.01 mg to about 5000 mg per day. In 0064. In some embodiments. Form B is stable for at least certain embodiments, doses employed for adult human treat about 1 month, at least about 2 months, at least about 4 ment are from about 1 mg to about 1000 mg per day. In certain months, at least about 6 months, at least about 12 months, at embodiments, a desired dose is conveniently presented in a least about 18 months, at least about 24 months, or at least single dose or in divided doses administered simultaneously about 3 years at about 25°C. and about 60% relative humidity. (or over a short period of time) or at appropriate intervals, for In some embodiments, Form B has substantially the same example, as two, three, four or more Sub-doses per day. XRPD pattern post storage for at least about 1 month, at least 0069. It will be understood that a specific dosage and about 2 months, at least about 4 months, at least about 6 treatment regimen for any particular subject may depend on a months, at least about 12 months, at least about 18 months, at variety of factors, including the activity of the specific com least about 24 months, or at least about 3 years at about 25°C. pound employed, age, body weight, general health, sex, diet, and about 60% relative humidity. In some embodiments, time of administration, rate of excretion, drug combination, Form B has substantially the same IR spectrum post storage and the judgment of the treating physician and the severity of for at least about 1 month, at least about 2 months, at least the particular disease being treated. The amount of a provided about 4 months, at least about 6 months, at least about 12 compound in the composition may also depend upon the months, at least about 18 months, at least about 24 months, or particular compound in the composition. at least about 3 years at about 25°C. and about 60% relative humidity. Methods of Preparing Form B 0065. In some embodiments. Form B is stable for at least 0070 The present invention also provides methods of pre about 1 month, at least about 2 months, at least about 4 paring Form B. In certain embodiments, methods of prepar months, at least about 6 months, at least about 8 months, at ing Form B comprise mixing a solution of compound 1 in least about 10 months, at least about 12 months, at least about methanol with an aqueous Solution of a base to provide a 18 months, or at least about 24 months at about 40° C. and mixture. In certain embodiments, the methods of preparing about 75% relative humidity. In some embodiments. Form B Form B further comprise lowering the temperature of the has substantially the same XRPD pattern post storage for at mixture to provide a solid. In certain embodiments, the meth least about 1 month, at least about 2 months, at least about 4 ods of preparing Form B further comprise isolating the Solid months, at least about 6 months, at least about 8 months, at from the mixture. least about 10 months, at least about 12 months, at least about 0071 Compound 1 useful in the preparation of Form B 18 months, or at least about 24 months at about 40° C. and may be substantially free of impurities. In certain embodi about 75% relative humidity. In some embodiments. Form B ments, compound 1 useful in the preparation of Form B is has substantially the same IR spectrum post storage for at about 90% free of impurities. In certain embodiments, com least about 1 month, at least about 2 months, at least about 4 pound 1 useful in the preparation of Form B is about 92% free months, at least about 6 months, at least about 8 months, at of impurities. In certain embodiments, compound 1 useful in least about 10 months, at least about 12 months, at least about the preparation of Form B is about 95% free of impurities. In 18 months, or at least about 24 months at about 40° C. and certain embodiments, compound 1 useful in the preparation about 75% relative humidity. of Form B is about 97% free of impurities. In certain embodi ments, compound 1 useful in the preparation of Form B is Pharmaceutical Compositions about 99% free of impurities. In certain embodiments, com 0066. In some embodiments, the present invention pro pound 1 useful in the preparation of Form B is about 99.5% vides a composition comprising crystalline Form B of com free of impurities. In certain embodiments, compound 1 use pound 1 described herein and optionally a pharmaceutically ful in the preparation of Form B includes compound 2 as an acceptable excipient. In certain embodiments, the pharma impurity: ceutical compositions are useful for treating a disease, disor der, or condition described herein. In certain embodiments, a 2 provided composition is formulated for administration to a O O Subject in need of such composition. In certain embodiments, a provided composition is formulated for oral administration to a Subject. In certain embodiments, a provided composition 21 CO2H. is formulated into an oral dosage form. In certain embodi ments, a provided composition is formulated into a tablet, Sn powder, pill, capsule, or the like, for oral ingestion by a Subject. 0067 Suitable techniques, carriers, and excipients include those found within, for example, Remington. The Science and US 2016/0039810 A1 Feb. 11, 2016

0072 Compound 1 may be present in the solution of com 0075. When the mixture of the inventive methods com pound 1 and methanol at any suitable concentration (e.g., prises a solid, the solid may be isolated from the mixture by a about 0.003 kg/L, about 0.01 kg/L, about 0.02 kg/L, about process known in the art, Such as by filtration and/or centri 0.03 kg/L, about 0.04 kg/L, about 0.05 kg/L, about 0.06 kg/L, fuge. The solid isolated form the mixture may optionally be about 0.08 kg/L, about 0.1 kg/L, about 0.2 kg/L, about 0.5 Subject to a reduced pressure and/or a Suitable temperature as kg/L, or about 1 kg/L), as the solubility of compound 1 described herein. In certain embodiments, the solid in the permits. In certain embodiments, the concentration of com mixture comprises Form B. In certain embodiments, the solid pound 1 in the Solution of compound 1 and methanol is about in the mixture comprises Form B that is substantially free of 0.04 kg/L. impurities. In certain embodiments, the solid isolated from the mixture comprises Form B. In certain embodiments, the 0073. The base useful in the preparation of Form B may be solid isolated from the mixture comprises Form B that is any inorganic base. In certain embodiments, the inorganic substantially free of impurities. In certain embodiments, the base is ammonia. In certain embodiments, the inorganic base solid isolated from the mixture comprises at least 99%, at is ammonium carbonate. In certain embodiments, the inor least 99.2%, at least 99.4%, at least 99.5%, at least 99.6%, at ganic base is ammonium hydroxide. In certain embodiments, least 99.7%, at least 99.8%, at least 99.9%, at least 99.95%, at the inorganic base is an alkali metal carbonate. In certain least 99.99%, at least 99.995%, or at least 99.999%. Form B by embodiments, the inorganic base is LiCO, Na2CO, weight. KCO, Rb2CO, or CsCO. In certain embodiments, the inorganic base is an alkali metal bicarbonate. In certain 0076. The steps of preparing Form B may be performed at embodiments, the inorganic base is LiHCO, NaHCO any Suitable temperature, e.g., a Suitable temperature of at KHCO, RbHCO, or CshCO. In certain embodiments, the least about 60° C. and lower than about 65° C. Other ranges inorganic base is an alkali metal hydroxide. In certain are also possible. In certain embodiments, the Suitable tem embodiments, the inorganic base is LiOH, NaOH, KOH, perature is about 0°C. In certain embodiments, the suitable RbOH, or CsCH. In certain embodiments, the inorganic base temperature is about 23°C. In certain embodiments, the suit is an alkaline earth metal carbonate. In certain embodiments, able temperature is about 60°C. In certain embodiments, the the inorganic base is BeCO, MgCO, CaCO, SrCO, or suitable temperature is about 65° C. A suitable temperature BaCO. In certain embodiments, the inorganic base is an may be a variable temperature during one or more steps of a alkaline earth metal bicarbonate. In certain embodiments, the method of the invention. In certain embodiments, the tem inorganic base is Be(HCO), Mg(HCO), Ca(HCO), perature of the solution of compound 1 in methanol is a Sr(HCO), or Ba(HCO). In certain embodiments, the inor suitable temperature described herein (e.g., about 60 to 65° ganic base is an alkaline earth metal hydroxide. In certain C.). In certain embodiments, the temperature of the aqueous embodiments, the inorganic base is Be(OH), Mg(OH), solution of the base is a suitable temperature described herein Ca(OH), Sr(OH), or Ba(OH). The base useful in the prepa (e.g., about 60 to 65° C.). The temperature of the solution of ration of Form B may also be an organic base. In certain compound 1 in methanol and the temperature of the aqueous embodiments, the organic base is an aliphatic amine. In cer solution of the base may be the same or different. In the step tain embodiments, the organic base is an aromatic amine. In oflowering the temperature of the mixture, the temperature of certain embodiments, the organic base is a primary amine. In the mixture may be lowered by about 10°C., about 20°C., certain embodiments, the organic base is a secondary amine. about 30°C., about 35° C., about 40°C., about 45° C., about In certain embodiments, the organic base is a tertiary amine. 50° C., about 60° C., about 65° C., about 70° C., about 80°C., In certain embodiments, the organic base is triethylamine, about 90° C., or about 100° C. In certain embodiments, the DIPEA, or DBU. In certain embodiments, the organic base is temperature of the mixture is lowered by at least about 35 and Substituted pyridine. In certain embodiments, the organic less than about 45°C. In certain embodiments, the mixture is base is 2.6-lutidine or DMAP. In certain embodiments, the substantially homogeneous before the temperature of it is organic base is unsubstituted pyridine. The base may be lowered. In certain embodiments, the mixture is substantially present in the aqueous solution at any suitable concentration free of solid materials before the temperature of the mixture is (e.g., about 0.01 g/L, about 0.03 g/L, about 0.1 g/L, about 0.2 lowered. In certain embodiments, the mixture is heteroge g/L, about 0.3 g/L, about 0.4 g/L, about 0.5g/L, about 0.7 g/L, neous after the temperature of it is lowered. In certain about 1 g/L, about 3 g/L, about 10 g/L, or about 30 g/L), as the embodiments, the mixture comprises a Solid after the tem solubility of the base permits. In certain embodiments, the perature of the mixture is lowered. In certain embodiments, base is present in the aqueous solution at about 0.2 g/L. the mixture comprises a solid and a liquid after the tempera 0074. In certain embodiments, the solution of compound 1 ture of the mixture is lowered. in methanol is Substantially homogeneous. In certain embodi 0077. A suitable condition may also include a suitable ments, the Solution of compound 1 in methanol is Substan pressure under which one or more steps of the inventive tially free of solid materials. In certain embodiments, the methods are performed. In certain embodiments, the suitable aqueous solution of the base is Substantially homogeneous. In pressure is about 1 atmosphere. A Suitable pressure may also certain embodiments, the aqueous solution of the base is be higher or lower than 1 atmosphere (i.e., a reduced pres substantially free of solid materials. In certain embodiments, Sure). A reduced pressure may be a pressure lower than about the mixture of the inventive methods is a substantially homo 10' atmosphere, lower than about 10° atmosphere, lower geneous solution. In certain embodiments, the mixture is than about 10 atmosphere, lower than about 10" atmo heterogeneous. In certain embodiments, the mixture com sphere, lower than about 10 atmosphere, lower than about prises a Solid. In certain embodiments, the mixture comprises 10' atmosphere, lower than about 107 atmosphere, lower a solid and a liquid. In certain embodiments, the mixture than about 10 atmosphere, lower than about 10 atmo comprises Form B. In certain embodiments, the mixture com sphere, lower than about 10' atmosphere, or lower than prises Form B that is substantially free of impurities. about 10' atmosphere. US 2016/0039810 A1 Feb. 11, 2016

0078. A suitable condition may also include a suitable maceutical compositions of compound 1 described herein, or atmosphere under which one or more steps of the inventive a pharmaceutically acceptable preparation thereof, to a Sub methods are performed. In certain embodiments, the suitable ject in need thereof. atmosphere is air. In certain embodiments, the Suitable atmo I0084 As used herein mood disorders are broadly recog sphere is an inert atmosphere. In certain embodiments, the nized and clearly defined by the relevant DSM-IV-TR (Diag Suitable atmosphere is a nitrogen or argon atmosphere. nostic and Statistical Manual of Mental Disorders, 4th Edi 0079 A suitable condition may also include a suitable tion, Text Revision) criteria. Thus, there are depressive time duration that one or more steps of the method lasts. In disorders of which the best known and most researched is certain embodiments, the suitable time duration is in the order major depressive disorder (MDD) commonly called clinical of minutes (e.g., about 30 min), hours (e.g., about 1 hour, depression or major depression, and bipolar disorder (BD), about 2 hours, about 3 hours, about 6 hours, or about 12 formerly known as manic depression and characterized by hours), days (e.g., about 1 day or about 2 days) or weeks (e.g., intermittent episodes of mania or hypomania, usually inter about 1 week). For example, in the step of lowering the laced with depressive episodes. Other depressive disorders temperature of the mixture, the temperature of the mixture include: atypical depression, melancholic depression, psy may be lowered over a suitable time duration described chotic major depression, catatonic depression, postpartum herein. depression, seasonal affective disorder, dysthymia, depres sive disorder not otherwise specified (DD-NOS) (e.g., recur Treatment Methods rent brief depression, minor depressive disorder), Substance 0080. The present disclosure contemplates the treatment induced mood disorders (e.g., alcohol induced mood disor or prophylaxis of a disease of the central nervous system, Such ders, benzodiazepine induced mood disorders, interferon as mood disorders (e.g., depression), anxiety disorders, and alpha induced mood disorders). neurodegenerative diseases. The term neurodegenerative dis I0085 Persons of skill in the art will be familiar with the lag ease encompasses a condition leading to the progressive loss period of traditional antidepressant medications, and with the of structure or function of neurons, including death of neu heightened anxiety produced by the newer generation antide rons. Examples of neurodegenerative diseases contemplated pressants, including SSRIs, SNRIs and NRI's in the early herein include AIDS dementia complex, adrenoleukodystro stages of treatment before the antidepressant effects are seen phy, alexander disease, Alpers disease, amyotrophic lateral (within 2-4 weeks). Thus, in certain embodiments, the com Sclerosis, ataxia telangiectasia, Batten disease, bovine pounds described herein can be administered to a Subject in spongiform encephalopathy, brainstem and cerebellum atro need thereof as a substitute or replacement for traditional phy, Canavan disease, corticobasal degeneration, antidepressant medication. In other embodiments, com Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal pounds described herein can be administered to a Subject in familial insomnia, Friedrich's ataxia, familial spastic para need thereof as a Supplement to traditional antidepressant paresis, frontotemporal lobar degeneration, Huntington's medication. In other embodiments, there is provided a disease, infantile Refsum disease, Kennedy's disease, Krabbe method for treating or preventing depression in a subject, the disease, Lyme disease, Machado-Joseph disease, monomelic method including the step of administering to said Subject a amyotrophy, multiple Sclerosis, multiple system atrophy, compound (e.g., Form B of compound 1), or an embodiment neuroacanthocytosis, Niemann-Pick disease, neurodegenera thereof, described herein, or a pharmaceutical composition tion with brain iron accumulation, opSoclonus myoclonus, thereof, in the absence of adjunct antidepressant therapy. Parkinson's disease, Pick's disease, primary lateral Sclerosis, I0086 Replacing traditional antidepressant medication progranulin, progressive multifocal leukoencephalopathy, with the present compounds can be advantageous, particu progressive Supranuclear palsy, protein aggregation, Refsum larly where the traditional medication is associated with one disease, Sandhoff disease, diffuse myelinoclastic sclerosis, or more adverse effects (e.g., anxiety, nausea, headaches, Shy-Drager syndrome, spinocerebellar ataxia, spinal muscu erectile dysfunction, early-onset Suicidal tendencies, etc). lar atrophy, spinal and bulbar muscular atrophy, Subacute Examples of traditional antidepressant medication would be combined degeneration of spinal cord, Tabes dorsalis, Tay known to those skilled in the art and include, but are not Sachs disease, toxic encephalopathy, transmissible spongi limited to, selective serotonin re-uptake inhibitors (SSRI), form encephalopathy, and Wobbly hedgehog syndrome. serotonin/noradrenalin re-uptake inhibitors, selective norad 0081. In certain embodiments, compound 1, and/or one or renalin re-uptake inhibitors, monoamine oxidase inhibitors, more pharmaceutical compositions of compound 1, can be tricyclic antidepressants, lithium and other mood stabilisers, used to treat, ameliorate the signs and/or symptoms of pre atypical antidepressants, and hormones such as estrogen or vent, or otherwise delay the onset or development of the CNS progestogen. disease, disorder, or condition. I0087. In other embodiments, the present compounds are 0082 Taught herein, therefore, is the use of compound 1. administered to a subject in need thereof, together with tra and/or one or more pharmaceutical compositions of com ditional antidepressants for a period of about 2-4 weeks, to pound 1 described herein, or a pharmaceutically acceptable address the symptoms of depression, with the option of dis preparation thereof, in the manufacture of a medicament for continuing treatment with the present compounds whilst con treating and/or preventing central nervous system disorders, tinuing with the traditional therapy. In other embodiments, Such as mood disorders (e.g., depression), anxiety disorders, the Subject is treated with both a present compound and one or or neurodegenerative diseases, in a subject in need thereof. more traditional antidepressant medications (administered 0083. Also provided herein are methods of treating and/or sequentially or in combination) for the duration of the treat preventing central nervous system disorders, such as mood ment period. Such combination therapy may be particularly disorders (e.g., depression), anxiety disorders, or neurode useful, for example, where the combination of a present com generative diseases comprising the administration of an poundandone or more traditional antidepressant medications effective amount of compound 1, and/or one or more phar provides relief from depression in the acute lag phase of the US 2016/0039810 A1 Feb. 11, 2016 treatment period and/or where an additive or synergistic anti opiates, antidepressants, and benzodiazepines. The com depressant therapeutic effect is desired. pound, or pharmaceutical compositions thereof described 0088. Depression relapse can also occur in patients treated herein also can be used as a combination therapy, e.g., com with traditional antidepressant medication. Many Such com bining the treatment with other antidepressants such as ben pounds are administered for anywhere from months to years Zodiazepines (e.g., alprazolam, diazepam, lorazepam, clon and a reduction in efficacy is often seen with Such long-term ezepam), selective serotonin re-uptake inhibitors (SSRI) use, leading to significant continuing depression and, dys (e.g., citalopram, dapoxetine, escitalopram, fluoxetine, flu function. Depression relapse may be Sudden onset for some Voxamine, indalpine, paroxetine, Sertraline, Zimelidine, patients, while for others it might be evident as a gradual Vilaxodone), serotonin norepinephrine reuptake inhibitors decline in mood and function, which diminishes over time as (SNRI) (e.g., venlafaxine, dulloxetine, desvenlafaxine, mil the patient approaches the state of relapse. Thus, patients who nacipran), monoamine oxidase inhibitors (e.g., phenelZine, experience Sudden onset of depression relapse or a gradual moclobemide), tricyclic antidepressants (e.g., trimipramine, depression relapse would benefit from the methods disclosed imipramine), tetracyclic antidepressants (e.g., mertazepine, herein, as the present compound, or pharmaceutical compo maprotiline), mood stabilisers (e.g. lithium, Sodium val sitions thereof, can offset the diminishing effect of traditional proate, Valproic acid), atypical antidepressants (e.g., bupro antidepressant therapy. Thus, the use of the present com pion), acetylcholinesterase inhibitors (e.g., donepezil, galan pound, or pharmaceutical compositions thereof may prevent tamine, rivastigmine), atypical antipsychotics (e.g., or partly alleviate depression relapse often seen in patients risperidone, aripiprizole, quetiapine, olanzapine), and hor taking traditional antidepressant medication. mones such as estrogen and progestogen. 0089. Thus, in certain embodiments, provided herein are 0095. It will thus be understood that compound 1, or phar methods for treating or preventing relapse in a subject receiv maceutical compositions thereof, can be used in the treatment ing antidepressant therapy, the method including the step of and/or prevention of any disease state, disorder, or condition administering to said subject Form B of compound 1, or a which may be ameliorated by enhancement of neurite out pharmaceutical composition thereof. growth. 0090 The traditional antidepressant therapies that are 0096. In certain embodiments, the neurite outgrowth-re associated with potential depression relapse in a subject sponsive disease is a neurodegenerative disease. In a certain would be known to those skilled in the art. Examples include, embodiments, the neurodegenerative disease is multiple scle but are not limited to, dosage increases, alternative SSRIs or rosis or a Parkinsonian related disorder. In a further embodi SNRIs, and non-SSRI antidepressants such as noradrenaline ment, the neurodegenerative disease is multiple sclerosis. In a re-uptake inhibitors, monoamine oxidase inhibitors, tricyclic further embodiment the disease may involve a condition antidepressants, lithium and other mood stabilisers, atypical which involves neural damage including wound healing, spi antidepressants and hormones such as estrogen and progesto nal cord injury, peripheral nerve disorders. gen, also referred to herein as “second antidepressant com pounds.” 0097. Also contemplated herein is a sub-threshold dis ease, condition, state, disorder or trauma. In an embodiment, 0091. The desired therapeutic activity, or effect, will typi the disease, condition, state, disorder, or trauma is defined by cally depend on the condition being treated. For example, its symptoms. Hence, compound 1, or a pharmaceutical com where the subject is being treated for depression, the thera position thereof contemplated herein, is useful in ameliorat peutic effect may be a reduction in at least one clinical Symp ing the symptoms of a disease, condition, state, disorder, or tom of depression, including, but not limited to, cognitive trauma of the CNS. By “trauma' this includes stroke, brain impairment, loss of appetite, mood, and/or inactivity. haemorrhage, or another condition or event of the systemic 0092. In certain embodiments, compound 1, or pharma vasculature which affects the CNS. The symptoms of a dis ceutical compositions thereof described herein, or a pharma ease, condition, state, disorder, or trauma of the CNS would ceutically acceptable preparation thereof, is administered to be familiar to those skilled in the art. Examples of such said Subject sequentially (i.e., before or after) or in combina symptoms include mood disorders, such as depression. Thus, tion with a second antidepressant compound (e.g., with exist in certain embodiments, the compound forms described ing antidepressant therapy). herein are used in the treatment of depression attributed to (or 0093. In certain embodiments, the present compound, or associated with) a neurodegenerative disease in the Subject. pharmaceutical compositions thereof, have the further added 0098. The compound forms described herein may also be advantage over traditional therapy in that they exhibit reduced used as therapy, e.g., combining the treatment with other sedative side effects which may adversely affect a subjects neurodegenerative treatments, such as acetylcholinesterase quality of life. In certain embodiments, the present com inhibitors (e.g., Aricept, Exelon), and treatments for multiple pound, or pharmaceutical compositions thereof, are free of Sclerosis (e.g., Avonex, Betaseron, Copaxone, TySabri, measurable sedative side effects. Gilenya). 0094 Sudden discontinuation of antidepressant medica tion may produce withdrawal effects caused by physical 0099. In a further embodiment there is also provided a dependence on the drug. Compounds can be evaluated for method of treatment of disorders of the central nervous sys physical dependence in a simple animal model where, fol tem comprising the administration of an effective amount of lowing a period of chronic dosing (e.g., for 14-20 days), the compound 1, or a pharmaceutical composition thereof, to a study drug is stopped and measurements of food intake, body subject in need thereof. weight and body temperature are taken over the next 5 days. 0100. It will be understood that compound 1, or a pharma The symptoms of abrupt discontinuation of the drug are ceutical composition thereofas described herein, can be used manifest as significantly reduced appetite, weight loss, and in the treatment of anxiety or conditions/disease states asso drop in body temperature. This model is suitable for detecting ciated with anxiety such as irritable bowel syndrome and the effects across a broad range of drug classes including fibromyalgia. US 2016/0039810 A1 Feb. 11, 2016

0101. In certain embodiments, an anxiety disorder is clas vider. Some people can have many of the aforementioned sified as one of the following: symptoms and cope with them well enough to maintain a high 0102 panic disorder, level of functioning. 0103 obsessive-compulsive disorder (OCD), (vi) The condition is not due to a Substance or medical issue. 0104 post-traumatic stress disorder (PTSD), I0120 In certain embodiments, a subject to be treated with 0105 social phobia (or social anxiety disorder SAD), compound 1, or a pharmaceutical composition thereof, as 0106 specific phobias, described herein may be identified by one or more of the 0107 generalized anxiety disorder (GAD), above criteria for generalized anxiety disorder. 0108 substance-induced anxiety disorder, and 0121. In certain embodiments, compound 1, or a pharma 0109 acute stress disorder (ASD). ceutical composition thereof, as described herein may be used 0110. In certain embodiments, compound 1, or a pharma to treat or prevent one or more symptoms associated with an ceutical composition thereof, as described herein may be used anxiety disorder. in the treatment of a panic disorder. 0.122 Each anxiety disorder has different symptoms, but 0111. In certain embodiments, compound 1, or a pharma all the symptoms cluster around excessive, irrational fear and ceutical composition thereof, as described herein may be used dread. in the treatment of obsessive-compulsive disorder (OCD). I0123. In another embodiment compound 1, or a pharma 0112 In certain embodiments, compound 1, or a pharma ceutical composition thereof, as described herein may be used ceutical composition thereof, as described herein may be used in the treatment of depression, for instance, major depressive in the treatment of post-traumatic stress disorder (PTSD). disorder. 0113. In an embodiment compound 1, or a pharmaceutical 0.124 Major depressive disorder criteria include: composition thereof, as described herein may be used in the (i) At least five of the following symptoms have been present treatment of Social phobia (or social anxiety disorder— during the same 2-week period and represent a change from SAD). previous functioning: at least one of the symptoms is either 0114. In certain embodiments, compound 1, or a pharma 0.125 1) depressed mood or ceutical composition thereof, as described herein may be used in the treatment of specific phobias. In certain embodiments, 0.126 2) loss of interest or pleasure. compound 1 or a pharmaceutical composition thereof, as (ii) Depressed mood most of the day, nearly every day, as described herein may be used foragoraphobia or agoraphobia indicated either by Subjective report (e.g., feels sad or empty) without history of panic disorder. In certain embodiments, or observation made by others (e.g., appears tearful). compound 1 or a pharmaceutical composition thereof, as (iii) Markedly diminished interest or pleasure in all, or almost described herein may be used for animal phobia. all, activities most of the day, nearly every day (as indicated 0115. In certain embodiments, compound 1, or a pharma either by subjective account or observation made by others). ceutical composition thereof, as described herein may be used (iv) Significant weight loss when not dieting or weight gain in the treatment of Substance-induced anxiety disorder. (e.g., a change of more than 5% of body weight in a month), 0116. In certain embodiments, compound 1, or a pharma or decrease or increase in appetite nearly every day. ceutical composition thereof, as described herein may be used (v) Insomnia or hypersomnia nearly every day. in the treatment of acute stress disorder (ASD). (vi) Psychomotor agitation or retardation nearly every day 0117. In certain embodiments, compound 1, or a pharma (observable by others, not merely subjective feelings of rest ceutical composition thereof, as described herein may be used lessness or being slowed down). in the treatment of generalized anxiety disorder (GAD). (vii) Fatigue or loss of energy nearly every day. 0118 Generalised anxiety disorder criteria include: (viii) Feelings of worthlessness or excessive or inappropriate (i) At least 6 months of “excessive anxiety and worry' about guilt (Which may be delusional) nearly every day (not merely a variety of events and situations. Generally, “excessive' can self-reproach or guilt about being sick). be interpreted as more than would be expected for a particular (ix) Diminished ability to think or concentrate, or indecisive situation or event. Most people become anxious over certain ness, nearly every day (either by Subjective account or as things, but the intensity of the anxiety typically corresponds observed by others). to the situation. (X) Recurrent thoughts of death (not just fear of dying), recur (ii) There is significant difficulty in controlling the anxiety rent Suicidal ideation without a specific plan, or a suicide and worry. If someone has a very difficult struggle to regain attempt or specific plan for committing Suicide control, relax, or cope with the anxiety and worry, then this (xi) The symptoms do not meet criteria for a mixed episode. requirement is met. (xii) The symptoms cause clinically significant distress or (iii) The presence for most days over the previous six months impairment in Social, occupational, or other important areas of 3 or more (only 1 for children) of the following symptoms: of functioning. 1. Feeling wound-up, tense, or restless (xiii) The symptoms are not due to the direct physiological 2. Easily becoming fatigued or worn-out effects of a Substance (e.g. a drug of abuse, a medication) or 3. Concentration problems a general medical condition (e.g., hypothyroidism). 4. Irritability (xiv) The symptoms are not better accounted for by bereave ment, i.e., after the loss of a loved one, the symptoms persist 0119) 5. Significant tension in muscles for longer than 2 months or are characterized by marked 6. Difficulty with sleep functional impairment, morbid preoccupation with worth (iv) The symptoms are not part of another mental disorder. lessness, Suicidal ideation, psychotic symptoms, or psycho (v) The symptoms cause “clinically significant distress' or motor retardation. problems functioning in daily life. “Clinically significant is 0127. The above criteria have been sourced from the the part that relies on the perspective of the treatment pro American Psychiatric Association (2000) Diagnostic and US 2016/0039810 A1 Feb. 11, 2016

Statistical Manual of Mental Disorders (4th Ed., Text Revi between primary prophylaxis (to prevent the development of sion). Washington D.C.: American Psychiatric Association. a disease or symptom) and secondary prophylaxis (whereby 0128. In certain embodiments, a subject to be treated with the disease or symptom has already developed and the Subject compound 1, or a pharmaceutical composition thereof, as is protected against worsening of this process). described herein may be identified by one or more of the 0.136. As used herein, the term “effective amount” relates above criteria for major depressive disorder. to an amount of a compound, or pharmaceutical composition 0129. In another embodiment compound 1, or a pharma thereof, which, when administered according to a desired ceutical composition thereof, as described herein may be used dosing regimen, provides the desired therapeutic activity. to treat or prevent one or more symptoms associated with Dosing may occurat intervals of minutes, hours, days, weeks, depression. months or years or continuously over any one of these peri 0130. Further disorders for which compound 1, or a phar ods. Suitable dosages lie within the range of about 0.1 ng per maceutical composition thereof, as described herein may be kg of body weight to 1 g per kg of body weight per dosage. of benefit include pain and nociception; emesis, including The dosage may be in the range of 1 Jug to, 1 g per kg of body acute, delayed and anticipatory emesis, in particular emesis weight perdosage, such as is in the range of 1 mg to 1 g per kg induced by chemotherapy or radiation, as well as motion of body weight per dosage. In one embodiment, the dosage sickness, and post-operative nausea and Vomiting; eating dis may be in the range of 1 mg to 500 mg per kg of body weight orders including anorexia nervosa and bulimia nervosa; pre per dosage. In another embodiment, the dosage may be in the menstrual syndrome; muscle spasm or spasticity, e.g. in range of 1 mg to 250 mg per kg of body weight per dosage. In paraplegic Subjects; hearing disorders, including tinnitus and yet another embodiment, the dosage may be in the range of 1 age-related hearing impairment, urinary incontinence; and mg to 100 mg per kg of body weight per dosage, such as up to the effects of substance abuse or dependency, including alco 50 mg per body weight per dosage. hol withdrawal, neuroses, convulsions, migraine, depressive 0.137 In certain embodiments, a provided method com disorder, bipolar disorder, psychotic disorder, neurodegen prises administering to a Subject in need thereof the present eration arising from cerebral ischemia, attention deficit compound, or pharmaceutical composition thereof, in a dos hyperactivity disorder, Tourette's syndrome, speech disorder, age to provide an effective amount in vivo that will enhance disorders of circadian rhythm, single-episode or recurrent neurite outgrowth (neurogenesis), including, but not limited major depressive disorder, dysthymic disorder, bipolar I or to the acute stages of treatment (e.g., within 1, 2, 3, or 4 weeks bipolar II manic disorder, cyclothymic disorder, Schizophre from the commencement of treatment). In an embodiment, an nia, and stuttering. effective amount in vivo has an in vitro equivalent concentra 0131. In an embodiment compound 1, or a pharmaceutical tion that is sufficient to increase neurite outgrowth by at least composition thereof, as described herein may be used in the 5%, at least 10%, at least 20%, or at least 50% in a neurite treatment of cerebralischemia. In certain embodiments, com outgrowth assay, for example, a neurite outgrowth assay pound 1, or a pharmaceutical composition thereof, as described herein. Methods of determining an in vitro equiva described herein may be used in the treatment of neurodegen lent concentration of the present compounds would be famil eration arising from cerebral ischemia. iar to the skilled artisan. For example, at from about 10 0.132. In an embodiment compound 1, or a pharmaceutical minutes to about 60 minutes after administration of the composition thereof, as described herein may be used in the present compounds to a Subject, a blood sample is taken and treatment of disorders of the circadian rhythm. assayed by HPLC, ELISA, gas chromatography, or by other 0133. In an embodiment compound 1, or a pharmaceutical suitable assay to determine the concentration per ml of blood. composition thereof, as described herein may be used in the An equivalent effective concentration can then be used in an treatment of pain and nociception. in vitro assay once factors such as the weight of the Subject, 0134. In an embodiment compound 1, or a pharmaceutical the appropriate blood volume of the subject and the appro composition thereof, as described herein may be used in the priate rate of diffusion of the present compound across the treatment of Alzheimer's disease. blood-brainbarrier are taken into account. In another embodi 0135) It should be appreciated that compound 1, or a phar ment, when the present compound is found to stimulate neu maceutical composition thereof, a described herein can be rite outgrowth in vitro (as compared to a control), an approxi administered to a subject in a treatment effective amount. In mate in vivo effective amount can be determined for a subject Some embodiments, a treatment effective amount is a thera by extrapolating the in vitro concentration to an in vivo peutically effective amount or a prophylactically effective equivalent. Factors such as the weight of the Subject, the amount. The term “therapeutically effective amount’ as used appropriate blood Volume of the Subject and the appropriate herein means that amount of active compound or pharmaceu rate of diffusion of the present compound across the blood tical agent that elicits the biological or medicinal response in brain barrier may be used to extrapolate an in vivo effective a tissue, system, animal or human that is being sought by a amount and hence the appropriate dosage amount that would researcher, Veterinarian, medical doctor, or other clinician. give rise to said in vivo effective amount. The therapeutically effective amount of the compound to be 0.138. Thereafter, treatment with the compound 1, or a administered will be governed by Such considerations, and is pharmaceutical composition thereof, may be continued the minimum amount necessary to ameliorate, cure, or treat throughout the treatment period or it may be ceased or the disease or disorder or one or more of its symptoms. The replaced with traditional therapeutic compounds. Methods of term “prophylactically effective amount” refers to an amount determining the effective amount of compound 1, or a phar effective in preventing or Substantially lessening the chances maceutical composition thereof, that is required for enhanc of acquiring a disease or disorder or in reducing the severity ing neurite outgrowth (neurogenesis) in vivo would be famil of the disease or disorder before it is acquired or reducing the iar to those skilled in the art. For example, enhancement of severity of one or more of its symptoms before the symptoms neurogenesis can be determined by measuring a symptom of develop. Roughly, prophylactic measures are divided the CNS disorder including, but not limited to, cognitive US 2016/0039810 A1 Feb. 11, 2016

impairment, degree and frequency of seizures or tremors, 0145 When co-administered with other agents, e.g., when motordysfunction, headaches and mood (e.g., degree of hap co-administered with another anti-anxiety or anti-depressant piness). medication, an “effective amount of the second agent will 0.139. The terms “administer”, “administering or depend on the type of drug used. Suitable dosages are known “administration' in reference to a compound, composition or for approved agents and can be adjusted by the skilled artisan formulation of the invention means introducing the com according to the condition of the Subject, the type of condition pound into the system of the animal in need of treatment. (s) being treated and the amount of a compound described When a compound of the invention is provided in combina herein being used. In cases where no amount is expressly tion with one or more other active agents, “administration' noted, an effective amount should be assumed. For example, and its variants are each understood to include concurrent compounds described herein can be administered to a subject and/or sequential introduction of the compound and the other in a dosage range from between about 0.01 to about 10,000 active agents. mg/kg body weight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01 to about 3000 mg/kg body 0140. In certain embodiments, an effective amount of weight/day, about 0.01 to about 1000 mg/kg body weight/day, compound 1, or a pharmaceutical composition thereof, for about 0.01 to about 500 mg/kg body weight/day, about 0.01 to administration one or more times a day to a 70kg adult human about 300 mg/kg body weight/day, about 0.01 to about 100 may comprise about 0.0001 mg to about 3000 mg, about mg/kg body weight/day. 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 0146 When “combination therapy” is employed, an effec 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about tive amount can be achieved using a first amount of com 1000 mg, about 1 mg to about 100 mg, about 10 mg to about pound 1, or a pharmaceutical composition thereof, and a 1000 mg. or about 100 mg to about 1000 mg. of a compound second amount of an additional Suitable therapeutic agent. per unit dosage form. 0.147. In certain embodiments, compound 1 or a pharma 0141. In certain embodiments, compound 1, or a pharma ceutical composition thereof as described herein, and the ceutical composition thereof, may be at dosage levels Suffi additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be cient to deliver from about 0.001 mg/kg to about 100 mg/kg, therapeutically effective if administered alone). In other from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 embodiments, compound 1 or a pharmaceutical composition mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 thereof as described herein, and the additional therapeutic mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about agent are each administered in an amount which alone does 0.1 mg/kg to about 10 mg/kg, and from about 1 mg/kg to not provide a therapeutic effect (a sub-therapeutic dose). In about 25 mg/kg, of Subject body weight per day, one or more yet other embodiments, compound 1 or a pharmaceutical times a day, to obtain the desired therapeutic effect. composition thereofas described herein can be administered 0142 Suitable dosage amounts and dosing regimens can in an effective amount, while the additional therapeutic agent be determined by the attending physician and may depend on is administered in a sub-therapeutic dose. In still other the particular condition being treated, the severity of the embodiments, compound 1 or a pharmaceutical composition condition as well as the general age, health and weight of the thereof as described herein, can be administered in a sub Subject. It will be appreciated that dose ranges as described therapeutic dose, while the additional therapeutic agent is herein provide guidance for the administration of provided administered in an effective amount. pharmaceutical compositions to an adult. The amount to be 0.148. As used herein, the terms “in combination' or “co administered to, for example, a child or an adolescent can be administration can be used interchangeably to refer to the determined by a medical practitioner or person skilled in the use of more than one therapy (e.g., one or more prophylactic art and can be lower or the same as that administered to an and/or therapeutic agents). The use of the terms does not adult. restrict the order in which therapies (e.g., prophylactic and/or 0143. The active ingredient may be administered in a therapeutic agents) are administered to a subject. single dose or a series of doses. While it is possible for the 0149 Co-administration encompasses administration of active ingredient to be administered alone, it is preferable to the first and second amounts of the compounds in an essen present it as a composition, preferably as a pharmaceutical tially simultaneous manner, such as in a single pharmaceuti composition. The formulation of Such compositions is well cal composition, for example, capsule or tablet having a fixed known to those skilled in the art. The composition may con ratio of first and second amounts, or in multiple, separate tain any suitable carriers, diluents or excipients. These capsules or tablets for each. In addition, Such co-administra include all conventional solvents, dispersion media, fillers, tion also encompasses use of each compound in a sequential Solid carriers, coatings, antifungal and antibacterial agents, manner in either order. When co-administration involves the dermal penetration agents, Surfactants, isotonic and absorp separate administration of the first amount of compound 1 or tion agents and the like. It will be understood that the com a pharmaceutical composition thereof as described herein, positions of the invention may also include other Supplemen and a second amount of an additional therapeutic agent, the tary physiologically active agents. compounds are administered Sufficiently close in time to have 0144. The compounds and pharmaceutical compositions the desired therapeutic effect. For example, the period of time described herein can be used in combination therapy with one between each administration which can result in the desired or more additional therapeutic agents. For combination treat therapeutic effect, can range from minutes to hours and can be ment with more than one active agent, where the active agents determined taking into account the properties of each com are in separate dosage formulations, the active agents may be pound Such as potency, Solubility, bioavailability, plasma administered separately or in conjunction. In addition, the half-life, and kinetic profile. For example, compound 1 or a administration of one element may be prior to, concurrent to, pharmaceutical composition thereofas described herein, and or Subsequent to the administration of the other agent. the second therapeutic agent can be administered in any order US 2016/0039810 A1 Feb. 11, 2016

within about 24 hours of each other, within about 16 hours of (Surodil, Timostenil), echinopsidine (Adepren), furazolidone each other, within about 8 hours of each other, within about 4 (Furoxone, Dependal-M), linezolid (Zyvox, Zyvoxam, hours of each other, within about 1 hour of each other or ZyVoxid), tranylcypromine (Parnate, Jatrosom), brofaromine within about 30 minutes of each other. (Consonar), metralindole (Inkazan), minaprine (Cantor), 0150 More, specifically, a first therapy (e.g., a prophylac moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), tic ortherapeutic agent such as a compound described herein) toloxatone (Humoryl), lazabemide (Pakio, Tempium), par can be administered prior to (e.g., 5 minutes, 15 minutes, 30 gyline (Eutonyl), rasagiline (AZilect), and selegiline (Depre minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 nyl, Eldepryl, Emsam). hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 0157. In certain embodiments, a second therapeutic agent weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 is a tricyclic antidepressant (TCA) selected from the group weeks before), concomitantly with, or Subsequent to (e.g., 5 consisting of amitriptyline (Tryptomer, Elavil, Tryptizol. minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, Laroxyl, Sarotex, Lentizol), butriptyline (Evadene, Evadyne, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 Evasidol, Centrolese), clomipramine (Anafranil), hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, desipramine (Norpramin, Pertofrane), dosulepin (Prothia 8 weeks, or 12 weeks after) the administration of a second den, Dothep, Thaden and Dopress), doxepin (Aponal, Adap therapy to a Subject. ine, Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, 0151 Examples of therapeutic agents that may be com Silenor), imipramine (Antideprin, Deprimin, Deprinol, Dep bined with compound 1, or a pharmaceutical composition Sol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Jan thereof, either administered separately or in the same phar imine, Melipramin, Surplix, Tofranil), lofepramine (Gama maceutical composition, include, but are not limited to, nil, Tymelyt, Lomont), nortriptyline (Sensoval, Aventyl, muscle relaxants, anticonvulsants, hypnotics, anesthetics, Pamelor, Norpress, Allegron, Noritren, Nortrilen), Protrip analgesics, cholinergics, antidepressants, mood stabilisers, tyline (Vivactil), and trimipramine (Surmontil, Rhotrimine, and anxiolytics. Stangyl). 0158. The compounds and compositions provided herein 0152. In certain embodiments, a second therapeutic agent can be administered by any route, including enteral (e.g., is a SSRI selected from the following: citalopram (Celexa, oral), parenteral, intravenous, intramuscular, intra-arterial, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Sero intramedullary, intrathecal, Subcutaneous, intraventricular, pram, Citox, Cital), dapoxetine (Priligy), escitalopram (Lex transdermal, interdermal, rectal, intravaginal, intraperitoneal, apro, Cipralex, Seroplex, Esertia), fluoxetine (Prozac, Fon topical (as by powders, ointments, creams, and/or drops), tex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, mucosal, nasal, bucal, Sublingual; by intratracheal instilla Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), tion, bronchial instillation, and/or inhalation; and/or as an Prodep (IND)), fluvoxamine (Luvox, Fevarin, Faverin, oral spray, nasal spray, and/or aerosol. Specifically contem Dumyrox. Favoxil, Movox), paroxetine (Paxil, Seroxat, Sere plated routes are oral administration, intravenous administra upin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, tion (e.g., systemic intravenous injection), regional adminis Loxamine, Deparoc), Sertraline (Zoloft, Lustral, Serlain, tration via blood and/or lymph Supply, and/or direct Asentra), and villazodone (Vibryd). administration to an affected site. In general, the most appro 0153. In certain embodiments, a second therapeutic agent priate route of administration will depend upon a variety of is a tetracyclic antidepressant (TeCA) selected from the group factors including the nature of the agent (e.g., its stability in consisting of amoxapine (Amokisan, Asendin, Asendis, the environment of the gastrointestinal tract), and/or the con Defanyl, Demolox, Moxadil), maprotiline (Deprilept, dition of the subject (e.g., whether the subject is able to Ludiomil, Psymion), mazindol (Mazanor, Sanorex), tolerate oral administration). mianserin (Bolvidon, Depnon, Norval, Tolvon), mirtazapine 0159. The exact amount of a compound required to (Remeron, Avanza, Zispin, Miro), and Setiptiline (Tecipul). achieve an effective amount will vary from subject to subject, 0154) In certain embodiments, a second therapeutic agent depending, for example, on species, age, and general condi is a serotonin-noradrenaline reuptake inhibitor (SNRI) tion of a subject, severity of the side effects or disorder, selected from the group consisting of desvenlafaxine (Pris identity of the particular compound(s), mode of administra tiq), dulloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, tion, and the like. The desired dosage can be delivered three DuZela), milnacipran (Ixel, Savella, Dalcipran, Toledomin), times a day, two times a day, once a day, every other day, every and venlafaxine (Effexor, Efexor). third day, every week, every two weeks, every three weeks, or 0155. In certain embodiments, a second therapeutic agent every four weeks. In certain embodiments, the desired dosage is a Noradrenaline reuptake inhibitor (NRI) selected from the can be delivered using multiple administrations (e.g., two, group consisting of atomoxetine (Tomoxetine, Strattera, three, four, five, six, seven, eight, nine, ten, eleven, twelve, Attentin), mazindol (Mazanor, Sanorex), reboxetine thirteen, fourteen, or more administrations). (Edronax, Norebox, Prolift, Solvex, Davedax, Vestra), and viloxazine (Vivalan, Emovit, Vivarint, Vicilan). EXAMPLES 0156. In certain embodiments, a second therapeutic agent 0160. In order that the invention described herein may be is a monoamine oxidase inhibitor (MAOI) selected from the more fully understood, the following examples are set forth. group consisting of benmoxin (Nerusil, Neuralex), hydrala These examples are for illustrative purposes only and are not Zine (Apresoline), iproclozide (Sursum), iproniazid (Mar to be construed as limiting this invention in any manner. silid, Iprozid, Ipronid, Rivivol, Propilniazida), isocarboxazid Example 1 (Marplan), isoniazid (Laniazid, Nydrazid), mebanazine (Ac tomol), nialamide (Niamid), octamoxin (Ximaol, Nimaol), General Methods of Instrumental Measurements phenelzine (Nardil, Nardelzine), pheniprazine (Catron), phe 0.161 FT-Raman Spectroscopy. noxypropazine (Drazine), pivalylbenzhydrazine (Tersavid), (0162 Bruker RFS100 with OPUS 6.5 software or Multi procarbazine (Matulane, Natulan, Indicarb), caroxazone RAM with OPUS 7.0 software; Nd:YAG 1064-nm excitation, US 2016/0039810 A1 Feb. 11, 2016

Ge detector,3500-100 cm range; typical measurement con TABLE 6 ditions: 50-300 mW nominal laser power, 64-128 scans, 2 cm' resolution. HPLC methods. 0163 XRPD. Instrument Agilent 1100 series 0164 Bruker D8; reflection geometry, Bragg-Brentano: Column Waters Xterra C18, 100 x 4.6 mm, 5um (FK-CC01E) Mobile Phase A HO + 0.1%TFA Cu-K radiation, 40 kV/40 mA: variable divergence slit; Mobile Phase B MeCN LynxEye detector with 3° window; 0.02° 20 step size: 37 s Reference conc. 0.2-0.05 mg/mL step time. The samples were rotated during the measurement. Retention time 10.48 min Sample preparation: The samples were generally prepared Gradient O min 95% A 5% B 20 min 5%. A 95% B without any special treatment other than the application of 20.5 min 95% A 5% B slight pressure to get a flat Surface. Silicon single crystal 22 min 95% A 5% B sample holder, 0.1 mm deep. Flow 1.00 mL/min Injection Volume 10 L 0165 H-NMR. Column temp. 25o C. (0166 Bruker DPX300 spectrometer; proton frequency of Wavelength 240mm 300. 13 MHz; 30 excitation pulse; recycle delay of 1s; accu mulation of 16 scans; deuterated DMSO as the solvent; sol vent peak used for referencing; chemical shifts reported on Example 2 the TMS Scale. 0167 TG-FTIR. Preparation and Characterization of Form B (0168 Netzsch Thermo-Microbalance TG 209 with Bruker 0187 3.2 kg of compound 1 containing <0.5% impurity A FT-IR Spectrometer Vector 22; aluminum crucible (with (compound 2)) was dissolved in 100 L of methanol with micro-hole), N atmosphere, 10 K/min heating rate, 25-250° refluxing, and 140 L of water at 72-75° C. was added. Upon C. or 25-350° C. range. completion of addition of water, the resulting mixture was (0169. DSC. allowed to cool very slowly to crystallize out a solid. The solid (0170 Perkin Elmer DSC 7: closed gold crucibles, sample was isolated by filtration to give Form B in about 90% yield. filled in an N environment, 10 K/min heating rate, -50 to 0188 This method was fine-tuned to work on a kilogram 250° C. range, at times quench cooling (at -200 K min') to scale. However, the impurity A was retained in crystallized -50° C. between scans. material. The crystallization procedure was modified to 0171 DVS. remove any acidic impurity by using water containing (0172 Projekt Messtechnik Sorptions Prüfsystem SPS NaCO or NaHCO. Impurity A (compound 2) level was 11-100n or Surface Measurement Systems DVS-1. The dropped from about 0.8% to about 0.1% after crystallization sample was placed on an aluminum or platinum holder on top from MeOH and water containing NaCO or NaHCO. In of a microbalance and allowed to equilibrate for 2 h at 50% one set of experiments, 2.36 kg of compound 1 (containing rh.. before starting one of two pre-defined humidity pro 0.85% impurity A) was dissolved in 59 L of methanol with refluxing (60-65°C.) and 59 L of water (containing 11.8g of grams: NaCO) at 60-65°C. was added. Upon completion of addi (0173 (1) 2 hat 50% rh.: tion of water, the mixture was allowed to cool very slowly to 0.174 (2) 50->0% rh. (5%/h); 5 h at 0% rh.; crystallize out a solid. The solid was separated by filtration to (0175 (3) 0->95% rh. (5%/h); 5 hat 95% rh.; and give Form B in about 90% yield (containing 0.1% impurity (0176 (4) 95->50% rh. (5%/h); 2 hat 50% rh.; A). FT-Raman spectrum (FIG. 2) shows narrow, intense peaks and no fluorescence. 0177 or (0189 The XRPD pattern (FIG. 1) confirms the crystallin 0178 (1) 2 hat 50% rh.: ity of Form B. 0179 (2) 50->95% rh. (5%/h); 5 h at 95% rh.; (0190. The H-NMR spectrum (FIG. 6) agrees with the 0180 (3) 95->0% rh. (5%/h); 5 h at 0% rh.; and given structure. 0181 (4) 0->50% rh. (5%/h); 2 hat 50% rh. (0191). The TG-FTIR thermogram (FIG. 5) shows the loss 0182. The hygroscopicity was classified based on the mass of about 2.0 wt % HO between 100° C. and 230° C. and gain at 85% rh. relative to the initial mass as follows: deli decomposition at >250° C. The water is most likely bound quescent (Sufficient water adsorbed to form a liquid), very within the structure. The theoretical water content of a hemi hygroscopic (mass increase of >15%), hygroscopic (mass hydrate is 2.1 wt %. Thus, Form B is likely a hemihydrate increase <15% and 22%), slightly hygroscopic (mass and/or a non-stoichiometric hydrate. increase <2% and >0.2%), or non-hygroscopic (mass (0192. The DSC thermogram (FIG.3) shows an endotherm increase <0.2%). with several shoulders on the low temperature side and a peak maximum at a T of about 176.3°C. (AH of about 105.4 0183) Solvents. J/g), most likely corresponding to melting. After quench cool 0184 For all experiments, Fluka, Merck or ABCR analyti ing, a glass transition with a T of about 70.8°C. (ACp of cal grade solvents were used. about 0.48J/(gC.)) was observed in the second heating scan. 0185 HPLC. (0193 During the DVS measurement (FIG. 4), the relative 0186 HPLC methods given in Table 6 were used. Stan humidity was first lowered from 50% rh.. to 0% rh., then dard solutions of the SP196-FD-P1 free drug of compound 1 raised from 0% rh. to 95% rh. and loweredback again to 50% and the L-malate salt of compound 1 (SP196-MLA-P4) were rh. The sample shows a mass loss of about 0.1 wt % upon prepared in the concentration range of 0.2-0.05 mg/mL for lowering the relative humidity from 50% r.h.. to 0% rh. Upon the construction of a calibration curve. increasing the relative humidity to 95% rh., a gradual mass US 2016/0039810 A1 Feb. 11, 2016

gain of about 0.3 wt % (relative to the mass at 0% rh.) was TABLE 8 observed. Upon lowering the relative humidity from 95% rh. to 50% rh., the final mass was equal to the starting mass. The Stability of Form B stored at about 40° C. and about 75% rh. mass increase of 0.1 wt % at 85% rh. (relative to the starting Concentration of compound 1 mass at 50% rh.) classifies the sample as non-hygroscopic. Time by HPLC Assay 0194 The FT-Raman spectrum of the sample of Form B point (anhydrous basis) XRPD IR after the DVS measurement is unchanged compared to the Initial 99.5% wiw spectrum before the measurement, indicating that no trans 1 month 99.6% wiw formation has taken place. 2 months 99.3% wiw 0.195 Microscopic images of the sample of Form B show 3 months 99.3% wiw complies complies that the sample consists of very small granular crystals (FIGS. 6 months 99.4% wiw complies complies 7A and 7B). 0203 The results shown in Table 8 indicate that Form B is Example 3 stable upon storage for at least 6 months at about 40° C. and about 75% rh. Drying of Form B EQUIVALENTS AND SCOPE 0196. A solid sample of Form B was dried in an attempt to dehydrate it. The sample was stored under vacuum (<5 mbar 0204. In the claims articles such as “a” “an and “the (e.g., about 4 mbar)) at 40°C. overnight or for 1 day. may mean one or more than one unless indicated to the (0197) The XRPD pattern of the dried sample (FIG. 8) is contrary or otherwise evident from the context. Claims or unchanged compared to the pattern of the sample before descriptions that include “or between one or more members drying. of a group are considered satisfied if one, more than one, or all (0198 The TG-FTIR thermogram of the dried sample of the group members are present in, employed in, or other (FIG.9) shows the loss of about 1.9 wt % HO from 50° C. to wise relevant to a given product or process unless indicated to 200° C. and decomposition at a temperature greater than the contrary or otherwise evident from the context. The inven tion includes embodiments in which exactly one member of about 200. 9 C. the group is present in, employed in, or otherwise relevant to 0199 Thus, the water seems tightly bound within a stable a given product or process. The invention includes embodi structure, no dehydration and loss of Solvent occurred. ments in which more than one, orall of the group members are present in, employed in, or otherwise relevant to a given Example 4 product or process. Stability Study 0205 Furthermore, the invention encompasses all varia tions, combinations, and permutations in which one or more 0200. A sample of Form B was stored at about 25°C. and limitations, elements, clauses, and descriptive terms from one about 60% rh.. for a period of time (e.g., 24 months). The or more of the listed claims is introduced into another claim. concentration of compound 1 in the sample was assayed using For example, any claim that is dependent on another claim HPLC, XRPD, and IRat different time points. The results are can be modified to include one or more limitations found in shown in Table 7. The term “complies' refers to substantially any other claim that is dependent on the same base claim. the same XRPD pattern and/or IR spectrum as the sample at Where elements are presented as lists, e.g., in Markush group the incept of the storage (time point initial). format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be TABLE 7 understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular ele Stability of Form B stored at about 25 C. and about 60% rh. ments and/or features, certain embodiments of the invention Concentration of compound 1 or aspects of the invention consist, or consist essentially of Time by HPLC Assay Such elements and/or features. For purposes of simplicity, point (anhydrous basis) XRPD IR those embodiments have not been specifically set forth in Initial 99.5% Wiw haec verbaherein. It is also noted that the terms “comprising 3 months 99.4% Wiw complies complies and “containing are intended to be open and permits the 6 months 99.6% Wiw complies complies inclusion of additional elements or steps. Where ranges are 12 months 99.3% Wiw complies complies given, endpoints are included. Furthermore, unless otherwise 18 months 99.4% Wiw complies complies indicated or otherwise evident from the context and under 24 months 99.2% Wiw complies complies standing of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or Sub 0201 The results shown in Table 7 indicate that Form B is range within the stated ranges in different embodiments of the stable upon storage for at least 24 months at about 25°C. and invention, to the tenth of the unit of the lower limit of the about 60% rh. range, unless the context clearly dictates otherwise. 0202 Another sample of Form B was stored at about 40° 0206. This application refers to various issued patents, C. and about 75% rh.. for a period of time (e.g., 6 months). published patent applications, journal articles, and other pub The concentration of compound 1 in the sample was assayed lications, all of which are incorporated herein by reference. If using HPLC, XRPD, and IR at different time points. The there is a conflict between any of the incorporated references results are shown in Table 8. The term “complies' refers to and the instant specification, the specification shall control. In substantially the same XRPD pattern and/or IR spectrum as addition, any particular embodiment of the present invention the sample at the incept of the storage (time point initial). that falls within the prior art may be explicitly excluded from US 2016/0039810 A1 Feb. 11, 2016

any one or more of the claims. Because Such embodiments are 9. The crystalline Form B of any one of claims 1 to 8, deemed to be known to one of ordinary skill in the art, they wherein the crystalline Form B is characterized by having may be excluded even if the exclusion is not set forth explic four or more peaks in its XRPD pattern selected from those in itly herein. Any particular embodiment of the invention can the following table: be excluded from any claim, for any reason, whether or not related to the existence of prior art. 0207 Those skilled in the art will recognize or be able to Angle ascertain using no more than routine experimentation many 2-Theta equivalents to the specific embodiments described herein. 13.94 14.52 The scope of the present embodiments described herein is not 16.27 intended to be limited to the above Description, but rather is 16.60 as set forth in the appended claims. Those of ordinary skill in 17.62 the art will appreciate that various changes and modifications 18.76 to this description may be made without departing from the 19.02 1929 spirit or scope of the present invention, as defined in the 1964 following claims. 22.32 0208. The reference in this specification to any prior pub 22.77 23.02 lication (or information derived from it), or to any matter 23.16. which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or 10. The crystalline Form B of any one of claims 1 to 9, known matter forms part of the common general knowledge wherein the crystalline Form B is characterized by having six in the field of endeavour to which this specification relates. or more peaks in its XRPD pattern selected from those in the 0209 Throughout this specification and the claims which following table: follow, unless the context requires otherwise, the word “com prise', and variations such as "comprises' and "comprising. Angle will be understood to imply the inclusion of a stated integer or 2-Theta step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 13.94 14.52 16.27 1. A crystalline Form B of compound 1 of formula: 16.60 17.62 18.76 19.02 1929 1964 22.32 22.77 23.02 r 23.16. 11. The crystalline Form B of any one of claims 1 to 10, wherein the crystalline Form B is characterized by having croc eight or more peaks in its XRPD pattern selected from those in the following table: 2. The crystalline Form B of claim 1, wherein the crystal line Form B is obtained from a mixture of methanol and water. 3. The crystalline Form B of claim 1 or claim 2, wherein the Angle crystalline Form B is a hydrate. 2-Theta 4. The crystalline Form B of any one of claims 1 to 3. 13.94 wherein the crystalline Form B is a hemihydrate. 14.52 16.27 5. The crystalline Form B of any one of claims 1 to 4, 16.60 wherein the crystalline Form B is a non-stoichiometric 17.62 hydrate. 18.76 19.02 6. The crystalline Form B of any one of claims 1 to 5, 1929 wherein the crystalline Form B is substantially free of amor 1964 phous compound 1. 22.32 22.77 7. The crystalline Form B of any one of claims 1 to 6, 23.02 wherein the crystalline Form B is substantially free of impu 23.16. rities. 8. The crystalline Form B of any one of claims 1 to 7, 12. The crystalline Form B of any one of claims 1 to 11, wherein the crystalline Form B is characterized by an X-ray wherein the crystalline Form B is characterized by having ten powder diffraction (XRPD) pattern substantially similar to or more peaks in its XRPD pattern selected from those in the the one depicted in FIG. 1. following table: US 2016/0039810 A1 Feb. 11, 2016 19

-continued Angle 2-Theta Angle 2-Theta 13.94 14.52 24.42

16.60 2597 17.62 26.82 18.76 27.51

1929 30.17 1964 31.10 22.32 31.65 22.77 34.96. 23.02 23.16. 15. The crystalline Form B of any one of claims 1 to 14, 13. The crystalline Form B of any one of claims 1 to 12, wherein the crystalline Form B is characterized by a Raman wherein the crystalline Form B is characterized by having spectrum substantially similar to the one depicted in FIG. 2. thirteen peaks in its XRPD pattern selected from those in the 16. The crystalline Form B of any one of claims 1 to 15, following table: wherein the crystalline Form B is characterized by a Raman spectrum with characteristic peaks selected from those in the following table: Angle 2-Theta 13.94 Wavenumber 14.52 (cm) E. 3322 17.62 3070 18.76 3007 19.02 2993 1929 2963 1964 2931 22.32 2910 22.77 2871 23.02 2842 23.16. 636 611 604 SO8 14. The crystalline Form B of any one of claims 1 to 13, 497 wherein the crystalline Form B is characterized by having 478 thirty-four peaks in its XRPD pattern selected from those in 459 the following table: 393 355 Angle 344 2-Theta 319 3O4 6.OS 285 6.48 271 8.78 243 9.00 225 12.16 208 13.94 150 14.25 136 14.52 112 16.27 095 16.60 O64 17.62 O39 18.09 O25 1831 O10 1876 996 19.02 957 1929 943 1964 849 20.78 819 20.95 810 22.32 789 22.77 741 23.02 713 23.16 681 23.39 603 US 2016/0039810 A1 Feb. 11, 2016 20

-continued 18. The crystalline Form B of any one of claims 1 to 17, wherein the crystalline Form B is characterized by a DSC Wavenumber thermogram substantially similar to the one depicted in FIG. (cm) 3. 585 555 19. The crystalline Form B of any one of claims 1 to 18, 5O1 wherein the crystalline Form B is characterized by a DSC 484 thermogram with an endotherm having a peak temperature 446 419 (T) of about 176°C. 372 349 20. The crystalline Form B of any one of claims 1 to 19, 316 wherein the crystalline Form Bis characterized by a DSC 261 thermogram with a AH of about 105 J/g. 234 185 21. The crystalline Form B of any one of claims 1 to 20, 141. wherein the crystalline Form B is characterized by a glass transition (T) of about 71° C. after quench cooling. 17. The crystalline Form B of any one of claims 1 to 16, 22. The crystalline Form B of any one of claims 1 to 21, wherein the crystalline Form B is characterized by a Raman wherein the crystalline Form B is characterized by a AC, of spectrum with characteristic peaks selected from those in the about 0.48 J/(g °C.) after quench cooling. following table: 23. The crystalline Form B of any one of claims 1 to 22, wherein the crystalline Form B is characterized a DVS iso Wavenumber therm substantially similar to the one depicted in FIG. 4. (cm) 24. The crystalline Form B of any one of claims 1 to 23, 1636 wherein the crystalline Form B is characterized by a TG 1611 FTIR thermogram substantially similar to the one depicted in 1604 FIG.S. 1446 1425 25. The crystalline Form B of any one of claims 1 to 24, 1393 1355 wherein the crystalline Form B is characterized by an IR 1344 spectrum substantially similar to the one depicted in FIG. 10. 1025 789 26. The crystalline Form B of any one of claims 1 to 25, 741. wherein the crystalline Form B is characterized by an IR spectrum with characteristic peaks selected from those in the following table:

No. Position Intensity No. Position Intensity No. Position Intensity

1 3389.28 18.88O3 2 3321.78 15.2998 3 3066.26 43.31.87 3O33.48 52.327 S 2991.OS 44.2454 6 2970.8 36.2048 7 2960.2 35.8651 8 2928.38 28.2099 9 2839.67 28.5464 10 276S.42 68.3886 11 2707.57 71.199 12 2684.43 72.4374 13 2.588.97 74.7507 14 2204.24 79.2123 1S 1976.68 81.6905 16 1954.5 80.4172 17, 1921.72 81.2251 18 1847.47 80.7596 19 1807.94 79.7842 2O 1680.66 59.904 21, 1632.45 1.12286 22 1593.88 O.229.197 23 1493.6 O.785332 24 1476.24 5.245O1 2S 1458.89 16.6916 26 1431.89 12.9634 27 1390.42 25.9737 28 1379.82 30.7322 29 1341.25 14.0312 3O 1318.11 20.5376 31 1301.72 49.2933 32 1269.9 6.91712 33 1244.83 7.5622 34 1216.86 21.9545 3S 1209.1S 26.0253 36 1128.15 SS.6498 37 1113.69 4.73713 38 109344 42.0985 39 1068.37 39.536 40 1036. SS 51.1775 41 1023.OS 68.0011 42 1005.7 62.1369 43 994.125 41S6SS 44 955.555 72.4243 45 940.128 SS.4283 46 90541S 77.3957 47 889.987 48.5083 48 848.525 48.9604 49 808.992 37.3274 50 789.707 46.8949 51 754.995 16.0235 52 743.424 52.7696 53 710.64 66.7717 S4 679.78S 46.5898 55 6O1682 34.7989 56 554.434 68.6904 57 S21.6S 76.6701 58 477.296 61.4961 59 442.583 77.4332 60 428.12 78.2972 61 410.763 75.3479 US 2016/0039810 A1 Feb. 11, 2016

27. The crystalline Form B of any one of claims 1 to 26, 45. The method of claim 44, wherein the neurodegenera wherein the crystalline Form B is characterized by an X-ray tive disease is AIDS dementia complex, adrenoleukodystro powder diffraction (XRPD) pattern substantially similar to phy, alexander disease, Alpers disease, Alzheimer's disease, the one depicted in FIG. 1; and a Raman spectrum Substan amyotrophic lateral Sclerosis, ataxia telangiectasia, Batten tially similar to the one depicted in FIG. 2. disease, bovine spongiform encephalopathy, brainstem and 28. The crystalline Form B of any one of claims 1 to 27, cerebellum atrophy, Canavan disease, corticobasal degenera wherein the crystalline Form B has an observed melting point tion, Creutzfeldt-Jakob disease, dementia with Lewy bodies, of about 155-168° C. fatal familial insomnia, Friedrich's ataxia, familial spastic 29. The crystalline Form B of any one of claims 1 to 28, paraparesis, frontotemporal lobar degeneration, Hunting wherein the crystalline Form B is characterized as having ton's disease, infantile Refsum disease, Kennedy's disease, substantially the same XRPD pattern post storage at about Krabbe disease, Lyme disease, Machado-Joseph disease, 25°C. and about 60% relative humidity for at least 24 months. monomelic amyotrophy, multiple Sclerosis, multiple system 30. The crystalline Form B of any one of claims 1 to 29, atrophy, neuroacanthocytosis, Niemann-Pick disease, neuro wherein the crystalline Form B is characterized as having degeneration with brain iron accumulation, opSoclonus myo substantially the same IR spectrum post storage at about 25° clonus, Parkinson's disease, Pick's disease, primary lateral C. and about 60% relative humidity for at least 24 months. Sclerosis, progranulin, progressive multifocal leukoencepha 31. The crystalline Form B of any one of claims 1 to 30, lopathy, progressive Supranuclearpalsy, protein aggregation, wherein the crystalline Form B is characterized as having Refsum disease, Sandhoff disease, diffuse myelinoclastic substantially the same XRPD pattern post storage at about Sclerosis, Shy-Drager syndrome, spinocerebellar ataxia, Spi 40° C. and about 75% relative humidity for at least 6 months. nal muscular atrophy, spinal and bulbar muscular atrophy, 32. The crystalline Form B of any one of claims 1 to 31, Subacute combined degeneration of spinal cord, Tabes dor wherein the crystalline Form B is characterized as having salis, Tay-Sachs disease, toxic encephalopathy, transmissible substantially the same IR spectrum post storage at about 40° spongiform encephalopathy, or Wobbly hedgehog syndrome. C. and about 75% relative humidity for at least 6 months. 46. The method of claim 35, wherein the disease is stroke, 33. A pharmaceutical composition comprising a crystalline brain haemorrhage, or cerebral ischemia. Form B of any one of claims 1 to 32, and optionally a phar 47. The method of claim 35, wherein the disease is a maceutically acceptable excipient. disorder of the circadian rhythm. 48. The method of claim 35, wherein the disease is pain or 34. The pharmaceutical composition of claim 33, wherein nociception. the crystalline Form B is in a therapeutically effective 49. The method of claim 35, wherein the disease is a amount. disease responsive to neurite outgrowth. 35. A method of treating a disease in a subject in need 50. The method of claim 35, wherein the subject is a thereof, the method comprising: human. administering to the subject a therapeutically effective 51. A method of preparing Form B of any one of claims 1 amount of a crystalline Form B of any one of claims 1 to to 32, the method comprising mixing a solution of compound 32, or a pharmaceutical composition of any one of 1 in methanol with an aqueous Solution of a base to provide a claims 33 to 34. mixture. 36. The method of claim 35, wherein the disease is a 52. The method of claim 51 further comprising lowering disease of the central nervous system. the temperature of the mixture to provide a solid. 37. The method of claim 36, wherein the disease of the 53. The method of claim 52 further comprising isolating central nervous system is a mood disorder. the solid from the mixture. 38. The method of claim 35, wherein the mood disorder is 54. The method of any one of claims 51 to 53 wherein the depression. base is selected from NaCO or NaHCO. 39. The method of claim 38, wherein the depression is 55. The method of claim 54 wherein the base is Na,CO. major depressive disorder (MDD), bipolar disorder (BD), 56. The methodofany one of claims 51 to 55 wherein Form atypical depression, melancholic depression, psychotic B is prepared in greater than 99% purity. major depression, catatonic depression, postpartum depres 57. Use of a therapeutically effective amount of a crystal Sion, seasonal affective disorder, dysthymia, a depressive dis line Form B of any one of claims 1 to 32, or a pharmaceutical order not otherwise specified (DD-NOS), or a substance composition of any one of claims 33 to 34 in the manufacture induced mood disorder. of a medicament for the treatment of a disease in a Subject in 40. The method of claim 36, wherein the disease of the need thereof. central nervous system is an anxiety disorder. 58. The use of claim 57, wherein the disease is a disease of 41. The method of claim 40, wherein the anxiety disorder the central nervous system. is panic disorder, obsessive-compulsive disorder (OCD), 59. The use of claim 58, wherein the disease of the central post-traumatic stress disorder (PTSD), generalized anxiety nervous system is a mood disorder. disorder (GAD), Substance-induced anxiety disorder, acute 60. The use of claim 59, wherein the mood disorder is stress disorder (ASD), irritable bowel syndrome, or fibromy depression. algia. 61. The use of claim 60, wherein the depression is major 42. The method of claim 40, wherein the anxiety disorder depressive disorder (MDD), bipolar disorder (BD), atypical is a phobia. depression, melancholic depression, psychotic major depres 43. The method of claim 42, wherein the phobia is social Sion, catatonic depression, postpartum depression, seasonal phobia, agoraphobia, or animal phobia. affective disorder, dysthymia, a depressive disorder not oth 44. The method of claim 36, wherein the disease of the erwise specified (DD-NOS), or a substance induced mood central nervous system is a neurodegenerative disease. disorder. US 2016/0039810 A1 Feb. 11, 2016 22

62. The use of claim 58, wherein the disease of the central 77. The use of claim 76, wherein the depression is major nervous system is an anxiety disorder. depressive disorder (MDD), bipolar disorder (BD), atypical 63. The use of claim 62, wherein the anxiety disorder is depression, melancholic depression, psychotic major depres panic disorder, obsessive-compulsive disorder (OCD), post Sion, catatonic depression, postpartum depression, seasonal traumatic stress disorder (PTSD), generalized anxiety disor affective disorder, dysthymia, a depressive disorder not oth der (GAD), Substance-induced anxiety disorder, acute stress erwise specified (DD-NOS), or a substance induced mood disorder (ASD), irritable bowel syndrome, or fibromyalgia. disorder. 64. The use of claim 62, wherein the anxiety disorder is a 78. The use of claim 74, wherein the disease of the central phobia. nervous system is an anxiety disorder. 65. The use of claim 64, wherein the phobia is social 79. The use of claim 78, wherein the anxiety disorder is phobia, agoraphobia, or animal phobia. panic disorder, obsessive-compulsive disorder (OCD), post 66. The use of claim 58, wherein the disease of the central traumatic stress disorder (PTSD), generalized anxiety disor nervous system is a neurodegenerative disease. der (GAD), Substance-induced anxiety disorder, acute stress 67. The use of claim 66, wherein the neurodegenerative disorder (ASD), irritable bowel syndrome, or fibromyalgia. disease is AIDS dementia complex, adrenoleukodystrophy, 80. The use of claim 78, wherein the anxiety disorder is a alexander disease, Alpers disease, Alzheimer's disease, phobia. amyotrophic lateral Sclerosis, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, brainstem, and 81. The use of claim 80, wherein the phobia is social cerebellum atrophy, Canavan disease, corticobasal degenera phobia, agoraphobia, or animal phobia. tion, Creutzfeldt-Jakob disease, dementia with Lewy bodies, 82. The use of claim 78, wherein the disease of the central fatal familial insomnia, Friedrich's ataxia, familial spastic nervous system is a neurodegenerative disease. paraparesis, frontotemporal lobar degeneration, Hunting 83. The use of claim 82, wherein the neurodegenerative ton's disease, infantile Refsum disease, Kennedy's disease, disease is AIDS dementia complex, adrenoleukodystrophy, Krabbe disease, Lyme disease, Machado-Joseph disease, alexander disease, Alpers disease, Alzheimer's disease, monomelic amyotrophy, multiple Sclerosis, multiple system amyotrophic lateral Sclerosis, ataxia telangiectasia, Batten atrophy, neuroacanthocytosis, Niemann-Pick disease, neuro disease, bovine spongiform encephalopathy, brainstem and degeneration with brain iron accumulation, opSoclonus myo cerebellum atrophy, Canavan disease, corticobasal degenera clonus, Parkinson's disease, Pick's disease, primary lateral tion, Creutzfeldt-Jakob disease, dementia with Lewy bodies, Sclerosis, progranulin, progressive multifocal leukoencepha fatal familial insomnia, Friedrich's ataxia, familial spastic lopathy, progressive Supranuclearpalsy, protein aggregation, paraparesis, frontotemporal lobar degeneration, Hunting Refsum disease, Sandhoff disease, diffuse myelinoclastic ton's disease, infantile Refsum disease, Kennedy's disease, Sclerosis, Shy-Drager syndrome, spinocerebellar ataxia, Spi Krabbe disease, Lyme disease, Machado-Joseph disease, nal muscular atrophy, spinal and bulbar muscular atrophy, monomelic amyotrophy, multiple Sclerosis, multiple system Subacute combined degeneration of spinal cord, Tabes dor atrophy, neuroacanthocytosis, Niemann-Pick disease, neuro salis, Tay-Sachs disease, toxic encephalopathy, transmissible degeneration with brain iron accumulation, opSoclonus myo spongiform encephalopathy, or Wobbly hedgehog syndrome. clonus, Parkinson's disease, Pick's disease, primary lateral 68. The use of claim 57, wherein the disease is stroke, brain Sclerosis, progranulin, progressive multifocal leukoencepha haemorrhage, or cerebral ischemia. lopathy, progressive Supranuclearpalsy, protein aggregation, 69. The use of claim 57, wherein the disease is a disorder of Refsum disease, Sandhoff disease, diffuse myelinoclastic the circadian rhythm. Sclerosis, Shy-Drager syndrome, spinocerebellar ataxia, Spi 70. The use of claim 57, wherein the disease is pain or nal muscular atrophy, spinal and bulbar muscular atrophy, nociception. Subacute combined degeneration of spinal cord, Tabes dor 71. The use of claim 57, wherein the disease is a disease salis, Tay-Sachs disease, toxic encephalopathy, transmissible responsive to neurite outgrowth. spongiform encephalopathy, or Wobbly hedgehog syndrome. 72. The use of claim 57, wherein the subject is a human. 84. The use of claim 73, wherein the disease is stroke, brain 73. Use of a therapeutically effective amount of a crystal haemorrhage, or cerebral ischemia. line Form B of any one of claims 1 to 32, or a pharmaceutical 85. The use of claim 73, wherein the disease is a disorder of composition of any one of claims 33 to 34 for the treatment of the circadian rhythm. a disease in a Subject in need thereof. 86. The use of claim 73, wherein the disease is pain or 74. The use of claim 73, wherein the disease is a disease of nociception. the central nervous system. 87. The use of claim 73, wherein the disease is a disease 75. The use of claim 74, wherein the disease of the central responsive to neurite outgrowth. nervous system is a mood disorder. 76. The use of claim 75, wherein the mood disorder is 88. The use of claim 73, wherein the subject is a human. depression. k k k k k