Methods of preparing compounds for treating pain and solid forms thereof

Abstract

Processes for preparing Compound I, and pharmaceutically acceptable salts and solvates thereof, pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms of Compound I, pharmaceutical compositions comprising the same, methods of treating pain using the same, and methods for making the same are disclosed.

Description

[0001] METHODS OF PREPARING COMPOUNDS FOR TREATING PAIN AND SOLID FORMS THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] [1] This application claims the benefit of U.S. Provisional Application No. 63 / 592,507, filed October 23, 2023, and U.S. Provisional Application No. 63 / 592,556, filed October 23, 2023, each of which is incorporated by reference in its entirety.

[0004] FIELD

[0005] [2] Disclosed herein are process and methods of making a voltage-gated sodium channel (Nav) inhibitor, solid forms thereof, pharmaceutical compositions thereof, methods of treating pain therewith, and processes for making the solid forms.

[0006] BACKGROUND

[0007] [3] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless, there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Acute and chronic pain are two common pain states and can be distinguished by the duration of the pain. Acute pain can arise for many reasons (e.g., a hospital procedure) and treatment options are generally limited by poor efficacy and / or adverse events. Like acute pain, chronic pain can arise for many reasons and treatment options are limited by poor efficacy and / or adverse events.

[0008] [4] Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J.P., et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic damage to the nerve and pain caused by a discrete nerve injury. Hie metabolic neuropathies include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injury indications include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

[0009] [5] Voltagc-gatcd sodium channels (Navs) arc involved in pain signaling. NavS arc biological mediators of electrical signaling as they mediate the rapid upstroke of the action potential of many excitable cell types, for example, neurons, skeletal myocytes, cardiac myocytes (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). The evidence for the role of these channels in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to the central role of Navs in pain sensation (Rush, A.M. and T.R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nayl.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12). p. 1849-64 (2008); Krafte. D. S. and Bannon. A. W.. Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p. 50-56 (2008)). Because of tire role Navs play in the initiation and propagation of neuronal signals, antagonists that reduce Nav currents can prevent or reduce neural signaling and Nav channels have been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Nav channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Nav channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, G. K., Mitchell. J., and Wang, S. Y., Block of persistent late Na+currents by antidepressant sertraline and paroxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

[0010] [6] The Navs form a subfamily of the voltage-gated ion channel super-family and comprises 9 isofonns, designated Navl.l - Navi .9. The tissue localizations of the nine isoforms vary. NavL4 is the primary sodium channel of skeletal muscle, and Navi.5 is primary sodium channel of cardiac myocytes. Navs 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Navs 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage -dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XL VIE Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

[0011] [7] Upon their discovery, Navi .8 channels were identified as likely targets for analgesia (Akopian, A.N., L. Sivilotti. and LN. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, NavL8 has been shown to be a carrier of the sodium current that maintains action potential firing in small dorsal root ganglia (DRG) neurons (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX) -sensitive Na+current, TTX-resistant Na+current, and Ca2+current in tire action potentials of nociceptive sensory neurons. J. Neurosci.. 2002. 22(23): p. 10277-90). NavL 8 is involved in spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+channel NavL8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, a potent and selective Navi.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Set. U S A, 2007. 104(20): p. 8520-5; Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel Navi.8 in inflammatory and neuropathic, but not postoperative, pain states. Pain. 2006. 123(1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel. Navi.8. Pain, 2002. 95(1-2): p. 143-52; Dong, X.W., et aL, Small interfering RNA-mediated selective knockdown ofNavl.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol.. 2008. 64(6): p. 644-53; Coward, K., et al.. Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50; Yiangou, Y ., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (Navi.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47). The small DRG neurons where Navi.8 is expressed include the nociceptors involved in pain signaling, where Navi.8 mediates large amplitude action potentials (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+current, TTX-resistant Na+current, and Ca2+current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277- 90). Navi.8 is necessary' for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactions between Navi.7 and Navi.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T.R. Cummins, and S.G. Waxman. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., The tetrodotoxin-resistant Na+channel Navi.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 55O(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Navi.8 appears to be a driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models. Navi .8 mRNA expression levels have been shown to increase in the DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of Nav1.7, Nav1.8 and Nav1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72; Qiu, F., et aL, Increased expression of tetrodotoxin-resistant sodium channels Navi.8 and Navi .9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6).

[0012] [8] Tire inventors have discovered that some voltage-gated sodium channel inhibitors have limitations as therapeutic agents due to, for example, a poor therapeutic window (e.g., due to a lack of Nav isoform selectivity, low potency, and / or other reasons). Accordingly, there remains a need to develop selective voltage-gated sodium channel inhibitors, such as selective Nav 1.8 inhibitors.

[0013] [9] Compound I, 2-(4-tert-butyl-5-chloro-2-methyl-phenyl)-4-oxo-17f-l,6-naphthyridine-5- carboxamide, is aNavinhibitor and thus useful in treating pain. Compound I has the following structure:

[0014]

[0010] Compound I is disclosed in PCT International Application No. PCT / US2023 / 066065. Solid (e.g., crystalline or amorphous) forms are of interest in the pharmaceutical industry', where the control of the form(s) of the active ingredient may be desirable or even required. Reproducible processes for producing a compound with a particular form in high purity may be desirable for compounds intended to be used in pharmaceuticals, as different forms may possess different properties. For example, different solid (e.g., crystalline or amorphous) forms may possess different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit a higher level of purity, chemical stability, and / or physical stability compared to the forms produced in PCT / US2023 / 066065. Certain crystalline forms (e.g., cry stalline free form, cry stalline salt, cry stalline salt solvate, and crystalline salt hydrate forms of Compound I (collectively referred to as ‘‘crystalline forms”)) may exhibit lower hygroscopicity than any preexisting forms. Tirus, the solid (e.g., crystalline or amorphous) forms of this disclosure may provide advantages during drug substance manufacturing, storage, and handling over the amorphous forms produced in PCT / US2023 / 066065. Thus, pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms of Compound I may be particularly useful for the production of drugs for the treatment of pain.

[0015]

[0011] In addition, there remains a need for more efficient processes for the synthesis of Compound I that deliver this compound, or pharmaceutically acceptable salts thereof, for example, in higher yield, with higher selectivity, and / or with higher purity relative to known processes. BRIEF SUMMARY

[0012] In one aspect, the invention relates to a method of preparing Compound I I or a solvate or a tautomer or a pharm ereof.

[0013] In a some embodiments, the method comprises converting any of compounds of formulae A1, A1-1, A1-2, A1-3, A1-4, A1-5, A2, A2-1, A3, A3-1, A3-2, B1, B1-1, B1-2, B1-3, B2, C1, C2, and C3to Compound I or a solvate thereof or a tautomer or a pharmaceutically acceptable salt thereof following the reaction steps described herein.

[0014] In another aspect, compounds are selected from: , , pharm

[0015] In another aspect, the invention provides solid forms of Compound I wherein the solid forms of Compound I include Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Fonn C, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, Compound I TFA Salt A, and Amorphous Compound I.

[0016]

[0016] In other aspects, the invention provides a pharmaceutical composition comprising such solid forms, medical uses of such solid forms, and methods of preparing such solid forms.

[0017] BRIEF DESCRIPTION OF THE FIGURES

[0018]

[0017] Figure 1 provides the X-ray powder diffraction (XRPD) pattern of crystalline Compound Bi.

[0019]

[0018] Figure 2 provides the X-ray powder diffraction (XRPD) pattern of crystalline Compound A2.

[0020]

[0019] Figure 3 provides the X-ray powder diffraction (XRPD) pattern of Compound C2Form A.

[0021]

[0020] Figure 4 provides the X-ray powder diffraction (XRPD) pattern of Compound C2Form B.

[0022]

[0021] Figure 5 provides the X-ray powder diffraction (XRPD) pattern of Compound C4 HC1 salt, AcOH solvate.

[0023]

[0022] Figure 6 provides the X-ray powder diffraction (XRPD) pattern of Compound C4Hydrate Form A.

[0024]

[0023] Figure 7 provides the X-ray powder diffraction (XRPD) pattern of Compound C4Benzenesulfonic Acid Salt Form A.

[0025]

[0024] Figure 8 provides the X-ray powder diffraction (XRPD) pattern of Compound I Neat Form A.

[0026]

[0025] Figure 9A provides the13C solid-state NMR (SSNMR) spectrum of Compound I Neat Form

[0027] A.

[0028]

[0026] Figure 9B provides a comparison of13C solid-state NMR (SSNMR) spectra of Compound I Neat Form A samples at different conditions.

[0029]

[0027] Figure 10 provides the X-ray powder diffraction (XRPD) pattern of Compound I Neat Form

[0030] B.

[0028] Figure 11 provides the13C solid-state NMR (SSNMR) spectrum of Compound I Neat Form

[0031] B.

[0032]

[0029] Figure 12 provides the X-ray powder diffraction (XRPD) pattern of Compound I Neat Form

[0033] C.

[0034]

[0030] Figure 13 provides the13C solid-state NMR (SSNMR) spectrum of Compound I Neat Form C.

[0035]

[0031] Figure 14 provides the XRPD pattern of Compound I Hcmi-Hydratc.

[0036]

[0032] Figure 15 provides the13C SSNMR spectrum of Compound I Hemi-Hydrate.

[0037]

[0033] Figure 16 provides the XRPD pattern of Compound I Monohydrate.

[0038]

[0034] Figure 17 provides the XRPD pattern of Compound I Methanol Solvate.

[0039]

[0035] Figure 18 provides the13C SSNMR spectrum of Compound I Methanol Solvate.

[0040]

[0036] Figure 19 provides the XRPD pattern of Compound I nPA Solvate Mixture A.

[0041]

[0037] Figure 20 provides a13C SSNMR spectrum of Compound I nPA Solvate Mixture A.

[0042]

[0038] Figure 21 provides a13C SSNMR spectrum of Compound I nPA Solvate Mixture A.

[0043]

[0039] Figure 22 provides the XRPD pattern of Compound I nPA Solvate B.

[0044]

[0040] Figure 23 provides the13C SSNMR spectrum of Compound I nPA Solvate B.

[0045]

[0041] Figure 24 provides the XRPD pattern of Compound I nPA Solvate C.

[0046]

[0042] Figure 25 provides the XRPD pattern of Compound I Na Hemi Salt nPA Solvate.

[0047]

[0043] Figure 26 provides the13C SSNMR spectrum of Compound I Na Hemi Salt nPA Solvate.

[0048]

[0044] Figure 27 provides the XRPD pattern of Compound I nPA Solvate J.

[0049]

[0045] Figure 28 provides the XRPD pattern of Compound I 2-MeTHF Solvate A.

[0050]

[0046] Figure 29 provides the XRPD pattern of Compound I 2-MeTHF Solvate Mixture A.

[0051]

[0047] Figure 30 provides the XRPD pattern of Compound I 2-MeTHF Solvate Mixture C.

[0052]

[0048] Figure 31 provides the XRPD pattern of Compound I Mandelic Acid Cocrystal.

[0053]

[0049] Figure 32 provides the XRPD pattern of Compound I Oxalic Acid Cocrystal.

[0054]

[0050] Figure 33 provides the13C SSNMR spectrum of Compound I Oxalic Acid Cocrystal.

[0055]

[0051] Figure 34 provides the XRPD pattern of Compound I TFA Salt A.

[0056]

[0052] Figure 35 provides the13C SSNMR spectrum of Compound I TFA Salt A.

[0057]

[0053] Figure 36 provides the XRPD pattern of Amorphous Compound I.

[0058]

[0054] Figure 37 provides the13C SSNMR spectrum of Amorphous Compound I. DETAILED DESCRIPTION

[0059] Definitions

[0060]

[0055] The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms are used within their accepted meanings.

[0061]

[0056] ‘‘Compound I” as used throughout this disclosure refers to 2-[2-(3,4-difluoro-2-methyl- phenoxy)-4-methyl-5-(trifluoromethyl)-3 -pyridyl ]-4-oxo- l / / - l .6-naphthyndinc-5-carboxamide. and has the following structure:

[0062]

[0057] Compound I and methods for making and using Compound I, deuterated derivatives of Compound I, solvates of Compound I, and pharmaceutically acceptable salts of any of the foregoing are disclosed in PCT / US2023 / 066065, incorporated herein by reference.

[0063]

[0058] As used herein, the term "compound, ” when referring to the compounds described in this application, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound ” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0064]

[0059] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0065]

[0060] In some embodiments, the compounds described in the present application include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0066]

[0061] In some embodiments, the compounds described in the present application, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively. For example, as used in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely ’H and D.

[0067]

[0062] The term the “compound of formula” followed by a number (typically Roman number) and the term “compound” followed by the same number (Roman or otherwise) may interchangeably be used. For example, the “compound of formula V” and “compound V” denote the same compound.

[0068]

[0063] The temr “reacting, ” when referring to a chemical reaction, means to add or mix two or more reagents under appropriate conditions to produce the indicated and / or the desired product. It should be appreciated that the reaction w hich produces the indicated and / or the desired product may not necessarily result directly from the combination of tw o reagents which were initially added, i.e., there may be one or more intermediates w hich are produced in the mixture w hich ultimately leads to the formation of the indicated and / or the desired product.

[0069]

[0064] The temr “conducted in a solvent, ” when referring to a reaction, means that the substrate(s) and reagent(s) are dissolved or suspended in the specified solvent or in a mixture of solvents comprising the specified solvent.

[0070]

[0065] The tenn “chromatographic purification ” refers to any method of purification based on differential retention by a stationary phase. Methods of chromatographic purification include flash chromatography, medium pressure liquid chromatography, preparative thin layer chromatography, and high performance liquid chromatography.

[0071]

[0066] Tire terms “converting ” and “transforming” as used herein refer to a step of converting a first compound or salt to a second compound or salt, and refers to a process of transforming the first compound or salt to the second compound or salt in one or more chemical steps.

[0072]

[0067] The temr “acid ” refers to a chemical species having a pKa (in water) of less than 7. The term includes inorganic (mineral) acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, and the like. The term also includes organic acids such as acetic acid, propionic acid, zz-butyric acid, z -butyric acid, n-valcric acid, z-valeric acid, zz-hexanoic acid, succinic acid, glutaric acid, adipic acid, aspartic acid, formic acid, citric acid, o-chlorobenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, nicotinic acid, lactic acid, oxalic acid, picric acid, picolinic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, phthalic acid, isophthalic acid, terephthalic acid, maleic acid, malonic acid, and the like.

[0068] The term ‘base ” refers to a chemical species whose conjugate acid has a pKa (in water) of greater than 7. The term includes “inorganic bases, ” such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di-, or tri -basic), sodium hydride, and potassium hydride, lire term also includes “anionic organic bases. " such as methyl lithium, butyl lithium, lithium diisopropyl amide, and sodium acetate. The term also includes “neutral organic bases, ” such as trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimcthyl-n-nonylaminc, tri-n-butylaminc, di-n-hcxylmcthylaminc, dimcthyl-n-dodccylaminc, tri-n- pentylamine, l,4-diazabicyclo[2.2.2] octane (DABCO), dimethylaminopyridine (DMAP), 1,5- diazabicyclo[4.3.0] non-5-ene (DBN). 1, 8 -diazabicyclo [5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6- collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[0073]

[0069] Tire tenn “alcohol protecting group ” refers to a chemical moiety suitable to protect an alcohol group against undesirable side reactions during synthetic procedures. Common alcohol protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacctyl. trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. Other alcohol protecting groups also are well known in the art. See, e.g., P.G.M. Wuts et al., Greene ’s Protective Groups in Organic Synthesis (4th ed. 2006).

[0074]

[0070] Tire term “deprotecting ” refers to a step of reacting a compound or salt containing a protecting group, such as an alcohol protecting group, under conditions suitable to remove the protecting group and reveal the protected moiety. For example, where a compound or salt contains an alcohol protecting group, the tenn “deprotecting ” refers to reacting the compound or salt under conditions suitable to remove the alcohol protecting group and reveal the alcohol. Conditions for removing various protecting groups are well known in the art. See, e.g., P.G.M. Wuts et aL, Greene ’s Protective Groups in Organic Synthesis (4th ed. 2006).

[0075]

[0071] The term “hydrogenation catalyst” refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of benzylic carbon -oxygen single bonds. Suitable hydrogenation catalysts are well-known in the art and include, for example, palladium on activated carbon, platinum oxide, and Raney Nickel.

[0076]

[0072] Tire tenn “coupling, ” when referring to a reaction between a carboxylic acid or acid halide and an amine, refers to a net transformation linking the carboxylic acid or acid halide and the amine to form an amide. Hie term includes a direct reaction between the carboxylic acid and the amine, as well as a reaction between an activated derivative of the carboxylic acid (such as the derivative formed by the reaction between the carboxylic acid and a coupling reagent) and the amine.

[0073] The term “coupling reagent” refers to a reagent suitable to react with a carboxylic acid to activate the carboxylic acid for coupling with an amine to form an amide bond. Coupling reagents are well known in the art. Coupling reagents include, but are not limited to, thionyl chloride, oxalyl chloride, 1,1'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI), 1,1'- carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N, N’- dicyclohexylcarbodiimide (DCC), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0074] The term “monovalent cation” refers to any cation with a charge of +1, such as alkali metal cations, NH4+, and tetraalkylammonium.

[0075] The term “alkali metal cation” refers to a cation derived from a Group I metal atom, including without limitation lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+).

[0076] The term “substituted benzyl” refers to a benzyl group that is substituted with 1-3 substituents selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, halogen, and cyano.

[0077] The term “ketone solvent” refers to a compound having the formula CnH2n+1C(O)CmH2m+1, wherein n and m are each independently an integer between 1 and 6. The CnH2n+1and CmH2m+1and groups may be linear or branched and each may be substituted with up to 3 halogens. Ketone solvents include without limitation acetone, methyl ethyl ketone, 3-pentanone, and methyl tert-butyl ketone.

[0078] The term “ethereal solvent” refers to an organic solvent having at least one ether moiety. Ethereal solvents include without limitation tetrahydofuran, dimethoxyethane, dioxane, and dialkyl ethers such as diethyl ether and methyl isobutyl ether.

[0079] The term “ester solvent” refers to a compound having the formula CnH2n+1OC(O)CmH2m+1, wherein n and m are each independently an integer between 1 and 6. The CnH2n+1and CmH2m+1and groups may be linear or branched and each may be substituted with up to 3 halogens. Ester solvents include without limitation ethyl acetate, isopropyl acetate, butyl acetate, and ethylpropionate.

[0080] The term “halogenated solvent” refers to a C1-C6alkane or C2-C6alkene substituted with up to six halogens. Halogenated solvents include without limitation dichloromethane, dichloroethane, chloroform, tetrachloroethylene, and carbon tetrachloride.

[0081] The term “aromatic solvent” refers to a C6-10aromatic hydrocarbon. The aromatic hydrocarbon may be substituted with up to six halogens. Aromatic solvents include without limitation benzene, trifluoromethylbenzene, xylene, and toluene.

[0082] The term about ” means that the stated number can vary from that value by ± 10%. Where the term defines a temperature, the stated temperature can vary by ±10%. For example, about 80°C means between 72°C and 88°C. Where the term defines pressure, the temr “about” means the pressure can vary by ±10%. Thus, about 100 bars means between 90 and 110 bars. Where the term defines quantity (such as equivalents or weight), the term means the quantity can vary by ±10%. For example, about 1 equivalent means between 0.9 and 1.1 equivalents. Where the term defines time, the term means the stated time can vary by ±10%. For example, about 1 hourmeans between 0.9 and 1.1 hours.

[0077]

[0083] Tire term “leaving group ” is a chemical group that is readily displaced by a desired incoming chemical moiety. Thus, the choice of the specific suitable leaving group is predicated upon its ability to be readily displaced by the incoming chemical moiety such as a CN group. Suitable leaving groups are well known in the art, e.g., see, "Advanced Organic Chemistry. ” Jerry March, 5.sup.th Ed., pp. 351-357, John Wiley and Sons, N.Y.

[0078]

[0084] As used here, the term “cyanating agent” refers to a reagent, such as trimethylsilyl cyanide (TMSCN), diethylaluminum cyanide, KCN, NaCN, TBACN, HCN and the like, useful in the synthesis of compounds disclosed herein, e.g., compound Ai, A2, and A3. In one embodiment, the cyanating agent (e.g., trimethylsilyl cyanide) may be combined with a Lewis acid. In some embodiments, the Lewis acid is trifluoromethanesulfonic anhydride (TLO). boron trifluoride ethyl etherate (BFiOEb)- TiCL. InCE, AgSbFg, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCL, TMSOTf, SnCL, and the like. In further embodiments, the Lewis acid is trifluoromethanesulfonic anhydride (Tf2O). The cyanation reaction may be conducted in an organic solvent, for example toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1.2-dichloroethane, nitromethane, and the like.

[0079]

[0085] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0080]

[0086] Tire terms "patient" and "subject" are used interchangeably and refer to an animal including humans.

[0081]

[0087] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in pain or a symptom of pain, or lessening the severity of pain or a symptom of pain). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) Hie Art, Science and Technology of Pharmaceutical Compounding).

[0082]

[0088] As used herein, the terms "treatment," "treating," and the like generally mean the improvement of pain or one or more of its symptoms or lessening the severity of pain or one or more of its symptoms in a subject. "Treatment," as used herein, includes, but is not limited to, the following: Chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0083]

[0089] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrently with, or subsequent to each other.

[0084]

[0090] "Selected from" and "chosen from" are used interchangeably herein.

[0085]

[0091] As used herein, the term "ambient conditions" means room temperature, open air condition and uncontrolled humidity condition. As used herein, tire terms "room temperature" and "ambient temperature" mean 15 °C to 30 °C.

[0086]

[0092] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product > 1 g / L).

[0087]

[0093] Tire term "stable," as used herein, refers to compounds or solid forms that are not substantially altered when subjected to conditions to allow' for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0088]

[0094] The temr "chemically stable," as used herein, means that the solid form of Compound I does not decompose into one or more different chemical compounds when subjected to specified conditions, e.g., 40 °C / 75% relative humidity, for a specific period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or longer. In some embodiments, less than 25% of tire solid form of Compound I decomposes. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1 %, less than about 0.5% of the form of Compound I decomposes under the conditions specified. In some embodiments, no detectable amount of the solid form of Compound I decomposes.

[0089]

[0095] Tire term "physically stable," as used herein, means that the solid form of Compound I does not change into one or more different physical fomrs of Compound I (e g., different solid forms as measured by XRPD, DSC, etc.) when subjected to specific conditions, e.g., 40 °C / 75 % relative humidity, for a specific period of time, e.g, 1 day. 2 days. 3 days. 1 week, 2 weeks, or longer. In some embodiments, less than 25% of the solid form of Compound I changes into one or more different physical forms when subjected to specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1 %, less than about 0.5% of the solid form of Compound I changes into one or more different physical forms of Compound I when subjected to specified conditions. In some embodiments, no detectable amount of the solid form of Compound I changes into one or more physically different solid forms of Compound I.

[0090]

[0096] As used herein, the term "hydrate" refers to any crystalline Compound I that contains water in its crystal lattice. The stoichiometry of a Compound I hydrate can vary. For example, a hydrate of Compound I can be a quarter hydrate, hemihydrate, monohydrate, dihydrate, or a partially dehydrated form.

[0091]

[0097] As used herein, the term "pharmaceutically acceptable solid form" refers to a solid form of Compound I of this disclosure wherein the solid fonn (e. g. , crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) of Compound I is nontoxic and suitable for use in pharmaceutical compositions.

[0092]

[0098] As used herein, the term "amorphous" refers to a solid material having no long-range order in the position of its molecules. Amorphous solids are generally rather isotropic, i.e., exhibit similar properties in all directions. Amorphous solids do not have definite melting points. Amorphous solids are generally glasses or supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See US 2004 / 0006237 for a comparison of XRPDs of an amorphous material and crystalline material. In some embodiments, a solid material may comprise an amorphous compound, and the material may, for example, be characterized by a lack of sharp characteristic crystalline peak(s) in its XRPD spectrum (i.e.. the material is not crystalline, but is amorphous, as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may appear in the XRPD pattern of the material. See US 2004 / 0006237 for a comparison of XRPDs of an amorphous material and crystalline material. A solid material, comprising an amorphous compound, may be characterized by, for example, a wider temperature range for the melting of the solid material, as compared to the range for the melting of a pure crystalline solid. Other techniques, such as, for example, solid state NMR may also be used to characterize crystalline or amorphous forms.

[0093]

[0099] As used herein, the terms "cry stal form," "crystalline form," and "Fonn" interchangeably refer to a cry stal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD). single cry stal X-ray diffraction, and13C solid state nuclear magnetic resonance (13C SSNMR). Accordingly, as used herein, the terms "crystalline Form [X] of Compound (I)" and "crystalline Form [C] potassium salt of Compound (I)" refer to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, XRPD, single crystal X-ray diffraction, and13C SSNMR In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified degree two-theta values (°20).

[0094]

[0100] As used herein, the term "free form" refers to a non-ionized version of the compound in the solid state. Examples of free fonns include free bases and free acids.

[0095]

[0101] As used herein, the term "neat form" refers to an unsolvated and unhydrated free form version of a compound in the solid state.

[0096]

[0102] As used herein, the term "solvate" refers to a crystal form comprising one or more molecules of a compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate."

[0097]

[0103] As used herein, the temr "hydrate" refers to any crystalline Compound I that contains water in its crystal lattice. The stoichiometry of a Compound I hydrate can vary, i.e., Compound I can be a variable hydrate. For example, a hydrate of Compound I can be a quarter hydrate, hemihydrate, monohydrate, dihydrate, or a partially dehydrated form.

[0098]

[0104] In some embodiments, a solid material may comprise a mixture of crystalline solids and amorphous solids. A solid material comprising an amorphous compound may also, for example, contain up to 30% of a crystalline solid. In some embodiments, a solid material prepared to comprise an amorphous compound may also, for example, contain up to 25%, 20%, 15%, 10%, 5%, or 2% of a crystalline solid. In embodiments wherein the solid material contains a mixture of crystalline solids and amorphous solids, the characterizing data, such as XRPD, may contain indicators of both cry stalline and amorphous solids. In some embodiments, a crystalline form of this disclosure may contain up to 30% amorphous compound. In some embodiments, a crystalline preparation of Compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% of an amorphous solid.

[0099]

[0105] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than 15% cry stal Unity (e.g., less than 10% crystallinity, less than 5% crystallinity, or less than 2% cry stallinity). It is also noted that the tenn "substantially amorphous" includes the descriptor, "amorphous," which refers to materials having no (0%) crystallinity.

[0100]

[0106] As used herein, the term "substantially crystalline" refers to a solid material having little or no amorphous molecules. For example, substantially crystalline materials have less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term "substantially crystalline" includes the descriptor "crystalline." which refers to materials that are 100% crystalline form.

[0101]

[0107] As used herein, a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid fonn(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of tire sum of all solid form(s) in a sample.

[0102]

[0108] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," "XRPD spectrum" interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate).

[0103]

[0109] A "signal" or "peak" as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. An XRPD peak is identified by its angular value as measured in degrees 20 (°20), depicted on tire abscissa of an X-ray powder diffractogram, which may be expressed, for example, as "a signal at ... degrees two-theta." "a signal at [a] two-theta value(s) of ... " and / or "a signal at at least ... two-theta value(s) selected from .... "

[0104] [HO] The repeatability of the measured angular values is in the range of ±0.2° 20, i.e., the angular value can be at the recited angular value +0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[0105] [Hl] One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[0106]

[0112] The terms "signal intensities" and "peak intensities" interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0107]

[0113] As used herein, an X-ray powder diffractogram is "substantially similar to that in [a particular] Figure" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and / or signal positions in XRPD diffractograms even for the same crystalline form. Tirus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta) generally mean that value is identified as ±0.2 degrees two-theta of the reported value, an art-recognized variance.

[0114] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard and brittle "glassy" amorphous solid becomes viscous or rubbery supercooled liquid.

[0115] As used herein, the term "melting temperature", "melting point", or "Tm" refers to the temperature at which a crystalline material is in equilibrium with liquid phase.

[0116] As used herein, the term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase or, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase. Methods for Synthesis of Compound I

[0117] Compound I can be prepared from known materials by the methods described herein, including in the Examples, by other similar methods, and by other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006).

[0118] In one embodiment, the skilled artisan could start with any compounds of formulae A1, A1-1, A1-2, A1-3, A1-4, A1-5, A2, A2-1, A3, A3-1, A3-2, B1, B1-1, B1-2, B1-3, B2, C1, C2, and C3to prepare Compound I or any of the intermediate compounds of formulae A1, A1-1, A1-2, A1-3, A1-4, A1-5, A2, A2-1, A3, A3-1, A3-2, B1, B1-1, B1-2, B1-3, B2, C1, C2, and C3by following the reactions illustrated in Schemes 1-11.

[0119] The method steps described herein may refer to conversion of a starting compound of formulae A1, A1-1, A1-2, A1-3, A1-4, A1-5, A2, A2-1, A3, A3-1, A3-2, B1, B1-1, B1-2, B1-3, B2, C1C2, and C3to Compound I. The skilled artisan would understand that such methods can also be used to prepare any intermediate between any starting compound and Compound I. For example, conversion of the compound of formula A1-2to Compound I goes through intermediate compound C2. As such, the skilled artisan would understand that the methods described for converting the compound of formula A1-2to Compound I can be used to prepare intermediate compounds A2-1, A2, and C2from the compounds of formula A1-2.

[0120] Similarly, conversion of the compound of formula A3-2to Compound I goes through preparation of intermediate compounds A3-1, A3, and C3. As such, the skilled artisan would understand that the methods described for converting the compound of formula A3-2to Compound I can be used to prepare any of intermediate compounds A3-1, A3, and C3starting with the compound of formula A3-2or any intermediate compound can be converted to the desired intermediate compound using the methods described herein. Thus, the present application contemplates preparing intermediate compounds A1, A1-1, A1-2, A1-3, A1-4, A1-5, A2, A2-1, A3, A3-1, A3-2, B1, B1-1, B1-2, B1-3, B2, C1C2, and C3starting with any intermediate or starting material that precedes the intermediate that is being prepared. For example, intermediate compound C2may be prepared starting with any of compounds A1-2, A1-3, A1-4, A1-5, A2, A2-1, B1, B1-1, B1-2, B1-3, and B2. Similarly, compound A2-1may be prepared starting with any of compounds A1-2, A1-3, A1-4, and A1-5. Scheme 1

[0108] Scheme 2 Scheme 6

[0109] Scheme 8

[0110] Scheme 9

[0111] Scheme 11

[0112]

[0121] In one embodiment, the present application provides a process for preparing Compound I and solvates thereof: comprising transforming a compound of formula (Ai): to Compound I; wherein each of X1and X2are independently selected from halogen.

[0113]

[0122] In some embodiments, X1and X2are the same. In some embodiments, each of X1and X2are fluoro. In some embodiments, each of X1and X2are chloro. In some embodiments, each of X1and X2are bromo. In some embodiments, each of X1and X2are iodo.

[0114]

[0123] In some embodiments, X1and X2are different.

[0115]

[0124] In some embodiments, the step of transforming tire compound of formula (Ai) to Compound

[0116] I comprises transfonning the compound of fonnula (Ai) to a compound of fonnula (Ci): .

[0125] In some embodiments, th ompound of formula (A1) to the compound of formula (C1) comprises contacting the compound of formula (A1) with a compound of formula (B1) or (B2): .

[0126] In some embodi d of formula (A1) to the compound of formula (C1) comprises contacting the compound of formula (A1) with a compound of formula (B1). In some embodiments, the step of transforming the compound of formula (A1) to the compound of formula (C1) comprises contacting the compound of formula (A1) with a compound of formula (B2).

[0127] In some embodiments, the step of contacting the compound of formula (A1) with a compound of formula (B1) or (B2) is performed in the presence of a first palladium catalyst and a first base.

[0128] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0129] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium phosphate. In some embodiments, the first base is potassium carbonate.

[0130] In some embodiments, the step of transforming the compound of formula (A1) to Compound I further comprises transforming the compound of formula (C1) to Compound I. In some embodiments, the step of transforming the compound of formula (C1) to Compound I comprises treating the compound of formula (C1) with a first acid. In some embodiments, the first acid is selected from trifluoroacetic acid, sulfuric acid, phosphoric acid, and methane sulfonic acid. In some embodiments, the first acid is trifluoroacetic acid. In some embodiments, the first acid is sulfuric acid. In some embodiments, the first acid is methane sulfonic acid.

[0131] In some embodiments, the step of transforming the compound of formula (C1) to Compound I comprises transforming the compound of formula (C1) to a compound of formula (C4): nd transforming the compound of form me embodiments, the compound of formula (C4) is obtained as a salt. In some embodiments, the salt is an HCl salt or a benzenesulfonic acid salt. In some embodiments, the compound of formula (C4) is obtained as a solvate. In some embodiments, the solvate is an AcOH solvate. In some embodiments, the compound of formula (C4) is obtained as an HCl salt, AcOH solvate. In some embodiments, the compound of formula (C4) is obtained as a hydrate.

[0132] In some embodiments, the step of transforming the compound of formula (C1) to the compound of formula (C4) comprises treating the compound of formula (C1) with an acid to afford the compound of formula (C4). In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is selected from acetic acid, formic acid, sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, oxalic acid, para-toluenesulfonic acid, and trifluoroacetic acid. In some embodiments, the compound of formula (C1) is treated with an acid in the presence of water. In some embodiments, the compound of formula (C1) is treated with an acid in a solvent selected from dimethylsulfoxide (DMSO), toluene, N-methylpyrrolidone (NMP), and 1,2-dichloroethane (DCE). In some embodiments, the compound of formula (C1) is treated with an acid at a temperature of 60-100 °C, e.g., about 100 °C. In some embodiments, the compound of formula (C1) is the limiting reagent, and the acid is present in excess. In some embodiments, the compound of formula (C1) is the limiting reagent, the acid is acetic acid (in excess), and the reaction is conducted at a temperature of 60-100 °C, e.g., about 100 °C.

[0133] In some embodiments, the step of transforming the compound of formula (C1) to the compound of formula (C4) comprises treating the compound of formula (C1) with a base to afford the compound of formula (C4). In some embodiments, the base is potassium acetate. In some embodiments, the compound of formula (C1) is treated with base in the presence of water. In some embodiments, the compound of formula (C1) is treated with a base in N,N-dimethylformamide as a solvent. In some embodiments, the compound of formula (C1) is treated with a base at a temperature of 80-100 °C. In some embodiments, the compound of formula (C1) is the limiting reagent, and the base is present in excess. In some embodiments, the compound of formula (C1) is the limiting reagent, the base is potassium acetate (in excess), and the reaction is conducted at a temperature of 80-100 °C.

[0134] In some embodiments, the compound of formula (C1) is a compound of formula (C2), i.e., X2is chloro: . Thus, in these embodiments, the step und of formula (C ) to Compound I 1comprises transforming the compound of formula (C2) to Compound I (see, e.g., Schemes 8 and 9).

[0135] In some embodiments, the step of transforming the compound of formula (C2) to Compound I comprises treating the compound of formula (C2) with a first acid to afford Compound I. In some embodiments, the first acid is selected from trifluoroacetic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid. In some embodiments, the first acid is trifluoroacetic acid. In some embodiments, the first acid is sulfuric acid. In some embodiments, the first acid is methanesulfonic acid.

[0136] In some embodiments, the step of transforming the compound of formula (C2) to Compound I comprises transforming the compound of formula (C2) to a compound of formula (C4): nd transforming the compound of form

[0137] In some embodiments, the step of transforming the compound of formula (C2) to the compound of formula (C4) comprises treating the compound of formula (C2) with an acid to afford the compound of formula (C4). In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is selected from acetic acid, formic acid, sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, oxalic acid, para-toluenesulfonic acid, and trifluoroacetic acid. In some embodiments, the compound of formula (C2) is treated with an acid in the presence of water. In some embodiments, the compound of formula (C2) is treated with an acid in a solvent selected from dimethylsulfoxide (DMSO), toluene, N-methylpyrrolidone (NMP), and 1,2-dichloroethane (DCE). In some embodiments, the compound of formula (C2) is treated with an acid at a temperature of 60-100 °C, e.g., about 100 °C. In some embodiments, the compound of formula (C2) is the limiting reagent, and the acid is present in excess. In some embodiments, the compound of formula (C2) is the limiting reagent, the acid is acetic acid (in excess), and the reaction is conducted at a temperature of 60-100 °C, e.g., about 100 °C.

[0117]

[0138] In some embodiments, the step of transforming the compound of formula (C2) to the compound of formula (C4) comprises treating the compound of formula (C2) with a base to afford the compound of formula (C4). In some embodiments, the base is potassium acetate. In some embodiments, the compound of formula (C2) is treated with base in the presence of water. In some embodiments, the compound of formula (C2) is treated with a base in N JV-dimethy 1 formamide as a solvent. In some embodiments, the compound of formula (C2) is treated with a base at a temperature of 80-100 °C. In some embodiments, the compound of formula (C2) is the limiting reagent, and the base is present in excess. In some embodiments, the compound of formula (C2) is the limiting reagent, the base is potassium acetate (in excess), and the reaction is conducted at a temperature of 80-100 °C.

[0118]

[0139] In some embodiments, tire step of transfonning the compound of formula (C4) to Compound I comprises treating the compound of formula (C4) with an acid to afford Compound I. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is selected from sulfuric acid, phosphoric acid, and oxalic acid. In some embodiments, the compound of formula (C4) is treated with an acid in the presence of water. In some embodiments, the compound of formula (C4) is treated with an acid in a solvent selected from toluene, acetic acid, anisole, y-valerolactone, and sulfolane. In some embodiments, the compound of formula (C4) is treated with an acid at a temperature of 20-100 °C, e.g., about 60 °C. In some embodiments, the compound of formula (C4) is the limiting reagent, and the acid is present in excess. In some embodiments, the compound of formula (C4) is the limiting reagent, the acid is sulfuric acid (in excess), and the reaction is conducted at a temperature of 20-100 °C, e.g., about 60 °C, in toluene. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is selected from Cu(OTf)2, Cu(OAc)2, In(OTf)3, InCl3, WOCL, VCI3, and Sc(OTf)3. In some embodiments, the compound of formula (C4) is treated with an acid in the presence of water. In some embodiments, the compound of formula (C4) is treated with an acid in a solvent or cosolvent selected from toluene, acetic acid, anisole, y- valerolactone, sulfolane, 2-methyltetrahydrofiiran, cyclopentyl methyl ether, AA'-dimcthylacctamide. isobutyl acetate, A-methylcaprolactam, and water. In some embodiments, the compound of formula (C4) is treated with an acid at a temperature of 20-100 °C, e.g., about 100 °C. In some embodiments, the compound of formula (C4) is the limiting reagent. In some embodiments, the compound of formula (C4) is the limiting reagent, the acid is Cu(OTf)2, acetic acid is present in excess, and the reaction is conducted at a temperature of 20-100 °C. e.g., about 60 °C.

[0140] In one embodiment, the present application provides a process for preparing Compound I: comprising transforming a compound of formula (A3): to Compound I.

[0119]

[0141] In some embodiments, tire step of transforming the compound of formula (As) to Compound

[0120] I comprises transfonning the compound of formula (A3) to a compound of formula (C3):

[0121]

[0142] In some embodiments, the step of transforming the compound of formula (A3) to the compound of formula (C3) comprises contacting the compound of formula (A3) with a compound of formula (Bi) or (B2):

[0122]

[0143] In some embodiments, the step of transforming the compound of formula (A3) to the compound of formula (C3) comprises contacting the compound of formula (A3) with a compound of formula (Bi). In some embodiments, the step of transforming the compound of formula (A3) to the compound of formula (C3) comprises contacting the compound of formula (A3) with a compound of formula (B2).

[0123]

[0144] In some embodiments, the step of contacting the compound of formula (A3) with a compound of formula (Bi) or (B2) is performed in the presence of a first palladium catalyst and a first base.

[0124]

[0145] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the first palladium catalyst is PdCfifdtbdpf).

[0125]

[0146] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, tire first base is potassium phosphate. In some embodiments, the first base is potassium carbonate.

[0126]

[0147] In some embodiments, the step of transforming the compound of formula (A3) to Compound I further comprises transforming the compound of formula (C3) to Compound I.

[0127]

[0148] In some embodiments, the step of transforming the compound of formula (C3) to Compound I comprises treating the compound of formula (C3) with a first acid. In some embodiments, the first acid is selected from trifluoroacetic acid, sulfuric acid, phosphoric acid, and methane sulfonic acid. In some embodiments, the first acid is trifluoroacetic acid. In some embodiments, the first acid is sulfuric acid. In some embodiments, the first acid is methane sulfonic acid.

[0128]

[0149] In another aspect, the invention relates to a process for preparing Compound I according to Scheme 12.

[0129] Scheme 12

[0150] In one embodiment, the invention relates to a process for preparing Compound I: comprising transforming a compound of formula (A2): to Compound I.

[0130]

[0151] In some embodiments, the step of transforming the compound of formula (A2) to Compound

[0131] I comprises transforming the compound of formula (A2) to a compound of formula (C2): transforming the compound of formula (C2) to Compound I. In some embodiments, transforming the compound of formula (A2) to the compound of formula (C2) comprises treating the compound of formula (A2) with a compound of formula (Bi) or (B2):

[0132]

[0152] In some embodiments, tire step of transforming the compound of formula (A2) to the compound of formula (C2) comprises treating the compound of formula (A2) with a compound of formula (Bi). In some embodiments, the step of transforming the compound of formula (A2) to the compound of formula (C2) comprises treating the compound of formula (A2) with a compound of formula (B2).

[0133]

[0153] In some embodiments, the step of treating the compound of formula (A2) with a compound of fonnula (Bi) or (B2) is performed in the presence of a first palladium catalyst and a first base.

[0134]

[0154] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0135]

[0155] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, tire first base is potassium phosphate. In some embodiments, the first base is potassium carbonate.

[0136]

[0156] In some embodiments, the step of transforming the compound of formula (C2) to Compound I comprises transforming the compound of formula (C2) to a compound of formula (Csa): wherein R is Ci-Ce alkyl: and transforming the compound of formula (C3a) to Compound I. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl. In some embodiments, transforming the compound of formula (C2) to the compound of formula (C3a) comprises treating the compound of formula (C2) with NaOR to afford the compound of formula (C3a). For example, in some embodiments where R is ethyl, transfonning the compound of fonnula (C2) to the compound of formula (C3a) comprises treating the compound of formula (C2) with NaOEt in ethanol at room temperature. In some embodiments, transforming the compound of formula (C2) to the compound of formula (C3a) comprises treating the compound of formula (C2) with ROH and acetic acid at elevated temperature, e.g., 80-100 °C.

[0137]

[0157] In some embodiments, the step of transfonning tire compound of fonnula (A2) to Compound I comprises transfonning the compound of formula (A2) to a compound of fonnula (A3a): wherein R is Ci-C6alkyl; and transforming the compound of fonnula (A3a) to Compound I. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl. In some embodiments, transfonning the compound of formula (A2) to the compound of formula (A3a) comprises treating the compound of formula (A2) with NaORto afford the compound of formula (A3a). For example, in some embodiments where R is ethyl, transforming the compound of formula (A2) to tire compound of formula (A3a) comprises treating the compound of formula (A2) with NaOEt in ethanol at room temperature. In some embodiments, transforming tire compound of formula (A2) to the compound of formula (A3a) comprises treating the compound of formula (A2) with ROH and acetic acid at elevated temperature, e.g., 80-100 °C.

[0138]

[0158] In some embodiments, the step of transforming the compound of formula (A3a) to Compound I comprises transforming the compound of formula (A3a) to a compound of formula (C3a): wherein R is Ci-Ce alkyl; and transforming the compound of formula (C3a) to Compound I. In some embodiments, transforming the compound of formula (A3a) to tire compound of fonnula (C3a) comprises treating the compound of fonnula (A3a) with a compound of formula (Bi) or (B2):

[0139]

[0159] In some embodiments, the step of transforming the compound of formula (A3a) to the compound of formula (C3a) comprises treating the compound of formula (A3a) with a compound of formula (Bi). In some embodiments, the step of transforming the compound of formula (A3a) to the compound of formula (C3a) comprises treating the compound of fonnula (A3a) with a compound of formula (B2).

[0140]

[0160] In some embodiments, the step of treating the compound of formula (A3a) with a compound of formula (Bi) or (B2) is perfonned in the presence of a first palladium catalyst and a first base.

[0141]

[0161] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0162] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium phosphate. In some embodiments, the first base is potassium carbonate.

[0163] In some embodiments, the step of transforming the compound of formula (C3a) to Compound I comprises transforming the compound of formula (C3a) to a compound of formual (C8a): ; wherein R is C1-C6alkyl; and trans formula (C8a) to Compound I. In some embodiments, transforming the compound of formula (C3a) to the compound of formula (C8a) comprises treating the compound of formula (C3a) with trifluoroacetic acid in the presence of water to afform the compound of formula (C8a).

[0164] In some embodiments, the step of transforming the compound of formula (C8a) to Compound I comprises treating the compound of formula (C8a) with BBr3to afford Compound I.

[0165] In another aspect, the invention relates to a process for preparing Compound I according to Scheme 13.

[0142] Scheme 13

[0143]

[0166] In one embodiment, the invention relates to a process for preparing Compound I: comprising transforming a compound of formula (A2-I):

[0144] (A2-1 ) to Compound I.

[0167] In some embodiments, the step of transforming the compound of formula (A2-1) to Compound I comprises transforming the compound of formula (A2-1) to a compound of formula (C5): nd transforming the compound of form me embodiments, transforming the compound of formula (A ) to 2-1the compound of formula (C5) comprises treating the compound of formula (A2-1) with a compound of formula (B1) or (B2): .

[0168] In some embodi d of formula (A2-1) to the compound of formula (C5) comprises treating the compound of formula (A2-1) with a compound of formula (B1). In some embodiments, the step of transforming the compound of formula (A2-1) to the compound of formula (C5) comprises treating the compound of formula (A2-1) with a compound of formula (B2).

[0169] In some embodiments, the step of treating the compound of formula (A2-1) with a compound of formula (B1) or (B2) is performed in the presence of a first palladium catalyst and a first base.

[0170] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0171] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium phosphate. In some embodiments, the first base is potassium carbonate.

[0172] In some embodiments, the step of transforming the compound of formula (C5) to Compound I comprises transforming the compound of formula (C5) to a compound of formula (C2): nd transforming the compound of form me embodiments, transforming the compound of formula (C5) to the com pound o ormu a (C2) comprises treating the compound of formula (C5) with a cyanating agent (e.g., TMSCN) and a Lewis acid (e.g., Tf2O) to afford the compound of formula (C2).

[0173] In some embodiments, the step of transforming the compound of formula (C2) to Compound I comprises transforming the compound of formula (C2) to a compound of formula (C7): nd transforming the compound of form e embodiments, transforming the compound of formula (C2) to the compound of formula (C7) comprises treating the compound of formula (C2) with aqueous base (e.g., NaOH, KOH) to afford the compound of formula (C7).

[0174] In some embodiments, the step of transforming the compound of formula (C5) to Compound I comprises transforming the compound of formula (C5) to a compound of formula (C6): nd transforming the compound of form

[0175] In some embodiments, the step of transforming the compound of formula (C5) to the compound of formula (C6) comprises treating the compound of formula (C5) with an acid to afford the compound of formula (C6). In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is selected from acetic acid, formic acid, sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, oxalic acid, para-toluenesulfonic acid, and trifluoroacetic acid. In some embodiments, the compound of formula (C5) is treated with an acid in the presence of water. In some embodiments, the compound of formula (C5) is treated with an acid in a solvent selected from dimethylsulfoxide (DMSO), toluene, N-methylpyrrolidone (NMP), and 1,2-dichloroethane (DCE). In some embodiments, the compound of formula (C5) is treated with an acid at a temperature of 60-100 °C, e.g., about 100 °C. In some embodiments, the compound of formula (C5) is the limiting reagent, and the acid is present in excess. In some embodiments, the compound of formula (C5) is the limiting reagent, the acid is acetic acid (in excess), and the reaction is conducted at a temperature of 60-100 °C, e.g., about 100 °C.

[0176] In some embodiments, the step of transforming the compound of formula (C5) to the compound of formula (C6) comprises treating the compound of formula (C5) with a base to afford the compound of formula (C6). In some embodiments, the base is potassium acetate. In some embodiments, the compound of formula (C5) is treated with base in the presence of water. In some embodiments, the compound of formula (C5) is treated with a base in N,N-dimethylformamide as a solvent. In some embodiments, the compound of formula (C5) is treated with a base at a temperature of 80-100 °C. In some embodiments, the compound of formula (C5) is the limiting reagent, and the base is present in excess. In some embodiments, the compound of formula (C5) is the limiting reagent, the base is potassium acetate (in excess), and the reaction is conducted at a temperature of 80-100 °C.

[0177] In some embodiments, the step of transforming the compound of formula (C6) to Compound I comprises transforming the compound of formula (C6) to a compound of formula (C4): nd transforming the compound of form me embodiments, transforming the compound of formula (C6) to the compound of formula (C4) comprises treating the compound of formula (C6) with a cyanating agent (e.g., TMSCN) and a Lewis acid (e.g., Tf2O) to afford the compound of formula (C4).

[0178] In some embodiments, the step of transforming the compound of formula (C4) to Compound I comprises transforming the compound of formula (C4) to a compound of formula (C7): nd transforming the compound of form e embodiments, transforming the compound of formula (C4) to the co mpound of formula (C7) comprises treating the compound of formula (C4) with aqueous base (e.g., NaOH, KOH) to afford the compound of formula (C7).

[0179] In some embodiments, the step of transforming the compound of formula (C7) to Compound I comprises treating the compound of formula (C7) with a peptide coupling reagent (e.g., T3P or CDI) and ammonia to afford Compound I. Preparation of Compound of Formula (A1)

[0180] In some embodiments, the process of preparing Compound I further comprises the step of transforming a compound of formula (A1-1): to the compound of formula (A1).

[0181] In some embodiments, the step of transforming a compound of formula (A1-1) to the compound of formula (A1) comprises the steps of: treating the compound of formula (A1-1) with trifluoromethanesulfonic anhydride to form a triflyl intermediate; treating the triflyl intermediate with a cyanation reagent; treating the cyanated intermediate with a second base to form a cyanated triflyl intermediate; and treating the cyanated triflyl intermediate with an aqueous base to form the compound of formula (A1).

[0182] In some embodiments, the cyanation reagent is selected from trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. In some embodiments, the cyanation reagent is trimethylsilyl cyanide. In some embodiments, the cyanation reagent is sodium cyanide. In some embodiments, the cyanation reagent is potassium cyanide.

[0183] In some embodiments, the second base is selected from 4-methylmorpholine, triethylamine, and Hunig’s base. In some embodiments, the second base is 4-methylmorpholine. In some embodiments, the second base is triethylamine. In some embodiments, the second base is Hunig’s base.

[0184] In some embodiments, the aqueous base is aqueous sodium bicarbonate.

[0185] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A1-2): to the compound of formula (A1-1).

[0186] In some embodiments, the step of transforming the compound of formula (A1-2) to the compound of formula (A1-1) comprises treating the compound of formula (A1-2) with a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from HCl, oxalyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphonic dichloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, thionyl chloride, p- toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating reagent is phosphorous oxychloride. In some embodiments, the chlorinating reagent is selected from Cl2(with / without oxidant), HCl / Cl - plus oxidant, N-chlorosuccinimide (NCS) / dichlorodimethylhydantoin (DCDMH) / trichloroisocyanuric acid (TCCA) sodium dichloroiso- cyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating reagent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating reagent is phosphorus oxychloride.

[0187] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A1-3): to the compound of formula (A1-2).

[0188] In some embodiments, the step of transforming a compound of formula (A1-3) to the compound of formula (A1-2) comprises treating the compound of formula (A1-3) with a second acid. In some embodiments, the second acid is a monoprotic acid selected from aqueous hydrochloric acid, acetic acid, nitric acid, and benzoic acid. In some embodiments, the second acid is a polyprotic acid. In some embodiments, the second acid is a diprotic acid selected from sulfuric acid, carbonic acid, hydrogen sulfide, chromic acid, sulfurous acid, and oxalic acid. In some embodiments, the second acid is a triprotic acid selected from phosphoric acid and citric acid. In some embodiments, the second acid is aqueous hydrochloric acid.

[0189] In some embodiments, the step of transforming a compound of formula (A1-3) to the compound of formula (A1-2) comprises heating the compound of formula (A1-3).

[0190] In some embodiments, the step of transforming a compound of formula (A1-3) to the compound of formula (A1-2) comprises treating the compound of formula (A1-3) with aqueous base (e.g., aqueous sodium hydroxide) to afford the compound of formula (A1-2).

[0191] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A1-4): to the compound of formula (A1-3).

[0192] In some embodiments, the step of transforming a compound of formula (A1-4) to the compound of formula (A1-3) comprises treating the compound of formula (A1-4) with diethyl malonate in the presence of a third base. In some embodiments, the third base is an alkaline alkoxide. In some embodiments, the third base is an alkaline methoxide. In some embodiments, the third base is selected from lithium methoxide, sodium methoxide, and potassium methoxide. In some embodiments, the third base is lithium methoxide. In some embodiments, the third base is sodium methoxide. In some embodiments, the third base is potassium methoxide. In some embodiments, the third base is an alkaline ethoxide. In some embodiments, the third base is selected from lithium ethoxide, sodium ethoxide, and potassium ethoxide. In some embodiments, the third base is lithium ethoxide. In some embodiments, the third base is sodium ethoxide. In some embodiments, the third base is potassium ethoxide. In some embodiments, the third base is an alkaline tert-butoxide. In some embodiments, the third base is selected from lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. In some embodiments, the third base is lithium tert-butoxide. In some embodiments, the third base is sodium tert-butoxide. In some embodiments, the third base is potassium tert-butoxide. In some embodiments, third base is an alkaline tert-pentoxide. In some embodiments, the third base is selected from lithium tert-pentoxide, sodium tert- – 40 – pentoxide, and potassium tert-pentoxide. In some embodiments, the third base is lithium tert-pentoxide. In some embodiments, the third base is sodium tert-pentoxide. In some embodiments, the third base is potassium tert-pentoxide. In some embodiments, the third base is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide. In some embodiments, the third base is lithium bis(trimethylsilyl)amide. In some embodiments, the third base is sodium bis(trimethylsilyl)amide. In some embodiments, the third base is potassium bis(trimethylsilyl) amide. In some embodiments, the third base is an alkaline hydride. In some embodiments, the third base is selected from lithium hydride, sodium hydride, and potassium hydride. In some embodiments, the third base is lithium hydride. In some embodiments, the third base is sodium hydride. In some embodiments, the third base is potassium hydride.

[0193] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A1-5): to the compound of formula (A1-4).

[0194] In some embodiments, the step of transforming the compound of formula (A1-5) to the compound of formula (A1-4) comprises treating the compound of formula (A1-5) with carbon monoxide in the presence of a fourth base, a second palladium catalyst, and a first suitable ligand.

[0195] In some embodiments, the fourth base is selected from triethylamine, Hunig’s Base, 4- methylmorpholine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-Diazabicyclo[2.2.2]octane (DABCO). In some embodiments, the fourth base is triethylamine. In some embodiments, the fourth base is Hunig’s Base. In some embodiments, the fourth base is 4-methylmorpholine. In some embodiments, the fourth base is DBU. In some embodiments, the fourth base is DABCO.

[0196] In some embodiments, the second palladium catalyst is Pd(OAc)2.

[0197] In some embodiments, the first suitable ligand is selected from 1,1'- bis(diphenylphosphino)ferrocene (DPPF), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), triphenylphosphine (PPh3), and 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (BINAP). In some embodiments, the first suitable ligand is DPPF. In some embodiments, the first suitable ligand is XantPhos. In some embodiments, the first suitable ligand is PPh3. In some embodiments, the first suitable ligand is BINAP. Preparation of Compound of Formula (A2)

[0198] In another aspect, the invention relates to processes for preparing a compound of formula (A2), as set forth herein. Accordingly, in some embodiments, the invention relates to a process for preparing a compound of formula (A2), as set forth herein. In other embodiments, the invention relates to a process for preparing Compound I, wherein the compound of formula (A2) is prepared as set forth herein.

[0199] In another aspect, the invention relates to a process for preparing a compound of formula (A2) according to Scheme 14. Scheme 14 nd of formula (A2): , comprising transforming a compound of formula (A2-1): to the compound of formula (A2). In some embodiments, the step of transforming a compound of formula (A2-1) to the compound of formula (A2) comprises treating the compound of formula (A2-1) with trifluoromethanesulfonic anhydride, followed by a cyanating agent, to form a cyanated triflyl intermediate; and then treating the cyanated triflyl intermediate with an aqueous base to form the compound of formula (A2). In some embodiments, the step of transforming a compound of formula (A2-1) to the compound of formula (A2) comprises treating the compound of formula (A2-1) with a cyanating agent, followed by trifluoromethanesulfonic anhydride, to form a cyanated triflyl intermediate; and then treating the cyanated triflyl intermediate with an aqueous base to form the compound of formula (A2).

[0201] In some embodiments, the cyanating agent is selected from trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. In some embodiments, the cyanation reagent is trimethylsilyl cyanide. In some embodiments, the cyanation reagent is sodium cyanide. In some embodiments, the cyanation reagent is potassium cyanide.

[0202] In some embodiments, the aqueous base is aqueous sodium bicarbonate and sodium thiosulfate.

[0203] In some embodiments, the process further comprises the step of transforming a compound of formula (A1-2): to the compound of formula (A2-1). In some embodiments, the step of transforming the compound of formula (A1-2) to the compound of formula (A2-1) comprises treating the compound of formula (A1-2) with a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from HCl, oxalyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphonic dichloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, thionyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating reagent is phosphorous oxychloride. In some embodiments, the chlorinating reagent is selected from Cl2(with / without oxidant), HCl / Cl - plus oxidant, N-chlorosuccinimide (NCS) / dichlorodimethylhydantoin (DCDMH) / trichloroisocyanuric acid (TCCA) sodium dichloroiso- cyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating reagent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating reagent is phosphorus oxychloride.

[0204] In some embodiments, the process further comprises the steps of (1) transforming a compound of formula (A1-3) to the compound of formula (A1-2); and / or (2) transforming a compound of formula (A1-4) to the compound of formula (A1-3); and / or (3) transforming a compound of formula (A1-5) to the compound of formula (A1-4), as set forth above in connection with the preparation of the compound of formula (A1). Preparation of Compound of Formula (A3)

[0205] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A3-1): to the compound of formula (A3).

[0206] In some embodiments, the step of transforming a compound of formula (A3-1) to the compound of formula (A3) comprises treating the compound of formula (A3-1) with a cyanation reagent and a second base.

[0207] In some embodiments, the cyanation reagent is selected from trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. In some embodiments, the cyanation reagent is trimethylsilyl cyanide. In some embodiments, the cyanation reagent is sodium cyanide. In some embodiments, the cyanation reagent is potassium cyanide.

[0208] In some embodiments, the second base is selected from triethylamine, 4-methylmorpholine, and Hunig’s base. In some embodiments, the second base is triethylamine. In some embodiments, the second base is 4-methylmorpholine. In some embodiments, the second base is Hunig’s base.

[0209] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (A3-2): to the compound of formula (A3-1).

[0210] In some embodiments, the step of transforming a compound of formula (A3-2) to the compound of formula (A3-1) comprises treating the compound of formula (A3-2) with benzyl alcohol in the presence of a third base. In some embodiments, the third base is an alkaline alkoxide. In some embodiments, the third base is lithium tert-butoxide.

[0145] Preparation of Compound of Formula (B1)

[0211] In another aspect, the invention relates to processes for preparing a compound of formula (B1), as set forth herein. Accordingly, in some embodiments, the invention relates to a process for preparing a compound of formula (B1), as set forth herein. In other embodiments, the invention relates to a process for preparing Compound I, wherein the compound of formula (B1) is prepared as set forth herein.

[0212] In some embodiments, the process for preparing Compound I comprises transforming a compound of formula (B1-1): to the compound of formula (B1).

[0213] In some embodiments, the step of transforming the compound of formula (B1-1) to the compound of formula (B1) comprises treating the compound of formula (B1-1) with bis(pinacolato)diboron in the presence of a third palladium catalyst and a fifth base.

[0214] In some embodiments, the third palladium catalyst is selected from Pd(dppf)Cl2, Pd(PCy3)2, and Pd2dba3. In some embodiments, the third palladium catalyst is Pd(dppf)Cl2. In some embodiments, the third palladium catalyst is Pd(PCy3)2. In some embodiments, the third palladium catalyst is Pd2dba3.

[0215] In some embodiments, the fifth base is selected from KOPh, triethylamine, Hunig’s Base, KOEt, and KOAc. In some embodiments, the fifth base is KOPh. In some embodiments, the fifth base is triethylamine. In some embodiments, the fifth base is Hunig’s Base. In some embodiments, the fifth base is KOEt. In some embodiments, the fifth base is KOAc.

[0216] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (B1-2): to the compound of formula (B1-1).

[0217] In some embodiments, the step of transforming the compound of formula (B1-2) to the compound of formula (B1-1) comprises contacting the compound of formula (B1-2) with trifluoromethanesulfonic anhydride, optionally in the presence of a sixth base. In some embodiments, the sixth base is pyridine.

[0218] In some embodiments, the process of preparing Compound I comprises transforming a compound of formula (B1-3): to the compound of formula (B1-2).

[0219] In some embodiments, the step o trans orm ng the compound of formula (B1-3) to the compound of formula (B1-2) comprises treating the compound of formula (B1-3) with tert-butanol and a third acid. In some embodiments, the third acid is sulfuric acid.

[0220] In another aspect, the invention relates to a process for preparing a compound of formula (B1) according to Scheme 15. Scheme 15 (B1): , comprising transforming a compound o to the compound of formula (B1). In some embodiments, the step of transforming the compound of formula (B1-1a) to the compound of formula (B1) comprises treating the compound of formula (B1-1a) with bis(pinacolato)diboron in the presence of a palladium catalyst and a base.

[0222] In some embodiments, the palladium catalyst is selected from Pd(OAc)2and dppf, Pd(dppf)Cl2, Pd(PCy3)2, and Pd2dba3. In some embodiments, the palladium catalyst is Pd(OAc)2and dppf. In some embodiments, the palladium catalyst is Pd(dppf)Cl2. In some embodiments, the palladium catalyst is Pd(PCy3)2. In some embodiments, the palladium catalyst is Pd2dba3.

[0223] In some embodiments, the base is selected from KOPh, triethylamine, Hunig’s Base, KOEt, and KOAc. In some embodiments, the base is KOPh. In some embodiments, the base is triethylamine. In some embodiments, the base is Hunig’s Base. In some embodiments, the base is KOEt. In some embodiments, the base is KOAc.

[0224] In some embodiments, the process further comprises the step of transforming a compound of formula (B1-2): to the compound of formula (B1-1a). In som the step of transforming the compound of formula (B1-2) to the compound of formula (B1-1a) comprises treating the compound of formula (B1-2) with sulfuryl fluoride (SO2F2) and a base (e.g., trimethylamine) to afford the compound of formula (B1-1a).

[0225] In some embodiments, the process further comprises the step of transforming a compound of formula (B1-3): to the c the step of transforming the compound of formula (B1-3) to the compound of formula (B1-2) comprises treating the compound of formula (B1-3) with tert-butanol and an acid. In some embodiments, the acid is sulfuric acid.

[0226] In some embodiments, the compound of formula (B1-1a) may be replaced in the foregoing process with any one of the compounds of formulas (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), and (B1-1g), which may be used in the foregoing process under conditions similar to those used with the compound of formula (B1-1a):

[0146] . Preparation of Solid Forms of Compound I

[0227] In some embodiments, the process of preparing Compound I further comprises transforming Compound I to a solvate of Compound I.

[0228] In some embodiments, the step of transforming Compound I to the solvate of Compound I comprises recrystallizing Compound I from an appropriate solvent. In some embodiments, the appropriate solvent is 1-propanol.

[0229] In some embodiments, the solvate of Compound I is a compound of formula (D): .

[0230] In some embodimen nd I comprises transforming the solvate of Compound I to Form A of Compound I.

[0231] In some embodiments, the step of transforming the solvate of Compound I to Form A of Compound I comprises a methanol solvent exchange and drying.

[0232] In one aspect, the invention relates to a compound selected from: , ,

[0233] , , C6alkyl. In some

[0234] In another aspect, the invention relates to a compound selected from:Cl Br, compounds is disclosed, the compounds selected from: , ,

[0236] In another aspect of the present disclosure, a composition is disclosed comprising Compound I and a compound of formula (C2): .

[0237] In some embodiments, the composition comprising Compound I and a compound of formula (C2) further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0238] In another aspect of the present disclosure, a composition is disclosed comprising Compound I and a compound of formula (C3): .

[0239] d of formula (C3) further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0240] In another aspect of the present disclosure, a composition is disclosed comprising a compound of formula (C2), a compound of formula (A1), and a compound of formula (B1): . [24 compound of formula (C3), a compound of formula (A3), and a compound of formula (B1): .

[0242] In another aspect of the present disclosure, a composition is disclosed comprising a compound of formula (C2), a compound of formula (A2), and a compound of formula (B2): . [243 comp ound of formula (C3), a compound of formula (A3), and a compound of formula (B2): . [244 ompound I: , or a solvate thereof or a pharmaceutic repared by any of the processes disclosed herein. Solid Forms of Compound I

[0245] Another aspect of the disclosure provides solid forms of Compound I (e.g., amorphous forms, crystalline forms, solvates, hydrates, and cocrystals), which can be used in the methods of treatment and pharmaceutical compositions described herein. In some embodiments, the invention provides neat crystalline forms of Compound I. In some embodiments, the invention provides solvate crystalline forms of Compound I. In some embodiments, the invention provides hydrate crystalline forms of Compound I. In some embodiments, the invention provides hemihydrate crystalline forms of Compound I. In some embodiments, the invention provides cocrystal crystalline forms of Compound I. In some embodiments, the invention provides amorphous forms of Compound I. A. Crystalline Compound I Neat Form A

[0246] In some embodiments, the invention provides neat crystalline forms of Compound I. In some embodiments, the invention provides crystalline Compound I Neat Form A.

[0247] In some embodiments, Compound I Neat Form A is substantially pure. In some embodiments, Compound I Neat Form A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Neat Form A is substantially 100% crystalline. In some embodiments, Compound I Neat Form A is 100% crystalline.

[0248] In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having a signal at 5.5 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having a signal at 9.0 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form A is characterized by an X- ray powder diffractogram having a signal at 10.4 ± 0.2 degrees two-theta.

[0249] In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, and 20.4 ± 0.2 degrees two-theta.

[0250] In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.5 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, and 20.4 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 8.0 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two- theta.

[0251] In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram having signals at 5.5 ± 0.2 degrees two-theta, 8.0 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 11.1 ± 0.2 degrees two-theta, 11.7 ± 0.2 degrees two-theta, 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two- theta, 20.4 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.9 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, 27.7 ± 0.2 degrees two-theta, 29.5 ± 0.2 degrees two-theta, and 29.9 ± 0.2 degrees two- theta.

[0252] In some embodiments, Compound I Neat Form A is characterized by an X-ray powder diffractogram substantially similar to FIG.8.

[0253] In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm. In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having peaks at 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm.

[0254] In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.8 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.7 ± 0.2 ppm, 168.3 ± 0.2 ppm, 156.0 ± 0.2 ppm, 153.1 ± 0.2 ppm, 152.4 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.4 ± 0.2 ppm, 148.3 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.8 ± 0.2 ppm, 135.7 ± 0.2 ppm, 134.6 ± 0.2 ppm, 132.8 ± 0.2 ppm, 130.9 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.5 ± 0.2 ppm, 36.4 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having peaks at 178.8 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.7 ± 0.2 ppm, 168.3 ± 0.2 ppm, 156.0 ± 0.2 ppm, 153.1 ± 0.2 ppm, 152.4 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.4 ± 0.2 ppm, 148.3 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.8 ± 0.2 ppm, 135.7 ± 0.2 ppm, 134.6 ± 0.2 ppm, 132.8 ± 0.2 ppm, 130.9 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.5 ± 0.2 ppm, 36.4 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm.

[0255] In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.7 ± 0.2 ppm, 178.8 ± 0.2 ppm, 177.6 ± 0.2 ppm, 174.8 ± 0.2 ppm, 169.8 ± 0.2 ppm, 168.3 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.9 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.4 ± 0.2 ppm, 151.1 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.7 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 135.0 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.4, 36.3 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 20.5 ± 0.2 ppm. In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum having peaks at 179.7 ± 0.2 ppm, 178.8 ± 0.2 ppm, 177.6 ± 0.2 ppm, 174.8 ± 0.2 ppm, 169.8 ± 0.2 ppm, 168.3 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.9 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.4 ± 0.2 ppm, 151.1 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.7 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 135.0 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.4, 36.3 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 20.5 ± 0.2 ppm.

[0256] In some embodiments, Compound I Neat Form A is characterized by a13C SSNMR spectrum substantially similar to FIG. 9A. In some embodiments, it is characterized by a13C SSNMR spectrum substantially similar to the bottom / lower trace of FIG. 9B, which was collected when a sample of Compound I Neat Form A was maintained at ambient conditions. In some embodiments, it is characterized by a13C SSNMR spectrum substantially similar to the middle trace of FIG.9B, which was collected when a sample of Compound I Neat Form A was dried at 80°C for 3 hours. In some embodiments, it is characterized by a13C SSNMR spectrum substantially similar to the top / upper trace of FIG.9B, which was collected when a sample of Compound I Neat Form A was dried at 80°C for 3 hours and then re-humidified at 75% relative humidity at room temperature for 12 hours.

[0257] In some embodiments, Compound I Neat Form A is characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.0 ± 0.1 Å α 98.0 ± 0.1° b 11.2 ± 0.1 Å β 93.1 ± 0.1° c 15.9 ± 0.1 Å γ 95.8 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0258] In some embodiments, the invention provides a method of making Compound I Neat Form A, comprising (i) suspending Compound I amorphous material in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Neat Form A. B. Crystalline Compound I Neat Form B

[0259] In some embodiments, the invention provides Compound I Neat Form B.

[0260] In some embodiments, Compound I Neat Form B is substantially pure. In some embodiments, Compound I Neat Form B is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Neat Form B is substantially 100% crystalline. In some embodiments, Compound I Neat Form B is 100% crystalline.

[0261] In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, and 9.8 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having a signal at 5.8 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having a signal at 9.5 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form B is characterized by an X- ray powder diffractogram having a signal at 9.8 ± 0.2 degrees two-theta.

[0262] In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, and 9.8 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 7.7 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta.

[0263] In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, and 9.8 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 7.7 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, and 21.2 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two- theta, and 18.7 ± 0.2 degrees two-theta; and (c) one, two or three signals selected from 12.5 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, and 17.4 ± 0.2 degrees two-theta.

[0264] In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram having signals at 5.8 ± 0.2 degrees two-theta, 7.7 ± 0.2 degrees two-theta, 9.5 ± 0.2 degrees two-theta, 12.5 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 16.8 ± 0.2 degrees two-theta, 17.4 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two- theta, 19.7 ± 0.2 degrees two-theta, 21.2 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 25.3 ± 0.2 degrees two-theta, 25.6 ± 0.2 degrees two-theta, and 27.7 ± 0.2 degrees two- theta.

[0265] In some embodiments, Compound I Neat Form B is characterized by an X-ray powder diffractogram substantially similar to FIG.10.

[0266] In some embodiments, Compound I Neat Form B is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 176.6 ± 0.2 ppm, 174.4 ± 0.2 ppm, 169.7 ± 0.2 ppm, 157.5 ± 0.2 ppm, 152.8 ± 0.2 ppm, 151.6 ± 0.2 ppm, 150.2 ± 0.2 ppm, 149.4 ± 0.2 ppm, 147.5 ± 0.2 ppm, 145.2 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.8 ± 0.2 ppm, 133.4 ± 0.2 ppm, 132.4 ± 0.2 ppm, 131.1 ± 0.2 ppm, 130.6 ± 0.2 ppm, 115.5 ± 0.2 ppm, 114.2 ± 0.2 ppm, 113.9 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 30.9 ± 0.2 ppm, 29.1 ± 0.2 ppm, 19.8 ± 0.2 ppm, and 18.1 ± 0.2 ppm. In some embodiments, Compound I Neat Form B is characterized by a13C SSNMR spectrum having peaks at 177.9 ± 0.2 ppm, 176.6 ± 0.2 ppm, 174.4 ± 0.2 ppm, 169.7 ± 0.2 ppm, 157.5 ± 0.2 ppm, 152.8 ± 0.2 ppm, 151.6 ± 0.2 ppm, 150.2 ± 0.2 ppm, 149.4 ± 0.2 ppm, 147.5 ± 0.2 ppm, 145.2 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.8 ± 0.2 ppm, 133.4 ± 0.2 ppm, 132.4 ± 0.2 ppm, 131.1 ± 0.2 ppm, 130.6 ± 0.2 ppm, 115.5 ± 0.2 ppm, 114.2 ± 0.2 ppm, 113.9 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 30.9 ± 0.2 ppm, 29.1 ± 0.2 ppm, 19.8 ± 0.2 ppm, and 18.1 ± 0.2 ppm.

[0267] In some embodiments, Compound I Neat Form B is characterized by a13C SSNMR spectrum substantially similar to FIG.11.

[0268] In some embodiments, Compound I Neat Form B is characterized by triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.1 ± 0.1 Å α 87.6 ± 0.1° b 11.5 ± 0.1 Å β 88.2 ± 0.1° c 15.0 ± 0.1 Å γ 88.9 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0269] In some embodiments, the invention provides a method of making Compound I Neat Form B, comprising (i) suspending Amorphous Compound I in nitromethane to form a mixture, (ii) agitating the mixture at room temperature for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours. C. Crystalline Compound I Neat Form C

[0270] In some embodiments, the invention provides Compound I Neat Form C.

[0271] In some embodiments, Compound I Neat Form C is substantially pure. In some embodiments, Compound I Neat Form C is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Neat Form C is substantially 100% crystalline. In some embodiments, Compound I Neat Form C is 100% crystalline.

[0272] In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.0 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having a signal at 6.0 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having a signal at 13.9 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having a signal at 19.7 ± 0.2 degrees two-theta.

[0273] In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.0 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 15.4 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, and 18.3 ± 0.2 degrees two-theta.

[0274] In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.0 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 15.4 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, and 18.3 ± 0.2 degrees two-theta; and (c) one, two or three signals selected from 9.3 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, and 17.2 ± 0.2 degrees two- theta.

[0275] In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten, or more signals selected from 6.0 ± 0.2 degrees two-theta, 9.3 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two- theta, 20.1 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 23.4 ± 0.2 degrees two-theta, 24.1 ± 0.2 degrees two-theta, 24.8 ± 0.2 degrees two-theta, 25.2 ± 0.2 degrees two-theta, 26.4 ± 0.2 degrees two-theta, 26.8 ± 0.2 degrees two-theta, and 28.8 ± 0.2 degrees two-theta. In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram having signals at 6.0 ± 0.2 degrees two-theta, 9.3 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 15.6 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 21.6 ± 0.2 degrees two-theta, 22.3 ± 0.2 degrees two- theta, 22.8 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 23.4 ± 0.2 degrees two-theta, 24.1 ± 0.2 degrees two-theta, 24.8 ± 0.2 degrees two-theta, 25.2 ± 0.2 degrees two-theta, 26.4 ± 0.2 degrees two-theta, 26.8 ± 0.2 degrees two-theta, and 28.8 ± 0.2 degrees two-theta.

[0276] In some embodiments, Compound I Neat Form C is characterized by an X-ray powder diffractogram substantially similar to FIG.12.

[0277] In some embodiments, Compound I Neat Form C is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 176.5 ± 0.2 ppm, 173.9 ± 0.2 ppm, 169.3 ± 0.2 ppm, 157.8 ± 0.2 ppm, 153.9 ± 0.2 ppm, 151.5 ± 0.2 ppm, 149.8 ± 0.2 ppm, 148.4 ± 0.2 ppm, 147.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.0 ± 0.2 ppm, 131.3 ± 0.2 ppm, 130.4 ± 0.2 ppm, 115.6 ± 0.2 ppm, 115.4 ± 0.2 ppm, 114.5 ± 0.2 ppm, 114.1 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.3 ± 0.2 ppm, 31.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 20.9 ± 0.2 ppm, and 17.9 ± 0.2 ppm. In some embodiments, Compound I Neat Form C is characterized by a13C SSNMR spectrum having peaks at 177.9 ± 0.2 ppm, 176.5 ± 0.2 ppm, 173.9 ± 0.2 ppm, 169.3 ± 0.2 ppm, 157.8 ± 0.2 ppm, 153.9 ± 0.2 ppm, 151.5 ± 0.2 ppm, 149.8 ± 0.2 ppm, 148.4 ± 0.2 ppm, 147.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.0 ± 0.2 ppm, 131.3 ± 0.2 ppm, 130.4 ± 0.2 ppm, 115.6 ± 0.2 ppm, 115.4 ± 0.2 ppm, 114.5 ± 0.2 ppm, 114.1 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.3 ± 0.2 ppm, 31.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 20.9 ± 0.2 ppm, and 17.9 ± 0.2 ppm.

[0278] In some embodiments, Compound I Neat Form C is characterized by a13C SSNMR spectrum substantially similar to FIG.13.

[0279] In some embodiments, Compound I Neat Form C is characterized by triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.3 ± 0.1 Å α 84.3 ± 0.1° b 11.5 ± 0.1 Å β 68.8 ± 0.1° c 15.2 ± 0.1 Å γ 89.0 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0280] In some embodiments, Compound I Neat Form C is characterized by triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 298K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.4 ± 0.1 Å α 84.2 ± 0.1° b 11.6 ± 0.1 Å β 69.6 ± 0.1° c 15.3 ± 0.1 Å γ 88.9 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0281] In some embodiments, the invention provides a method of making Compound I Neat Form C, comprising (i) suspending Compound I Neat Form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20 °C for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours. D. Crystalline Compound I Hemi-Hydrate

[0282] In some embodiments, the invention provides Compound I Hemi-Hydrate.

[0283] In some embodiments, Compound I Hemi-Hydrate is substantially pure. In some embodiments, Compound I Hemi-Hydrate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Hemi-Hydrate is substantially 100% crystalline. In some embodiments, Compound I Hemi-Hydrate is 100% crystalline.

[0284] In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.1 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 12.3 ± 0.2 degrees two-theta. In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having a signal at 5.1 ± 0.2 degrees two-theta. In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having a signal at 10.2 ± 0.2 degrees two-theta. In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having a signal at 12.3 ± 0.2 degrees two-theta.

[0285] In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.1 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 12.3 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 14.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.6 ± 0.2 degrees two-theta.

[0286] In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.1 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 12.3 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 14.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.6 ± 0.2 degrees two-theta; and (c) one or two signals selected from 11.1 ± 0.2 degrees two-theta and 21.3 ± 0.2 degrees two-theta.

[0287] In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram having signals at 5.1 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 11.1 ± 0.2 degrees two-theta, 12.3 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.6 ± 0.2 degrees two-theta.

[0288] In some embodiments, Compound I Hemi-Hydrate is characterized by an X-ray powder diffractogram substantially similar to FIG.14.

[0289] In some embodiments, Compound I Hemi-Hydrate is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.1 ± 0.2 ppm, 169.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 154.0 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.4 ± 0.2 ppm, 137.6 ± 0.2 ppm, 137.0 ± 0.2 ppm, 133.4 ± 0.2 ppm, 129.0 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.6 ± 0.2 ppm, 113.0 ± 0.2 ppm, 35.4 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 21.1 ± 0.2 ppm. In some embodiments, Compound I Hemi-Hydrate is characterized by a13C SSNMR spectrum having peaks at 178.1 ± 0.2 ppm, 169.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 154.0 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.4 ± 0.2 ppm, 137.6 ± 0.2 ppm, 137.0 ± 0.2 ppm, 133.4 ± 0.2 ppm, 129.0 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.6 ± 0.2 ppm, 113.0 ± 0.2 ppm, 35.4 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 21.1 ± 0.2 ppm.

[0290] In some embodiments, Compound I Hemi-Hydrate is characterized by a13C SSNMR spectrum substantially similar to FIG.15.

[0291] In some embodiments, the invention provides a method of making Compound I Hemi-Hydrate, comprising (i) suspending Compound I in water, (ii) shaking at 40 °C for at least 1 week, at least 2 weeks, at least three weeks, or at least 4 weeks, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Hemi-Hydrate. E. Crystalline Compound I Monohydrate

[0292] In some embodiments, the invention provides Compound I Monohydrate.

[0293] In some embodiments, Compound I Monohydrate is substantially pure. In some embodiments, Compound I Monohydrate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Monohydrate is substantially 100% crystalline. In some embodiments, Compound I Hemi-Hydrate is 100% crystalline.

[0294] In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.0 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 14.2 ± 0.2 degrees two-theta. In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having a signal at 5.0 ± 0.2 degrees two-theta. In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having a signal at 10.2 ± 0.2 degrees two-theta.

[0295] In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.0 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 14.2 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 12.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.5 ± 0.2 degrees two-theta.

[0296] In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.0 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, and 14.2 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 12.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.5 ± 0.2 degrees two-theta; and (c) one or two signals selected from 17.1 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, and 23.5 ± 0.2 degrees two-theta.

[0297] In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram having signals at 5.0 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.8 ± 0.2 degrees two-theta, 18.1 ± 0.2 degrees two-theta, 20.3 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two- theta, 23.5 ± 0.2 degrees two-theta, 26.5 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, and 31.7 ± 0.2 degrees two-theta.

[0298] In some embodiments, Compound I Monohydrate is characterized by an X-ray powder diffractogram substantially similar to FIG.16.

[0299] In some embodiments, the invention provides a method of making Compound I Monohydrate, comprising (i) suspending Compound I in water, (ii) shaking at 40 °C for no more than 48 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Monohydrate. F. Crystalline Compound I Methanol Solvate

[0300] In some embodiments, the invention provides Compound I Methanol Solvate.

[0301] In some embodiments, Compound I Methanol Solvate is substantially pure. In some embodiments, Compound I Methanol Solvate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Methanol Solvate is substantially 100% crystalline. In some embodiments, Compound I Methanol Solvate is 100% crystalline.

[0302] In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having a signal at 6.6 ± 0.2 degrees two-theta. In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having a signal at 8.4 ± 0.2 degrees two-theta. In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having a signal at 10.6 ± 0.2 degrees two-theta.

[0303] In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 20.9 ± 0.2 degrees two-theta.

[0304] In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 20.9 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta.

[0305] In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram having signals at 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta.

[0306] In some embodiments, Compound I Methanol Solvate is characterized by an X-ray powder diffractogram substantially similar to FIG.17.

[0307] In some embodiments, Compound I Methanol Solvate is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2 ppm, 170.3 ± 0.2 ppm, 156.9 ± 0.2 ppm, 154.1 ± 0.2 ppm, 151.9 ± 0.2 ppm, 150.0 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.4 ± 0.2 ppm, 135.0 ± 0.2 ppm, 134.0 ± 0.2 ppm, 132.9 ± 0.2 ppm, 131.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.2 ± 0.2 ppm, 115.0 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 49.5 ± 0.2 ppm, 49.3 ± 0.2 ppm, 49.0 ± 0.2 ppm, 36.4 ± 0.2 ppm, 35.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 28.2 ± 0.2 ppm, 19.1 ± 0.2 ppm, and 18.8 ± 0.2 ppm. In some embodiments, Compound I Methanol Solvate is characterized by a13C SSNMR spectrum having peaks at 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2 ppm, 170.3 ± 0.2 ppm, 156.9 ± 0.2 ppm, 154.1 ± 0.2 ppm, 151.9 ± 0.2 ppm, 150.0 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.4 ± 0.2 ppm, 135.0 ± 0.2 ppm, 134.0 ± 0.2 ppm, 132.9 ± 0.2 ppm, 131.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.2 ± 0.2 ppm, 115.0 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 49.5 ± 0.2 ppm, 49.3 ± 0.2 ppm, 49.0 ± 0.2 ppm, 36.4 ± 0.2 ppm, 35.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 28.2 ± 0.2 ppm, 19.1 ± 0.2 ppm, and 18.8 ± 0.2 ppm.

[0308] In some embodiments, Compound I Methanol Solvate is characterized by a13C SSNMR spectrum substantially similar to FIG.18.

[0309] In some embodiments, Compound I Methanol Solvate is characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 12.3 ± 0.1 Å α 100.4 ± 0.1° b 14.1 ± 0.1 Å β 105.3 ± 0.1° c 14.4 ± 0.1 Å γ 107.5 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0310] In some embodiments, the invention provides a method of making Compound I Methanol Solvate, comprising (i) suspending Compound I amorphous material in methanol, (ii) shaking at 40 °C for 1 hour, and (iii) collecting the solids to afford Compound I Methanol Solvate. G. Crystalline Compound I nPA Solvate Mixture A

[0311] In some embodiments, the invention provides Compound I nPA Solvate Mixture A.

[0312] In some embodiments, Compound I nPA Solvate Mixture A is substantially pure. In some embodiments, Compound I nPA Solvate Mixture A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I nPA Solvate Mixture A is substantially 100% crystalline. In some embodiments, Compound I nPA Solvate Mixture A is 100% crystalline.

[0313] In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having a signal at 5.3 ± 0.2 degrees two- theta. In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having a signal at 8.8 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having a signal at 10.6 ± 0.2 degrees two-theta.

[0314] In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 10.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta.

[0315] In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 10.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 13.5 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta.

[0316] In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 10.1 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.5 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 25.5 ± 0.2 degrees two-theta, and 26.1 ± 0.2 degrees two-theta.

[0317] In some embodiments, Compound I nPA Solvate Mixture A is characterized by an X-ray powder diffractogram substantially similar to FIG.19.

[0318] In some embodiments, Compound I nPA Solvate Mixture A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm. In some embodiments, Compound I nPA Solvate Mixture A is characterized by a13C SSNMR spectrum having peaks at 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm.

[0319] In some embodiments, Compound I nPA Solvate Mixture A is characterized by a13C SSNMR spectrum substantially similar to FIG.20.

[0320] In some embodiments, Compound I nPA Solvate Mixture A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 176.5 ± 0.2 ppm, 175.2 ± 0.2 ppm, 171.8 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.2 ± 0.2 ppm, 150.1 ± 0.2 ppm, 147.6 ± 0.2 ppm, 144.9 ± 0.2 ppm, 143.5 ± 0.2 ppm, 142.2 ± 0.2 ppm, 135.5 ± 0.2 ppm, 134.5 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.1 ± 0.2 ppm, 117.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.1 ± 0.2 ppm, 64.3 ± 0.2 ppm, 63.9 ± 0.2 ppm, 36.5 ± 0.2 ppm, 29.9 ± 0.2 ppm, 25.9 ± 0.2 ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm, and 11.7 ± 0.2 ppm. In some embodiments, Compound I nPA Solvate Mixture A is characterized by a13C SSNMR spectrum having peaks at 176.5 ± 0.2 ppm, 175.2 ± 0.2 ppm, 171.8 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.2 ± 0.2 ppm, 150.1 ± 0.2 ppm, 147.6 ± 0.2 ppm, 144.9 ± 0.2 ppm, 143.5 ± 0.2 ppm, 142.2 ± 0.2 ppm, 135.5 ± 0.2 ppm, 134.5 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.1 ± 0.2 ppm, 117.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.1 ± 0.2 ppm, 64.3 ± 0.2 ppm, 63.9 ± 0.2 ppm, 36.5 ± 0.2 ppm, 29.9 ± 0.2 ppm, 25.9 ± 0.2 ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm, and 11.7 ± 0.2 ppm.

[0321] In some embodiments, Compound I nPA Solvate Mixture A characterized by a13C SSNMR spectrum substantially similar to FIG.21.

[0322] In some embodiments, Compound I nPA Solvate Mixture A is characterized by monoclinic crystal system, C2 / c space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 19.9 ± 0.1 Å α 90 b 6.9 ± 0.1 Å β 93.9 ± 0.1° c 32.6 ± 0.1 Å γ 90 In some embodiments, the diffractometer is a Bruker diffractometer.

[0323] In some embodiments, the invention provides a method of making Compound I nPA Solvate Mixture A, comprising (i) suspending Compound I nPA Solvate B and NaTFA in nPA, (ii) mixing at room temperature for 6-18 hours, (iii) collecting the solids, and (iv) air-drying for 15-45 minutes to afford Compound I nPA Solvate Mixture A. H. Crystalline Compound I nPA Solvate B

[0324] In some embodiments, the invention provides Compound I nPA Solvate Mixture B.

[0325] In some embodiments, Compound I nPA Solvate Mixture B is substantially pure. In some embodiments, Compound I nPA Solvate Mixture B is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I nPA Solvate Mixture B is substantially 100% crystalline. In some embodiments, Compound I nPA Solvate Mixture B is 100% crystalline.

[0326] In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having a signal at 5.3 ± 0.2 degrees two- theta. In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having a signal at 8.8 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having a signal at 10.6 ± 0.2 degrees two-theta.

[0327] In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 9.9 ± 0.2 degrees two-theta, 13.2 ± 0.2 degrees two-theta, and 14.8 ± 0.2 degrees two-theta.

[0328] In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 9.9 ± 0.2 degrees two-theta, 13.2 ± 0.2 degrees two-theta, and 14.8 ± 0.2 degrees two-theta; and (c) one or two signals selected from 18.9 ± 0.2 degrees two-theta and 21.4 ± 0.2 degrees two-theta.

[0329] In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.9 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.2 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.0 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.9 ± 0.2 degrees two-theta, 24.6 ± 0.2 degrees two-theta, 25.7 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, 26.5 ± 0.2 degrees two- theta, and 28.1 ± 0.2 degrees two-theta.

[0330] In some embodiments, Compound I nPA Solvate Mixture B is characterized by an X-ray powder diffractogram substantially similar to FIG.22.

[0331] In some embodiments, Compound I nPA Solvate Mixture B is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, and 20.7 ± 0.2 ppm. In some embodiments, Compound I nPA Solvate Mixture B is characterized by a13C SSNMR spectrum having peaks at 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm.

[0332] In some embodiments, Compound I nPA Solvate Mixture B is characterized by a13C SSNMR spectrum substantially similar to FIG.23.

[0333] In some embodiments, Compound I nPA Solvate Mixture B is characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 6.8 ± 0.1 Å α 93.8 ± 0.1° b 10.5 ± 0.1 Å β 92.9 ± 0.1° c 16.4 ± 0.1 Å γ 105.8 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0334] In some embodiments, the invention provides a method of making Compound I nPA Solvate B, comprising (i) suspending Compound I nPA amorphous material in nPA, (ii) mixing at room temperature for 18-30 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I nPA Solvate B. I. Crystalline Compound I nPA Solvate C

[0335] In some embodiments, Compound I nPA Solvate C.

[0336] In some embodiments, Compound I nPA Solvate C is substantially pure. In some embodiments, Compound I nPA Solvate C is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I nPA Solvate C is substantially 100% crystalline. In some embodiments, Compound I nPA Solvate C is 100% crystalline.

[0337] In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.1 ± 0.2 degrees two-theta, 11.8 ± 0.2 degrees two-theta, and 12.2 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having a signal at 6.1 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having a signal at 11.8 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having a signal at 12.2 ± 0.2 degrees two-theta.

[0338] In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.1 ± 0.2 degrees two-theta, 11.8 ± 0.2 degrees two-theta, and 12.2 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 7.2 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, and 15.8 ± 0.2 degrees two-theta.

[0339] In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.1 ± 0.2 degrees two-theta, 11.8 ± 0.2 degrees two-theta, and 12.2 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 7.2 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, and 15.8 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 5.4 ± 0.2 degrees two-theta, 8.7 ± 0.2 degrees two-theta, and 10.2 ± 0.2 degrees two- theta.

[0340] In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 6.1 ± 0.2 degrees two-theta, 7.2 ± 0.2 degrees two-theta, 8.7 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 11.8 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two- theta, 19.1 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta.

[0341] In some embodiments, Compound I nPA Solvate C is characterized by an X-ray powder diffractogram substantially similar to FIG.24.

[0342] In some embodiments, the invention provides a method of making Compound I nPA Solvate C, comprising (i) dissolving Compound I in nPA, (ii) mixing at 90-100 °C for 1-2 hours, (iii) mixing at room temperature for 6-30 hours, and (iv) collecting the solids to afford Compound I nPA Solvate C. J. Crystalline Compound I Na Hemi Salt nPA Solvate

[0343] In some embodiments, the invention provides Compound I Na Hemi Salt nPA Solvate.

[0344] In some embodiments, Compound I Na Hemi Salt nPA Solvate is substantially pure. In some embodiments, Compound I Na Hemi Salt nPA Solvate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Na Hemi Salt nPA Solvate is substantially 100% crystalline. In some embodiments, Compound I Na Hemi Salt nPA Solvate is 100% crystalline.

[0345] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, and 14.9 ± 0.2 degrees two-theta. In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having a signal at 6.7 ± 0.2 degrees two- theta. In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having a signal at 14.1 ± 0.2 degrees two-theta. In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having a signal at 14.9 ± 0.2 degrees two-theta.

[0346] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, and 14.9 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 13.4 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two-theta.

[0347] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, and 14.9 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 13.4 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two-theta; and (c) one, two or three signals selected from 5.2 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.3 ± 0.2 degrees two-theta.

[0348] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram having signals at 5.2 ± 0.2 degrees two-theta, 6.7 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 13.4 ± 0.2 degrees two-theta, 13.6 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 14.9 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two- theta, 20.1 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, 24.6 ± 0.2 degrees two-theta, 26.4 ± 0.2 degrees two-theta, 26.6 ± 0.2 degrees two-theta, and 28.4 ± 0.2 degrees two-theta.

[0349] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by an X-ray powder diffractogram substantially similar to FIG.25.

[0350] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2 ppm, 152.1 ± 0.2 ppm, 151.1 ± 0.2 ppm, 150.4 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 144.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.4 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.5 ± 0.2 ppm, 119.6 ± 0.2 ppm, 118.8 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 114.0 ± 0.2 ppm, 111.6 ± 0.2 ppm, 65.1 ± 0.2 ppm, 62.6 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.7 ± 0.2 ppm, 26.2 ± 0.2 ppm, 24.8 ± 0.2 ppm, 21.4 ± 0.2 ppm, and 20.8 ± 0.2 ppm. In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by a13C SSNMR spectrum having peaks at 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2 ppm, 152.1 ± 0.2 ppm, 151.1 ± 0.2 ppm, 150.4 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 144.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.4 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.5 ± 0.2 ppm, 119.6 ± 0.2 ppm, 118.8 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 114.0 ± 0.2 ppm, 111.6 ± 0.2 ppm, 65.1 ± 0.2 ppm, 62.6 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.7 ± 0.2 ppm, 26.2 ± 0.2 ppm, 24.8 ± 0.2 ppm, 21.4 ± 0.2 ppm, and 20.8 ± 0.2 ppm.

[0351] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by a13C SSNMR spectrum substantially similar to FIG.26.

[0352] In some embodiments, Compound I Na Hemi Salt nPA Solvate is characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 10.3 ± 0.1 Å α 94.2 ± 0.1° b 13.3 ± 0.1 Å β 91.0 ± 0.1° c 16.7 ± 0.1 Å γ 104.0 ± 0.1° In some embodiments, the diffractometer is a Bruker diffractometer.

[0353] In some embodiments, the invention provides a method of making Compound I Na Hemi Salt nPA Solvate, comprising (i) treating 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6- naphthyridine-5-carbonitrile with water and TFA, (ii) mixing at 60 °C for 18-30 hours, (iii) treating the mixture with water and sodium hydroxide at room temperature, (iv) washing the mixture with aqueous sodium chloride, (v) diluting the mixture with 2-MeTHF and subsequently concentrating, (vi) treating the mixture with nPA and subsequently concentrating, (vii) heating the mixture to 90 °C and subsequently holding the mixture at 50 °C for 6-18 hours, (viii) cooling the mixture to room temperature, (ix) collecting the solids, and (s) drying under vacuum at 40 °C for 6-18 hours to afford Compound I Na Hemi Salt nPA Solvate. K. Crystalline Compound I nPA Solvate J

[0354] In some embodiments, the invention provides Compound I nPA Solvate J.

[0355] In some embodiments, Compound I nPA Solvate J is substantially pure. In some embodiments, Compound I nPA Solvate J is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I nPA Solvate J is substantially 100% crystalline. In some embodiments, Compound I nPA Solvate J is 100% crystalline.

[0356] In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 19.0 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having a signal at 5.3 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having a signal at 10.4 ± 0.2 degrees two-theta. In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having a signal at 19.0 ± 0.2 degrees two-theta.

[0357] In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 19.0 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 8.8 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 13.4 ± 0.2 degrees two-theta.

[0358] In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 19.0 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 8.8 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 13.4 ± 0.2 degrees two-theta; (c) one, two, or three signals selected from 14.1 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, and 26.0 ± 0.2 degrees two-theta.

[0359] In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram having signals at 3.1 ± 0.2 degrees two-theta, 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 10.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.4 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two- theta, 19.2 ± 0.2 degrees two-theta, 26.0 ± 0.2 degrees two-theta, and 26.4 ± 0.2 degrees two-theta.

[0360] In some embodiments, Compound I nPA Solvate J is characterized by an X-ray powder diffractogram substantially similar to FIG.27.

[0361] In some embodiments, the invention provides a method of making Compound I nPA Solvate J, comprising (i) treating a mixture of Compound I and 2-MeTHF with nPA, (ii) concentrating the mixture at 20-30 °C, (iii) treating the mixture with nPA and subsequently concentrating the mixture at 20-30 °C, (iv) heating the mixture to 80-100 °C, (v) cooling the mixture to room temperature over 8-16 hours, (v) collecting the solids, and (vi) drying under vacuum at 45 °C to afford Compound I nPA Solvate J. L. Crystalline Compound I 2-MeTHF Solvate A

[0362] In some embodiments, the invention provides Compound I 2-MeTHF Solvate A.

[0363] In some embodiments, Compound I 2-MeTHF Solvate A is substantially pure. In some embodiments, Compound I 2-MeTHF Solvate A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I 2-MeTHF Solvate A is substantially 100% crystalline. In some embodiments, Compound I 2-MeTHF Solvate A is 100% crystalline.

[0364] In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, and 14.0 ± 0.2 degrees two-theta. In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having a signal at 5.8 ± 0.2 degrees two-theta. In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having a signal at 9.4 ± 0.2 degrees two-theta. In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having a signal at 14.0 ± 0.2 degrees two-theta.

[0365] In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, and 14.0 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 9.8 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, and 15.4 ± 0.2 degrees two-theta.

[0366] In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, and 14.0 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 9.8 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, and 15.4 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 17.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta.

[0367] In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram having signals at 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 14.0 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two- theta, 20.1 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 24.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta.

[0368] In some embodiments, Compound I 2-MeTHF Solvate A is characterized by an X-ray powder diffractogram substantially similar to FIG.28.

[0369] In some embodiments, the invention provides a provides a method of making Compound I 2- MeTHF Solvate A, comprising (i) treating Compound I Form A with 2-MeTHF, (ii) agitating the mixture for 24 hours at about 22 °C, and (iii) isolating the solids. M. Crystalline Compound I 2-MeTHF Solvate Mixture A

[0370] In some embodiments, the invention provides Compound I 2-MeTHF Solvate Mixture A.

[0371] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is substantially pure. In some embodiments, Compound I 2-MeTHF Solvate Mixture A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I 2- MeTHF Solvate Mixture A is substantially 100% crystalline. In some embodiments, Compound I 2- MeTHF Solvate A is 100% crystalline.

[0372] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is characterized by an X-ray powder diffractogram having a signal at 4.6 ± 0.2 degrees two-theta.

[0373] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is characterized by an X-ray powder diffractogram having (a) a signal at 4.6 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 15.8 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta.

[0374] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is characterized by an X-ray powder diffractogram having (a) a signal at 4.6 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 15.8 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 12.4 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta.

[0375] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is characterized by an X-ray powder diffractogram having signals at 4.6 ± 0.2 degrees two-theta, 12.4 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two- theta, 21.9 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta.

[0376] In some embodiments, Compound I 2-MeTHF Solvate Mixture A is characterized by an X-ray powder diffractogram substantially similar to FIG.29.

[0377] In some embodiments, the invention provides a method of making Compound I 2-MeTHF Solvate Mixture A, comprising (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I 2-MeTHF Solvate Mixture A. N. Crystalline Compound I 2-MeTHF Mixture C

[0378] In some embodiments, the invention provides Compound I 2-MeTHF Mixture C.

[0379] In some embodiments, Compound I 2-MeTHF Mixture C is substantially pure. In some embodiments, Compound I 2-MeTHF Mixture C is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I 2-MeTHF Mixture C is substantially 100% crystalline. In some embodiments, Compound I 2-MeTHF Mixture C is 100% crystalline.

[0380] In some embodiments, Compound I 2-MeTHF Mixture C is characterized by an X-ray powder diffractogram having a signal at 4.9 ± 0.2 degrees two-theta.

[0381] In some embodiments, Compound I 2-MeTHF Mixture C is characterized by an X-ray powder diffractogram having (a) a signal at 4.9 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 8.2 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, and 18.5 ± 0.2 degrees two-theta.

[0382] In some embodiments, Compound I 2-MeTHF Mixture C is characterized by an X-ray powder diffractogram having (a) a signal at 4.9 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 8.2 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, and 18.5 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 15.3 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, and 23.1 ± 0.2 degrees two-theta.

[0383] In some embodiments, Compound I 2-MeTHF Mixture C is characterized by an X-ray powder diffractogram having signals at 4.9 ± 0.2 degrees two-theta, 8.2 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two- theta, 20.4 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 25.0 ± 0.2 degrees two-theta, and 25.2 ± 0.2 degrees two-theta.

[0384] In some embodiments, Compound I 2-MeTHF Mixture C is characterized by an X-ray powder diffractogram substantially similar to FIG.30.

[0385] In some embodiments, the invention provides a method of making Compound I 2-MeTHF Solvate Mixture C, comprising (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) warming the slurry to 90 °C to dissolve solids, (iv) cooling to 25 °C, (v) collecting the solids, and (iv) drying at 50 °C to afford Compound I 2-MeTHF Solvate Mixture C. O. Crystalline Compound I Mandelic Acid Cocrystal

[0386] In some embodiments, the invention provides Compound I Mandelic Acid Cocrystal.

[0387] In some embodiments, Compound I Mandelic Acid Cocrystal is substantially pure. In some embodiments, Compound I Mandelic Acid Cocrystal is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Mandelic Acid Cocrystal is substantially 100% crystalline. In some embodiments, Compound I Mandelic Acid Cocrystal is 100% crystalline.

[0388] In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta. In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 6.6 ± 0.2 degrees two- theta. In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 10.6 ± 0.2 degrees two-theta. In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 21.1 ± 0.2 degrees two-theta.

[0389] In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta; and (b) one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta.

[0390] In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta; (b) one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta; and (c) one, two, or three signals selected from 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, and 20.9 ± 0.2 degrees two-theta.

[0391] In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram having signals at 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta.

[0392] In some embodiments, Compound I Mandelic Acid Cocrystal is characterized by an X-ray powder diffractogram substantially similar to FIG.31.

[0393] In some embodiments, the invention provides a method of making Compound I Mandelic Acid Cocrystal, comprising (i) combining Compound I and Mandelic acid, (ii) diluting the mixture in DCM, (iii) agitating the mixture for at least 1 hour, (iv) collecting the resulting solid material, and (v) drying the collected solid material in a vacuum oven at 50 °C to afford Compound I Mandelic Acid Cocrystal. In some embodiments, the agitation comprises sonication. In some embodiments, the agitation comprises stirring. In some embodiments, the agitation comprises sonication followed by stirring. P. Crystalline Compound I Oxalic Acid Cocrystal

[0394] In some embodiments, the invention provides Compound I Oxalic Acid Cocrystal.

[0395] In some embodiments, Compound I Oxalic Acid Cocrystal is substantially pure. In some embodiments, Compound I Oxalic Acid Cocrystal is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I Oxalic Acid Cocrystal is substantially 100% crystalline. In some embodiments, Compound I Oxalic Acid Cocrystal is 100% crystalline.

[0396] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.9 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, and 14.5 ± 0.2 degrees two-theta. In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 8.9 ± 0.2 degrees two-theta. In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 11.6 ± 0.2 degrees two-theta. In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having a signal at 14.5 ± 0.2 degrees two-theta.

[0397] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 8.9 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, and 14.5 ± 0.2 degrees two-theta; and (b) one or two signals selected from 5.7 ± 0.2 degrees two-theta and 20.1 ± 0.2 degrees two-theta.

[0398] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 8.9 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, and 14.5 ± 0.2 degrees two-theta; (b) one or two signals selected from 5.7 ± 0.2 degrees two-theta and 20.1 ± 0.2 degrees two-theta; and (c) one, two or three signals selected from 10.6 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, and 22.9 ± 0.2 degrees two-theta.

[0399] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram having signals at 5.7 ± 0.2 degrees two-theta, 8.9 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, and 22.9 ± 0.2 degrees two-theta.

[0400] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by an X-ray powder diffractogram substantially similar to FIG.32.

[0401] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2 ppm, 162.4 ± 0.2 ppm, 161.5 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.7 ± 0.2 ppm, 149.3 ± 0.2 ppm, 148.0 ± 0.2 ppm, 146.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 134.9 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.9 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.1 ± 0.2 ppm, 117.7 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 29.3 ± 0.2 ppm, and 17.9 ± 0.2 ppm. In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by a13C SSNMR spectrum having peaks at 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2 ppm, 162.4 ± 0.2 ppm, 161.5 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.7 ± 0.2 ppm, 149.3 ± 0.2 ppm, 148.0 ± 0.2 ppm, 146.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 134.9 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.9 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.1 ± 0.2 ppm, 117.7 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 29.3 ± 0.2 ppm, and 17.9 ± 0.2 ppm.

[0402] In some embodiments, Compound I Oxalic Acid Cocrystal is characterized by a13C SSNMR spectrum substantially similar to FIG.33.

[0403] In some embodiments, the invention provides a method of making Compound I Oxalic Acid Cocrystal, comprising (i) suspending Compound I and oxalic acid (1:1) in DCM, (ii) stirring the resulting slurry at room temperature, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I Oxalic Acid Cocrystal. Q. Crystalline Compound I TFA Salt A

[0404] In some embodiments, the invention provides Compound I TFA Salt A.

[0405] In some embodiments, Compound I TFA Salt A is substantially pure. In some embodiments, Compound I TFA Salt A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). In some embodiments, Compound I TFA Salt A is substantially 100% crystalline. In some embodiments, Compound I TFA Salt A is 100% crystalline.

[0406] In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta. In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having a signal at 8.4 ± 0.2 degrees two-theta. In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having a signal at 15.1 ± 0.2 degrees two-theta. In some embodiments, Compound I TFA Salt A is characterized by an X- ray powder diffractogram having a signal at 19.7 ± 0.2 degrees two-theta.

[0407] In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; and (b) one or two signals selected from 4.4 ± 0.2 degrees two-theta and 11.4 ± 0.2 degrees two-theta.

[0408] In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; (b) one or two signals selected from 4.4 ± 0.2 degrees two-theta and 11.4 ± 0.2 degrees two-theta; and (c) one, two or three signals selected from 17.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, and 26.3 ± 0.2 degrees two-theta.

[0409] In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram having signals at 4.4 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 11.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, and 26.3 ± 0.2 degrees two-theta.

[0410] In some embodiments, Compound I TFA Salt A is characterized by an X-ray powder diffractogram substantially similar to FIG.34.

[0411] In some embodiments, Compound I TFA Salt A is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 171.9 ± 0.2 ppm, 169.2 ± 0.2 ppm, 160.7 ± 0.2 ppm, 159.5 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.8 ± 0.2 ppm, 136.1 ± 0.2 ppm, 133.7 ± 0.2 ppm, 132.1 ± 0.2 ppm, 131.0 ± 0.2 ppm, 118.1 ± 0.2 ppm, 116.0 ± 0.2 ppm, 113.0 ± 0.2 ppm, 36.6 ± 0.2 ppm, 31.3 ± 0.2 ppm, and 18.4 ± 0.2 ppm. In some embodiments, Compound I TFA Salt A is characterized by a13C SSNMR spectrum having peaks at 171.9 ± 0.2 ppm, 169.2 ± 0.2 ppm, 160.7 ± 0.2 ppm, 159.5 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.8 ± 0.2 ppm, 136.1 ± 0.2 ppm, 133.7 ± 0.2 ppm, 132.1 ± 0.2 ppm, 131.0 ± 0.2 ppm, 118.1 ± 0.2 ppm, 116.0 ± 0.2 ppm, 113.0 ± 0.2 ppm, 36.6 ± 0.2 ppm, 31.3 ± 0.2 ppm, and 18.4 ± 0.2 ppm.

[0412] In some embodiments, Compound I TFA Salt A is characterized by a13C SSNMR spectrum substantially similar to FIG.35.

[0413] In some embodiments, the invention provides a method of making Compound I TFA Salt A, comprising (i) suspending Compound I in DCM, (ii) treating the suspension with TFA, (iii) stirring at room temperature for 15-45 minutes, (iv) collecting the solids, and (v) drying at room temperature to afford Compound I TFA Salt A. R. Amorphous Compound I

[0414] In some embodiments, the invention provides Amorphous Compound I.

[0415] In some embodiments, Amorphous Compound I is substantially pure. In some embodiments, Amorphous Compound I is substantially amorphous (i.e., wherein less than 15% of Compound I is in crystalline form, wherein less than 10% of Compound I is in crystalline form, wherein less than 5% of Compound I is in crystalline form). In some embodiments, Amorphous Compound I is substantially 100% amorphous. In some embodiments, Amorphous Compound I is 100% amorphous.

[0416] In some embodiments, Amorphous Compound I is characterized by an X-ray powder diffractogram substantially similar to FIG.36.

[0417] In some embodiments, Amorphous I is characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.6 ± 0.2 ppm, 172.0 ± 0.2 ppm, 164.0 ± 0.2 ppm, 155.5 ± 0.2 ppm, 151.3 ± 0.2 ppm, 147.1 ± 0.2 ppm, 133.2 ± 0.2 ppm, 131.7 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 36.1 ± 0.2 ppm, 30.0 ± 0.2 ppm, 20.1 ± 0.2 ppm, 9.3 ± 0.2 ppm, 8.3 ± 0.2 ppm, and 7.6 ± 0.2 ppm. In some embodiments, Amorphous Compound I is characterized by a13C SSNMR spectrum having peaks at 177.6 ± 0.2 ppm, 172.0 ± 0.2 ppm, 164.0 ± 0.2 ppm, 155.5 ± 0.2 ppm, 151.3 ± 0.2 ppm, 147.1 ± 0.2 ppm, 133.2 ± 0.2 ppm, 131.7 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 36.1 ± 0.2 ppm, 30.0 ± 0.2 ppm, 20.1 ± 0.2 ppm, 9.3 ± 0.2 ppm, 8.3 ± 0.2 ppm, and 7.6 ± 0.2 ppm.

[0418] In some embodiments, Amorphous Compound I is characterized by a13C SSNMR spectrum substantially similar to FIG.37.

[0419] In some embodiments, the invention provides a method of making Amoprhous Compound I, comprising (i) combining Compound I and t-butanol to form a mixture, (ii) stirring the mixture at about 70 °C for about 1 hour, (iii) adding water to the mixture, (iv) freezing the mixture, and (v) isolating the solid material. Methods of Treatment

[0420] Compound I, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, acts as a voltage-gated sodium channel inhibitor. In some aspects, the voltage-gated sodium channel is NaV1.8. Accordingly, in another aspect, the disclosure features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0421] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject Compound I or a solvate thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0422] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound I, or a pharmaceutically acceptable salt thereof.

[0423] In another aspect, the disclosure relates to a method of treating or lessening the severity of pain in a subject, comprising administering to the subject Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0424] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0425] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0426] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycysctic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0427] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some aspects, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small-fiber neuropathy” shall be understood to include any small fiber neuropathy.

[0428] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post- amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0429] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of musculoskeletal pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis pain.

[0430] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0431] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0432] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0433] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0434] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain, wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0435] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of pathological cough wherein said method comprises administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0436] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of acute pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some aspects, the acute pain comprises acute post-operative pain.

[0437] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0438] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of bunionectomy pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0439] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of shoulder arthroplasty pain or shoulder arthroscopy pain comprising administering an effective amount of a compound of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0440] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of herniorrhaphy pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0441] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of abdominoplasty pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0442] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of visceral pain comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some aspects, the visceral pain comprises visceral pain from abdominoplasty.

[0443] In yet another aspect, the disclosure features a method of treating or lessening the severity in a subject of a neurodegenerative disease comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

[0444] In yet another aspect, the disclosure features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0445] In another aspect, the disclosure features a method of inhibiting a voltage-gated sodium channel in a biological sample comprising contacting the biological sample with an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

[0446] In another aspect, the disclosure features a method of treating or lessening the severity in a subject of acute pain, sub-acute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post- mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), cancer pain including chronic cancer pain and breakthrough cancer pain, stroke (e.g., post stroke central neuropathic pain), whiplash associated disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud’s Disease, scleroderma, systemic lupus erythematosus, Epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia reumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, spondylodyscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry’s disease, mastocytocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo- mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0447] In another aspect, the disclosure features a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic post-surgical pain (e.g., post amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain, comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0448] In another aspect, the disclosure features a method of treating or lessening the severity in a subject of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbrosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain, comprising administering an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof.

[0449] In some embodiments, the method of treating, or lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable crystalline (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I neat Form A. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I Neat Form B. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I Neat Form C. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I hemi-hydrate. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I monohydrate. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I methanol solvate. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate mixture A. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate B. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate C. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I Na hemi salt nPA solvate. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate J. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I 2-Me THF Solvate A. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I 2-Me THF Solvate Mixture A. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I 2-Me THF Mixture C. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I mandelic acid cocrystal. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I DL- oxalic acid cocrystal. In some embodiments the pharmaceutically acceptable crystalline form of Compound I is Compound I TFA Salt A. In some embodiments, the method of treating, or lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Amorphous Compound I, as disclosed herein.

[0450] In some embodiments, the method of treating, or lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof. In some embodiments, the method of treating, or lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Amorphous Compound I as disclosed herein or a pharmaceutical composition thereof.

[0451] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Compound I as any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the method of treating, lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Compound I as a solid form selected from Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Form C, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, and Compound I TFA Salt A, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the method of treating, lessening the severity of, or symptomatically treating pain in a patient comprises administering to the patient an effective amount of Amorphous Compound I as disclosed herein in combination with at least one additional active pharmaceutical ingredient.

[0452] In some embodiments, the disclosure features Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof for use in any of the foregoing methods.

[0453] In some embodiments, the disclosure features the use of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof for the manufacture of a medicament for use in any of the foregoing methods.

[0454] In some embodiments, the disclosure features Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein or a pharmaceutical composition thereof for use as a medicament. Additional Therapeutic Agents

[0455] It will also be appreciated that Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the compound in any one of the pharmaceutically acceptable solid forms, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: non- opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0456] In another embodiment, additional appropriate therapeutic agents are selected from the following:

[0457] (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin;

[0458] (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

[0459] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

[0460] (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

[0461] (5) a histamine (H1) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

[0462] (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

[0463] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0464] (8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3- fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone;

[0465] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l, 2,3,4- tetrahydroisoquinolin-2-yl)-5- (2-pyridyl) quinazoline;

[0466] (10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

[0467] (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

[0468] (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H- [l,4]diazocino[2,l-g][l,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4- triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]- methylamino]-2-phenylpiperidine (2S,3S);

[0469] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0470] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0471] (15) a coal-tar analgesic, in particular paracetamol;

[0472] (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

[0473] (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

[0474] (18) a beta-adrenergic such as propranolol;

[0475] (19) a local anesthetic such as mexiletine;

[0476] (20) a corticosteroid such as dexamethasone;

[0477] (21) a 5-HT receptor agonist or antagonist, particularly a 5-HT1B / 1Dagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

[0478] (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0479] (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[0480] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®);

[0481] (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulphonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)- 2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b]indole- l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7- propyl-3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l- ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)- 3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4- ethylpiperazin-l-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7-oxo-3-propyl-6,7-dihydro-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0482] (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl- 5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6- (aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H- [1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino- 4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0483] (27) a cannabinoid such as KHK-6188;

[0484] (28) metabotropic glutamate subtype 1 receptor (mGluRl) antagonist;

[0485] (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

[0486] (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

[0487] (31) a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

[0488] (32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2- [(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5- heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2- chloro-5- (trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5- thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2- carboxamidine, NXN-462, or guanidinoethyldisulfide;

[0489] (33) an acetylcholinesterase inhibitor such as donepezil;

[0490] (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6- dimethyl- lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(15)-l- ({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid;

[0491] (35) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)- cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

[0492] (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3- pyridylmethyl)-l,4-benzoquinone (CV-6504);

[0493] (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate;

[0494] (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035, and CN111217776, the entire contents of each application hereby incorporated by reference;

[0495] (38a) a NaV1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2- (trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin- 1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2- methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy- 6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl- 4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'- carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4- dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4- [2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]- 6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5- isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5- isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]- 6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1- methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)- 2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[1'-[4-methoxy-3- (trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2- dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [2-methyl-6-(1- methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

[0496] (39) a NaV1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014 / 120808 (US2014213616), WO2014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US2020140411), WO2020 / 261114, WO2020 / 140959, WO2020 / 144375, WO2020 / 151728, WO2021 / 032074, WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, CN112479996 (WO2021 / 047622), and CN114591293, the entire contents of each application hereby incorporated by reference;

[0497] (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4- yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5- chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2- dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo- 1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2- (trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2- dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4- (trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl- d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl- d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4- fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4- fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N- (3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2- (4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)- N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4- (trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)- 3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2- methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4- (perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2- methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2- methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2- methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro- 2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2- methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N- (3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4- fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3- sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- [2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4- trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5- [2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2- (difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]- 3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl- 4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3- carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2- pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2- fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2- fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4- (trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- (4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;

[0498] (40) a combined NaV1.7 and NaV1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;

[0499] (41) a 5-HT3 antagonist, such as ondansetron;

[0500] (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

[0501] (43) a nicotinic receptor antagonist, such as varenicline;

[0502] (44) an N-type calcium channel antagonist, such as Z-160;

[0503] (45) a nerve growth factor antagonist, such as tanezumab;

[0504] (46) an endopeptidase stimulant, such as senrebotase;

[0505] (47) an angiotensin II antagonist, such as EMA-401;

[0506] (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®));

[0507] (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®)); and

[0508] (50) bupivacaine and meloxicam combination (e.g., HTX-011).

[0509] In one embodiment, the additional appropriate therapeutic agents are selected from V-116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

[0510] In another embodiment, the additional appropriate therapeutic agents are selected from N-(6- amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4- (trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0511] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04.

[0512] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0513] In another embodiment, the additional therapeutic agent is a NaV1.7 blocker such as ST-2427, ST-2578 and / or those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and WO2022 / 036297 the entire contents of each application hereby incorporated by reference.

[0514] In another embodiment, the additional therapeutic agent is selected from ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL- 017881, NTM-006, Opiranserin (UnafraTM), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC- 17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS- 2031, MEDI 7352, and XT-150.

[0515] In another embodiment, the additional therapeutic agent is selected from Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905 and ACD440.

[0516] In another embodiment, the additional therapeutic agent is selected from HRS4800, ODM- 111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, OLP-1002, ATX01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, BL-017881, Profervia (Cilnidipine), LS-04, vixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0517] In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the NaV1.7 and NaV1.8 blockers identified above.

[0518] The amount of additional therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0519] Compound I in any one of the pharmaceutically acceptable solid forms disclosed herein or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising Compound I in any one of the pharmaceutically acceptable solid forms described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising Compound I in any one of the pharmaceutically acceptable solid forms described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0520] Another aspect of the invention relates to inhibiting NaV1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with Compound I in any one of the pharmaceutically acceptable solid forms disclosed herein, or a pharmaceutical composition thereof. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0521] Inhibition of NaV1.8 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors. Pharmaceutical Compositions

[0522] Another aspect of the invention provides pharmaceutical compositions comprising Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical composition comprises Compound I in a solid form selected from Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Form C, Amorphous Compound I, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, and Compound I TFA Salt A.

[0523] In some embodiments, the invention provides a pharmaceutical composition comprising (a) Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, and (b) at least one pharmaceutically acceptable carrier.

[0524] In some embodiments, the invention provides pharmaceutical compositions comprising (a) Compound I in a solid form selected from Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Form C, Amorphous Compound I, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, and Compound I TFA Salt A and (b) at least one pharmaceutically acceptable carrier.

[0525] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Radiolabeled Analogs of Compound I

[0526] In another aspect, the invention relates to radiolabeled analogs of Compound I. The radiolabeled analogs may be in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein and may be prepared by any of the methods described herein.

[0527] As used herein, the term “radiolabeled analogs of Compound I” refers to compounds that are identical to Compound I, as described herein, except that one or more atoms has been replaced with a radioisotope of the atom present in Compound I.

[0528] As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0529] The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and / or carbon-14 (14C)- labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.

[0530] In another aspect, the invention relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with Compound I.

[0531] In another aspect, the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with Compound I.

[0532] In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with Compound I.

[0533] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with Compound I.

[0534] In another aspect, the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with Compound I.

[0535] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with Compound I. Non-Limiting Exemplary Embodiments

[0536] Further embodiments of the disclosure are set out in the following numbered clauses: 1. Compound I Neat Form A. The Compound I Neat Form A of Embodiment 1, wherein the Compound I Neat Form A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I Neat Form A according to Embodiment 1 or 2, wherein the Compound I Neat Form A is substantially 100% crystalline. The Compound I Neat Form A according to any one of Embodiments 1-3, wherein the Compound I Neat Form A is 100% crystalline. The Compound I Neat Form A according to any one of Embodiments 1-4, characterized by an X- ray powder diffractogram having one, two, or three signals selected from 5.5 ± 0.2 degrees two- theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta. The Compound I Neat Form A according to Embodiment 5, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, and 20.4 ± 0.2 degrees two-theta. The Compound I Neat Form A according to Embodiment 6, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.0 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two-theta. The Compound I Neat Form A according to any one of Embodiments 1-4, characterized by an X- ray powder diffractogram having signals at 5.5 ± 0.2 degrees two-theta, 8.0 ± 0.2 degrees two-theta, 9.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 11.1 ± 0.2 degrees two-theta, 11.7 ± 0.2 degrees two-theta, 12.8 ± 0.2 degrees two-theta, 16.0 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.9 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, 27.7 ± 0.2 degrees two-theta, 29.5 ± 0.2 degrees two-theta, and 29.9 ± 0.2 degrees two-theta. The Compound I Neat Form A according to any one of Embodiments 1-4, characterized by an X- ray powder diffractogram substantially similar to FIG.8. The Compound I Neat Form A according to any one of Embodiments 1-9, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm. The Compound I Neat Form A according to any one of Embodiments 1-9, characterized by a13C SSNMR spectrum having peaks at 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm. The Compound I Neat Form A according to any one of Embodiments 1-9, characterized by a13C SSNMR spectrum substantially similar to FIG.9A. The Compound I Neat Form A according to any one of Embodiments 1-12, characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.0 ± 0.1 Å α 98.0 ± 0.1° b 11.2 ± 0.1 Å β 93.1 ± 0.1° c 15.9 ± 0.1 Å γ 95.8 ± 0.1° Compound I Hemi-Hydrate. The Compound I Hemi-Hydrate of Embodiment 14, wherein the Compound I Hemi-Hydrate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I Hemi-Hydrate according to Embodiment 14 or 15, wherein the Compound I Hemi-Hydrate is substantially 100% crystalline. The Compound I Hemi-Hydrate according to any one of Embodiments 14-16, wherein the Compound I Hemi-Hydrate is 100% crystalline. The Compound I Hemi-Hydrate according to any one of Embodiments 14-17, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.1 ± 0.2 degrees two- theta, 10.2 ± 0.2 degrees two-theta, and 12.3 ± 0.2 degrees two-theta. The Compound I Hemi-Hydrate according to Embodiment 18, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 14.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.6 ± 0.2 degrees two-theta. The Compound I Hemi-Hydrate according to Embodiment 19, characterized by an X-ray powder diffractogram having one or two signals selected from 11.1 ± 0.2 degrees two-theta and 21.3 ± 0.2 degrees two-theta. The Compound I Hemi-Hydrate according to any one of Embodiments 14-17, characterized by an X-ray powder diffractogram having signals at 5.1 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two- theta, 11.1 ± 0.2 degrees two-theta, 12.3 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.6 ± 0.2 degrees two-theta. The Compound I Hemi-Hydrate according to any one of Embodiments 14-17, characterized by an X-ray powder diffractogram substantially similar to FIG.14. The Compound I Hemi-Hydrate according to any one of Embodiments 14-22, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.1 ± 0.2 ppm, 169.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 154.0 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.4 ± 0.2 ppm, 137.6 ± 0.2 ppm, 137.0 ± 0.2 ppm, 133.4 ± 0.2 ppm, 129.0 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.6 ± 0.2 ppm, 113.0 ± 0.2 ppm, 35.4 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 21.1 ± 0.2 ppm. The Compound I Hemi-Hydrate according to any one of Embodiments 14-22, characterized by a13C SSNMR spectrum having peaks at 178.1 ± 0.2 ppm, 169.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 154.0 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.4 ± 0.2 ppm, 137.6 ± 0.2 ppm, 137.0 ± 0.2 ppm, 133.4 ± 0.2 ppm, 129.0 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.6 ± 0.2 ppm, 113.0 ± 0.2 ppm, 35.4 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 21.1 ± 0.2 ppm. The Compound I Hemi-Hydrate according to any one of Embodiments 14-22, characterized by a13C SSNMR spectrum substantially similar to FIG.15. Compound I Monohydrate. The Compound I Monohydrate of Embodiment 26, wherein the Compound I Monohydrate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). . The Compound I Monohydrate according to Embodiment 26 or 27, wherein the Compound I Monohydrate is substantially 100% crystalline. . The Compound I Monohydrate according to any one of Embodiments 26-28, wherein the Compound I Hemi-Hydrate is 100% crystalline. . The Compound I Monohydrate according to any one of Embodiments 26-29, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.0 ± 0.2 degrees two- theta, 10.2 ± 0.2 degrees two-theta, and 14.2 ± 0.2 degrees two-theta. . The Compound I Monohydrate according to Embodiment 30, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 12.2 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, and 26.5 ± 0.2 degrees two-theta. . The Compound I Monohydrate according to Embodiment 31, characterized by an X-ray powder diffractogram having one or two signals selected from 17.1 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, and 23.5 ± 0.2 degrees two-theta. . The Compound I Monohydrate according to any one of Embodiments 26-29, characterized by an X-ray powder diffractogram having signals at 5.0 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two- theta, 12.2 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 17.1 ± 0.2 degrees two-theta, 17.8 ± 0.2 degrees two-theta, 18.1 ± 0.2 degrees two-theta, 20.3 ± 0.2 degrees two-theta, 21.3 ± 0.2 degrees two-theta, 22.0 ± 0.2 degrees two-theta, 23.5 ± 0.2 degrees two-theta, 26.5 ± 0.2 degrees two-theta, 27.4 ± 0.2 degrees two-theta, and 31.7 ± 0.2 degrees two-theta. . The Compound I Monohydrate according to any one of Embodiments 26-29, characterized by an X-ray powder diffractogram substantially similar to FIG.16. . Compound I Methanol Solvate. . The Compound I Methanol Solvate of Embodiment 35, wherein the Compound I Methanol Solvate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I Methanol Solvate according to Embodiment 35 or 36, wherein the Compound I Methanol Solvate is substantially 100% crystalline. The Compound I Methanol Solvate according to any one of Embodiments 35-37, wherein the Compound I Methanol Solvate is 100% crystalline. The Compound I Methanol Solvate according to any one of Embodiments 35-38, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. The Compound I Methanol Solvate according to Embodiment 39, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 20.9 ± 0.2 degrees two-theta. The Compound I Methanol Solvate according to Embodiment 40, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta. The Compound I Methanol Solvate according to any one of Embodiments 35-38, characterized by an X-ray powder diffractogram having signals at 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta. The Compound I Methanol Solvate according to any one of Embodiments 35-38, characterized by an X-ray powder diffractogram substantially similar to FIG.17. The Compound I Methanol Solvate according to any one of Embodiments 35-43, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2 ppm, 170.3 ± 0.2 ppm, 156.9 ± 0.2 ppm, 154.1 ± 0.2 ppm, 151.9 ± 0.2 ppm, 150.0 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.4 ± 0.2 ppm, 135.0 ± 0.2 ppm, 134.0 ± 0.2 ppm, 132.9 ± 0.2 ppm, 131.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.2 ± 0.2 ppm, 115.0 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 49.5 ± 0.2 ppm, 49.3 ± 0.2 ppm, 49.0 ± 0.2 ppm, 36.4 ± 0.2 ppm, 35.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 28.2 ± 0.2 ppm, 19.1 ± 0.2 ppm, and 18.8 ± 0.2 ppm. . The Compound I Methanol Solvate according to any one of Embodiments 35-43, characterized by a13C SSNMR spectrum having peaks at 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2 ppm, 170.3 ± 0.2 ppm, 156.9 ± 0.2 ppm, 154.1 ± 0.2 ppm, 151.9 ± 0.2 ppm, 150.0 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.4 ± 0.2 ppm, 135.0 ± 0.2 ppm, 134.0 ± 0.2 ppm, 132.9 ± 0.2 ppm, 131.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.2 ± 0.2 ppm, 115.0 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 49.5 ± 0.2 ppm, 49.3 ± 0.2 ppm, 49.0 ± 0.2 ppm, 36.4 ± 0.2 ppm, 35.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 28.2 ± 0.2 ppm, 19.1 ± 0.2 ppm, and 18.8 ± 0.2 ppm. . The Compound I Methanol Solvate according to any one of Embodiments 35-43, characterized by a13C SSNMR spectrum substantially similar to FIG.18. . The Compound I Methanol Solvate according to any one of Embodiments 35-46, characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 12.3 ± 0.1 Å α 100.4 ± 0.1° b 14.1 ± 0.1 Å β 105.3 ± 0.1° c 14.4 ± 0.1 Å γ 107.5 ± 0.1° . Compound I Neat Form B in any of the embodiments set forth above in Section B. . Compound I Neat Form C in any of the embodiments set forth above in Section C. . Amorphous Compound I in any of the embodiments set forth above in Section R. . Compound I nPA Solvate Mixture A. . The Compound I nPA Solvate Mixture A of Embodiment 51, wherein the Compound I nPA Solvate Mixture A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). . The Compound I nPA Solvate Mixture A according to Embodiment 51 or 52, wherein the Compound I nPA Solvate Mixture A is substantially 100% crystalline. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-53, wherein the Compound I nPA Solvate Mixture A is 100% crystalline. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-54, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. . The Compound I nPA Solvate Mixture A according to Embodiment 55, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 10.1 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta. . The Compound I nPA Solvate Mixture A according to Embodiment 56, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 13.5 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, and 25.5 ± 0.2 degrees two-theta. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-54, characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 10.1 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.5 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.3 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 18.4 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 25.5 ± 0.2 degrees two-theta, and 26.1 ± 0.2 degrees two-theta. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-54, characterized by an X-ray powder diffractogram substantially similar to FIG.19. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm. . The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum having peaks at 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm. The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum substantially similar to FIG.20. The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 176.5 ± 0.2 ppm, 175.2 ± 0.2 ppm, 171.8 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.2 ± 0.2 ppm, 150.1 ± 0.2 ppm, 147.6 ± 0.2 ppm, 144.9 ± 0.2 ppm, 143.5 ± 0.2 ppm, 142.2 ± 0.2 ppm, 135.5 ± 0.2 ppm, 134.5 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.1 ± 0.2 ppm, 117.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.1 ± 0.2 ppm, 64.3 ± 0.2 ppm, 63.9 ± 0.2 ppm, 36.5 ± 0.2 ppm, 29.9 ± 0.2 ppm, 25.9 ± 0.2 ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm, and 11.7 ± 0.2 ppm. The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum having peaks at 176.5 ± 0.2 ppm, 175.2 ± 0.2 ppm, 171.8 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.2 ± 0.2 ppm, 150.1 ± 0.2 ppm, 147.6 ± 0.2 ppm, 144.9 ± 0.2 ppm, 143.5 ± 0.2 ppm, 142.2 ± 0.2 ppm, 135.5 ± 0.2 ppm, 134.5 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.1 ± 0.2 ppm, 117.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.1 ± 0.2 ppm, 64.3 ± 0.2 ppm, 63.9 ± 0.2 ppm, 36.5 ± 0.2 ppm, 29.9 ± 0.2 ppm, 25.9 ± 0.2 ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm, and 11.7 ± 0.2 ppm. The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-59, characterized by a13C SSNMR spectrum substantially similar to FIG.21. The Compound I nPA Solvate Mixture A according to any one of Embodiments 51-65, characterized by monoclinic crystal system, C2 / c space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 19.9 ± 0.1 Å α 90. b 6.9 ± 0.1 Å β 93.9 ± 0.1° c 32.6 ± 0.1 Å γ 90 Compound I nPA Solvate Mixture B. The Compound I nPA Solvate Mixture B of Embodiment 67, wherein the Compound I nPA Solvate Mixture B is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I nPA Solvate Mixture B according to Embodiment 67 or 68, wherein the Compound I nPA Solvate Mixture B is substantially 100% crystalline. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-69, wherein the Compound I nPA Solvate Mixture B is 100% crystalline. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-70, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta. The Compound I nPA Solvate Mixture B according to Embodiment 71, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 9.9 ± 0.2 degrees two-theta, 13.2 ± 0.2 degrees two-theta, and 14.8 ± 0.2 degrees two-theta. The Compound I nPA Solvate Mixture B according to Embodiment 72, characterized by an X-ray powder diffractogram having one or two signals selected from 18.9 ± 0.2 degrees two-theta and 21.4 ± 0.2 degrees two-theta. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-70, characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.9 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.2 ± 0.2 degrees two-theta, 13.9 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.0 ± 0.2 degrees two-theta, 18.9 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 22.6 ± 0.2 degrees two-theta, 22.9 ± 0.2 degrees two-theta, 24.6 ± 0.2 degrees two-theta, 25.7 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, 26.5 ± 0.2 degrees two-theta, and 28.1 ± 0.2 degrees two-theta. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-70, characterized by an X-ray powder diffractogram substantially similar to FIG.22. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-75, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, and 20.7 ± 0.2 ppm. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-75, characterized by a13C SSNMR spectrum having peaks at 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-75, characterized by a13C SSNMR spectrum substantially similar to FIG.23. The Compound I nPA Solvate Mixture B according to any one of Embodiments 67-78, characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 6.8 ± 0.1 Å α 93.8 ± 0.1° b 10.5 ± 0.1 Å β 92.9 ± 0.1° c 16.4 ± 0.1 Å γ 105.8 ± 0.1° Compound I nPA Solvate C. The Compound I nPA Solvate C of Embodiment 80, wherein the Compound I nPA Solvate C is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I nPA Solvate C according to Embodiment 80 or 81, wherein the Compound I nPA Solvate C is substantially 100% crystalline. The Compound I nPA Solvate C according to any one of Embodiments 80-82, wherein the Compound I nPA Solvate C is 100% crystalline. The Compound I nPA Solvate C according to any one of Embodiments 80-83, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.1 ± 0.2 degrees two- theta, 11.8 ± 0.2 degrees two-theta, and 12.2 ± 0.2 degrees two-theta. . The Compound I nPA Solvate C according to Embodiment 84, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 7.2 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, and 15.8 ± 0.2 degrees two-theta. . The Compound I nPA Solvate C according to Embodiment 85, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.4 ± 0.2 degrees two-theta, 8.7 ± 0.2 degrees two-theta, and 10.2 ± 0.2 degrees two-theta. . The Compound I nPA Solvate C according to any one of Embodiments 80-83, characterized by an X-ray powder diffractogram having signals at 5.3 ± 0.2 degrees two-theta, 6.1 ± 0.2 degrees two- theta, 7.2 ± 0.2 degrees two-theta, 8.7 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 11.8 ± 0.2 degrees two-theta, 12.2 ± 0.2 degrees two-theta, 14.6 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 19.1 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, and 20.5 ± 0.2 degrees two-theta. . The Compound I nPA Solvate C according to any one of Embodiments 80-83, characterized by an X-ray powder diffractogram substantially similar to FIG.24. . Compound I Na Hemi Salt nPA Solvate. . The Compound I Na Hemi Salt nPA Solvate of Embodiment 89, wherein the Compound I Na Hemi Salt nPA Solvate is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). . The Compound I Na Hemi Salt nPA Solvate according to Embodiment 89 or 90, wherein the Compound I Na Hemi Salt nPA Solvate is substantially 100% crystalline. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-91, wherein the Compound I Na Hemi Salt nPA Solvate is 100% crystalline. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-92, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, and 14.9 ± 0.2 degrees two-theta. . The Compound I Na Hemi Salt nPA Solvate according to Embodiment 93, characterized by an X- ray powder diffractogram having one, two, or three signals selected from 13.4 ± 0.2 degrees two- theta, 17.3 ± 0.2 degrees two-theta, and 18.7 ± 0.2 degrees two-theta. . The Compound I Na Hemi Salt nPA Solvate according to Embodiment 94, characterized by an X- ray powder diffractogram having one, two or three signals selected from 5.2 ± 0.2 degrees two- theta, 8.8 ± 0.2 degrees two-theta, and 10.3 ± 0.2 degrees two-theta. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-92, characterized by an X-ray powder diffractogram having signals at 5.2 ± 0.2 degrees two-theta, 6.7 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, 10.2 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 13.4 ± 0.2 degrees two-theta, 13.6 ± 0.2 degrees two-theta, 13.7 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 14.2 ± 0.2 degrees two-theta, 14.9 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 18.7 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.0 ± 0.2 degrees two-theta, 24.6 ± 0.2 degrees two-theta, 26.4 ± 0.2 degrees two-theta, 26.6 ± 0.2 degrees two-theta, and 28.4 ± 0.2 degrees two-theta. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-92, characterized by an X-ray powder diffractogram substantially similar to FIG.25. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-97, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2 ppm, 152.1 ± 0.2 ppm, 151.1 ± 0.2 ppm, 150.4 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 144.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.4 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.5 ± 0.2 ppm, 119.6 ± 0.2 ppm, 118.8 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 114.0 ± 0.2 ppm, 111.6 ± 0.2 ppm, 65.1 ± 0.2 ppm, 62.6 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.7 ± 0.2 ppm, 26.2 ± 0.2 ppm, 24.8 ± 0.2 ppm, 21.4 ± 0.2 ppm, and 20.8 ± 0.2 ppm. . The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-97, characterized by a13C SSNMR spectrum having peaks at 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2 ppm, 152.1 ± 0.2 ppm, 151.1 ± 0.2 ppm, 150.4 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 144.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.4 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.5 ± 0.2 ppm, 119.6 ± 0.2 ppm, 118.8 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 114.0 ± 0.2 ppm, 111.6 ± 0.2 ppm, 65.1 ± 0.2 ppm, 62.6 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.7 ± 0.2 ppm, 26.2 ± 0.2 ppm, 24.8 ± 0.2 ppm, 21.4 ± 0.2 ppm, and 20.8 ± 0.2 ppm. 100. The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89-97, characterized by a13C SSNMR spectrum substantially similar to FIG.26. 101. The Compound I Na Hemi Salt nPA Solvate according to any one of Embodiments 89- 100, characterized by triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 10.3 ± 0.1 Å α 94.2 ± 0.1° b 13.3 ± 0.1 Å β 91.0 ± 0.1° c 16.7 ± 0.1 Å γ 104.0 ± 0.1° 102. Compound I nPA Solvate J. 103. The Compound I nPA Solvate J of Embodiment 102, wherein the Compound I nPA Solvate J is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). 104. The Compound I nPA Solvate J according to Embodiment 102 or 103, wherein the Compound I nPA Solvate J is substantially 100% crystalline. 105. The Compound I nPA Solvate J according to any one of Embodiments 102-104, wherein the Compound I nPA Solvate J is 100% crystalline. 106. The Compound I nPA Solvate J according to any one of Embodiments 102-105, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, and 19.0 ± 0.2 degrees two-theta. 107. The Compound I nPA Solvate J according to Embodiment 106, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.8 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 13.4 ± 0.2 degrees two-theta. The Compound I nPA Solvate J according to Embodiment 107, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 14.1 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, and 26.0 ± 0.2 degrees two-theta. The Compound I nPA Solvate J according to any one of Embodiments 102-105, characterized by an X-ray powder diffractogram having signals at 3.1 ± 0.2 degrees two-theta, 5.3 ± 0.2 degrees two-theta, 8.8 ± 0.2 degrees two-theta, 10.0 ± 0.2 degrees two-theta, 10.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.4 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 19.0 ± 0.2 degrees two-theta, 19.2 ± 0.2 degrees two-theta, 26.0 ± 0.2 degrees two-theta, and 26.4 ± 0.2 degrees two-theta. The Compound I nPA Solvate J according to any one of Embodiments 102-105, characterized by an X-ray powder diffractogram substantially similar to FIG.27. Compound I 2-MeTHF Solvate A. The Compound I 2-MeTHF Solvate A of Embodiment 111, wherein the Compound I 2- MeTHF Solvate A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I 2-MeTHF Solvate A according to Embodiment 111 or 112, wherein the Compound I 2-MeTHF Solvate A is substantially 100% crystalline. The Compound I 2-MeTHF Solvate A according to any one of Embodiments 111-113, wherein the Compound I 2-MeTHF Solvate A is 100% crystalline. The Compound I 2-MeTHF Solvate A according to any one of Embodiments 111-114, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, and 14.0 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate A according to Embodiment 115, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 9.8 ± 0.2 degrees two- theta, 10.3 ± 0.2 degrees two-theta, and 15.4 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate A according to Embodiment 116, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 17.3 ± 0.2 degrees two- theta, 19.7 ± 0.2 degrees two-theta, and 20.8 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate A according to any one of Embodiments 111-114, characterized by an X-ray powder diffractogram having signals at 5.8 ± 0.2 degrees two-theta, 9.4 ± 0.2 degrees two-theta, 9.8 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 14.0 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 18.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, 20.8 ± 0.2 degrees two-theta, 24.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate A according to any one of Embodiments 111-114, characterized by an X-ray powder diffractogram substantially similar to FIG.28. Compound I 2-MeTHF Solvate Mixture A. The Compound I 2-MeTHF Solvate Mixture A of Embodiment 120, wherein the Compound I 2-MeTHF Solvate Mixture A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I 2-MeTHF Solvate Mixture A according to Embodiment 120 or 121, wherein the Compound I 2-MeTHF Solvate Mixture A is substantially 100% crystalline. The Compound I 2-MeTHF Solvate Mixture A according to any one of Embodiments 120- 122, wherein the Compound I 2-MeTHF Solvate A is 100% crystalline. The Compound I 2-MeTHF Solvate Mixture A according to any one of Embodiments 120- 123, characterized by an X-ray powder diffractogram having a signal at 4.6 ± 0.2 degrees two- theta. The Compound I 2-MeTHF Solvate Mixture A according to Embodiment 124, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 15.8 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate Mixture A according to Embodiment 125, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 12.4 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate Mixture A according to any one of Embodiments 120- 124, characterized by an X-ray powder diffractogram having signals at 4.6 ± 0.2 degrees two-theta, 12.4 ± 0.2 degrees two-theta, 14.8 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 19.4 ± 0.2 degrees two-theta, 21.9 ± 0.2 degrees two-theta, and 25.3 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Solvate Mixture A according to any one of Embodiments 120- 124, characterized by an X-ray powder diffractogram substantially similar to FIG.29. Compound I 2-MeTHF Mixture C. The Compound I 2-MeTHF Mixture C of Embodiment 129, wherein the Compound I 2- MeTHF Mixture C is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I 2-MeTHF Mixture C according to Embodiment 129 or 130, wherein the Compound I 2-MeTHF Mixture C is substantially 100% crystalline. The Compound I 2-MeTHF Mixture C according to any one of Embodiments 129-131, wherein the Compound I 2-MeTHF Mixture C is 100% crystalline. The Compound I 2-MeTHF Mixture C according to any one of Embodiments 129-132, characterized by an X-ray powder diffractogram having a signal at 4.9 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Mixture C according to Embodiment 133, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.2 ± 0.2 degrees two- theta, 17.2 ± 0.2 degrees two-theta, and 18.5 ± 0.2 degrees two-theta. The Compound I 2-MeTHF Mixture C according to Embodiment 134, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 15.3 ± 0.2 degrees two- theta, 15.8 ± 0.2 degrees two-theta, and 23.1 ± 0.2 degrees two-theta. . The Compound I 2-MeTHF Mixture C according to any one of Embodiments 129-132, characterized by an X-ray powder diffractogram having signals at 4.9 ± 0.2 degrees two-theta, 8.2 ± 0.2 degrees two-theta, 10.3 ± 0.2 degrees two-theta, 11.3 ± 0.2 degrees two-theta, 15.3 ± 0.2 degrees two-theta, 15.7 ± 0.2 degrees two-theta, 15.8 ± 0.2 degrees two-theta, 17.2 ± 0.2 degrees two-theta, 18.5 ± 0.2 degrees two-theta, 19.6 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 23.1 ± 0.2 degrees two-theta, 25.0 ± 0.2 degrees two-theta, and 25.2 ± 0.2 degrees two-theta.. The Compound I 2-MeTHF Mixture C according to any one of Embodiments 129-1329, characterized by an X-ray powder diffractogram substantially similar to FIG.30. . Compound I Mandelic Acid Cocrystal. . The Compound I Mandelic Acid Cocrystal of Embodiment 138, wherein the Compound I Mandelic Acid Cocrystal is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). . The Compound I Mandelic Acid Cocrystal according to Embodiment 138 or 139, wherein the Compound I Mandelic Acid Cocrystal is substantially 100% crystalline. . The Compound I Mandelic Acid Cocrystal according to any one of Embodiments 138-140, wherein the Compound I Mandelic Acid Cocrystal is 100% crystalline. . The Compound I Mandelic Acid Cocrystal according to any one of Embodiments 138-141, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta. . The Compound I Mandelic Acid Cocrystal according to Embodiment 142, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, and 18.8 ± 0.2 degrees two-theta. . The Compound I Mandelic Acid Cocrystal according to Embodiment 143, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, and 20.9 ± 0.2 degrees two-theta. . The Compound I Mandelic Acid Cocrystal according to any one of Embodiments 138-141, characterized by an X-ray powder diffractogram having signals at 6.6 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 13.3 ± 0.2 degrees two-theta, 15.9 ± 0.2 degrees two-theta, 17.6 ± 0.2 degrees two-theta, 18.8 ± 0.2 degrees two-theta, 20.9 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta. . The Compound I Mandelic Acid Cocrystal according to any one of Embodiments 138-141, characterized by an X-ray powder diffractogram substantially similar to FIG.31. . Compound I Oxalic Acid Cocrystal. . The Compound I Oxalic Acid Cocrystal of Embodiment 147, wherein the Compound I Oxalic Acid Cocrystal is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). . The Compound I Oxalic Acid Cocrystal according to Embodiment 147 or 148, wherein the Compound I Oxalic Acid Cocrystal is substantially 100% crystalline. . The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-149, wherein the Compound I Oxalic Acid Cocrystal is 100% crystalline. . The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-150, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.9 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, and 14.5 ± 0.2 degrees two-theta. . The Compound I Oxalic Acid Cocrystal according to Embodiment 151, characterized by an X-ray powder diffractogram having one or two signals selected from 5.7 ± 0.2 degrees two-theta and 20.1 ± 0.2 degrees two-theta. . The Compound I Oxalic Acid Cocrystal according to Embodiment 152, characterized by an X-ray powder diffractogram having one, two or three signals selected from 10.6 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, and 22.9 ± 0.2 degrees two-theta. . The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-150, characterized by an X-ray powder diffractogram having signals at 5.7 ± 0.2 degrees two-theta, 8.9 ± 0.2 degrees two-theta, 10.6 ± 0.2 degrees two-theta, 11.6 ± 0.2 degrees two-theta, 13.8 ± 0.2 degrees two-theta, 14.5 ± 0.2 degrees two-theta, 20.1 ± 0.2 degrees two-theta, and 22.9 ± 0.2 degrees two-theta. The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-150, characterized by an X-ray powder diffractogram substantially similar to FIG.32. The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-155, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2 ppm, 162.4 ± 0.2 ppm, 161.5 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.7 ± 0.2 ppm, 149.3 ± 0.2 ppm, 148.0 ± 0.2 ppm, 146.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 134.9 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.9 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.1 ± 0.2 ppm, 117.7 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 29.3 ± 0.2 ppm, and 17.9 ± 0.2 ppm. The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-155, characterized by a13C SSNMR spectrum having peaks at 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2 ppm, 162.4 ± 0.2 ppm, 161.5 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.7 ± 0.2 ppm, 149.3 ± 0.2 ppm, 148.0 ± 0.2 ppm, 146.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 134.9 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.9 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.1 ± 0.2 ppm, 117.7 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 29.3 ± 0.2 ppm, and 17.9 ± 0.2 ppm. The Compound I Oxalic Acid Cocrystal according to any one of Embodiments 147-155, characterized by a13C SSNMR spectrum substantially similar to FIG.33. Compound I TFA Salt A. The Compound I TFA Salt A of Embodiment 159, wherein the Compound I TFA Salt A is substantially crystalline (i.e., wherein less than 15% of Compound I is in amorphous form, wherein less than 10% of Compound I is in amorphous form, wherein less than 5% of Compound I is in amorphous form). The Compound I TFA Salt A according to Embodiment 159 or 160, wherein the Compound I TFA Salt A is substantially 100% crystalline. The Compound I TFA Salt A according to any one of Embodiments 159-161, wherein the Compound I TFA Salt A is 100% crystalline. The Compound I TFA Salt A according to any one of Embodiments 159-162, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 8.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta. 164. The Compound I TFA Salt A according to Embodiment 163, characterized by an X-ray powder diffractogram having one or two signals selected from 4.4 ± 0.2 degrees two-theta and 11.4 ± 0.2 degrees two-theta. 165. The Compound I TFA Salt A according to Embodiment 164, characterized by an X-ray powder diffractogram having one, two or three signals selected from 17.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, and 26.3 ± 0.2 degrees two-theta. 166. The Compound I TFA Salt A according to any one of Embodiments 159-162, characterized by an X-ray powder diffractogram having signals at 4.4 ± 0.2 degrees two-theta, 8.4 ± 0.2 degrees two-theta, 11.4 ± 0.2 degrees two-theta, 15.1 ± 0.2 degrees two-theta, 17.3 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 20.4 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, and 26.3 ± 0.2 degrees two-theta. 167. The Compound I TFA Salt A according to any one of Embodiments 159-162, characterized by an X-ray powder diffractogram substantially similar to FIG.34. 168. The Compound I TFA Salt A according to any one of Embodiments 159-167, characterized by a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 171.9 ± 0.2 ppm, 169.2 ± 0.2 ppm, 160.7 ± 0.2 ppm, 159.5 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.8 ± 0.2 ppm, 136.1 ± 0.2 ppm, 133.7 ± 0.2 ppm, 132.1 ± 0.2 ppm, 131.0 ± 0.2 ppm, 118.1 ± 0.2 ppm, 116.0 ± 0.2 ppm, 113.0 ± 0.2 ppm, 36.6 ± 0.2 ppm, 31.3 ± 0.2 ppm, and 18.4 ± 0.2 ppm. 169. The Compound I TFA Salt A according to any one of Embodiments 159-167, characterized by a13C SSNMR spectrum having peaks at 171.9 ± 0.2 ppm, 169.2 ± 0.2 ppm, 160.7 ± 0.2 ppm, 159.5 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.8 ± 0.2 ppm, 136.1 ± 0.2 ppm, 133.7 ± 0.2 ppm, 132.1 ± 0.2 ppm, 131.0 ± 0.2 ppm, 118.1 ± 0.2 ppm, 116.0 ± 0.2 ppm, 113.0 ± 0.2 ppm, 36.6 ± 0.2 ppm, 31.3 ± 0.2 ppm, and 18.4 ± 0.2 ppm. 170. The Compound I TFA Salt A according to any one of Embodiments 159-167, characterized by a13C SSNMR spectrum substantially similar to FIG.35. 171. A pharmaceutical composition comprising the Compound I according to any one of Embodiments 1-170. 172. The pharmaceutical composition according to Embodiment 171, further comprising one or more additional therapeutic agents. 173. The Compound I according to any one of Embodiments 1-170, or the pharmaceutical composition according to Embodiment 198 or 199, for use in treating or lessening the severity in a subject of pain. 174. The Compound I or pharmaceutical composition for use according to Embodiment 173, wherein the pain comprises chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. 175. The Compound I or pharmaceutical composition for use according to Embodiment 174, wherein the pain comprises neuropathic pain. 176. The Compound I or pharmaceutical composition for use according to Embodiment 175, wherein the neuropathic pain comprises post-herpetic neuralgia. 177. The Compound I or pharmaceutical composition for use according to Embodiment 175, wherein the neuropathic pain comprises small-fiber neuropathy. 178. The Compound I or pharmaceutical composition for use according to Embodiment 175, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 179. The Compound I or pharmaceutical composition for use according to Embodiment 175, wherein the neuropathic pain comprises diabetic neuropathy. 180. The Compound I or pharmaceutical composition for use according to Embodiment 179, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 181. The Compound I or pharmaceutical composition for use according to Embodiment 173, wherein the pain comprises musculoskeletal pain. 182. The Compound I or pharmaceutical composition for use according to Embodiment 181, wherein the musculoskeletal pain comprises osteoarthritis pain. 183. The Compound I or pharmaceutical composition for use according to Embodiment 173, wherein the pain comprises acute pain. 184. The Compound I or pharmaceutical composition for use according to Embodiment 183, wherein the acute pain comprises acute post-operative pain. 185. The Compound I or pharmaceutical composition for use according to Embodiment 173, wherein the pain comprises postsurgical pain. 186. The Compound I or pharmaceutical composition for use according to Embodiment 185, wherein the postsurgical pain comprises bunionectomy pain. 187. The Compound I or pharmaceutical composition for use according to Embodiment 185, wherein the postsurgical pain comprises abdominoplasty pain. 188. The Compound I or pharmaceutical composition for use according to Embodiment 185, wherein the postsurgical pain comprises herniorrhaphy pain. 189. The Compound I or pharmaceutical composition for use according to Embodiment 173, wherein the pain comprises visceral pain. 190. The Compound I or pharmaceutical composition for use according to any one of Embodiments 173-189, wherein the Compound or pharmaceutical composition is for administration in combination with one or more additional therapeutic agents. 191. The Compound I or pharmaceutical composition for use according to Embodiment 190, wherein the one or more additional therapeutic agents comprise one or more additional pain modulating compounds. 192. Use of the Compound I according to any one of Embodiments 1-170, or the pharmaceutical composition according to Embodiment 171 or 172, in the manufacture of a medicament for treating or lessening the severity in a subject of pain. 193. The use according to Embodiment 192, wherein the pain comprises chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. 194. The use according to Embodiment 193, wherein the pain comprises neuropathic pain. 195. The use according to Embodiment 194, wherein the neuropathic pain comprises post- herpetic neuralgia. 196. The use according to Embodiment 194, wherein the neuropathic pain comprises small-fiber neuropathy. 197. The use according to Embodiment 194, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 198. The use according to Embodiment 194, wherein the neuropathic pain comprises diabetic neuropathy. 199. The use according to Embodiment 198, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 200. The use according to Embodiment 193, wherein the pain comprises musculoskeletal pain. 201. The use according to Embodiment 200, wherein the musculoskeletal pain comprises osteoarthritis pain. 202. The use according to Embodiment 193, wherein the pain comprises acute pain. 203. The use according to Embodiment 202, wherein the acute pain comprises acute post- operative pain. 204. The use according to Embodiment 193, wherein the pain comprises postsurgical pain. 205. The use according to Embodiment 204, wherein the postsurgical pain comprises bunionectomy pain. 206. The use according to Embodiment 204, wherein the postsurgical pain comprises abdominoplasty pain. 207. The use according to Embodiment 204, wherein the postsurgical pain comprises herniorrhaphy pain. 208. The use according to Embodiment 193, wherein the pain comprises visceral pain. 209. The use according to any one of Embodiments 192-208, wherein the medicament is for administration in combination with one or more additional therapeutic agents. 210. The use according to Embodiment 209, wherein the one or more additional therapeutic agents comprise one or more additional pain modulating compounds. 211. A method of treating or lessening the severity in a subject of pain comprising administering the Compound I according to any one of Embodiments 1-170, or the pharmaceutical composition according to Embodiment 171 or 172, to the subject. 212. The method according to Embodiment 211, wherein the pain comprises chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. 213. The method according to Embodiment 212, wherein the pain comprises neuropathic pain. 214. The method according to Embodiment 213, wherein the neuropathic pain comprises post- herpetic neuralgia. 215. The method according to Embodiment 213, wherein the neuropathic pain comprises small- fiber neuropathy. 216. The method according to Embodiment 213, wherein the neuropathic pain comprises idiopathic small-fiber neuropathy. 217. The method according to Embodiment 213, wherein the neuropathic pain comprises diabetic neuropathy. 218. The method according to Embodiment 217, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy. 219. The method according to Embodiment 212, wherein the pain comprises musculoskeletal pain. 220. The method according to Embodiment 219, wherein the musculoskeletal pain comprises osteoarthritis pain. 221. The method according to Embodiment 212, wherein the pain comprises acute pain. 222. The method according to Embodiment 221, wherein the acute pain comprises acute post- operative pain. 223. The method according to Embodiment 212, wherein the pain comprises postsurgical pain. 224. The method according to Embodiment 223, wherein the postsurgical pain comprises bunionectomy pain. 225. The method according to Embodiment 223, wherein the postsurgical pain comprises abdominoplasty pain. 226. The method according to Embodiment 223, wherein the postsurgical pain comprises herniorrhaphy pain. 227. The method according to Embodiment 212, wherein the pain comprises visceral pain. 228. The method according to any one of Embodiments 211-227, wherein the medicament is for administration in combination with one or more additional therapeutic agents. 229. The method according to Embodiment 228, wherein the one or more additional therapeutic agents comprise one or more additional pain modulating compounds. 230. A method of making Compound I Neat Form A, comprising (i) suspending Compound I amorphous material in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Neat Form A. 231. A method of making Compound I Neat Form B, comprising (i) suspending Amorphous Compound I in nitromethane to form a mixture, (ii) agitating the mixture at room temperature for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form B. 232. A method of making Compound I Neat Form C, comprising (i) suspending Compound I Neat Form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20 °C for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form C. 233. A method of making Compound I Hemi-Hydrate, comprising (i) suspending Compound I in water, (ii) shaking at 40 °C for at least 1 week, at least 2 weeks, at least three weeks, or at least 4 weeks, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Hemi-Hydrate. 234. A method of making Compound I Monohydrate, comprising (i) suspending Compound I in water, (ii) shaking at 40 °C for no more than 48 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Monohydrate. 235. A method of making Compound I Methanol Solvate, comprising (i) suspending Compound I amorphous material in methanol, (ii) shaking at 40 °C for 1 hour, and (iii) collecting the solids to afford Compound I Methanol Solvate. 236. A method of making Compound I nPA Solvate Mixture A, comprising (i) suspending Compound I nPA Solvate B and NaTFA in nPA, (ii) mixing at room temperature for 6-18 hours, (iii) collecting the solids, and (iv) air-drying for 15-45 minutes to afford Compound I nPA Solvate Mixture A. 237. A method of making Compound I nPA Solvate B, comprising (i) suspending Compound I nPA amorphous material in nPA, (ii) mixing at room temperature for 18-30 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I nPA Solvate B. 238. A method of making Compound I nPA Solvate C, comprising (i) dissolving Compound I in nPA, (ii) mixing at 90-100 °C for 1-2 hours, (iii) mixing at room temperature for 6-30 hours, and (iv) collecting the solids to afford Compound I nPA Solvate C. 239. A method of making Compound I Na Hemi Salt nPA Solvate, comprising (i) treating 2-(4- (tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6-naphthyridine-5-carbonitrile with water and TFA, (ii) mixing at 60 °C for 18-30 hours, (iii) treating the mixture with water and sodium hydroxide at room temperature, (iv) washing the mixture with aqueous sodium chloride, (v) diluting the mixture with 2-MeTHF and subsequently concentrating, (vi) treating the mixture with nPA and subsequently concentrating, (vii) heating the mixture to 90 °C and subsequently holding the mixture at 50 °C for 6-18 hours, (viii) cooling the mixture to room temperature, (ix) collecting the solids, and (s) drying under vacuum at 40 °C for 6-18 hours to afford Compound I Na Hemi Salt nPA Solvate. 240. A method of making Compound I nPA Solvate J, comprising (i) treating a mixture of Compound I and 2-MeTHF with nPA, (ii) concentrating the mixture at 20-30 °C, (iii) treating the mixture with nPA and subsequently concentrating the mixture at 20-30 °C, (iv) heating the mixture to 80-100 °, (v) cooling the mixture to room temperature over 8-16 hours, (v) collecting the solids, and (vi) drying under vacuum at 45 °C to afford Compound I nPA Solvate J. 241. A method of making Compound I 2-MeTHF Solvate A comprising (i) treating Compound I Form A with 2-MeTHF, (ii) agitating the mixture for 24 hours at about 22 °C, and (iii) isolating the solids to afford Compound I 2-MeTHF Solvate A. 242. A method of making Compound I 2-MeTHF Solvate Mixture A, comprising (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I 2-MeTHF Solvate Mixture A. 243. A method of making Compound I 2-MeTHF Solvate Mixture C, comprising (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) warming the slurry to 90 °C to dissolve solids, (iv) cooling to 25 °C, (v) collecting the solids, and (iv) drying at 50 °C to afford Compound I 2-MeTHF Solvate Mixture C. 244. A method of making Compound I Mandelic Acid Cocrystal, comprising (i) combining Compound I and Mandelic acid, (ii) diluting the mixture in DCM, (iii) agitating the mixture for at least 1 hour, (iv) collecting the resulting solid material, and (v) drying the collected solid material in a vacuum oven at 50 °C to afford Compound I Mandelic Acid Cocrystal. 245. A method of making Compound I Oxalic Acid Cocrystal, comprising (i) suspending Compound I and oxalic acid (1:1) in DCM, (ii) stirring the resulting slurry at room temperature, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I Oxalic Acid Cocrystal. 246. A method of making Compound I TFA Salt A, comprising (i) suspending Compound I in DCM, (ii) treating the suspension with TFA, (iii) stirring at room temperature for 15-45 minutes, (iv) collecting the solids, and (v) drying at room temperature to afford Compound I TFA Salt A. 247. A method of making Amorphous Compound I, comprising (i) combining Compound I and t-butanol to form a mixture, (ii) stirring the mixture at about 70 °C for about 1 hour, (iii) adding water to the mixture, (iv) freezing the mixture, and (v) isolating the solid material to afford Amorphous Compound I.

[0537] Still further embodiments of the disclosure are set out in the following numbered clauses: 1. A substantially crystalline Compound I I wherein the substantially crystalline Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Form C, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, and Compound I TFA Salt A. 2. The substantially crystalline Compound I according to Embodiment 1, wherein less than 15% of Compound I is in amorphous form. 3. The substantially crystalline Compound I according to Embodiment 1, wherein less than 10% of Compound I is in amorphous form. 4. The substantially crystalline Compound I according to Embodiment 1, wherein less than 5% of Compound I is in amorphous form. 5. The substantially crystalline Compound I according to Embodiment 1, wherein 100% of Compound I is crystalline. 6. The substantially crystalline Compound I according to any one of Embodiments 1-5, characterized by crystal lattice parameters. 7. The substantially crystalline Compound I according to any one of Embodiments 1-6, characterized by an X-ray powder diffractogram (XRPD). 8. The substantially crystalline Compound I according to any one of Embodiments 1-7, characterized by13C solid-state nuclear magnetic resonance (13C SSNMR) spectrum. 9. An amorphous Compound I I. 10. The amorphous Compound I 9, characterized by an X-ray powder diffractogram (XRPD). 11. The amorphous Compound I according to Embodiment 9 or 10, characterized by13C solid-state nuclear magnetic resonance (13C SSNMR) spectrum. 12. A pharmaceutical composition comprising the substantially crystalline Compound I according to any one of Embodiments 1-8 or the amorphous Compound I according to any one of Embodiments 9-11. 13. The pharmaceutical composition according to Embodiment 12, further comprising one or more additional therapeutic agents. 14. The substantially crystalline Compound I according to any one of Embodiments 1-8, the amorphous Compound I according to any one of Embodiments 9-11, or the pharmaceutical composition according to Embodiment 12 or 13, for use in treating or lessening the severity in a subject of pain. 15. The substantially crystalline Compound I, amorphous compound I, or pharmaceutical composition for use according to Embodiment 14, wherein the pain comprises chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. 16. Use of the substantially crystalline Compound I according to any one of Embodiments 1-8, the amorphous Compound I according to any one of Embodiments 9-11, or the pharmaceutical composition according to Embodiment 12 or 13, in the manufacture of a medicament for treating or lessening the severity in a subject of pain. 17. A method of treating or lessening the severity in a subject of pain comprising administering the substantially crystalline Compound I according to any one of Embodiments 1-8, the amorphous Compound I according to any one of Embodiments 9-11, or the pharmaceutical composition according to Embodiment 12 or 13, to the subject. 18. The compound or composition for use of Embodiment 14 or 15, the use of Embodiment 16, or the method of Embodiment 17, wherein the substantially crystalline Compound I according to any one of Embodiments 1-8, the amorphous Compound I according to any one of Embodiments 9-11, or the composition according to Embodiment 12 or 13 is administered in combination with one or more additional therapeutic agents. 19. The compound or composition for use, the use, or the method of Embodiment 18, wherein the one or more additional therapeutic agents comprise one or more additional pain modulating compounds. 20. A method of preparing a solid form of Compound I, comprising: (a) (i) suspending Compound I amorphous material in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Neat Form A; (b) (i) suspending Amorphous Compound I in nitromethane to form a mixture, (ii) agitating the mixture at room temperature for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form B; (c) (i) suspending Compound I Neat Form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20 °C for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form C; (d) (i) suspending Compound I in water, (ii) shaking at 40 °C for at least 1 week, at least 2 weeks, at least three weeks, or at least 4 weeks, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Hemi-Hydrate; (e) (i) suspending Compound I in water, (ii) shaking at 40 °C for no more than 48 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Monohydrate; (f) (i) suspending Compound I amorphous material in met...

Claims

CLAIMS What is claimed is:

1. A process for preparing Compound I: , comprising transforming a compounX2CN N to Compound I; 12wherein each of X and X are independently selected from halogen.

2. The process of claim 1, wherein transforming the compound of formula (A1) to Compound I comprises transforming the compound of formula (A1) to a compound of formula (C1): and transforming the compound of for.

3. The process of claim 2, wherein transforming the compound of formula (A1) to the compound of formula (C1) comprises contacting the compound of formula (A1) with a compound of formula (B1) or (B2):.

4. The process of claimof formula (C1) to Compound I comprises transforming the compound of formula (C1) to a compound of formula (C4): nd transforming the compound of form4p .

5. The process of any one of claims 1 to 4, further comprising transforming a compound of formula (A1-1): X2N to the compound of formula (A1).

6. The process of claim 5, further comprising transforming a compound of formula (A1-2): to the compound of formula (A1-1).

7. The process of claim 6, further comprising transforming a compound of formula (A1-3):to the compound of formula (A1-2).

8. The process of claim 7, further comprising transforming a compound of formula (A1-4): to the compound of formula (A1-3).

9. The process of claim 8, further comprising transforming a compound of formula (A1-5): to the compound of formula (A1-4).

10. The process of any one of claims 1 to 9, wherein X1and X2are both chloro.

11. A process for preparing Compound I: , comprising transforming a compounto Compound I.

12. The process of claim 11, wherein the step of transforming the compound of formula (A2) to Compound I comprises transforming the compound of formula (A2) to a compound of formula (C2): nd transforming the compound of form13. The process of claim 12, wherein the step of transforming the compound of formula (C2) to Compound I comprises transforming the compound of formula (C2) to a compound of formula (C3a): ; wherein R is C1-C6alkyl; and transforrmula (C3a) to Compound I.

14. The process of claim 11, wherein the step of the step of transforming the compound of formula (A2) to Compound I comprises transforming the compound of formula (A2) to a compound of formula (A3a): ;wherein R is C1-C6alkyl; and transforming the compound of formula (A3a) to Compound I.

15. The process of claim 14, wherein the step of transforming the compound of formula (A3a) to Compound I comprises transforming the compound of formula (A3a) to a compound of formula (C3a): ; wherein R is C1-C6alkyl; and transformula (C3a) to Compound I.

16. The process of claim 13 or 15, wherein the step of transforming the compound of formula (C3a) to Compound I comprises transforming the compound of formula (C3a) to a compound of formual (C8a): ;wherein R is C1-C6alkyl; and transforming the compound of formula (C8a) to Compound I.

17. A process for preparing Compound I: comprising transforming a compound(A3) to Compound I.

18. The process of claim 17, wherein transforming the compound of formula (A3) to Compound I comprises transforming the compound of formula (A3) to a compound of formula (C3): and transforming the compound of for .

19. The process of claim 18, wherein transforming the compound of formula (A3) to the compound of formula (C3) comprises contacting the compound of formula (A3) with a compound of formula (B1) or (B2): .

20. The process of any one o c a ms 7 to , urt er compr s ng trans orming a compound of formula (A3-1): to the compound of formula (A3).

21. The process of claim 20, further comprising transforming a compound of formula (A3-2): to the compound of formula (A3-1).

22. A process for preparing Compound I:, comprising transforming a compounto Compound I.

23. The process of claim 22, wherein the step of transforming the compound of formula (A2-1) to Compound I comprises transforming the compound of formula (A2-1) to a compound of formula (C5): ndtransforming the compound of formula (C5) to Compound I.

24. The process of claim 23, wherein transforming the compound of formula (A2-1) to the compound of formula (C5) comprises treating the compound of formula (A2-1) with a compound of formula (B1) or (B2): .

25. The process of claim 23 or 24, wherein the step of transforming the compound of formula (C5) to Compound I comprises transforming the compound of formula (C5) to a compound of formula (C2): nd transforming the compound of form26. The process of claim 25, wherein the step of transforming the compound of formula (C2) to Compound I comprises transforming the compound of formula (C2) to a compound of formula (C7): nd transforming the compound of formu a (C7) to Compound I.

27. The process of claim 23 or 24, wherein the step of transforming the compound of formula (C5) to Compound I comprises transforming the compound of formula (C5) to a compound of formula (C6): ndtransforming the compound of formula (C6) to Compound I.

28. The process of claim 27, wherein the step of transforming the compound of formula (C6) to Compound I comprises transforming the compound of formula (C6) to a compound of formula (C4):nd transforming the compound of form29. The process of claim 28, wherein the step of transforming the compound of formula (C4) to Compound I comprises transforming the compound of formula (C4) to a compound of formula (C7): nd transforming the compound of formu a (7) o ompoun .

30. The process of any one of claims 3 to 10, 19 to 21, and 24 to 29, further comprising transforming a compound of formula (B1-1): to the compound of formula (B1).

31. The process of claim 30, further comprising transforming a compound of formula (B1-2): to the compound of formula (B1-1).

32. The process of any one of claims 3 to 10, 19 to 21, and 24 to 29, further comprising transforming a compound of formula (B1-1a), (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), or (B1-1g): ,to the compound of formula (B1).

33. The process of claim 32, further comprising transforming a compound of formula (B1-2):to the compound of formula (B1-1a), (B1-1b), (B1-1c), (B1-1d), (B1-1e), (B1-1f), or (B1-1g).

34. The process of claim 31 or 33, further comprising transforming a compound of formula (B1-3): to the compound of formula (B1-2).

35. The process of any one of claims 1 to 34, further comprising transforming Compound I to a solvate of Compound I.

36. The process of claim 35, wherein the solvate of the compound of formula (I) is a compound of formula (D): .

37. The process of claim 35the solvate of Compound I to Form A of Compound I.

38. A compound selected from: , ,39. A compound selected from: , ,, wherein R is C1-C6alkyl. In some40. A compound selected from: ,42. A substantially crystalline Compound I Iwherein the substantially crystalline Compound I is selected from Compound I Neat Form A, Compound I Neat Form B, Compound I Neat Form C, Compound I hemi-hydrate, Compound I monohydrate, Compound I methanol solvate, Compound I nPA solvate mixture A, Compound I nPA solvate B, Compound I nPA solvate C, Compound I Na hemi salt nPA solvate, Compound I nPA solvate J, Compound I 2-Me THF Solvate A, Compound I 2-Me THF Solvate Mixture A, Compound I 2-Me THF Mixture C, Compound I mandelic acid cocrystal, Compound I DL-oxalic acid cocrystal, and Compound I TFA Salt A.

43. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I Neat Form A, optionally wherein Compound I Neat Form A is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.5 ± 0.2 degrees two- theta, 9.0 ± 0.2 degrees two-theta, and 10.4 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.8; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.6 ± 0.2 ppm, 178.7 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.6 ± 0.2 ppm, 169.7 ± 0.2 ppm, 168.2 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.8 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.3 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.7 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 129.7 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 113.3 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm, and 20.4 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.8 ± 0.2 ppm, 177.5 ± 0.2 ppm, 174.7 ± 0.2 ppm, 168.3 ± 0.2 ppm, 156.0 ± 0.2 ppm, 153.1 ± 0.2 ppm, 152.4 ± 0.2 ppm, 150.9 ± 0.2 ppm, 149.4 ± 0.2 ppm, 148.3 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 144.8 ± 0.2 ppm, 135.7 ± 0.2 ppm, 134.6 ± 0.2 ppm, 132.8 ± 0.2 ppm, 130.9 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.5 ± 0.2 ppm, 36.4 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.7 ± 0.2 ppm, and 20.5 ± 0.2 ppm; and / or (e) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 179.7 ± 0.2 ppm, 178.8 ± 0.2 ppm, 177.6 ± 0.2 ppm, 174.8 ± 0.2 ppm, 169.8 ± 0.2 ppm, 168.3 ± 0.2 ppm, 155.9 ± 0.2 ppm, 154.9 ± 0.2 ppm, 153.0 ± 0.2 ppm, 152.4 ± 0.2 ppm, 151.1 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.8 ± 0.2 ppm, 145.7 ± 0.2 ppm, 144.7 ± 0.2 ppm, 135.6 ± 0.2 ppm, 135.0± 0.2 ppm, 132.8 ± 0.2 ppm, 131.0 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.1 ± 0.2 ppm, 113.5 ± 0.2 ppm, 111.4, 36.3 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 20.5 ± 0.2 ppm; and / or (f) a13C SSNMR spectrum substantially similar to FIG.9A; and / or (g) a13C SSNMR spectrum substantially similar to FIG.9B (bottom trace); and / or (h) a13C SSNMR spectrum substantially similar to FIG.9B (middle trace); and / or (i) a13C SSNMR spectrum substantially similar to FIG.9B (top trace); and / or (j) a triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.0 ± 0.1 Å α 98.0 ± 0.1° b 11.2 ± 0.1 Å β 93.1 ± 0.1° c 15.9 ± 0.1 Å γ 95.8 ± 0.1° 44. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I Neat Form B, optionally wherein Compound I Neat Form B is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two- theta, 9.5 ± 0.2 degrees two-theta, and 9.8 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.10; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 176.6 ± 0.2 ppm, 174.4 ± 0.2 ppm, 169.7 ± 0.2 ppm, 157.5 ± 0.2 ppm, 152.8 ± 0.2 ppm, 151.6 ± 0.2 ppm, 150.2 ± 0.2 ppm, 149.4 ± 0.2 ppm, 147.5 ± 0.2 ppm, 145.2 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.8 ± 0.2 ppm, 133.4 ± 0.2 ppm, 132.4 ± 0.2 ppm, 131.1 ± 0.2 ppm, 130.6 ± 0.2 ppm, 115.5 ± 0.2 ppm, 114.2 ± 0.2 ppm, 113.9 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 30.9 ± 0.2 ppm, 29.1 ± 0.2 ppm, 19.8 ± 0.2 ppm, and 18.1 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.11; and / or (e) a triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.1 ± 0.1 Å α 87.6 ± 0.1° –b 11.5 ± 0.1 Å β 88.2 ± 0.1° c 15.0 ± 0.1 Å γ 88.9 ± 0.1° 45. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I Neat Form C, optionally wherein Compound I Neat Form C is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 6.0 ± 0.2 degrees two- theta, 13.9 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.12; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.9 ± 0.2 ppm, 176.5 ± 0.2 ppm, 173.9 ± 0.2 ppm, 169.3 ± 0.2 ppm, 157.8 ± 0.2 ppm, 153.9 ± 0.2 ppm, 151.5 ± 0.2 ppm, 149.8 ± 0.2 ppm, 148.4 ± 0.2 ppm, 147.8 ± 0.2 ppm, 145.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.5 ± 0.2 ppm, 133.0 ± 0.2 ppm, 131.3 ± 0.2 ppm, 130.4 ± 0.2 ppm, 115.6 ± 0.2 ppm, 115.4 ± 0.2 ppm, 114.5 ± 0.2 ppm, 114.1 ± 0.2 ppm, 111.4 ± 0.2 ppm, 36.5 ± 0.2 ppm, 36.3 ± 0.2 ppm, 31.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 20.9 ± 0.2 ppm, and 17.9 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.13; and / or (e) a triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.3 ± 0.1 Å α 84.3 ± 0.1° b 11.5 ± 0.1 Å β 68.8 ± 0.1° c 15.2 ± 0.1 Å γ 89.0 ± 0.1° and / or (f) a triclinic crystal system, a P-1 space group, and unit cell dimensions measured at 298K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 11.4 ± 0.1 Å α 84.2 ± 0.1° b 11.6 ± 0.1 Å β 69.6 ± 0.1° c 15.3 ± 0.1 Å γ 88.9 ± 0.1° 46. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I hemi-hydrate, optionally wherein Compound I hemi-hydrate is characterized by:(a) an X-ray powder diffractogram having one, two, or three signals selected from 5.1 ± 0.2 degrees two- theta, 10.2 ± 0.2 degrees two-theta, and 12.3 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.14; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.1 ± 0.2 ppm, 169.2 ± 0.2 ppm, 155.4 ± 0.2 ppm, 154.0 ± 0.2 ppm, 147.7 ± 0.2 ppm, 146.4 ± 0.2 ppm, 137.6 ± 0.2 ppm, 137.0 ± 0.2 ppm, 133.4 ± 0.2 ppm, 129.0 ± 0.2 ppm, 127.2 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.6 ± 0.2 ppm, 113.0 ± 0.2 ppm, 35.4 ± 0.2 ppm, 29.6 ± 0.2 ppm, and 21.1 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.

15.

47. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I monohydrate, optionally wherein Compound I monohydrate is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.0 ± 0.2 degrees two- theta, 10.2 ± 0.2 degrees two-theta, and 14.2 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

16.

48. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I methanol solvate, optionally wherein Compound I methanol solvate is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two- theta, 8.4 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.17; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2 ppm, 170.3 ± 0.2 ppm, 156.9 ± 0.2 ppm, 154.1 ± 0.2 ppm, 151.9 ± 0.2 ppm, 150.0 ± 0.2 ppm, 149.2 ± 0.2 ppm, 147.8 ± 0.2 ppm, 146.4 ± 0.2 ppm, 135.0 ± 0.2 ppm, 134.0 ± 0.2 ppm, 132.9 ± 0.2 ppm, 131.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 116.2 ± 0.2 ppm, 115.0 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.0 ± 0.2 ppm, 49.5 ± 0.2 ppm, 49.3 ± 0.2 ppm, 49.0 ± 0.2 ppm, 36.4 ± 0.2 ppm, 35.3 ± 0.2 ppm, 30.2 ± 0.2 ppm, 28.2 ± 0.2 ppm, 19.1 ± 0.2 ppm, and 18.8 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.18; and / or(e) a triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 12.3 ± 0.1 Å α 100.4 ± 0.1° b 14.1 ± 0.1 Å β 105.3 ± 0.1° c 14.4 ± 0.1 Å γ 107.5 ± 0.1° 49. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I nPA solvate mixture A, optionally wherein Compound I nPA solvate mixture A is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two- theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.19; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, 20.7 ± 0.2 ppm, and 11.9 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.20; and / or (e) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 176.5 ± 0.2 ppm, 175.2 ± 0.2 ppm, 171.8 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.2 ± 0.2 ppm, 150.1 ± 0.2 ppm, 147.6 ± 0.2 ppm, 144.9 ± 0.2 ppm, 143.5 ± 0.2 ppm, 142.2 ± 0.2 ppm, 135.5 ± 0.2 ppm, 134.5 ± 0.2 ppm, 132.6 ± 0.2 ppm, 131.1 ± 0.2 ppm, 117.0 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.1 ± 0.2 ppm, 64.3 ± 0.2 ppm, 63.9 ± 0.2 ppm, 36.5 ± 0.2 ppm, 29.9 ± 0.2 ppm, 25.9 ± 0.2 ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm, and 11.7 ± 0.2 ppm; and / or (f) a13C SSNMR spectrum substantially similar to FIG.21; and / or (g) a monoclinic crystal system, C2 / c space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 19.9 ± 0.1 Å α 90 b 6.9 ± 0.1 Å β 93.9 ± 0.1° c 32.6 ± 0.1 Å γ 9050. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I nPA solvate B, optionally wherein Compound I nPA solvate B is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two- theta, 8.8 ± 0.2 degrees two-theta, and 10.6 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.22; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 175.2 ± 0.2 ppm, 172.3 ± 0.2 ppm, 155.1 ± 0.2 ppm, 149.7 ± 0.2 ppm, 147.2 ± 0.2 ppm, 145.3 ± 0.2 ppm, 143.5 ± 0.2 ppm, 135.3 ± 0.2 ppm, 134.7 ± 0.2 ppm, 132.6 ± 0.2 ppm, 130.9 ± 0.2 ppm, 117.1 ± 0.2 ppm, 112.9 ± 0.2 ppm, 64.3 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.4 ± 0.2 ppm, 24.8 ± 0.2 ppm, and 20.7 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.23; and / or (e) a triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 6.8 ± 0.1 Å α 93.8 ± 0.1° b 10.5 ± 0.1 Å β 92.9 ± 0.1° c 16.4 ± 0.1 Å γ 105.8 ± 0.1° 51. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I nPA solvate C, optionally wherein Compound I nPA solvate C is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 6.1 ± 0.2 degrees two- theta, 11.8 ± 0.2 degrees two-theta, and 12.2 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

24.

52. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I Na hemi salt nPA solvate, optionally wherein Compound I Na hemi salt nPA solvate is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 6.7 ± 0.2 degrees two- theta, 14.1 ± 0.2 degrees two-theta, and 14.9 ± 0.2 degrees two-theta; and / or(b) an X-ray powder diffractogram substantially similar to FIG.25; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2 ppm, 152.1 ± 0.2 ppm, 151.1 ± 0.2 ppm, 150.4 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 144.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 135.4 ± 0.2 ppm, 134.4 ± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.5 ± 0.2 ppm, 119.6 ± 0.2 ppm, 118.8 ± 0.2 ppm, 115.9 ± 0.2 ppm, 114.4 ± 0.2 ppm, 114.0 ± 0.2 ppm, 111.6 ± 0.2 ppm, 65.1 ± 0.2 ppm, 62.6 ± 0.2 ppm, 36.5 ± 0.2 ppm, 30.7 ± 0.2 ppm, 26.2 ± 0.2 ppm, 24.8 ± 0.2 ppm, 21.4 ± 0.2 ppm, and 20.8 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.26; and / or (e) triclinic crystal system, P-1 space group, and unit cell dimensions measured at 100K on a diffractometer utilizing Cu Kαradiation (λ=1.54178 Å) of: a 10.3 ± 0.1 Å α 94.2 ± 0.1° b 13.3 ± 0.1 Å β 91.0 ± 0.1° c 16.7 ± 0.1 Å γ 104.0 ± 0.1° 53. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I nPA solvate J, optionally wherein Compound I nPA solvate J is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.3 ± 0.2 degrees two- theta, 10.4 ± 0.2 degrees two-theta, and 19.0 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

27.

54. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I 2-Me THF Solvate A, optionally wherein Compound I 2-Me THF Solvate A is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees two- theta, 9.4 ± 0.2 degrees two-theta, and 14.0 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.28.

55. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I 2-Me THF Solvate Mixture A, optionally wherein Compound I 2-Me THF Solvate Mixture A is characterized by: (a) an X-ray powder diffractogram having a signal at 4.6 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

29.

56. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I 2-Me THF Mixture C, optionally wherein Compound I 2-Me THF Mixture C is characterized by: (a) an X-ray powder diffractogram having a signal at 4.9 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

30.

57. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I mandelic acid cocrystal, optionally wherein Compound I mandelic acid cocrystal is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 6.6 ± 0.2 degrees two- theta, 10.6 ± 0.2 degrees two-theta, and 21.1 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.

31.

58. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I DL-oxalic acid cocrystal, optionally wherein Compound I DL-oxalic acid cocrystal is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 8.9 ± 0.2 degrees two- theta, 11.6 ± 0.2 degrees two-theta, and 14.5 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.32; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2 ppm, 162.4 ± 0.2 ppm, 161.5 ± 0.2 ppm, 154.3 ± 0.2 ppm, 153.7 ± 0.2 ppm, 149.3 ± 0.2 ppm, 148.0 ± 0.2 ppm, 146.4 ± 0.2 ppm, 146.1 ± 0.2 ppm, 134.9± 0.2 ppm, 133.0 ± 0.2 ppm, 132.0 ± 0.2 ppm, 130.9 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.1 ± 0.2 ppm, 117.7 ± 0.2 ppm, 114.6 ± 0.2 ppm, 112.4 ± 0.2 ppm, 36.3 ± 0.2 ppm, 29.3 ± 0.2 ppm, and 17.9 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.

33.

59. The substantially crystalline Compound according to claim 42, where the substantially crystalline Compound I is Compound I TFA Salt A, optionally wherein Compound I TFA Salt A is characterized by: (a) an X-ray powder diffractogram having one, two, or three signals selected from 8.4 ± 0.2 degrees two- theta, 15.1 ± 0.2 degrees two-theta, and 19.7 ± 0.2 degrees two-theta; and / or (b) an X-ray powder diffractogram substantially similar to FIG.34; and / or (c) a13C SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 171.9 ± 0.2 ppm, 169.2 ± 0.2 ppm, 160.7 ± 0.2 ppm, 159.5 ± 0.2 ppm, 149.1 ± 0.2 ppm, 147.4 ± 0.2 ppm, 146.8 ± 0.2 ppm, 136.1 ± 0.2 ppm, 133.7 ± 0.2 ppm, 132.1 ± 0.2 ppm, 131.0 ± 0.2 ppm, 118.1 ± 0.2 ppm, 116.0 ± 0.2 ppm, 113.0 ± 0.2 ppm, 36.6 ± 0.2 ppm, 31.3 ± 0.2 ppm, and 18.4 ± 0.2 ppm; and / or (d) a13C SSNMR spectrum substantially similar to FIG.

35.

60. An amorphous Compound I I.

61. A pharmaceutical composition comprising the substantially crystalline Compound I according to any one of claims 42 to 59 or the amorphous Compound I according to claim 60.

62. The substantially crystalline Compound I according to any one of claims 42 to 59, the amorphous Compound I according to claim 60, or the pharmaceutical composition according to claim 61, for use in treating or lessening the severity in a subject of pain, optionally wherein the pain comprises chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

63. Use of the substantially crystalline Compound I according to any one of claims 42 to 59, the amorphous Compound I according to claim 60, or the pharmaceutical composition according to claim 61, in the manufacture of a medicament for treating or lessening the severity in a subject of pain.

64. A method of treating or lessening the severity in a subject of pain comprising administering the substantially crystalline Compound I according to any one of claims 42 to 59, the amorphous Compound I according to claim 60, or the pharmaceutical composition according to claim 61, to the subject.

65. A method of preparing a solid form of Compound I, comprising: (a) (i) suspending Compound I amorphous material in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Neat Form A; (b) (i) suspending Amorphous Compound I in nitromethane to form a mixture, (ii) agitating the mixture at room temperature for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form B; (c) (i) suspending Compound I Neat Form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20 °C for about 1 hour, (iii) isolating the solids from the mixture, and (iv) drying the solids in an oven for about 72 hours to afford Compound I Neat Form C; (d) (i) suspending Compound I in water, (ii) shaking at 40 °C for at least 1 week, at least 2 weeks, at least three weeks, or at least 4 weeks, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Hemi-Hydrate; (e) (i) suspending Compound I in water, (ii) shaking at 40 °C for no more than 48 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I Monohydrate; (f) (i) suspending Compound I amorphous material in methanol, (ii) shaking at 40 °C for 1 hour, and (iii) collecting the solids to afford Compound I Methanol Solvate; (g) (i) suspending Compound I nPA Solvate B and NaTFA in nPA, (ii) mixing at room temperature for 6-18 hours, (iii) collecting the solids, and (iv) air-drying for 15-45 minutes to afford Compound I nPA Solvate Mixture A; (h) (i) suspending Compound I nPA amorphous material in nPA, (ii) mixing at room temperature for 18-30 hours, (iii) collecting the solids, and (iv) drying under vacuum at 40 °C to afford Compound I nPA Solvate B; (i) (i) dissolving Compound I in nPA, (ii) mixing at 90-100 °C for 1-2 hours, (iii) mixing at room temperature for 6-30 hours, and (iv) collecting the solids to afford Compound I nPA Solvate C;(j) (i) treating 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6-naphthyridine-5-carbonitrile with water and TFA, (ii) mixing at 60 °C for 18-30 hours, (iii) treating the mixture with water and sodium hydroxide at room temperature, (iv) washing the mixture with aqueous sodium chloride, (v) diluting the mixture with 2-MeTHF and subsequently concentrating, (vi) treating the mixture with nPA and subsequently concentrating, (vii) heating the mixture to 90 °C and subsequently holding the mixture at 50 °C for 6-18 hours, (viii) cooling the mixture to room temperature, (ix) collecting the solids, and (s) drying under vacuum at 40 °C for 6-18 hours to afford Compound I Na Hemi Salt nPA Solvate; (k) (i) treating a mixture of Compound I and 2-MeTHF with nPA, (ii) concentrating the mixture at 20-30 °C, (iii) treating the mixture with nPA and subsequently concentrating the mixture at 20-30 °C, (iv) heating the mixture to 80-100 °, (v) cooling the mixture to room temperature over 8-16 hours, (v) collecting the solids, and (vi) drying under vacuum at 45 °C to afford Compound I nPA Solvate J; (l) (i) treating Compound I Form A with 2-MeTHF, (ii) agitating the mixture for 24 hours at about 22 °C, and (iii) isolating the solids to afford Compound I 2-MeTHF Solvate A; (m) (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I 2-MeTHF Solvate Mixture A; (n) (i) obtaining a solution of Compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) warming the slurry to 90 °C to dissolve solids, (iv) cooling to 25 °C, (v) collecting the solids, and (iv) drying at 50 °C to afford Compound I 2-MeTHF Solvate Mixture C; (o) (i) combining Compound I and Mandelic acid, (ii) diluting the mixture in DCM, (iii) agitating the mixture for at least 1 hour, (iv) collecting the resulting solid material, and (v) drying the collected solid material in a vacuum oven at 50 °C to afford Compound I Mandelic Acid Cocrystal; (p) (i) suspending Compound I and oxalic acid (1:1) in DCM, (ii) stirring the resulting slurry at room temperature, (iii) collecting the solids, and (iv) drying under vacuum at 50 °C to afford Compound I Oxalic Acid Cocrystal; (q) (i) suspending Compound I in DCM, (ii) treating the suspension with TFA, (iii) stirring at room temperature for 15-45 minutes, (iv) collecting the solids, and (v) drying at room temperature to afford Compound I TFA Salt A; or (r) (i) combining Compound I and t-butanol to form a mixture, (ii) stirring the mixture at about 70 °C for about 1 hour, (iii) adding water to the mixture, (iv) freezing the mixture, and (v) isolating the solid material to afford Amorphous Compound I.

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