Solid forms of a gabaa receptor modulator and methods of its use

Abstract

Solid crystalline forms of GABA a receptor modulator 7-ethyl-4- (4'-(ethylsulfonyl)-6-fluoro-2'-methoxy-[l, I '-bipheny l]-3-yl)-7 H- imidazo[ 4,5-c ]pyridazine, as well as methods of making and using the same. Formula (I).

Description

Jones Day Docket No.13371-344-228 SOLID FORMS OF A GABAARECEPTOR MODULATOR AND METHODS OF ITS USE 1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 613,256, filed December 21, 2023, the disclosure of which is incorporated by reference herein in its entirety. 2. FIELD

[0002] The present disclosure provides solid forms of a GABAA receptor modulator and methods of its therapeutic use. 3. BACKGROUND

[0003] Gamma-aminobutyric acid (GABA) has been identified as a major inhibitory neurotransmitter, and agents that modulate GABAergic neurotransmission are used extensively in the treatment of conditions such as epilepsy, anxiety, and depression. Two families of GABA receptor have been described, termed GABAA and GABAB.

[0004] There is a continuing interest in finding new compounds that interact with GABAA receptors, and particularly for compounds that have a reduced propensity for causing the adverse events such as drowsiness that are associated with the currently available GABAA receptor modulators such as benzodiazepines.

[0005] For the production of a drug substance intended for use in humans, procedures need to be in place that can control the levels of impurities and ensure that API products are produced, which consistently meet their predetermined specifications. Thus, a need exists for a process to prepare drug compounds suitable for human use, particularly on a commercial scale, that is, inter alia, safe, scalable, efficient, economically viable, and / or having other desirable properties. Among other entities, provided herein are solid forms and pharmaceutical compositions comprising such solid forms to address these needs and provide exemplary advantages. 4. SUMMARY

[0006] The present disclosure provides various crystalline forms of Compound (I): NAI-1538907928v1 1Jones Day Docket No.13371-344-228 N N , or a pharmaceutically acceptable

[0007] In one embodiment, (I) comprises the free base of Compound (I).

[0008] In one embodiment, the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 13.9, 14.5, 16.9, 19.9, 20.1, and 25.0° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least one peak selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least two peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

[0009] In one embodiment, the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern comprising peaks at approximately 14.5, 16.9, and 19.9° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by NAI-1538907928v1 2Jones Day Docket No.13371-344-228 an XRPD pattern that further comprises peaks at approximately 12.8, 13.9, and 20.1° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern that further comprises a peak selected from the group consisting of approximately 15.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

[0010] In one embodiment, the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern essentially as shown in FIG.1. In one embodiment, the crystalline form of Compound (I) exhibits a thermal event with an onset temperature of about 186 °C as characterized by DSC. In one embodiment, the crystalline form of Compound (I)exhibits a weight loss of about 0.21% upon heating from about 25 °C to about 200 °C. In one embodiment, a single crystal Compound (I) is characterized by the following triclinic cell parameters: a = 7.1681(6) Å, b = 12.7377(16) Å, c = 12.8951(13) Å, α=113.21°, β = 104.05°, γ = 92.80°, V = 1035.81(19) Å3.

[0011] In one embodiment, the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks at approximately 8.5, 9.1, 11.5, 17.0, 18.2, 21.5, 23.6, and 24.0° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least one peak selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least two peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ.

[0012] In one embodiment, the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern comprising peaks at approximately 8.5, 9.1, and 17.0° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is designated as NAI-1538907928v1 3Jones Day Docket No.13371-344-228 “Form 2” and is characterized by an XRPD pattern further comprises peaks at approximately 11.5, 11.8, and 18.2° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern further comprises a peak selected from the group consisting of approximately 14.2, 15.5, 21.5 and 22.4° 2θ ± 0.2 °2θ.

[0013] In one embodiment, the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern essentially as shown in FIG.2.

[0014] In one embodiment, the crystalline form of Compound (I) comprises a sulfate salt of Compound (I). In one embodiment, the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ.

[0015] In one embodiment, the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern comprising peaks at approximately 7.6, 13.2, and 24.3° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern further comprising peaks at approximately 17.5, 17.9, and 19.9° 2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern further comprising a peak selected from the group consisting of approximately 21.0, 21.4, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ.

[0016] In one embodiment, the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern essentially as shown in FIG.6. In one embodiment, the crystalline form of Compound (I)exhibits, as characterized by DSC, a thermal event with an onset temperature of about 209 °C. In one embodiment, the crystalline form of Compound (I) exhibits a weight loss of about 1.6% upon heating from about 50 °C to about 200 °C. In one embodiment, the crystalline form of Compound (I) exhibits a further weight loss of about 4% upon heating from about 200 °C to about 300 °C.

[0017] In one embodiment, the crystalline form of Compound (I) is is anhydrous. NAI-1538907928v1 4Jones Day Docket No.13371-344-228

[0018] In another aspect, the present disclosure provides a composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3), wherein the chemical purity of the composition is at least about 98%. In one embodiment, the composition comprises not more than about 0.2% by weight of any single impurity.

[0019] In another aspect, the present disclosure provides a pharmaceutical composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) a composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition further comprising carbamazepine. In one embodiment, the pharmaceutical composition is a solid intended for reconstitution prior to use. In one embodiment, the pharmaceutical composition is an oral dosage form. In one embodiment, the pharmaceutical composition is an oral tablet.

[0020] In another aspect, the present disclosure provides a method of treating a disorder for which a GABAA positive allosteric modulator is indicated in a subject comprising administering therapeutically effective amount of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof (or prepared therefrom) to the subject.

[0021] In another aspect, the present disclosure provides a method of treating pain in a subject comprising administering a therapeutically effective amount of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof (or prepared therefrom) to the subject.

[0022] In another aspect, the present disclosure provides a method of treating a panic disorder in a subject comprising administering a therapeutically effective of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof to the subject. In one embodiment, the pharmaceutical composition does not comprise carbamazepine and the method further comprising administering a therapeutically effective amount of carbamazepine to the subject.

[0023] In another aspect, the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in acetonitrile; (b) exchanging the acetonitrile for ethyl acetate; and (c) crystallizing Form 1 of Compound (I) from the ethyl acetate. NAI-1538907928v1 5Jones Day Docket No.13371-344-228

[0024] In another aspect, the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in acetonitrile; and (b) crystallizing Form 1 of Compound (I) from the acetonitrile.

[0025] In another aspect, the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in ethanol; and (b) crystallizing Form 1 of Compound (I) from the ethanol.

[0026] In another aspect, the present disclosure provides a method for preparing the crystalline Form 2 of Compound (I), the method comprising: (a) dissolving a Compound (I) in a 90:10 mixture of THF and water; and (b) rapidly evaporating the mixture of THF and water to form the crystalline form of the Compound (I). 5. DRAWINGS

[0027] FIG.1 is a representative X-ray powder diffraction (XRPD) pattern of Form 1 of Compound (I).

[0028] FIG.2 is a representative thermogravimetric analysis (TGA) thermogram of Form 1 of Compound (I).

[0029] FIG.3 is a representative differential scanning calorimetry (DSC) thermogram of Form 1 of Compound (I).

[0030] FIG.4 is an overlay of the1H NMR spectra of Form 1 of Compound (I) and Form 2 of Compound (I).

[0031] FIG.5 is a representative XRPD pattern of Form 2 of Compound (I).

[0032] FIG.6 is a representative XRPD pattern of Form 3 of Compound (I), which is a sulfate salt.

[0033] FIG.7 is a calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure of Form 1 of Compound (I).

[0034] FIG.8 is a representative DSC thermogram of Form 3 of Compound (I).

[0035] FIG.9 is a representative TGA thermogram of Form 3 of Compound (I). NAI-1538907928v1 6Jones Day Docket No.13371-344-228 6. DETAILED DESCRIPTION

[0036] Provided herein are solid forms of Compound (I): NN, or a pharmaceutically the solid form is acrystalline form of the free . the solid form is a crystalline form of a sulfate salt of Compound (I). Methods for using compounds, such as Compound (I) have been previously disclosed, e.g., in WO 2014 / 091368 A1 by Pfizer Limited, which is incorporated by reference herein in its entirety, particularly with respect to its disclosure of Compound (I), pharmaceutical compositions comprising the same, methods of using it, use of it in combination with other therapeutic agents, methods of synthesizing the compound, and any data collected using Compound (I). The solid forms of Compound (I) as disclosed herein may be any solid form, such as disclosed in Section 5.1. Such solid forms may be prepared as described in Section 5.2. Compositions and pharmaceutical compositions as described in Section 5.3 may comprise a solid form of Compound (I) as described in any embodiment in Section 5.1. The solid forms of Compound (I) and pharmaceutical compositions comprising the same may be used to treat a disease, disorder, or condition, such as pain or a panic disorder, in subject as described in Section 5.4 and in Section 5.5.

[0037] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below.

[0038] All publications, patents and patent applications cited herein, whether supra or infra, are incorporated by reference in their entirety. NAI-1538907928v1 7Jones Day Docket No.13371-344-228

[0039] In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

[0040] As used herein, and unless otherwise specified, the term “about” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the term “about” contemplates a dose, amount, or weight percent within 10%, such as within 5% of the specified dose, amount, or weight percent.

[0041] Analytical Methods

[0042] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data obtained by analyzing a sample of a solid via these techniques may be used to identify a particular solid form, because different solid forms, such as different crystal forms, will provide different diffraction patterns when analyzed by XRPD, the particular methods of which are described in greater detail in Section 6 (Examples), and in many cases will also provide different results when analyzed by DSC or TGA. One skilled in the art appreciates that these analyses are subject to experimental error, and that, when comparing, for example, two XRPD patterns, the patterns can be assigned to the same solid form even if one or more, and in some cases all, of the peaks in the pattern vary within the experimental error. Thus, as an example, values of degrees 2θ derived from XRPD, even when presented as exact numbers, should therefore be understood as encompassing those deviations from the presented values that would be considered to be within experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.5 degrees 2θ while still describing the particular XRPD peak, due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.2 degrees 2θ while still describing the particular XRPD peak due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.1 degrees 2θ due to, for example, experimental error. In some embodiment, the value of XRPD peak position may vary by up to ± 0.05 degrees 2θ due to, for example, experimental error. NAI-1538907928v1 8Jones Day Docket No.13371-344-228

[0043] Unless otherwise indicated, the methods disclosed in the examples were used to characterize the various solid forms disclosed herein.

[0044] The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments. 6.1 Solid Forms of Compound (I)

[0045] Solid forms of Compound (I), which has a chemical name of 7-ethyl-4-(4'- (ethylsulfonyl)-6-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)-7H-imidazo[4,5-c]pyridazine, include crystalline solids and amorphous solids. Solid forms may be crystalline, amorphous, or mixtures of crystalline and amorphous forms. The crystal forms described herein, therefore, may have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and may be 0 – 100% crystalline. Methods of determining the degree of crystallinity are known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, N.J., 1995, pp.187 – 199, which is incorporated herein by reference in its entirety.

[0046] The solid forms provided herein may be used as active pharmaceutical ingredients in the preparation of pharmaceutical compositions for use in animals or humans. Thus, embodiments herein encompass the use of these solid forms as a final drug product.

[0047] “Crystalline,” as used herein, refers to a solid formed by a repeating, three- dimensional pattern of atoms, ions or molecules having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern. Notwithstanding the homogenous nature of an ideal crystal, a perfect crystal rarely, if ever, exists. “Crystalline,” as used herein, encompasses crystalline forms that include crystalline defects, for example, crystalline defects commonly formed by manipulating (e.g., preparing, purifying) the crystalline forms described herein. A person skilled in the art is capable of determining whether a sample of a compound is crystalline notwithstanding the presence of such defects. Crystalline forms can be characterized by analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR), single crystal x-ray diffraction, Raman spectroscopy, Fourier transform NAI-1538907928v1 9Jones Day Docket No.13371-344-228 infrared spectroscopy (FTIR) and / or any other suitable analytical techniques. In particular, crystalline forms of a solid can be distinguished from non-crystalline forms by the presence of sharp, distinct peaks in the XRPD patterns of crystalline forms.

[0048] In certain embodiments, the term “substantially pure” with respect to any solid form, e.g., a single crystalline form as disclosed herein (e.g., Form 1, 2, or 3), means no detectable amount of another crystalline form as determined by observing no detectable significant differences in an XRPD and / or DSC pattern between the single crystalline form and a crystalline composition of Compound (I). However, a “substantially pure” solid form can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis. In certain embodiments, “substantially pure” refers to a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least 99.8%.

[0049] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data provided by these techniques may be used to identify a particular solid form. For example, an XRPD pattern, DSC thermogram or TGA thermal curve that “matches” or, interchangeably, is “essentially as shown” with one or more figures herein showing an XRPD pattern or DSC thermogram or TGA thermal curve, respectively, is one that would be considered by one skilled in the art to represent the same single crystalline form of the compound as the sample of the compound that provided the pattern or thermogram or thermal curve of one or more figures provided herein. Thus, an XRPD pattern or DSC thermogram or TGA thermal curve that matches or is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures. For example, an XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffraction pattern presented herein and / or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern or DSC thermogram or TGA thermal curve of the sample NAI-1538907928v1 10Jones Day Docket No.13371-344-228 and the corresponding XRPD pattern or DSC thermogram or TGA thermal curve disclosed herein.

[0050] In one aspect, the present disclosure provides a solid form of 7-ethyl-4-(4'- (ethylsulfonyl)-6-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)-7H-imidazo[4,5-c]pyridazine (Compound (I)) or a pharmaceutically acceptable solvate thereof: NN.

[0051] It is of solid forms. In oneembodiment, the solid form comprising Compound (I) can be a crystalline form, a partially crystalline form, or a mixture of crystalline form(s), or amorphous form(s). In one embodiment, provided herein is a solid form comprising a crystalline form of Compound (I).

[0052] In one embodiment, the solid form is substantially pure.

[0053] In one embodiment, the solid form is anhydrous. In one embodiment, the solid form comprises less than 1% water by weight.

[0054] Compound (I) is described in International Patent Application No. PCT / IB2013 / 060631, which published as WO 2014 / 091368 A1, the entirety of which is incorporated herein by reference.

[0055] As will be discussed herein, the various solid forms of Compound (I) may be characterized by, inter alia, XRPD, TGA, DSC, amongst others. 6.1.1 Form 1 of Compound (I)

[0056] In one embodiment, provided herein is Form 1 of Compound (I).

[0057] In one embodiment, Form 1 of Compound (I) may be characterized by an XRPD pattern essentially as shown in FIG.1. NAI-1538907928v1 11Jones Day Docket No.13371-344-228

[0058] In one embodiment, provided herein is a solid form (e.g., Form 1) of Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 peaks, each of which is located at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 12.8, 13.0, 13.9, 14.5, 15.6, 16.9, 19.9, 20.1, 21.0, 21.6, 22.0, 23.4, and 25.0° 2θ. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (11) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 13) of the identified peaks.

[0059] In one embodiment, the solid form (e.g., Form 1) of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks (e.g., 3, 4, 5, or 6 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 13.9, 14.5, 16.9, 19.9, 20.1, and 25.0° 2θ. In one embodiment, the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, or 7 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ. In one embodiment, the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ. In one embodiment, the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ. In one embodiment, the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ.

[0060] In one embodiment, the solid form is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising peaks at approximately (e.g., ± 0.2 °2θ) 14.5, 16.9, and 19.9° 2θ. In one embodiment, the XRPD pattern further comprises comprising peaks at approximately (e.g., ± 0.2 °2θ) 12.8, 13.9, and 20.1° 2θ. In one embodiment, the XRPD pattern NAI-1538907928v1 12Jones Day Docket No.13371-344-228 further comprises comprising at least one peak (e.g., 1, 2, or 3 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 15.6, 22.0, and 23.4° 2θ.

[0061] In one embodiment, a single crystal of the solid form is characterized by triclinic cell parameters as follows: a = 7.1681(6) Å, b = 12.7377(16) Å, c = 12.8951(13) Å, α=113.21°, β = 104.05°, γ = 92.80°, V = 1035.81(19) Å3.

[0062] In one embodiment, the solid form undergoes a weight loss of about 0.21% upon heating from about 25 °C to about 200 °C when analyzed by TGA. In one embodiment, the solid form is characterized by TGA by heating a sample of the solid form from 0 °C to 350 °C at a rate of 10 °C / min. In one embodiment, the solid form is characterized by a TGA thermogram essentially as shown in FIG.2.

[0063] In one embodiment, the solid form undergoes a thermal event at about 186 °C when characterized by DSC. In one embodiment, the solid form has a melting point of about 186 °C. In one embodiment, the solid form is characterized by DSC by heating a sample of the solid form from -30 °C to 250 °C at a rate of 10 °C / min. In one embodiment, the solid form is characterized by a DSC thermogram essentially as shown in FIG.3.

[0064] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.1.

[0065] In one embodiment, the XRPD pattern is measured by XRPD using Cu Kα radiation having a wavelength of 1.5406 Å.

[0066] In one embodiment, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.1 °2θ. In certain embodiments, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.05 °2θ.

[0067] In some embodiments, provided herein is a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 1) of free base of Compound (I). In some embodiments, the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I). In some embodiments, the solid form is substantially free of Form 2 of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some embodiments, the solid form is NAI-1538907928v1 13Jones Day Docket No.13371-344-228 substantially free of salts of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure (e.g., at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure. In some embodiments, the solid form is substantially physically pure.

[0068] All of the combinations of the above embodiments are encompassed by this application. 6.1.2 Form 2 of Compound (I)

[0069] In one embodiment, provided herein is Form 2 of Compound (I).

[0070] In one embodiment, Form 2 may be characterized by an XRPD pattern essentially as shown in FIG.5.

[0071] In one embodiment, provided herein is a solid form (e.g., Form 2) of Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks, each of which is located at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 8.5, 9.1, 11.5, 11.8, 13.0, 14.2, 15.3, 15.5, 17.0, 18.2, 21.5, 22.2, 22.4, 23.6, and 24.0° 2θ. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (11) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least thirteen (13) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 15) of the identified peaks.

[0072] In one embodiment, the solid form (e.g., Form 2) of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks (e.g., 3, 4, 5, 6, 7, or 8 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 8.5, 9.1, 11.5, 17.0, 18.2, 21.5, 23.6, and 24.0° 2θ. In one embodiment, the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, or 7 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 11.8, 13.0, 14.2, 15.3, 15.5, NAI-1538907928v1 14Jones Day Docket No.13371-344-228 22.2, and 22.4° 2θ. In one embodiment, the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ. In one embodiment, the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ. In one embodiment, the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, or 7 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ.

[0073] In one embodiment, the solid form is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising peaks at approximately (e.g., ± 0.2 °2θ) 8.5, 9.1, and 17.0° 2θ. In one embodiment, the XRPD pattern further comprises comprising peaks at approximately (e.g., ± 0.2 °2θ) 11.5, 11.8, and 18.2° 2θ. In one embodiment, the XRPD pattern further comprises comprising at least one peak (e.g., 1, 2, 3, or 4 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 14.2, 15.5, 21.5 and 22.4° 2θ.

[0074] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.5.

[0075] In one embodiment, the XRPD pattern is measured by XRPD using Cu Kα radiation having a wavelength of 1.5406 Å.

[0076] In one embodiment, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.1 °2θ. In certain embodiments, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.05 °2θ.

[0077] In some embodiments, provided herein is a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 2) of free base of Compound (I). In some embodiments, the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I). In some embodiments, the solid form is a mixture of Form 1 of Compound (I), as described herein, and Form 2 of Compound (I). In some embodiments, the solid form is substantially free of Form 1 of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some NAI-1538907928v1 15Jones Day Docket No.13371-344-228 embodiments, the solid form is substantially free of salts of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure.

[0078] All of the combinations of the above embodiments are encompassed by this application. 6.1.3 Form 3 of Compound (I)

[0079] In one embodiment, provided herein is Form 3 of Compound (I).

[0080] In one embodiment, Form 3 may be characterized by an XRPD pattern essentially as shown in FIG.6.

[0081] In one embodiment, provided herein is a solid form (e.g., Form 3) of Compound (I) comprising a sulfate salt of Compound (I), characterized an XRPD pattern, collected when measured using Cu Kα radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks, each of which is located at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7 °2θ. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 12) of the identified peaks.

[0082] In one embodiment, the solid form (e.g., Form 3) of Compound (I) is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks (e.g., 3, 4, or 5 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 7.6, 13.2, 17.5, 21, and 24.3° 2θ. In one embodiment, the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2θ. In one embodiment, the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, 78, 9, 10, 11, or 12 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, NAI-1538907928v1 16Jones Day Docket No.13371-344-228 21.4, 23.2, 23.3, and 27.7° 2θ. In one embodiment, the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2θ. In one embodiment, the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks), each at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2θ.

[0083] In one embodiment, the solid form is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising peaks at approximately (e.g., ± 0.2 °2θ) 7.6, 13.2, and 24.3° 2θ. In one embodiment, the XRPD pattern further comprises comprising peaks at approximately (e.g., ± 0.2 °2θ) 17.5, 17.9, and 19.9° 2θ. In one embodiment, the XRPD pattern further comprises comprising at least one peak (e.g., 1, 2, 3, 4, or 5 peaks) at a 2θ angle selected from the group consisting of approximately (e.g., ± 0.2 °2θ) 21.0, 21.4, 26.5, 26.7, and 27.7° 2θ.

[0084] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.6.

[0085] In one embodiment, the XRPD pattern is measured by XRPD using Cu Kα radiation having a wavelength of 1.5406 Å.

[0086] In one embodiment, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.1 °2θ. In certain embodiments, the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ± 0.05 °2θ.

[0087] In some embodiments, provided herein is a solid form comprising a sulfate salt of Compound (I), which is a crystalline anhydrate (Form 3) of a sulfate salt of Compound (I). In some embodiments, the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some embodiments, the solid form is substantially free of a free base of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure. NAI-1538907928v1 17Jones Day Docket No.13371-344-228

[0088] All of the combinations of the above embodiments are encompassed by this application. 6.2 Methods of Preparing Solid Forms of Compound (I) 6.2.1 Form 1 of Compound (I)

[0089] In one aspect, the present disclosure provides methods for preparing Form 1 of Compound (I): .

[0090] In one embodiment, a 1 of Compound (I) comprises:(a) dissolving Compound (I) in acetonitrile (ACN) to form a solution; (b) exchanging the ACN for ethyl acetate (EtOAc) to form a solvent-exchanged solution; and (c) subjecting the solvent-exchanged solution to conditions effective to crystallize Compound (I).

[0091] In one embodiment, dissolving Compound (I) in ACN to form a solution is carried out at a temperature of about 80 °C. In one embodiment, the crystallizing comprises cooling the solvent-exchanged solution to crystallize Compound (I). In certain embodiments, the obtained crystalline form of Compound (I) is purified by dissolving in EtOAc and recrystallizing. In certain embodiments, crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane).

[0092] In one embodiment, a method for preparing Form 1 of Compound (I) comprises: (a) dissolving Compound (I) in ACN to form a solution; NAI-1538907928v1 18Jones Day Docket No.13371-344-228 (b) subjecting the solution to conditions effective to crystalline Compound (I).

[0093] In certain embodiments, crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane). In one embodiment, the conditions effective to crystalline Compound (I) comprise cooling the solution. In one embodiment, the solution is filtered, e.g., through diatomaceous earth, prior to crystallizing Compound (I).

[0094] In one embodiment, a method for preparing Form 1 of Compound (I) comprises: (a) dissolving Compound (I) in ethanol (EtOH) to form a solution; (b) subjecting the solution to conditions effective to crystalline Compound (I).

[0095] In one embodiment, charcoal is also added to the solution. In one embodiment, the solution of Compound (I) in EtOH, and optionally charcoal, is heated. In certain embodiments, crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane). In one embodiment, the conditions effective to crystalline Compound (I) comprise cooling the solution.

[0096] A method for preparing Form 1 of Compound (I) may also comprise, in any embodiment, any method in Section 7 (Examples) indicated as resulting in Form 1 of Compound (I). 6.2.2 Form 2 of Compound (I)

[0097] In one aspect, the present disclosure provides methods for preparing solid Form 2 of Compound (I): NAI-1538907928v1 19Jones Day Docket No.13371-344-228 .

[0098] In one embodiment, 2 of Compound (I) comprises:(a) dissolving a a of tetrahydrofuran (THF) and water to form a solution; and (b) evaporating the mixture of THF and water to form solid Form 2 of Compound (I).

[0099] In certain embodiments, evaporating the mixture of THF and water comprises maintaining the solution in a vessel without a lid at ambient temperature and allowing the mixture to evaporate over time. 6.3 Compositions and Pharmaceutical Compositions

[0100] In one embodiment, crystallizing Compound (I), which may be in any form (e.g., crude Compound (I) or amorphous Compound (I)), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially chemically pure (e.g., comprising not more than 2% by weight of one or more compounds other than Compound (I)). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of one or more compounds other than Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of one or more compounds other than Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight, such as not more than 0.03% by weight, of any single compound other than Compound (I). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure. In certain embodiments, the one or more compounds other than Compound (I) that may be present as an impurity comprise an intermediate or a reagent used in the synthesis of NAI-1538907928v1 20Jones Day Docket No.13371-344-228 Compound (I), such as disclosed in the Examples, or a side product generated in the synthesis of Compound (I). One of skill in the art would recognize the various side products that could be generated in the synthesis of Compound (I) as disclosed in the Examples.

[0101] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially crystalline (e.g., comprising not more than 2% by weight of amorphous material). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of amorphous material. In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of amorphous material. Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% crystalline, at least about 99% crystalline, at least about 99.5% crystalline, or 100% crystalline (e.g., no detectable amorphous content).

[0102] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially physically pure (e.g., comprising not more than 2% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I)). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 1% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% by weight of Form 1 of Compound (I), at least about 99% by weight of Form 1 of Compound (I), or at least about 99.5% by weight of Form 1 of Compound (I).

[0103] In one embodiment, crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate a composition comprising Form 1 and Form 2, as an impurity. In one embodiment, the present disclosure provides a composition comprising Form 1 of Compound (I) and not more than about 5% by weight (e.g., 0% to 5%) of Form 2 of Compound (I). In certain embodiments, a composition comprises Form 1 of Compound (I) and not more than about 4% by weight (e.g., 0% to 4%) of Form 2 of Compound (I). In certain embodiments, a composition comprises Form 1 of Compound (I) and not more than about 3% by weight (e.g., 0% to 2%) of Form 2 of Compound (I). In certain embodiments, a composition NAI-1538907928v1 21Jones Day Docket No.13371-344-228 comprises Form 1 of Compound (I) and not more than about 4% by weight (e.g., 0% to 2%) of Form 2 of Compound (I). In certain embodiments, a composition comprises Form 1 of Compound (I) and not more than about 1% by weight (e.g., 0% to 1%) of Form 2 of Compound (I).

[0104]

[0059] The present disclosure also provides compositions, such as pharmaceutical compositions, formulated from a solid form of Compound (I) (e.g., Form 1, 2, or 3) and one or more pharmaceutically acceptable excipients. In one embodiment, a pharmaceutical composition comprises a composition comprising a solid form of Compound (I) (e.g., Form 1, 2, or 3). In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2 or 3) is mixed with one or more liquid excipients, e.g., water, to generate a pharmaceutical composition comprising Compound (I). In one embodiment, a pharmaceutical composition comprises Form 1 of Compound (I) and one or more pharmaceutically acceptable excipients. In one embodiment, a pharmaceutical composition comprises or is prepared from solid Form 2 of Compound (I) and one or more pharmaceutically acceptable excipients. In one embodiment, a pharmaceutical composition comprises or is prepared from solid Form 3 of Compound (I) and one or more pharmaceutically acceptable excipients.

[0105] Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington: The Science and Practice of Pharmacy", 23rd Edition (Academic Press, 2020).

[0106] Suitable modes of administration for a solid form of Compound (I), as disclosed herein, include oral, parenteral, topical, inhaled, intranasal, rectal / intravaginal, and ocular / aural administration. Pharmaceutical compositions suitable for the aforementioned modes of administration may be formulated, e.g., to be immediate and / or modified release. Modified release dosage forms include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0107] In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for oral administration. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Pharmaceutical compositions suitable for oral administration include NAI-1538907928v1 22Jones Day Docket No.13371-344-228 solid dosage forms, liquids, powders, lozenges (including liquid-filled), chewable dosage forms, multi- and nano-particulates, gels, solid solutions, liposomal dosage forms, films, ovules, sprays, and buccal / mucoadhesive patches. Non-limiting examples of liquid oral dosage forms include suspensions, solutions, syrups, and elixirs. Non-limiting examples of solid oral dosage forms include tablets, capsules, and the like.

[0108] In some embodiments, a pharmaceutical composition, e.g., tablet, may comprise about 1 wt. % to about 99%, such as about 1 wt. % to about 80 wt. % of a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3). In some embodiment, a pharmaceutical composition, e.g., tablet, may comprise about 5 wt.% to 60 wt.% of a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3). In some embodiments, a pharmaceutical composition, e.g., tablet or capsule, may comprise about 1 mg, about 2.5 mg, about 4 mg, about 5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 35 mg, about 40 mg, or about 50 mg of Compound (I) in a solid form disclosed here (e.g., Form 1, 2, or 3). In some embodiments, a pharmaceutical composition is formulated for immediate release and comprises about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg of Compound (I) in a solid form disclosed here (e.g., Form 1, 2, or 3). In some embodiments, a pharmaceutical composition is formulated for modified release and comprises about 20 mg, about 22.5 mg, about 25 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 35 mg, about 40 mg, or about 50 mg of Compound (I) in a solid form disclosed here (e.g., Form 1, 2, or 3).

[0109] In some embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more disintegrants. Examples of disintegrants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In some embodiments, a pharmaceutical composition, e.g., tablet, may comprise about 1 wt.% to about 25 wt.%, such as about 5 wt.% to about 20 wt.% of one or more disintegrants. NAI-1538907928v1 23Jones Day Docket No.13371-344-228

[0110] In some embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more binders. Binders are generally used to impart cohesive qualities to a formulated pharmaceutical composition. Examples of binders that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0111] In some embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more diluents. Examples of diluents that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0112] In some embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more surface active agents (“surfactants”). Examples of surfactants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, sodium lauryl sulfate and polysorbate 80. In some embodiments, a pharmaceutical composition may comprise about 0.2 wt.% to about 5 wt.% of one or more surfactants. In some embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more glidants, such as silicon dioxide and / or talc. In some embodiments, a pharmaceutical composition may comprise about 0.2 wt.% to about 1 wt.% of one or more glidants.

[0113] In certain embodiments, a pharmaceutical composition, e.g., tablet, may contain one or more lubricants. Examples of lubricants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. In some embodiments, a pharmaceutical composition may comprise about 0.25 wt.% to 10 wt.%, such as about 0.5 wt.% to 3 wt.% of a lubricant. In certain embodiments, a pharmaceutical composition, e.g., tablet, may further comprise one or more additional ingredients, including, but not limited to, antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents. NAI-1538907928v1 24Jones Day Docket No.13371-344-228

[0114] In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for administration directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. In certain embodiments, a pharmaceutical composition intended for parenteral administration may be prepared prior to use, e.g., by reconstituting a solid composition comprising a solid form of Compound (I) (e.g., Form 1, 2, or 3) with a liquid, such as sterile water (e.g., water for injection). Such a solid composition may also comprise one or more excipients, such as a carbohydrate and / or buffering agent. The preparation of pharmaceutical compositions intended for parenteral administration under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0115] In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for administration topically to the skin or mucosa, that is, dermally or transdermally. Typical pharmaceutical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated. In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for administration intranasally or by inhalation. In certain embodiment, a pharmaceutical composition comprising a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine), e.g., for use in a dry powder inhaler, or as an aerosol spray for use with a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane. For intranasal use, a powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. A pressurized container, pump, spray, atomizer, or nebulizer may comprise a solution or suspension prepared from a solid form of Compound (I) (e.g., Form NAI-1538907928v1 25Jones Day Docket No.13371-344-228 1, 2, or 3) for example, in ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0116] In some embodiments, prior to use in a dry powder or suspension, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be micronized to a size suitable for delivery by inhalation (e.g., less than 5 microns). Capsules, which may be made, for example, from gelatin or hydroxypropyl methylcellulose, blisters and cartridges for use in an inhaler or insufflator may be formulated from a solid form of Compound (I) (e.g., Form 1, 2, or 3) to contain a powder mix of Compound (I), a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol, or magnesium stearate. In some embodiments, the lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0117] A suitable solution for use in an atomizer using electrohydrodynamics to produce a fine mist may be prepared from a solid form of Compound (I) (e.g., Form 1, 2, or 3) to contain from 1 µg to 20 mg of Compound (I) per actuation. Actuation volume may vary from 1 µL to 100 µL.

[0118] In one embodiment, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for administration directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other pharmaceutical compositions suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such compositions may also be delivered by iontophoresis.

[0119] The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste- masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. NAI-1538907928v1 26Jones Day Docket No.13371-344-228

[0120] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0121] Further contemplated is a kit comprising a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient. Such a kit may further comprise means for separately retaining said pharmaceutical composition in discreet dosage amounts, such as a container, divided bottle, or divided foil packet. One example of such a kit is a blister pack, such as is commonly employed for the packaging of tablets, capsules, and the like. Such a kit may be suitable for administering different dosage forms, such as, oral, and parenteral, for administering the pharmaceutical composition at a prescribed dosage interval. Such a kit may further comprise directions for administration and may be provided. 6.4 Methods of Use

[0122] Compound (I), including the solid forms thereof disclosed herein are useful because Compound (I) exhibits pharmacological activity as a GABAA channel modulator, more particularly, as a positive allosteric modulator of the GABAAchannel. Compound (I) and solid forms thereof may therefore be used in the treatment of diseases, disorders, or conditions in animals, such as humans, for which a GABAA positive allosteric modulator is indicated. As such, the present disclosure provides a method for treating a disease, disorder, or condition for which a GABAApositive allosteric modulator is indicated in a subject, such as a human subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a solid form of Compound (I), as disclosed herein (e.g., Form 1, 2, or 3) to the subject. In one embodiment, a method for treating a disease, disorder, or condition for which a GABAApositive allosteric modulator is indicated in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition prepared from a solid form of Compound (I) (e.g., reconstituting a solid form of Compound (I)), to the subject. NAI-1538907928v1 27Jones Day Docket No.13371-344-228

[0123] The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, rats, mice, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys. In certain embodiments, the subject is a human. As used herein and unless otherwise specified, a human subject to which administration of a therapeutic (e.g., a compound as described herein) is contemplated in order to treat, prevent, or manage a disease, disorder, or condition, or symptoms thereof, is also called a “patient.”

[0124] As used herein and unless otherwise specified, the terms “treatment” and “treating” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, disorder, or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In one embodiment, “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0125] A “therapeutically effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect.

[0126] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be used in the preparation for a medicament for treating a disease, disorder, or condition for which a GABAA positive allosteric modulator is indicated, a subject (e.g., a human subject). In yet further embodiments, provided herein is a solid form of Compound (I), such as Form 1, 2, or 3, or a pharmaceutical composition comprising or formulated from the same, for treating a disease, disorder, or condition for which a GABAA positive allosteric modulator is indicated in a subject (e.g, a human subject).

[0127] In some embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be used to treat a disease, disorder, or condition for which a GABAA positive allosteric modulator, NAI-1538907928v1 28Jones Day Docket No.13371-344-228 such as a α2 / 3 / 5 subunit‐selective positive allosteric modulator, in a subject in need thereof, in a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 75 mg, or about 100 mg. In some embodiments, the solid form of Compound (I) may be administered once daily or multiples times daily (e.g., two or more times a daily). In some embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be administered in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg of Compound (I), at a frequency of twice daily. In some embodiments, the aforementioned amounts of Compound (I) may be administered in a pharmaceutical composition (e.g., liquid pharmaceutical composition) prepared from (e.g., reconstituted from) a solid form of Compound (I). In some embodiments, the method of treatment involves a dosing titration period of about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, or about 21 days. In some embodiments the method of treatment does not require of a dose titration period.

[0128] For example, in certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an analgesic and e.g., be administered to a subject as part of a method of treating pain, including acute pain, chronic pain, neuropathic pain, nociceptive (including inflammatory) pain, somatic pain, visceral pain, and dysfunctional pain. In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be administered to a subject as part of a method for treating a pain condition where there is a brain or spinal component to the underlying mechanism of the pain.

[0129] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as anticonvulsant and e.g., be administered to a subject as part of a method of treating epilepsy and / or epilepsy associated disorders, including Lennox-Gastaut syndrome, Dravet's disease, and generalized epilepsy with febrile seizures plus (GEFS+).

[0130] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an anxiolytic agent and e.g., be administered to a subject as part of a method of treating panic disorder, generalized anxiety disorder, a stress disorder (such as post-traumatic stress disorder, acute stress disorder NAI-1538907928v1 29Jones Day Docket No.13371-344-228 and / or substance-induced stress disorder), a phobia (such as agoraphobia, social phobia and animal phobias), and / or obsessive-compulsive disorder.

[0131] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as a muscle relaxant and e.g., be administered to a subject as part of a method of treating muscle spasm, dystonia, spasticity (including generalized and focal spasticity), and / or essential tremor.

[0132] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an antipsychotic agent and e.g., be administered to a subject as part of a method of treating schizophrenia.

[0133] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be administered to a subject as part of a method of treating autism.

[0134] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an antidepressant agent and e.g., be administered to a subject as part of a method of treating a depressive disorder, bipolar disorder, and / or cyclothymia.

[0135] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an antiemetic agent and e.g., be administered to a subject as part of a method of treating chemotherapy- or radiation- induced emesis, post-operative nausea and vomiting, and / or motion sickness.

[0136] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as a cognition-enhancing agent and e.g., be administered to a subject as part of a method of treating a neurodegenerative disorder, such as Alzheimer's disease or cerebral ischemia.

[0137] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as a sleep improving agent and e.g., be administered to a subject as part of a method of treating a sleep disorder, such as insomnia, and / or a circadian rhythm disorder, such as jetlag.

[0138] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as a premedication prior to anesthesia or endoscopy. NAI-1538907928v1 30Jones Day Docket No.13371-344-228

[0139] In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used and administered to a subject as part of a method of treating an addiction phenotype, such as alcoholism. In certain embodiments, a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used and administered to a subject as part of a method of treating Angelman syndrome, attention deficit hyperactivity disorder, bladder urgency, bowel abnormalities, an eating disorder, such as anorexia nervosa or bulimia nervosa, Fragile X syndrome, a hearing disorder, such as tinnitus and age-related hearing impairment, multiple sclerosis, a neurosis, overactive bladder with sensory disturbance, premenstrual syndrome, restless legs syndrome, and / or urinary incontinence.

[0140] Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurons and is activated by noxious stimuli via peripheral transducing mechanisms (see, e.g., Meyer et al., 2006, Wall and Melzack’s Textbook of Pain (5th Ed), Chapter 1). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities, of which there are two main types, A- delta fibers (myelinated) and C fibers (non-myelinated). Nociceptors encode the intensity, duration, and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus. The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

[0141] Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain, or a sprain. Acute pain does not generally result in any persistent psychological response. When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a heightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors which may better enable repair processes to NAI-1538907928v1 31Jones Day Docket No.13371-344-228 take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury or alteration which can be associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768). As such, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain, but may include any chronic painful condition affecting any system, such as those described by the International Association for the Study of Pain (Classification of Chronic Pain, a publication freely available for download at http: / / www.iasp-pain.org).

[0142] The clinical manifestation of pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms can include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of 15 Pain (5th Ed), Chapter 1). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Apart from acute or chronic, pain can also be broadly categorized into nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells), or neuropathic pain.

[0143] Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5thEd), Chapter 1). Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a NAI-1538907928v1 32Jones Day Docket No.13371-344-228 prominent feature of pain from strains / sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, cancer pain and back pain. Cancer pain may be chronic pain such as tumor related pain (e.g., bone pain, headache, facial pain, or visceral pain) or pain associated with cancer therapy (e.g., in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy). Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but, in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

[0144] Nociceptive pain can also be related to inflammatory states. The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter 3). A common inflammatory condition associated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Rheumatoid arthritis is an immune-mediated, chronic, inflammatory polyarthritis disease, mainly affecting peripheral synovial joints. It is one of the commonest chronic inflammatory conditions in developed countries and is a major cause of pain.

[0145] In regard to nociceptive pain of visceral origin, visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart, 25 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter 48). This includes the reproductive organs, spleen, liver, gastrointestinal and urinary tracts, airway structures, cardiovascular system and other organs contained within the abdominal cavity. As such visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowel syndrome, endometriosis and dysmenorrheal (Classification of Chronic Pain, available at http: / / www.iasp-pain.org). Currently the potential for a neuropathic contribution (either through NAI-1538907928v1 33Jones Day Docket No.13371-344-228 central changes or nerve injury / damage) to visceral pain states is poorly understood but may play a role in certain conditions (Aziz et al., 2009, Dig Dis 27, Suppl 1, 31-41)

[0146] Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many 5 disorders with diverse etiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Dworkin, 2009, Am J Med, 122, S1- S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Dworkin, 2009, Am J Med, 122, S 1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

[0147] It should be noted that some types of pain have multiple etiologies and thus can be classified in more than one area, e.g., back pain, cancer pain and even migraine headaches may include both nociceptive and neuropathic components. Similarly other types of chronic pain, perhaps less well understood, are not easily defined by the simplistic definitions of nociceptive or neuropathic. Such conditions include in particular fibromyalgia and chronic regional pain syndrome, which are often described as dysfunctional pain states e.g., fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http: / / www.iasp-pain.org).

[0148] In one embodiment, a solid form of Compound (I) or a pharmaceutical composition prepared therefrom is used in a method of treating pain, as described in any embodiment herein, in a subject. In one embodiment, the solid form of Compound (I) is Form 1 as characterized NAI-1538907928v1 34Jones Day Docket No.13371-344-228 according to any embodiment disclosed herein. In one embodiment, the pain is acute. In one embodiment, the pain is chronic. The pain may be central and / or peripheral origin. The pain may be of a neuropathic, nociceptive, and / or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems. 6.5 Combination Therapies

[0149] In some embodiments, a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be administered in combination with one or more additional therapeutic agents to treat a disease, disorder, or condition in a subject. In certain embodiments, a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) may be administered to a subject, e.g., to treat pain in that subject, in combination with one or more agents selected from the group consisting of: • an anticonvulsant, e.g., carbamazepine; • a selective Nav1.3 channel modulator, such as a compound disclosed in WO2008 / 118758; • a selective Nav1.7 channel modulator, such as a compound disclosed in WO2010 / 079443, e.g., 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2- fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)-4- (trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1, 3-thiazol-4-ylbenzenesulfonamide, or a pharmaceutically acceptable salt of either; • a selective Nav1.8 channel modulator; • a selective Nav1.9 channel modulator; • a compound which modulates activity at more than one Nav channel, such as a non- selective modulator, e.g., bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine or phenytoin; • an inhibitor of nerve growth factor (NGF) signaling, such as an agent that binds to NGF and inhibits NGF biological activity and / or downstream pathway(s) mediated by NGF signaling (e.g., tanezumab), a TrkA antagonist or a P75 antagonist, or an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signaling; • an inhibitor of neurotrophic pathways, where such inhibition is achieved by: (a) an agent that binds to one or more of nerve growth factor (NGF) (e.g., tanezumab, fasinumab, or NAI-1538907928v1 35Jones Day Docket No.13371-344-228 fulranumab), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4 (NT-4), e.g., soluble P75; or (b) an agent that inhibits receptor function at one or more of TrKA, TrKB, TrKC or P75, either at the orthosteric site, an allosteric site or by inhibition of the catalytic activity of the receptor(s); • a compound which increases the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase (MAGL) activity; • an analgesic, such as paracetamol; • an opioid analgesic, such as: buprenorphine, butorphanol, cocaine, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan, levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine; • an opioid analgesic which preferentially stimulates a specific intracellular pathway, e.g, a G-protein pathway as opposed to beta-arrestin recruitment, such as TRV130; • an opioid analgesic with additional pharmacology, such as noradrenaline (norepinephrine) reuptake inhibitory (NRI) activity, e.g., tapentadol; serotonin and norepinephrine reuptake inhibitory (SNRI) activity, e.g., tramadol; or nociception receptor (NOP) agonist activity, e.g., GRT6005; • a nonsteroidal anti-inflammatory drug (NSAID), such as a non-selective cyclooxygenase (COX) inhibitor, e.g., aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; or a COX-2 selective inhibitor, e.g., celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib; • a prostaglandin E2subtype 4 (EP4) antagonist; • a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor; • a sedative, such as glutethimide, meprobamate, methaqualone or dichloralphenazone; • a GABAA modulator with broad subtype modulatory effects mediated via the benzodiazepine binding site, such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam; NAI-1538907928v1 36Jones Day Docket No.13371-344-228 • a GABAA modulator with subtype-selective modulatory effects mediated via the benzodiazepine binding site with reduced adverse effects, e.g., sedation, such as TPA023, TPA023B, L-838,417, CTP354 or NSD72; • a GABAA modulator acting via alternative binding sites on the receptor, such as barbiturates, e.g., amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental; neurosteroids such as alphaxalone, alphadolone or ganaxolone; β-subunit ligands, such as etifoxine; or δ- preferring ligands, such as gaboxadol; • a GlyR3 agonist or positive allosteric modulator; • a skeletal muscle relaxant, e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxolone, methocarbamol, or orphrenadine; • a glutamate receptor antagonist or negative allosteric modulator, such as an NMDA receptor antagonist, e.g., dextromethorphan, dextrorphan, ketamine or, memantine; or an mGluR antagonist or modulator; • an alpha-adrenergic, such as clonidine, guanfacine or dexmedetomidine; • a beta-adrenergic such as propranolol; • a tricyclic antidepressant, e.g., desipramine, imipramine, amitriptyline, or nortriptyline; • a tachykinin (NK) antagonist, such as aprepitant or maropitant; • a muscarinic antagonist, e.g., oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; • a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), varenicline or nicotine; • a Transient Receptor Potential V1 (TRPV1) receptor agonist (e.g., resinferatoxin or capsaicin) or antagonist (e.g., capsazepine or mavatrap); • a Transient Receptor Potential A1 (TRPA1) receptor agonist (e.g., cinnamaldehyde or mustard oil) or antagonist (e.g., GRC17536 or CB-625); • a Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g., menthol or icilin) or antagonist; • a Transient Receptor Potential V3 (TRPV3) receptor agonist or antagonist (e.g., GRC- 15300); NAI-1538907928v1 37Jones Day Docket No.13371-344-228 • a corticosteroid such as dexamethasone; • a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; • a 5-HT2A receptor antagonist; • a PDEV inhibitor, such sildenafil, tadalafil or vardenafil; • an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin; • a serotonin reuptake inhibitor (SRI) such as sertraline, demethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; • an NRI, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine, such as a selective noradrenaline reuptake inhibitor such as reboxetine; • an SNRI, such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran and imipramine; • an inducible nitric oxide synthase (iNOS) inhibitor; • a leukotriene B4 antagonist; • a 5-lipoxygenase inhibitor, such as zileuton; • a potassium channel opener or positive modulator, such as an opener or positive modulator of KCNQ / Kv7 (e.g., retigabine or flupirtine), a G protein-gated inwardly rectifying potassium channel (GIRK), a calcium-activated potassium channel (KCa channel) or a potassium voltage-gated channel such as a member of subfamily A (e.g., Kv1.1 ), subfamily B (e.g., Kv2.2) or subfamily K (e.g., TASK, TREK or TRESK); • a P2X3 receptor antagonist (e.g., AF219) or an antagonist of a receptor which contains as one of its subunits the P2X3 subunit, such as a P2X2 / 3 heteromeric receptor; • a Cav2.2 calcium channel blocker (N-type), such as ziconotide; and • a Cav3.2 calcium channel blocker (T-type), such as ethosuximide.

[0150] Further contemplated is administering of a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom to a subject together with one or more additional therapeutic agents that slow down the rate of metabolism of NAI-1538907928v1 38Jones Day Docket No.13371-344-228 Compound (I), thereby leading to increased exposure in the subject. For example, in one embodiment, an inhibitor of at least one isoform of CYP450 enzyme or an inhibitor of CYP3A4 may be administered to slow down the metabolism of Compound (I) and increase the exposure in the subject. Non-limiting examples of isoforms of CYP450 that may be used include CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2-{[(4- methoxypyridin-3-yl)amino]sulfonyl}benzamide and N-(1-(2-(5-(4-fluorobenzyl)-3-(pyridin-4- yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide.

[0151] In certain embodiments, a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be administered to a subject in combination with an anticonvulsant, e.g., to treat panic disorder. In certain embodiments, the anticonvulsant is carbamazepine.

[0152] The additional therapeutic agent or agents may be administered to the subject together or separately, both physically (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or in time (e.g., at least 30 minutes, 1 hour, 2 hours, 12 hours, or 24 hours apart). As such, it is contemplated that a pharmaceutical composition comprising or prepared from a solid form of Compound (I) and a pharmaceutically acceptable excipient may further comprise one or more additional therapeutic agents as described according to any embodiment herein. Further contemplated is a kit comprising two or more pharmaceutical compositions, at least one of which comprises or is prepared from a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient. The additional pharmaceutical composition(s) may comprise the one or more additional therapeutic agents, as disclosed herein. Such a kit may further comprise means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. One example of such a kit is a blister pack, such as is commonly employed for the packaging of tablets, capsules, and the like. Such a kit may be suitable for administering different dosage forms, such as, oral, and parenteral, for administering each pharmaceutical composition at different dosage intervals, or for titrating the separate compositions against one another. Such a kit may further comprise directions for administration and may be provided.

[0153] In another aspect, the present disclosure provides a pharmaceutical product (such as a dosage form or kit) comprising pharmaceutical composition comprising a solid form of NAI-1538907928v1 39Jones Day Docket No.13371-344-228 Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and one or more additional therapeutically active agents for simultaneous, separate, or sequential administration to a subject for the treatment of a disorder for which a Nav1.8 modulator is indicated. 7. EXAMPLES Example 1: Synthesis of Compound (I)

[0154] Compound (I) may be prepared as disclosed in International Patent Publication No. WO 2014 / 091368 A1, which is incorporated herein by reference in its entirety. All starting materials are available commercially or described in the literature. All temperatures are in °C. Proton (“1H”) nuclear magnetic resonance (“NMR”) spectra were recorded on a Varian Mercury 300 or 400 MHz NMR, Bruker Avance 400 MHz NMR or Jeol ECX 400 MHz NMR. Spectra were obtained as deuterated dimethyl sulfoxide (“DMSO-d6”) solutions (reported in parts per million (“ppm”)). Other NMR solvents, including deuterated chloroform (“CDCl3”) were used as needed. When peak multiplicities are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets.

[0155] Mass spectra (“MS”) were recorded using either electrospray ionization (“ESI”) or atmospheric pressure chemical ionization (“APCI”). Mass spectrometry was carried out using a Finnigan Navigator single quadrupole electrospray mass spectrometer, Finnigan AQA APCI mass spectrometer or Applied Biosystem Q-Trap.

[0156] High pressure liquid chromatography (“HPLC”) was run under the following conditions: Column: Gemini NX C18, 5 µm, 21.2 x 100 mm Temperature: Ambient Detection: Evaporative Light Scattering Detector-Mass Spectrometry Mobile Phase A: 0.1 % diethylamine in water Mobile Phase B: 0.1 % diethylamine in ACN Gradient: 100-95% A over 1 min, 95-2% A over 6 min, 2 min hold, 2-95% A over 0.1 min, 9.9 min hold Flow rate: 18 mL / min Injection volume: 1000 µL NAI-1538907928v1 40Jones Day Docket No.13371-344-228

[0157] Liquid chromatography-mass spectrometry (“LCMS”) indicates liquid chromatography mass spectrometry. “Rt” is retention time. Where ratios of solvents are given, the ratios are by volume. LCMS was primarily conducted using System 1 or System 2 as follows: System 1 Mobile Phase A: 10 mM ammonium acetate in water (basic buffer) Mobile Phase B: ACN Column: XBridge C18, 50 x 4.6 mm column, 5 μm particle size Gradient: 90-70% A over 1.5 min,70-10% A over 3.0 min, 4 min hold, 10- 90% A over in 5 min Flow Rate: 1.2 mL / min UV Wavelength: 220 nm Temperature: 25 °C System 2 Mobile Phase A: 0.05% formic acid in water (acidic buffer) Mobile Phase B: 0.05% formic acid in ACN Column: XBridge C18, 50 x 4.6 mm column, 5 μm particle size Gradient: 5-95% A over 3.5 min, 1 min hold, 95-5% A over 0.1 min UV Wavelength: 210 nm - 450 nm Diode Array Detector Flow Rate: 2 mL / min Temperature: 25 °C

[0158] The skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may have been modified for each specific reaction, and that it may nevertheless be necessary, or desirable, to employ different work-up or purification conditions. Preparation 1: 3,4,5-Trichloropyridazine NAI-1538907928v1Jones Day Docket No.13371-344-228

[0159] 4,5-dichloropyridazin-3(2H)-one (10.0g, 60.6 mmol) in POCl3 (60 mL, 642 mmol) was stirred at 110 °C for 18 hours. Toluene was added and the solvents removed under reduced pressure. EtOAc (200 mL) and water were added to the resulting residue and the organic layer washed with water and brine and then dried over MgSO4. Concentration under reduced pressure provided the desired product as an off-white solid in 90% yield, 10 g.1H NMR (400 MHz, CDCl3): δ ppm 9.10 (d, 1H). HPLC: Rt= 3.35 minutes. Preparation 2: 3,5-Dichloropyridazin-4-amine

[0160] A mixture 2.73 mmol) in EtOH(5.5 mL) and NH4OH (5.5 mL) was heated under microwave irradiation 120 °C for 25 minutes. Concentration under reduced pressure and purification via silica gel column chromatography eluting with acetone: CH2Cl2 (0-15% acetone), provided the title product in 36% yield, 163 mg.1H NMR (400 MHz, CDCl3): δ ppm 5.11 (br s, 2H), 8.74 (s, 1H); LCMS Rt = 0.27 min; MS m / z 164 [M+H]+. Preparation 3: 5-Chloro-N3-ethylpyridazine-3,4-diamine

[0161] A15 g, 92 mmol) and anhydrous ethylamine (50 mL) was heated to 120 °C for 48 hours in a sealed tube. The reaction mixture was cooled to room temperature, and then added to a mixture of water (500 mL) and EtOAc (50 mL). The resulting precipitate was separated by filtration and the filter cake was washed with tert-butyl dimethyl ether and dried under vacuum to afford the title compound as off-white solid in 51 % yield, 8.1 g.1H NMR (400 MHz, DMSO-d6): δ ppm 1.18 (t, 3H), 3.41 (q, 2H), 6.08-6.11 (m, 3H), 8.09 (s, 1H). NAI-1538907928v1 42Jones Day Docket No.13371-344-228 Preparation 4: 4-Chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine

[0162] A mixture 3, 10.0 g,58 mmol) and were hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc and then the organic layers were washed with saturated brine solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound as a yellow solid in 45% yield, 4.8g. Preparation 5: 7-Ethyl-4-(4-fluorophenyl)-7H-imidazo[4, 5-c]pyridazine

[0163] pyridazine (Preparation 4, 9.6 g, 52.4 mmol) in dioxane (300 mL) was added 4-fluorobenzene boronic acid (8.8 g, 63 mmol) and an aqueous solution of Na2CO3 (1 M, 260 mL, 262 mmol). The reaction mixture was degassed and purged with nitrogen gas 3 times. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was then added and the mixture was heated to reflux for 4 hours. The organic solvent was removed in vacuo and the resulting aqueous mixture filtered. The filter cake was dried under vacuum to afford the title compound as NAI-1538907928v1 43Jones Day Docket No.13371-344-228 a yellow solid in 55% yield, 7 g.1H NMR (400 MHz, CDCl3): δ ppm 1.62 (t, 3H), 4.50 (q, 2H), 7.19 (t, 2H), 8.14-8.18 (m, 2H), 8.21 (s, 1H), 9.27 (s, 1H). Preparation 6: 7-Ethyl-4-(4-fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine

[0164] 4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 5, 825 mg, 2.4 mmol) surrounded by an ice bath, and the resultant reaction mixture was gently stirred at room temperature until a homogeneous solution was observed. To this was added 1,3-diiodo-5,5-dimethylhydantoin (1.36 g, 3.58 mmol) portion-wise, and stirring was continued for 5 minutes. The viscous mixture was then slowly poured into an aqueous sodium hydroxide solution (1 M, 10 mL) at 0 °C with stirring. The black suspension slowly dissolved to give a blue solution. CH2Cl2 (20 mL) was added, and the layers were separated. The organic layer was washed with saturated aqueous sodium bisulfite solution (20 mL) then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with heptane:EtOAc 1:1 to 0:100 to afford the title compound as a white solid in 95% yield, 1.19 g.1H NMR (400 MHz, CDCl3): δ ppm 1.70 (t, 3H), 4.58 (q, 2H), 8.19-8.23 (m, 1H), 8.29 (s, 1H), 8.65 (dd, 1H), 9.32 (s, 1H); LCMS Rt= 1.44 min; MS m / z 369 [M+H]+Preparation 7: 1-Bromo-4-(ethylsulfonyl)-2-fluorobenzene

[0165] To solution of 4-bromo-3-fluorobenzene-1-g, 0.184 mol) in THF (800 mL) at 0 °C was added hydrazine monohydrate (40-50%, 41.26 g, 0.644 mol) dropwise over 45 minutes. The reaction was stirred for 4 hours at room temperature and then the NAI-1538907928v1 44Jones Day Docket No.13371-344-228 solvent was removed under reduced pressure to low volume. Heptane (100 mL) was added and the solid was filtered and washed several times with heptanes. The resulting solid was dissolved in EtOH (800 mL). Sodium acetate (90.56 g, 1.104 mol) and ethyl iodide (143.49 g, 0.92 mol) were added, and the reaction heated to reflux for 18 hours. The reaction was allowed to cool to room temperature, the solvent was removed under reduced pressure to 30% of the initial volume. The reaction mixture was diluted with water (500 mL) and extracted 3 times with CH2Cl2(250 mL). The combined organic layers were washed twice with brine (300 mL), dried over Na2SO4, filtered, and reduced to dryness to give a yellow oil. The crude was absorbed onto silica and purified (using silica gel column chromatography eluting with cyclohexane:EtOAc 8:2 to give the title compound as yellow solid in 64% yield, 31.70 g.1H NMR (400 MHz, CDCl3): δ ppm 1.29 (t, 3H), 3.14 (q, 2H), 7.57-7.59 (m, 1H), 7.65 (dd, 1H), 7.89 (dd, 1H). LCMS (System 2): Rt = 2.26 min; MS m / z no ionization. Preparation 8: 1-Bromo-4-(ethylsulfonyl)-2-methoxybenzene

[0166] 7, 34.89 g, 0.131 mol) was dissolved in methanol (MeOH, 400 mL). Sodium methoxide (35.3 g, 0.653 mol) was added. The reaction was heated at 100 °C for 12 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water (750 mL) and the aqueous layer was extracted twice with CH2Cl2 (250 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and reduced to dryness to give a solid. The crude was purified by silica gel column chromatography eluting with a cyclohexane:EtOAc gradient from 95:5 to 8:2 to afford the title compound as colorless solid in 75% yield, 27.32 g.1H NMR (400 MHz, CDCl3): δ ppm 1.29 (t, 3H), 3.12 (q, 2H), 3.97 (s, 3H), 7.35-7.38 (m, 2H), 7.74 (d, 1H); LCMS (System 2): Rt= 2.26 min; MS no ionization.

[0167] 1-Bromo-4-(ethylsulfonyl)-2-methoxybenzene may also be prepared according to the following Preparation:

[0168] Step 1 NAI-1538907928v1 45Jones Day Docket No.13371-344-228

[0169] To a pre-cooled suspension of 2-bromo-5-fluorophenol (5 g, 26.18 mmol) and potassium carbonate (10.84 g, 78.54 mmol) in N,N-dimethylformamide (15 mL) at 0-5 °C, was added methyl iodide (4.75 mL, 39.27 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was further extracted 3 times with EtOAc (50 mL). The organic layers were combined, washed with saturated brine solution (20 mL) and dried over Na2SO4, filtered and concentrated in vacuo to afford 1-bromo-4-fluoro-2-methoxybenzene as a colorless liquid in 93% yield, 5.00 g.1H NMR (400 MHz, DMSO-d6): δ ppm 3.86 (s, 3H), 6.74-6.79 (m, 1H), 7.06 (dd, 1H), 7.57-7.65 (m, 1H).

[0170] Step 2

[0171] To a room temperature solution of 1-bromo-4-fluoro-2-methoxybenzene (5.00 g, 24.39 mmol) in N,N-dimethylformamide (15 mL) was added sodium ethanethiolate (2.66 g, 31.71 mmol) and the resulting reaction mixture was stirred for 72 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was further extracted 3 times with EtOAc (50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 98:2 to afford 1-bromo-4-ethylthio-2- methoxybenzene as a colorless liquid in 17% yield, 1.00 g.1H NMR (400 MHz, DMSO-d6): δ ppm 1.24 (t, 3H), 3.01 (q, 2H), 3.85 (s, 3H), 6.82 (dd, 1H), 6.98 (s, 1H), 7.48 (d, 1H).

[0172] Step 3

[0173] To a room temperature solution of 1-bromo-4-ethylthio-2-methoxybenzene (1.00 g, 4.05 mmol) in acetic acid (60 mL) was added sodium perborate monohydrate (889 mg, 8.91 mmol) and the resulting reaction mixture was stirred for 16 hours. The reaction was concentrated in vacuo and the resulting crude was partitioned between water (20 mL) and CH2Cl2(50 mL). The organic layer was separated, washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated to afford the title product as a colorless liquid in 88% yield, 900 mg.1H NMR (400 MHz, DMSO-d6): δ ppm 1.11 (t, 3H), 3.34 (q, 2H), 3.96 (s, 3H), 7.38 (dd, 1H), 7.47 (d, 1H), 7.88 (d, 1H). NAI-1538907928v1 46Jones Day Docket No.13371-344-228 Preparation 9: 2-(4-(Ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0174] A 8, 2.00 g,7.17 mmol), g, , bis(diphenylphosphino)ferrocene]dichloropalladium(II) (293 mg, 0.359 mmol) and potassium acetate (1.76 g, 17.93 mmol) in dioxane (40 mL) was degassed with nitrogen for 20 minutes and placed on a pre-heated hot plate at 100 °C. The reaction was stirred at 100 °C for 18 hours. The reaction was cooled to room temperature, filtered through celite, and washed with EtOAc (50 mL). Water (75 mL) was added, the product extracted twice with EtOAc (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with 15-65% methyl tert-butyl ether in heptanes to afford the title compound as a colorless solid in 42% yield, 985 mg.1H NMR (400 MHz, CDCl3): δ ppm 1.22 (t, 3H), 1.33 (s, 12H), 3.08 (q, 2H), 3.85 (s, 3H), 7.27 (s, 1H), 7.43 (s, 1H), 7.99 (s, 1H). Preparation 10: Synthesis of Compound (I)

[0175] c]pyridazine (Preparation 6, 100 mg, 0.27 mmol), 2-(4-ethylsulfonyl-2-methoxyphenyl)-4,4,5,5-tetramethyl- NAI-1538907928v1 47Jones Day Docket No.13371-344-228 [1,3,2]dioxaborolane (Preparation 9, 88 mg, 0.27 mmol) and cesium carbonate (177 mg, 0.54 mmol) in dioxane (5 mL) and water (1 mL) was degassed with argon for 10 minutes followed by the addition of 1,1'-bis(di-tert-butylphosphino) ferrocene palladium dichloride (4.4 mg, 0.005 mmol). The resulting mixture was heated at 100 °C for 16 hours, cooled to room temperature and diluted with EtOAc (15 mL). The organic layer was washed with water (10 mL) and saturated brine solution (10 mL) then dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 afforded the Compound (I) as off white solid in 13% yield, 15 mg.1H NMR (400MHz, CDCl3): δ ppm 1.36 (t, 3H), 1.68 (t, 3H), 3.18 (q, 2H), 3.90 (s, 3H), 4.58 (q, 2H), 7.35 (t, 1H), 7.50 (s, 1H), 7.54-7.60 (m, 2H), 8.21 (dd, 1H), 8.26 (s, 1H), 8.27-8.29 (m, 1H), 9.35 (s, 1H); LCMS (System 1) Rt= 2.94 min; MS m / z = 441 [M+H]+. Example 2: Preparation of Form 1 Process A

[0176] Compound (I) was dissolved in ACN and the reaction mixture was filtered through a Celite pad. Solvent was then exchanged from ACN to EtOAc from which Form 1 of Compound (I) was crystallized. The crystalized compound was then recrystallized in EtOAc to purify the Form 1 of Compound (I) having an impurity content of less than 0.05%, as measured by UPLC. Process B

[0177] Compound (I), charcoal, and EtOH were heated and the resulting suspension was filtered. The mixture was cooled to precipitate Form 1 of Compound (I). Process C

[0178] Compound (I) was crystallized in ACN. Obtained solids were filtered through Celite and rinsed with EtOAc to obtain Form 1 of Compound (I). Example 3: Purity of Form 1 of Compound (I)

[0179] Compound (I) as crystallized according to process B in Example 2 was assayed for purity using reverse-phase HPLC via one of two methods as described below: Method 1: Column: Waters Aquity BEH C18 Detection: UV Absorbance at 210 nm Mobile Phase A: 10 mM aqueous ammonium bicarbonate Mobile Phase B: ACN NAI-1538907928v1 48Jones Day Docket No.13371-344-228 Run time: 21 minutes

[0180] Quantification of impurities is achieved by area percent. Method 2: Column: Waters Aquity HSS T31.8µ Detection: UV Absorbance at 210 nm Mobile Phase A: 0.05% methane sulfonic acid in purified water Mobile Phase B: ACN Run time: 20 minutes

[0181] Presence of residual solvent(s) was assayed by Gas Chromatography as described below: Column: Fused Silica DB624 or equivalent Injection Temp: 180 °C split flow Column Temp: e.g., 40 °C (hold for 2.5 min), ramp to 50 °C at 4.44 °C / min, ramp to 225°C at 80 °C / min (hold for 1.06 min) Carrier Gas: Helium Flow Rate: 1.2 mL / min Run time: 8 minutes

[0182] Detection of water was conducted according to standard titrimetric procedures described in the U.S. Pharmacopeia, method USP <921> using Karl Fischer reagents.

[0183] ICP-MS was used to detect the presence of palladium, using procedures described in the U.S. Pharmacopeia, method USP <233>.

[0184] Residue on ignition was conducted using procedures described in the U.S. Pharmacopeia, method USP <281>. This test involves burning a material in the presence of sulfuric acid, then weighing any remaining ash to determine the presence of any residual inorganic material.

[0185] Assay and detection of one impurity, shown below was also quantified: . NAI-1538907928v1Jones Day Docket No.13371-344-228 Impurity 1

[0186] Table 1 below reports the results of the above-noted assays: Table 1: Impurities in Form 1 of Compound (I) Individual Impurities: Impurity 1 ≤ 0.2%

[0187] Solid Forms were characterized by Polarized Light Microscopy (PLM), high- resolution XRPD analysis,1H NMR spectroscopy, DSC, and TGA as follows:

[0188] X-Ray Powder Diffraction (XRPD) patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify the Si 111 peak position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry. A beam-stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position- sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b.

[0189] Differential Scanning Calorimetry (DSC) was performed using a TA Instrument Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed into an aluminum Tzero DSC pan, covered with NAI-1538907928v1 50Jones Day Docket No.13371-344-228 a lid, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration are displayed on the thermogram. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate, e.g., (-30)-250-10 means "from -30 °C to 250 °C, at 10 °C / min". The abbreviation of "T0C" on the thermogram means "Tzero pan and lid crimped".

[0190] Thermogravimetric analysis (TGA) was performed using a TA Instruments 2950 IR thermogravimetric analyzer. Sample was placed in an aluminum sample pan and inserted into the TG furnace. The data acquisition and processing parameters are displayed on each thermogram. Nickel and Alumel™ were used as the calibration standards. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate, e.g., 00-350-10 means "from 0 °C to 350 °C, at 10 °C / min".

[0191] Solution1H NMR spectrum was acquired at ambient with a VarianUNITYINOVA-400 spectrometer at a1H Larmor frequency of 399.795 MHz. The sample was dissolved in DMSO-d6 containing TMS. The spectrum was acquired with a1H pulse width of 8.9 µs, a 5 second acquisition time, a 2.5 second delay between scans, a spectral width of 6400 Hz with 64000 data points, and 40 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 131072 points and an exponential line broadening factor of 0.2 Hz to noise ratio. The residual peak from incompletely deuterated solvent (DMSO-d5) is at approximately 2.50 ppm. The singlet peak at approximately 3.33 ppm is due to water. The spectrum was referenced to internal tetramethylsilane (TMS) at 0.0 ppm.

[0192] Polarized Light Microscopy (PLM) was performed using a Leica MZ12.5 stereomicroscope or a Leica DM LP microscope. Various objectives from 0.8-10x were used with crossed-polarized light to view samples, utilizing a first order red compensator. Samples were viewed in situ. Images were acquired at ambient temperature with a Spot Insight color camera using Spot Advanced software version 4.5.9 build date June 9, 2005.

[0193] Characterization of Form 1 of Compound (I): Based on PLM observations, Form 1 is a white powder with pills consisting of tiny B / E particles. The XRPD pattern indicates Form 1 is crystalline and is shown in FIG.1. The DSC thermogram, shown in FIG.2, shows a sharp endotherm with peak maximum at 187 °C. TGA, shown in FIG.3, indicates no weight loss from NAI-1538907928v1 51Jones Day Docket No.13371-344-228 ambient temperature up to 150 °C and a 0.7% weight loss between 150 and 200 °C that is on the same order as the amount of EtOAc found by1H NMR. The1H NMR spectrum, shown as the bottom red trace in FIG.4, is consistent with the structure of Compound (I). A small amount of EtOAc (0.53 wt. %; 0.027 mol / mol API) and other possible impurities were observed.

[0194] Form 1 of Compound (I) has an aqueous solubility of about 15 µg / mL at pH 2 and about 2 µg / mL at pH 7.

[0195] The single crystal structure of Form 1 of Compound (I) was determined by single crystal X-ray diffraction. Single crystals suitable for X-ray data collection were isolated from a crash cool experiment (−80 °C) of the filtrate that was obtained from a 2-week ambient trituration of Compound (I) in acetone. A colorless plate of C22H21FN4O3S having approximate dimensions of 0.84 mm × 0.66 mm × 0.48 mm, was mounted on a fiber in random orientation. Preliminary examination and data collection were performed with Mo Kα radiation (λ = 0.71073 Å) on a Nonius Kappa CCD diffractometer equipped with a graphite crystal, incident beam monochromator. Refinements were performed using SHELX97. Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 9592 reflections in the range 2° < ^ < 27°. The refined mosaicity from DENZO / SCALEPACK is 0.47° indicating good crystal quality. The space group was determined by the program XPREP. There were no systematic absences, and the space group was determined to be P−1. The data were collected to a maximum 2^ value of 54.50º, at room temperature.

[0196] Frames were integrated with DENZO-SMN. A total of 9592 reflections were collected, of which 4515 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient is 0.198 mm-1for Mo Kα radiation. An empirical absorption correction using SCALEPACK was applied. Transmission coefficients ranged from 0.798 to 0.909. A secondary extinction correction was applied. The final coefficient, refined in least- squares, was 0.0730 (in absolute units). Intensities of equivalent reflections were averaged. The agreement factor for the averaging was 4.9% based on intensity.

[0197] The triclinic cell parameters and calculated volume are: a = 7.1681(6) Å, b = 12.7377(16) Å, c = 12.8951(13) Å, α = 113.21°, β = 104.05°, γ = 92.80°, V = 1035.81(19) Å3. The molecular weight of the asymmetric unit in the crystal structure of Compound (I) Form 1 is NAI-1538907928v1 52Jones Day Docket No. 13371-344-228 440.50 g·mol−1with Z = 2, resulting in a calculated density of 1.412 g·cm−3. The space group was determined to be P−1.

[0198] The structure was solved using the Patterson heavy-atom method which revealed the position of the S atom. The remaining atoms were located in succeeding difference Fourier syntheses. Hydrogen atoms were included in the refinement but restrained to ride on the atom to which they are bonded. The structure was refined in full-matrix least-squares by minimizing the function: The weight w is defined as 1 / [σ²(Fo2) + (0.0097P)2+(1.7895P)], where P = (Fo2+2Fc2) / 3.

[0199] Scattering factors were taken from the “International Tables for Crystallography.” Of the 4515 reflections used in the refinements, only the reflections with Fo2> 2σ( Fo2) were used in calculating the fit residual, R. A total of 3117 reflections were used in the calculation. The final cycle of refinement included 284 variable parameters and converged (largest parameter shift was < 0.01 times its estimated standard deviation) with unweighted and weighted agreement factors of:of unit weight (goodness of fit) was 1.074. The highest peak in the final difference Fourier had a height of 0.71 e / ų. The minimum negative peak had a height of −0.43 e / ų.

[0201] A calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure. FIG. 7 shows a calculated XRPD pattern of Form 1 of Compound (I), generated from the single crystal structure. All peaks in the experimental pattern of Form 1 of Compound (I) are represented in the calculated XRPD pattern, indicating that the prepared Form 1 is likely a single phase of Form 1. NAI-1538907928v1 53Jones Day Docket No.13371-344-228

[0202] To investigate the physical stability, samples were stored at 25°C / 60% RH for 12 months and 40°C / 75% RH for 6 months and no significant difference was observed in the XRPD patterns obtained, suggesting that the material is physically stable under these conditions.

[0203] Characterization of Form 2: Based on polarized light microscopy observations, the material consists of B / E needle fans and elongated angulars. The XRPD pattern, shown in FIG.5, was consistent with crystalline material. The1H NMR spectrum obtained from fast evaporation of Form 1 of Compound (I) in 90:10 THF:water, designated as Form 2, is shown as the top blue trace in FIG.4, was consistent with the structure of Compound (I) and showed no detectable THF. However, peaks not expected for Compound (I) were present, likely indicating the presence of impurities in Form 2.

[0204] However, peaks not expected for Compound (I) were present, likely indicating the presence of impurities. Three scale-up experiments in 90:10 v / v THF:water were done in an attempt to produce Form 2 for further characterization and elevated temperature competition slurry experiments. However, none was successful. In the first scale-up, a concentrated solution (53 mg / mL) of Compound (I) in 90:10 v / v THF:water was fast evaporated but resulted in a sticky oil. The resulting oil was redissolved in fresh solvent at a concentration of 106 mg / mL and fast evaporated, producing Form 1 of Compound (I). The second scale-up was a fast evaporation of a dilute solution using the concentration that initially produced Form 2 (5 mg / mL), but also resulted in Form 1 of Compound (I). In the third scale-up, the material from the second scale-up was redissolved at the same solvent volume, but a combination of rotary evaporation / vacuum oven drying at ambient temperature was used to remove the solvent. A murky, gelatinous oil was produced. Example 5: Solubility

[0205] Form 1 of Compound (I) was dissolved in thirteen (13) different organic solvents including acetone, ACN, chloroform, p-dioxane, EtOH, EtOAc, n-heptane, MeOH, t-butyl methyl ether (TBME), isopropyl alcohol (IPA), THF, toluene, and n-hexane, in water, and in seven aqueous binary mixtures with water activity above approximately 0.8, including 78:22 v / v, acetone:water, 90:10 v / v acetone:water, 88:12 v / v ACN:water, 52:48 v / v EtOH:water, 39:61 v / v MeOH:water, 95:5 v / v THF:water, and 90:10 v / v THF:water. Results are reported in Table 2 below: NAI-1538907928v1 54Jones Day Docket No.13371-344-228 Table 2: Results of Kinetic Solubility Screen Solvent ApproximateSolubility (mg / mL)Turbidityac Water Activity of ~0.7 d Water Activity of ~0.8 e Water Activity of ~1.1 f Tiny birefringent / extinguishable particles adhered to vial wall with settling of agglomerate mass Example 6: Slurry Triturations

[0206] Equilibrium solubilities were determined for Form 1 of Compound (I) for the aqueous binary systems at ambient temperature and acetone, EtOAc, and THF at 40 °C. All solvents, except where water was used, were dried over 3Å molecular sieves. Table 3 provides the results of the equilibrium solubilities in each system tested. Table 3: Equilibrium Solubilities of Compound (I) in various Solvent Systems Solvent Temperature Solubility XRPD ResultNAI-1538907928v1 55Jones Day Docket No.13371-344-228 acetone 40 °C 33 mg / mL Form 1 EtOAc 40 °C 9 mg / mL Form 1 ° su s an a y e same an cons s en w orm . Example 7: Limited Polymorph Screen

[0208] Centrifuge filtrates and selected solutions from the solubility screen were employed in a limited polymorph screen that utilized fast and slow evaporations, solvent-antisolvent additions (n-heptane, IPA, and THF) were tested, vapor diffusion, precipitations, and crash (- 80 °C), freezer (-25 to -15 °C), and refrigerator (2 to 8 °C) cooling, which are described as follows:

[0209] Fast Evaporation: Sample solutions, consisting of API and solvent(s), were evaporated in 2-mL, 20-mL, or 40-mL HPLC vials in a fume hood at ambient temperature. The resulting solids were screened with PLM for birefringent / extinguishable solid before analyzing by XRPD.

[0210] Slow Evaporation: Sample solutions, consisting of API and solvent(s), were slowly evaporated in 2-mL HPLC vials in a fume hood at ambient temperature by loosely lidding the caps to the vials. The resulting solids were screened with PLM for birefringent / extinguishable solid before analyzing by XRPD.

[0211] Solvent-Antisolvent Addition: Either n-heptane (~2:1 to 3:1 v / v), IPA (~5:1 to 7:1 v / v), or chlorhexidine (~2:1 v / v) was added to aliquots of the mother liquors from the equilibrium solubility study of the stable form screen in an effort to precipitate kinetic forms. Recovered solids were submitted for XRPD analysis at ambient temperature.

[0212] Cooling: Cooling experiments were conducted in either a refrigerator at 2 to 8 °C or in a freezer at -15 to -25 °C.

[0213] Crash Cooling: A sealed 2-mL HPLC vial containing an aliquot of mother liquor filtrate from the equilibrium solubility study was placed inside a parafilmed 20-mL scintillation vial, then transferred to a -80 °C freezer for 1 day. The resulting mixture was manually pressure- filtered on a 0.22-µm nylon membrane to isolate the solid.

[0214] Precipitation: Some solids formed as in situ precipitates in the mother liquor filtrates and were isolated. NAI-1538907928v1 56Jones Day Docket No.13371-344-228

[0215] Vapor Diffusion: A centrifuge tube containing the THF mother liquor filtrate for Compound (I) was placed uncovered into a 20 mL glass scintillation vial containing a few milliliters of n-heptane antisolvent. The outer vial was sealed with parafilm, and the sample was left at ambient temperature for ~8 days before isolating the solid.

[0216] Results are shown in Table 4 below. In Table 4, “RT” refers to room or ambient temperature. Table 4: Results of Polymorph Screen Solvent (temperature)Technique Result XRPD ResultNAI-1538907928v1 57Jones Day Docket No.13371-344-228 Solvent (temperature)Technique Result XRPD ResultNAI-1538907928v1 58Jones Day Docket No.13371-344-228 Solvent (temperature)Technique Result XRPD Resultm.

[0217] As shown, two materials were identified in addition to Form 1. A mixture with Form 1 (“Material B”) was produced from fast evaporation in methanol. Form 2 was produced from a fast evaporation in 90:10 v / v THF:water. NAI-1538907928v1 59Jones Day Docket No.13371-344-228 Example 8: Competitive Slurry

[0218] A competitive slurry was conducted in anhydrous acetone pre-saturated with of Compound (I) Form 1 at ambient temperature. The mixture with Form 1 and Form 2 were added and stirred / vortexed for five days. The slurry was centrifuge-filtered, and the wet cake was allowed to dry in air. The XRPD pattern of the resulting solid was consistent with Form 1. Example 9: Attempted Scale-Up of Form 2

[0219] Attempt 1: Compound (I) (105.8 mg) was dissolved in 90:10 v / v THF:water (2.0 mL). Solvent was rapidly evaporated. A sticky oil formed upon complete evaporation (~2 days). The oil was re-dissolved in fresh 90:10 v / v THF:water (1.0 mL) and fast evaporated ~12 days, producing white solid. The XRPD pattern for the material was consistent with Form 1.

[0220] Attempt 2: Compound (I) (100.1 mg) was dissolved in 90:10 v / v THF:water (21.3 mL). In this attempt, an effort was made to reproduce the conditions of that generated Form 2 in Example 7, which had previously generated Form 2 (4.71 mg Compound (I) / 1.0 mL solvent; sonication; ~6 days fast evaporation at RT). The evaporation for the scale-up took ~10 days. The XRPD pattern for the recovered material was consistent with Form 1.

[0221] Attempt 3: Solid from the Attempt 2 was re-dissolved in fresh 90:10 v / v THF: water (21.3 mL solvent) using sonication. A rotary evaporation was conducted over ~30 minutes at ambient temperature and reduced pressure followed by overnight drying in a vacuum oven at ambient temperature (~24-34 mTorr). A murky, gelatinous oil resulted. Example 10: Summary of Polymorph Screening

[0222] In summary, various methods were described herein that attempted to prepare and characterize the various polymorphs of Compound (I). Three unique XRPD patterns of the free base of Compound (I) were identified during the course of the screen: Form 1, Form 2 (from a fast evaporation in 90:10 THF:water) and Pattern B (Material B by SSCI annotation, from a fast evaporation in MeOH, mix of Form 1 and another pattern). Additionally, a sulfate salt of Compound (I) (“Form 3”) was also generated. Single crystals of Form 1 were isolated during the screen, the single crystal structure was solved, and a calculated powder pattern was generated. This calculated powder pattern was consistent with patterns of Form 1. Producing Form 2 in larger quantities was inefficient. Solution NMR on Form 2 did not show the presence of any residual solvents. Slurries with Form 1 as the starting material were run at ambient conditions and 40°C and Form 1 was isolated in all cases. Form 1, Form 2 and Pattern B solids were NAI-1538907928v1 60Jones Day Docket No.13371-344-228 competitively slurried in anhydrous acetone saturated with Form 1 for five days, which yielded Form 1. Therefore, it was concluded that Form 1 of Compound (I) is the most stable form at room temperature and 40°C. Example 11: Preparation and Characterization of Sulfate Salt

[0223] Compound (I) has a low pKa (2.77), which limits the number of counter ions which could form a salt. Additionally, formation of a salt runs a high risk of disproportionation in drug product. Nevertheless, a small-scale salt screening was conducted with mesylate, tosylate, sulfate and HCl counter ions. Only experiments utilizing HCl and sulfate yielded material that was different to the ingoing form. Further, it was difficult to replicate the form obtained from HCl.

[0224] A highly crystalline, high melting solid was produced when utilizing sulfate as a counter ion. The XRPD pattern obtained is shown in FIG.6 and is considered to be a sulfate salt of Compound (I). During thermal analysis, a deviation from the baseline was observed in DSC, shown in FIG.8, prior to the melt and some weight loss was observed in TGA experiments, shown in FIG.9, which can be indicative of solvent loss. This was investigated further utilizing hotstage XRPD, which indicated no form change up to 180 °C. It was hypothesized that degradation was occurring prior to the melt.

[0225] Although the suspected sulfate salt is classified as non-hygroscopic, it does sorb approximately 1.5% water at 90% relative humidity (RH). The material was further characterized by humidity XRPD whereupon it was analyzed between 25 and 90% RH, no shifts were seen in the XRPD peaks which might be expected if water molecules were moving in and out of the lattice.

[0226] To investigate the physical stability, samples were stored at 40°C / 75% RH and 70°C / 75% RH for two weeks and no significant difference was observed in the XRPD patterns obtained, suggesting that the material is physically stable under these conditions for two weeks. * * * * *

[0227] Throughout this application, various publications, patents, patent applications and other documents have been referenced. The disclosures of these publications, patents, patent applications and other documents in their entireties are hereby incorporated by reference in this application for all purposes, including in order to more fully describe the state of the art to which this the subject matter disclosed herein pertains. Although the disclosed subject matter has been described with reference to the examples provided above, it should be understood that various NAI-1538907928v1 61Jones Day Docket No.13371-344-228 modifications could be made without departing from the spirit of the disclosed subject matter. Many variations will become apparent to those skilled in the art upon review of this specification. NAI-1538907928v1 62

Claims

Jones Day Docket No.13371-344-228 CLAIMS What is claimed is:

1. A crystalline form comprising Compound (I), or a pharmaceutically acceptable salt thereof: N .

2. The crystalline form ofof Compound (I).

3. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 13.9, 14.5, 16.9, 19.9, 20.1, and 25.0° 2θ ± 0.2 °2θ.

4. The crystalline form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least one peak selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

5. The crystalline form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least two peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

6. The crystalline form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ. NAI-1538907928v1 63Jones Day Docket No.13371-344-228 7. The crystalline form of claim 3, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

8. The crystalline form of claim 2, which is characterized by an XRPD pattern comprising peaks at approximately 14.5, 16.9, and 19.9° 2θ ± 0.2 °2θ.

9. The crystalline form of claim 8, wherein the XRPD pattern further comprises peaks at approximately 12.8, 13.9, and 20.1° 2θ ± 0.2 °2θ.

10. The crystalline form of claim 9, wherein the XRPD pattern further comprises a peak selected from the group consisting of approximately 15.6, 22.0, and 23.4° 2θ ± 0.2 °2θ.

11. The crystalline form of claim 2, which is characterized by an XRPD pattern essentially as shown in FIG.

1.

12. The crystalline form of any one of claims 3 to 11, which exhibits a thermal event with an onset temperature of about 186 °C as characterized by DSC.

13. The crystalline form of any one of claims 3 to 12, which exhibits a weight loss of about 0.21% upon heating from about 25 °C to about 200 °C.

14. The crystalline form of any one of claims 2 to 13, wherein a single crystal Compound (I) is characterized by the following triclinic cell parameters: a = 7.1681(6) Å, b = 12.7377(16) Å, c = 12.8951(13) Å, α=113.21°, β = 104.05°, γ = 92.80°, V = 1035.81(19) Å3.

15. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks at approximately 8.5, 9.1, 11.5, 17.0, 18.2, 21.5, 23.6, and 24.0° 2θ ± 0.2 °2θ.

16. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least one peak selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ. NAI-1538907928v1 64Jones Day Docket No.13371-344-228 17. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least two peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ.

18. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ.

19. The crystalline form of claim 2, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, further comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2θ ± 0.2 °2θ.

20. The crystalline form of claim 2, which is characterized by an XRPD pattern comprising peaks at approximately 8.5, 9.1, and 17.0° 2θ ± 0.2 °2θ.

21. The crystalline form of claim 20, wherein the XRPD pattern further comprises peaks at approximately 11.5, 11.8, and 18.2° 2θ ± 0.2 °2θ.

22. The crystalline form of claim 21, wherein the XRPD pattern further comprises a peak selected from the group consisting of approximately 14.2, 15.5, 21.5 and 22.4° 2θ ± 0.2 °2θ.

23. The crystalline form of claim 2, which is characterized by an XRPD pattern essentially as shown in FIG.

2.

24. The crystalline form of claim 1, comprising a sulfate salt of Compound (I).

25. The crystalline form of claim 24, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least three peaks, each at a 2θ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ. NAI-1538907928v1 65Jones Day Docket No.13371-344-228 26. The crystalline form of claim 24, which is characterized by an XRPD pattern, when measured using Cu Kα radiation, comprising at least four peaks, each at a 2θ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ.

27. The crystalline form of claim 24, which is characterized by an XRPD pattern comprising peaks at approximately 7.6, 13.2, and 24.3° 2θ ± 0.2 °2θ.

28. The crystalline form of claim 1, wherein the XRPD pattern further comprises peaks at approximately 17.5, 17.9, and 19.9° 2θ ± 0.2 °2θ.

29. The crystalline form of claim 28, wherein the XRPD pattern further comprises a peak selected from the group consisting of approximately 21.0, 21.4, 26.5, 26.7, and 27.7° 2θ ± 0.2 °2θ.

30. The crystalline form of any one of claims 24 to 29, which exhibits, as characterized by DSC, a thermal event with an onset temperature of about 209 °C.

31. The crystalline form of any one of claims 24 to 30, which exhibits a weight loss of about 1.6% upon heating from about 50 °C to about 200 °C.

32. The crystalline form of claim 31, which exhibits a further weight loss of about 4% upon heating from about 200 °C to about 300 °C.

33. The crystalline form of claim 24, which is characterized by an XRPD pattern essentially as shown in FIG.

6.

34. The crystalline form of any one of claims 1 to 33, wherein the crystalline form is anhydrous.

35. A composition comprising the crystalline form of any one of claims 1 to 34, wherein the chemical purity of the composition is at least about 98%.

36. A composition comprising the crystalline form of any one of claims 1 to 35, wherein composition comprises not more than about 0.2% by weight of any single impurity. NAI-1538907928v1 66Jones Day Docket No.13371-344-228 37. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 34 or a composition of claim 35 or 36 and a pharmaceutically acceptable excipient.

38. The pharmaceutical composition of claim 37, further comprising carbamazepine.

39. The pharmaceutical composition of claim 37 or 38, which is a solid intended for reconstitution prior to use.

40. The pharmaceutical composition of claim 37 or 38, which is an oral dosage form.

41. The pharmaceutical composition of claim 40, which is an oral tablet.

42. A method of treating a disorder for which a GABAA positive allosteric modulator is indicated in a subject comprising administering a therapeutically effective amount of the crystalline form of any one of claims 1 to 34, or the pharmaceutical composition of any one of claims 37, 38, 40, and 41 to the subject.

43. A method of treating pain in a subject comprising administering a therapeutically effective amount of the crystalline form of any one of claims 1 to 34, or the pharmaceutical composition of any one of claims 37, 38, 40, and 41 to the subject.

44. A method of treating a panic disorder in a subject comprising administering a therapeutically effective amount of the crystalline form of any one of claims 1 to 34, or the pharmaceutical composition of any one of claims 37, 38, 40, and 41 to the subject.

45. The method of any one of claims 42 to 44, wherein the pharmaceutical composition does not comprise carbamazepine and the method further comprising administering a therapeutically effective amount of carbamazepine to the subject. NAI-1538907928v1 67Jones Day Docket No.13371-344-228 46. A method for preparing the crystalline form of any one of claims 3 to 14: comprising: (a) dissolving Compound (I) in(b) exchanging the acetonitrile for ethyl acetate; and (c) crystallizing Form 1 of Compound (I) from the ethyl acetate.

47. A method for preparing the crystalline form of any one of claims 3 to 14: comprising:(a) dissolving Compound (I) (b) crystallizing Form 1 of Compound (I) from the acetonitrile.

48. A method for preparing the crystalline form of any one of claims 3 to 14: NAI-1538907928v1 68Jones Day Docket No.13371-344-228 comprising: (a) dissolving Compound (I)(b) crystallizing Form 1 of Compound (I) from the ethanol.

49. A method of preparing the crystalline form of any one of claims 15 to 23: comprising:(a) dissolving a Compound (I) a and water; and (b) rapidly evaporating the mixture of THF and water to form the crystalline form of the Compound (I). NAI-1538907928v1 69

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