Methods of making compounds and solid forms thereof for the treatment of pain

Abstract

Disclosed are methods for preparing Compound I, as well as pharmaceutically acceptable salts and solvates thereof, pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms of Compound I, pharmaceutical compositions comprising the pharmaceutically acceptable solid forms of Compound I, methods of using the pharmaceutically acceptable solid forms of Compound I to treat pain, and processes (I) for preparing the pharmaceutically acceptable solid forms of Compound I.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefits 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 herein by reference in its entirety. Technical Field

[0003] This article discloses the preparation of voltage-gated sodium channels (Na... v Methods for using inhibitors, their solid forms, pharmaceutical compositions thereof, methods for using them to treat pain, and methods for preparing solid forms. Background Technology

[0004] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevents further damage to injured tissue. However, in many cases, pain persists beyond its effectiveness, or the patient would benefit from pain suppression. Acute pain and chronic pain are two common pain states and can be distinguished by the duration of pain. Acute pain can arise from many causes (e.g., hospital procedures), and treatment options are often limited by adverse effects and / or adverse events. Like acute pain, chronic pain can arise from many causes, and treatment options are limited by adverse effects and / or adverse events.

[0005] Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP et al., Incidence rates and treatment of neuropathic pain conditions in the general population). [Pain (…)] Pain (》, 2008.137(3): 681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by individual nerve damage. Metabolic neuropathy includes postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for individual nerve damage include post-amputation pain, postoperative nerve injury pain, and nerve entrapment injury, such as neuropathic back pain.

[0006] Voltage-gated sodium channel (Na V This involves pain signal transmission. VMediates the rapid ascending stroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes), and is therefore a biological mediator of electrical signal transduction (Hille, Bertil, excitable membrane ion channels). Ion Channels of Excitable Membranes (Sinauer Associates, Inc., Sunderland, MA, 2001), 3rd Edition. Evidence for the role of these channels in normal physiology, pathological conditions caused by sodium channel gene mutations, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all indicate that Na... V Central role in pain sensation (Rush, AM, and TR Cummins, Pain Research: Identifying a selective target for Na V Small molecule inhibitors of the 1,8 sodium channel ( Painful Research: Identification of a Small- Molecule Inhibitor that Selectively Targets Na V 1.8 Sodium Channels ). Molecular Intervention (Mol. Interv.), 2007. 7(4): 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Research Drug Expert Opinion ( Expert Opinion. Investigation. Drugs )》 17(12), pp. 1849-64 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Contemporary Pharmacological Perspectives ( Curr. Opin. Pharmacol. )》 8 (1), pp. 50-56 (2008)). Due to Na V Its role in the initiation and propagation of neuronal signals, reducing Na+ V Current antagonists can prevent or reduce nerve signal transmission, and Na... VChannels have been considered potential targets for pain relief under conditions of observed overexcitability (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders). [CNS and Neurological Disorders - Drug Targets] CNS Neurol. Disord. Drug Targets )》7(2), pp. 144-58 (2008). Several clinically applicable analgesics have been identified as Na V Inhibitors of the Na+ channel. Local anesthetics (such as lidocaine) work by inhibiting Na+ channels. V Blocking sodium channels can cause pain, and other compounds that have been shown to effectively reduce pain (such as carbamazepine, lamotrigine, and tricyclic antidepressants) have also been shown to work by inhibiting sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action). European Journal of Pain ( Eur. J. Pain )》Supplement 6A, pp. 3-9 (2002); Wang, GK, Mitchell, J. and Wang, SY, The effects of antidepressants sertraline and paroxetine on persistent late-night nausea + Block of persistent late Na + Currents by antidepressant sertraline and paroxetine. (Journal of Membrane Biology) J. Membr. Biol. )》 222 (2), pp. 79-90 (2008)).

[0007] Na V A subfamily of voltage-gated ion channels is formed, including one named Na. V 1.1 to Na V Nine isoforms of 1.9. These nine isoforms have different tissue localizations. Na V 1.4 is the main sodium channel in skeletal muscle, and Na V 1.5 is the main sodium channel in cardiomyocytes. V 1.7, 1.8, and 1.9 are mainly located in the peripheral nervous system, while Na... V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in the central and peripheral nervous systems. The nine isotypes share similar functional properties, but differ in details of their voltage dependence and kinetic properties (Catterall, WA, Goldin, AL, and Waxman, SG, *International Union of Pharmacology*, XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels, *Pharmacological Reviews*). Pharmacol. Rev. )》 57 (4), page 397 (2005)).

[0008] After its discovery, Na V Channel 1.8 was identified as a potential target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons). (Nature) Nature ( )》, 1996. 379(6562): pp. 257-62). Since then, Na V 1.8 shows that it is a sodium current carrier that maintains the firing of action potentials in dorsal root ganglion (DRG) neurons (Blair, NT and BP Bean, tetrodotoxin (TTX) sensitive Na). + Current, resistance to TTX Na + Current and Ca 2+ The role of electrical current in the action potentials of nociceptive sensory neurons (Roles of tetrodotoxin (TTX)-sensitive Na) + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials ofnociceptive sensory neurons ）. Journal of Neuroscience J. Neurosci. )》, 2002. 22(23): pp. 10277-90). NaV 1.8 Spontaneous firing in damaged neurons (such as those driving neuropathic pain) (Roza, C. et al., Na+ against tetrodotoxin) + Channel Na V 1.8 is crucial for the spontaneous expression of damaged sensory axons in mice (The tetrodotoxin-resistant Na+). + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice ）. Journal of Physiology J. Physiol. )》, 2003. 550(Part 3): 921-6; Jarvis, MF et al., A-803467, A potent selective Na V 1.8 Sodium channel blockers can alleviate neuropathic and inflammatory pain in rats (A-803467, apotent and selective Na+). V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. (Proceedings of the National Academy of Sciences of the United States of America) Proc. Natl. Acad. Sci. USA), 2007. 104(20): 8520-5; Joshi, SK et al., Anti-TTX sodium channel Na V 1.8 It is associated with inflammatory and neuropathic pain states, but not with postoperative pain states (Involvement of the TTX-resistant sodium channel Na) V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. *Pain*, 2006. 123(1-2): 75-82; Lai, J. et al., by reducing the sodium channel Na2 of anti-tetrodotoxin. V 1.8 expression inhibits neuropathic pain (Na) V1.8). Pain, 2002. 95(1-2): 143-52; Dong, XW et al., Small interfering RNA-mediated Na V 1.8 Small interfering RNA-mediated selective knockdown of Na+ channels reverses mechanical aberration pain in neuropathy rats. V 1.8 tetrodotoxin-resistantsodium channel reverses mechanical allodynia in neuropathic rats)》 . Neuroscience Neuroscience Huang, HL et al., 2007. 146(2): 812-21; Proteomic profiling of neurons reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. . Molecular Pain Mol. Pain ), 2008. 4: p. 33; Black, JA et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Annals of Neurology, ... Ann. Neurol. )》, 2008. 64(6): 644-53; Coward, K. et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states .Pain, 2000. 85(1-2): 41-50; Yiangou, Y. et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. . European Federation of Biochemical Societies Letters FEBS Lett. )》, 2000. 467(2-3): pp. 249-52; Ruangsri, S. et al., Axon voltage-gated sodium channel 1.8 (Na V 1.8) Relationship of mRNA accumulation and painful neuropathy induced by sciatic nerve injury in rats (Relationship of axonal voltage-gated sodium channel 1.8 (Na) V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats ） Journal of Biochemistry J. Biol. Chem .)》 286(46): Pages 39836-47). Expressing Na V The 1.8-inch small DRG neurons include nociceptors involved in pain signal transduction, in which Na V 1.8 Mediating large-amplitude action potentials (Blair, NT and BP bean, tetrodotoxin (TTX) sensitivity Na) + Current, resistance to TTX Na + Current and Ca 2+ The role of electrical current in the action potentials of nociceptive sensory neurons (Roles of tetrodotoxin (TTX)-sensitive Na) + current, TTX-resistant Na + current, and Ca 2+ (current in the action potentials of nociceptive sensory neurons). Journal of Neuroscience ( J. Neurosci .)》, 2002. 22(23): pp. 10277-90). Na V1.8 is essential for rapid repetitive action potentials in pain receptors and for spontaneous activity in damaged neurons. (Choi, JS and SG Waxman, Na) V 1.7 and Na V 1.8 Physiological interactions between sodium channels: a computer simulation study V 1.7 and Na V 1.8 sodium channels: acomputer simulation study) . Journal of Neurophysiology J. Neurophysiol. )》106(6): Pages 3173-84; Renganathan, M., TR Cummins and SG Waxman, Contribution of Na(V)1.8 sodium channels to the generation of action potentials in DRG neurons V )1.8 sodium channels to actionpotential electrogenesis in DRG neurons). Journal of Neurophysiology, 2001. 86(2): 629-40; Roza, C. et al., Na + Channel Na V 1.8 It is crucial for the spontaneous expression of damaged sensory axons in mice (The tetrodotoxin-resistant Na... + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice) . *Journal of Physiology*, 2003, 550 (Part 3): 921-96. In depolarized or damaged DRG neurons, Na... V1.8 appears to be a driver of hyperexcitability (Rush, AM et al., A single sodium channel mutation produces hyper or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences, 2006, 103(21): 8245-50). In some animal models of pain, sodium in the DRG has been shown to be a driver of hyperexcitability (Rush, AM et al., A single sodium channel mutation produces hyper or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences, 2006, 103(21): 8245-50). V 1.8 Increased mRNA expression levels (Sun, W. et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats). (Brain) Brain )》, 135(Part 2): 359-75; Strickland, IT et al., Na in different dorsal root ganglion populations innervating the rat knee joint in a model of chronic inflammatory arthritis V 1.7, Na V 1.8 and Na V 1.9 Changes in the expression of Na V 1.7, Na V 1.8 and Na V 1.9 in a distinct population of dorsalroot ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain) . European Journal of Pain Eur. J. Pain )》, 2008. 12(5): 564-72; Qiu, F. et al., Anti-tetrodotoxin sodium channel Na in dorsal root ganglia in a rat model of bone cancer pain V 1.8 and Na V 1.9 Increased expression of tetrodotoxin-resistant sodium channels Na V1.8and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain) . Neuroscience Letters Neurosci . Lett., )》 512(2):Pages 61-6).

[0009] The inventors have discovered that, for example, a poor therapeutic window (e.g., due to a lack of Na) V Due to factors such as homotypic selectivity, low potency, and / or other reasons, some voltage-gated sodium channel inhibitors have limitations as therapeutic agents. Therefore, there remains a need to develop selective voltage-gated sodium channel inhibitors, such as selective Na+... V 1.8 Inhibitor.

[0010] Compound I, 2-(4-tert-butyl-5-chloro-2-methyl-phenyl)-4-oxo-1 H -1,6-Naphthyl-5-carboxamide is Na v Inhibitors, and therefore can be used to treat pain. Compound I has the following structure:

[0011] .

[0012] 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 control over the form of the active ingredient may be desired or even necessary. For compounds intended for use in pharmaceuticals, reproducible methods for producing compounds in specific forms with high purity may be desired, as different forms can have different properties. For example, different solid (e.g., crystalline or amorphous) forms can have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystal forms disclosed herein may exhibit higher levels of purity, chemical stability, and / or physical stability compared to the forms produced in PCT / US2023 / 066065. Certain crystal forms (e.g., the crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate forms of Compound I (collectively, the “crystal forms”)) may exhibit lower hygroscopicity compared to any previously existing forms. Therefore, the solid (e.g., crystalline or amorphous) form of this disclosure can provide advantages over the amorphous form produced in PCT / US2023 / 066065 during the manufacture, storage, and handling of pharmaceutical substances. Thus, the pharmaceutically acceptable solid (e.g., crystalline or amorphous) form of Compound I can be particularly used to produce medicaments for the treatment of pain.

[0013] Furthermore, there is still a need for more efficient methods to synthesize compound I, such as delivering this compound or its pharmaceutically acceptable salt in higher yields, with higher selectivity and / or higher purity compared to known methods. Summary of the Invention

[0014] On one hand, the present invention relates to a method for preparing compound I:

[0015] I

[0016] Or its solvates, tautomers, or pharmaceutically acceptable salts.

[0017] In some embodiments, the method includes, after the reaction steps described herein, adding formulas A1 and A... 1-1 A 1-2 A 1-3 A 1-4 A 1-5 A2, A 2-1 A3, A 3-1 A 3-2 B1, B 1-1 B 1-2 B 1-3 Any of compounds B2, C1, C2, and C3 may be converted into compound I or its solvate or its tautomer or pharmaceutically acceptable salt.

[0018] On the other hand, the compounds are selected from:

[0019] , , , , , , , , and

[0020] Its pharmaceutically acceptable salts and their tautomers and combinations thereof.

[0021] On the other hand, the present invention provides a solid form of compound I.

[0022] I

[0023] The solid forms of compound I include pure form A, pure form B, pure form C, hemihydrate, monohydrate, methanol solvate, mixture A of nPA solvates, nPA solvate B, nPA solvate C, Na hemihydrate nPA solvate, nPA solvate J, 2-Me THF solvate A, mixture A of 2-Me THF solvates, mixture C of 2-Me THF solvates, mandelic acid eutectic, DL-oxalic acid eutectic, TFA salt A, and amorphous compound I.

[0024] In other respects, the present invention provides a pharmaceutical composition comprising such a solid form, the medical use of such a solid form, and a method for preparing such a solid form. Attached Figure Description

[0025] Figure 1 X-ray powder diffraction (XRPD) pattern of crystalline compound B1 is provided.

[0026] Figure 2 X-ray powder diffraction (XRPD) pattern of crystalline compound A2 is provided.

[0027] Figure 3 X-ray powder diffraction (XRPD) pattern of compound C2 form A is provided.

[0028] Figure 4 X-ray powder diffraction (XRPD) pattern of compound C2 form B is provided.

[0029] Figure 5 X-ray powder diffraction (XRPD) patterns of the compound C4 HCl salt (i.e., AcOH solvate) are provided.

[0030] Figure 6 X-ray powder diffraction (XRPD) pattern of compound C4 hydrate form A is provided.

[0031] Figure 7 X-ray powder diffraction (XRPD) pattern of compound C4 benzenesulfonate form A is provided.

[0032] Figure 8 X-ray powder diffraction (XRPD) pattern of compound I in its pure form A is provided.

[0033] Figure 9A Provides compound I in pure form A 13 solid-state NMR (SSNMR) spectrum.

[0034] Figure 9B Provides samples of compound I in pure form A under different conditions. 13 Comparison of C solid-state NMR (SSNMR) spectra.

[0035] Figure 10 X-ray powder diffraction (XRPD) pattern of compound I in its pure form B is provided.

[0036] Figure 11 Provided compound I in pure form B 13 solid-state NMR (SSNMR) spectrum.

[0037] Figure 12 X-ray powder diffraction (XRPD) pattern of compound I in its pure form C is provided.

[0038] Figure 13 Provides compound I in pure form C 13 solid-state NMR (SSNMR) spectrum.

[0039] Figure 14 An XRPD plot of the hemihydrate of compound I is provided.

[0040] Figure 15 Provided the hemihydrate of compound I 13 C SSNMR spectrum.

[0041] Figure 16 An XRPD plot of compound I monohydrate is provided.

[0042] Figure 17 XRPD plot of methanol solvate of compound I is provided.

[0043] Figure 18 Provided the methanol solvate of compound I 13 C SSNMR spectrum.

[0044] Figure 19 An XRPD plot of compound InPA solvate mixture A is provided.

[0045] Figure 20 Provided compound InPA solvate mixture A 13 C SSNMR spectrum.

[0046] Figure 21 Provided compound InPA solvate mixture A 13 C SSNMR spectrum.

[0047] Figure 22 An XRPD plot of compound InPA solvate B is provided.

[0048] Figure 23Provides the solvate B of compound InPA 13 C SSNMR spectrum.

[0049] Figure 24 An XRPD plot of compound InPA solvate C is provided.

[0050] Figure 25 XRPD plot of compound I Na semi-salt nPA solvate is provided.

[0051] Figure 26 Provides a solvate of compound I Na semi-salt nPA 13 C SSNMR spectra.

[0052] Figure 27 An XRPD plot of compound InPA solvate J is provided.

[0053] Figure 28 An XRPD plot of compound I 2-MeTHF solvate A is provided.

[0054] Figure 29 An XRPD plot of compound I 2-MeTHF solvate mixture A is provided.

[0055] Figure 30 An XRPD plot of the compound I 2-MeTHF solvate mixture C is provided.

[0056] Figure 31 XRPD images of compound I, mandelic acid eutectic, are provided.

[0057] Figure 32 XRPD images of the oxalic acid eutectic of compound I are provided.

[0058] Figure 33 Provided oxalic acid eutectic of compound I 13 C SSNMR spectrum.

[0059] Figure 34 XRPD plot of compound I TFA salt A is provided.

[0060] Figure 35 Provides the salt of compound I TFA A 13 C SSNMR spectrum.

[0061] Figure 36 XRPD plot of amorphous compound I is provided.

[0062] Figure 37 Provided amorphous compound I 13 C SSNMR spectra. Detailed Implementation

[0063] definition

[0064] The following definitions are intended to clarify, but are not limited to, the terms defined. If a particular term is not explicitly defined in this document, it should not be considered ambiguous. Rather, the term is used within the acceptable range of its meaning.

[0065] As used throughout this disclosure, "Compound I" refers to 2-[2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]-4-oxo-1 H -1,6-Naphthyl-5-carboxamide, and has the following structure:

[0066] .

[0067] Compound I and methods for preparing 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, which is incorporated herein by reference.

[0068] As used herein, when referring to the compounds described in this application, the terminology... " compound ” A molecule is a collection of molecules that have the same chemical structure except for the possibility of isotopic variations in their constituent atoms. (Terminology) " compound ” This includes a collection of such molecules, regardless of the purity of a given sample containing that collection of molecules. Therefore, the term... " compound ” This includes a collection of molecules in pure form, mixtures with one or more other substances (e.g., solutions, suspensions, colloids, or pharmaceutical compositions or dosage forms), or in hydrate, solvate, or eutectic form.

[0069] In the specification and claims, unless otherwise stated, any atom in any compound of the invention not specifically designated as a particular isotope is intended to represent any stable isotope of the specified element. In instances where atoms in any compound of the invention are not explicitly referred to as specific isotopes, no work has been done to enrich the atoms for specific isotopes, and therefore those skilled in the art will understand that such atoms may be present in a manner consistent with the natural abundance isotopic composition of the specified element.

[0070] In some embodiments, the compounds described in this application comprise each constituent atom in the approximate natural abundance isotopic composition of the specified elements.

[0071] In some embodiments, the compounds described herein and their pharmaceutically acceptable salts comprise one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the most abundant isotope of the specified element. " Isotope labeling ” (Compounds and salts). Examples of commercially available stable isotopes suitable for use in this invention include (but are not limited to) isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example, respectively. 2 H, 13 C 15 N、 18 O、 17 O and 31 P. For example, as used in the specification and claims, " H ” It refers to hydrogen and includes any stable isotopes of hydrogen, i.e. 1 H and D.

[0072] the term " Compounds followed by numbers (usually Roman numerals) ” and terminology " compound ” Followed by the same number (Roman numerals or other numerals) can be used interchangeably. For example, " Formula V compound ” and become" Compound V ” Indicates the same compound.

[0073] When referring to chemical reactions, the terminology... " reaction ” This means adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product may not necessarily be directly caused by the combination of the two reagents initially added; that is, one or more intermediates may be generated in the mixture that ultimately leads to the formation of the indicated and / or desired product.

[0074] the term " In a solvent ” When referring to a reaction, it means that the substrate and reagent are dissolved or suspended in a specified solvent or a mixture of solvents containing the specified solvent.

[0075] the term " Chromatographic purification ” Chromatographic purification refers to any purification method based on the difference in retention of the stationary phase. Chromatographic purification methods include rapid chromatography, medium-pressure liquid chromatography, preparative thin-layer chromatography, and high-performance liquid chromatography.

[0076] As used herein, terminology " Transformation ”It refers to the step of converting a first compound or salt into a second compound or salt, and to the method of converting a first compound or salt into a second compound or salt in one or more chemical steps.

[0077] the term " acid ” This refers to chemical substances with 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, and nitric acid. It also includes organic acids, such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, 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, pyridinecarboxylic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, phthalic acid, isophthalic acid, terephthalic acid, maleic acid, and malonic acid.

[0078] the term " alkali ” This refers to a conjugate acid that has a pKa greater than 7 (in water). The term includes... " Inorganic base ” Examples include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (mono-, di-, or ternary), sodium hydride, and potassium hydride. The term also includes... " Anionic organic bases ” Examples include methyllithium, butyllithium, diisopropylaminolithium, and sodium acetate. The term also includes... " neutral organic base ” For example, trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine, tri-n-pentylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8 -Dazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine, 2,3,4-trimethylpyridine, 2,4,5-trimethylpyridine, 2,5,6-trimethylpyridine, 2,4,6-trimethylpyridine, 3,4,5-trimethylpyridine and 3,5,6-trimethylpyridine.

[0079] the term " alcohol protecting group ”Protecting groups are chemical motifs suitable for protecting alcohol groups from unwanted side reactions during the synthetic process. Common protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. Other protecting groups are also well-known in the field. See, for example, PGM Wuts et al., "Protecting Groups in Green's Organic Synthesis" (…). Greene's Protective Groups in Organic Synthesis (4th edition, 2006).

[0080] the term " Remove protective groups ” This refers to the step of reacting a compound or salt containing a protecting group (e.g., an alcohol protecting group) under conditions suitable for removing the protecting group and exposing the protected moiety. For example, in the case where the compound or salt contains an alcohol protecting group, the term... " Remove protective groups ” This refers to reacting a compound or salt under conditions suitable for removing the alcohol protecting group and exposing the alcohol. The conditions used to remove various protecting groups are well known in the field. See, for example PGM Wuts et al., Protecting Groups in Green's Organic Synthesis (4th Edition, 2006).

[0081] the term " hydrogenation catalyst ” This refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of the carbon-oxygen single bond in benzyl groups. Suitable hydrogenation catalysts are well known in the art and include, for example, palladium / activated carbon, platinum oxide, and Raney nickel.

[0082] When referring to the reaction between carboxylic acids or acyl halides and amines, the terminology... " Coupling ” This refers to the net conversion of a carboxylic acid or acyl halide to an amine to form an amide. The term includes both direct reactions between carboxylic acids and amines, and reactions between activated derivatives of carboxylic acids (e.g., derivatives formed through reactions between carboxylic acids and coupling agents) and amines.

[0083] the term " Coupling reagents ”Coupling reagents are reagents suitable for reacting with carboxylic acids to activate carboxylic acids used for coupling with amines to form amide bonds. Coupling reagents are well-known in the field. They include (but are not limited to) thionyl chloride, oxaloyl 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]pyridine 3-oxide hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0084] the term " Monovalent cations ” It refers to any cation with a +1 charge, such as alkali metal cations, NH4+, etc. + and tetraalkylammonium.

[0085] the term " Alkali metal cations ” It refers to cations derived from Group I metal atoms, including (but not limited to) lithium (Li). + ), sodium (Na + ), potassium (K) + ), Rubidium (Rb + ) and cesium (Cs) + ).

[0086] the term " Substituted benzyl ” It refers to a benzyl group that is substituted by 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen and cyano groups.

[0087] the term " Ketone solvents ” It refers to having formula C n H 2n+1 C(O)C m H 2m+1 Compounds, where n and m are each independent integers between 1 and 6. C n H 2n+1 and C m H 2m+1 The groups can be straight-chain or branched, and each can be substituted by up to three halogens. Ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, 3-pentanone, and methyl tert-butyl ketone.

[0088] the term " ether solvent ”This refers to an organic solvent having at least one ether moiety. Ether solvents include, but are not limited to, tetrahydrofuran, dimethoxyethane, dioxane, and dialkyl ethers, such as diethyl ether and methyl isobutyl ether.

[0089] the term " Ester solvent ” It refers to having formula C n H 2n+1 OC(O)C m H 2m+1 Compounds, where n and m are each independent integers between 1 and 6. C n H 2n+1 and C m H 2m+1 The groups can be straight-chain or branched, and each can be substituted with up to three halogens. Ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, butyl acetate, and ethyl propionate.

[0090] the term " Halogenated solvents ” Halogenated solvents refer to C1-C6 alkanes or C2-C6 alkenes that are substituted with up to six halogens. Halogenated solvents include, but are not limited to, dichloromethane, dichloroethane, chloroform, tetrachloroethylene, and carbon tetrachloride.

[0091] the term " Aromatic solvents ” It refers to C 6-10 Aromatic hydrocarbons. Aromatic hydrocarbons can be substituted with up to six halogens. Aromatic solvents include, but are not limited to, benzene, trifluoromethylbenzene, xylene, and toluene.

[0092] the term " about ” The term "about" implies that the stated numerical value can vary by ±10%. When the term defines temperature, the stated temperature can vary by ±10%. For example, about 80°C means between 72°C and 88°C. When the term "about" defines pressure, the term implies that the pressure can vary by ±10%. Therefore, about 100 bar means between 90 bar and 110 bar. When the term defines quantity (such as equivalents or weight), the term implies that the quantity can vary by ±10%. For example, about 1 equivalent means between 0.9 and 1.1 equivalents. When the term defines time, the term implies that the stated time can vary by ±10%. For example, about 1 hour means between 0.9 and 1.1 hours.

[0093] the term " Leaving group ”It is a chemical group that is readily replaceable by the desired introduced chemical moiety. Therefore, the selection of a particular suitable leaving group is predicted based on its ability to be readily replaced by a chemical moiety introduced, such as a CN group. Suitable leaving groups are well known in the field, for example, see *Advanced Organic Chemistry*, Jerry March, 5th Supplement, pp. 351-357, John Wiley and Sons, NY.

[0094] As used herein, terminology " Cyanide ” "Reagent" refers to a reagent that can be used to synthesize the compounds disclosed herein, such as compounds A1, A2, and A3, such as trimethylsilyl cyanide (TMSCN), diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, etc. 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 (Tf2O), boron trifluoride ethyl ether (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, SnCl4, etc. In another embodiment, the Lewis acid is trifluoromethanesulfonic anhydride (Tf2O). The cyanation reaction can be carried out in organic solvents such as toluene, dichloromethane, 2-methylTHF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, etc.

[0095] As used herein, the terms “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refer to bioactive compounds.

[0096] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0097] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound that produces the desired effect of the administered compound (e.g., improvement of pain or symptoms of pain, or reduction of the severity of pain or symptoms of pain). The exact amount of an effective dose will depend on the therapeutic purpose and will be determined by someone skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0098] As used herein, the terms “treatment”, “treating,” etc., generally refer to improving a subject’s pain or one or more of its symptoms, or reducing the severity of pain or one or more of its symptoms. As used herein, “treatment” includes, but is not limited to, the following: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunion removal, hernia repair, or abdominoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia. Improvement in any of these symptoms or reduction in their severity can be readily assessed using standard methods and techniques known in the art.

[0099] As used herein, when referring to two or more compounds, agents or other active pharmaceutical ingredients, the term "in combination with" means administering two or more compounds, agents or active pharmaceutical ingredients to a patient before, at the same time as or after each other.

[0100] The terms “selected from” and “chosen from” can be used interchangeably in this article.

[0101] As used herein, the term "ambient conditions" means room temperature, outdoor conditions, and uncontrolled humidity conditions. As used herein, the terms "room temperature" and "ambient temperature" mean 15°C to 30°C.

[0102] As used herein, the term "solvent" means any liquid in which the product is at least partially soluble (the solubility of the product is > 1 g / L).

[0103] As used herein, the term “stable” means that a compound or solid form remains substantially unchanged when subjected to conditions permissible for its production, testing and preferably recovery, purification and use for one or more of the purposes disclosed herein.

[0104] As used herein, the term "chemically stable" means that the solid form of Compound I does not decompose into one or more different chemical compounds when subjected to specified conditions, such as 40°C / 75% relative humidity for a specified period of time, such as 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 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%, and less than about 0.5% of the form of Compound I decomposes under specified conditions. In some embodiments, a detectable amount of the solid form of Compound I does not decompose.

[0105] As used herein, the term "physically stable" means that the solid form of compound I does not transform into one or more different physical forms of compound I (e.g., different solid forms as measured by XRPD, DSC, etc.) when subjected to specified conditions, such as 40°C / 75% relative humidity for a specified period of time, such as 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 transforms 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%, and less than about 0.5% of the solid form of compound I transform into one or more different physical forms of compound I when subjected to specified conditions. In some embodiments, a detectable amount of the solid form of compound I does not change into one or more physically different solid forms of compound I.

[0106] As used herein, the term "hydrate" refers to any crystalline compound I containing water in its crystal lattice. The stoichiometry of hydrates of compound I can vary. For example, hydrates of compound I can be in the form of quarter-hydrate, hemihydrate, monohydrate, dihydrate, or partially dehydrated form.

[0107] As used herein, the term "pharmaceutically acceptable solid form" refers to the solid form of Compound I of this disclosure, wherein the solid form of Compound I (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) is non-toxic and suitable for pharmaceutical compositions.

[0108] As used herein, the term "amorphous" refers to a solid material that does not possess long-range order in the positions of its molecules. Amorphous solids are typically isotropic, meaning they exhibit similar properties in all directions. Amorphous solids do not have a definite melting point. Amorphous solids are typically glassy or supercooled liquids in which molecules are arranged in a random manner, such that there is no definite arrangement (e.g., molecular packing) and no long-range order. For example, an amorphous material is a solid material whose X-ray powder diffraction (XRPD) pattern does not have sharp characteristic crystalline peaks (i.e., it is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are a characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US 2004 / 0006237. In some embodiments, the solid material may comprise an amorphous compound, and said material may be characterized, for example, by the lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the material is amorphous rather than crystalline as determined by XRPD). Conversely, the XRPD plot of the material may show one or more broad peaks (e.g., halos). For a comparison of the XRPDs of amorphous and crystalline materials, see US 2004 / 0006237. Solid materials containing amorphous compounds are characterized, for example, by a wider melting temperature range compared to the melting range of purely crystalline solids. Other techniques, such as solid-state NMR, can also be used to characterize crystalline or amorphous forms.

[0109] As used herein, the terms “crystal form,” “crystal type,” and “form” are used interchangeably to refer to a crystal structure (or polymorph) having a specific molecular packing arrangement in a crystal lattice. Crystal types can be characterized by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, and... 13 C solid-state nuclear magnetic resonance (C 13 C SSNMR) can be used to identify and distinguish them from each other. Therefore, as used herein, the terms "crystal form [X] of compound (I)" and "crystal form [C] potassium salt of compound (I)" refer to those that can be identified and distinguished by one or more characterization techniques, including, for example, XRPD, single-crystal X-ray diffraction and 13 Unique crystal forms identified and distinguished from each other by C SSNMR. In some embodiments, the novel crystal form is characterized by an X-ray powder diffraction pattern having one or more signals at one or more specified degree 2θ values ​​(° 2θ).

[0110] As used herein, the term "free form" refers to the non-ionized version of a compound as a solid. Examples of free forms include free bases and free acids.

[0111] As used herein, the term "pure form" refers to the unsolvated and unhydrated free form of a compound in a solid state.

[0112] As used herein, the term "solvent" refers to a crystalline form comprising one or more molecules of a compound of the present disclosure and one or more molecules of one or more solvents incorporated in a chemimetric or non-chemimetric amount within a crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate".

[0113] As used herein, the term "hydrate" refers to any crystalline compound I containing water in its crystal lattice. The stoichiometry of a compound I hydrate can vary, meaning that compound I can be a variable hydrate. For example, a compound I hydrate can be a quarter-hydrate, a hemihydrate, a monohydrate, a dihydrate, or a partially dehydrated form.

[0114] In some embodiments, the solid material may comprise a mixture of crystalline solids and amorphous solids. Solid materials comprising amorphous compounds may also contain, for example, up to 30% crystalline solids. In some embodiments, solid materials prepared to comprise amorphous compounds may also contain, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material comprises a mixture of crystalline and amorphous solids, characterization data such as XRPD may include indications of both crystalline and amorphous solids. In some embodiments, the crystal form of this disclosure may contain up to 30% amorphous compound. In some embodiments, the crystalline formulation of compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0115] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in the positions of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10%, less than 5%, or less than 2%). It should also be noted that the term "substantially amorphous" includes the descriptive term "amorphous," which refers to a material that does not have (0%) crystallinity.

[0116] As used herein, the term "substantially crystalline" refers to a solid material having few or no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10%, less than 5%, or less than 2%). It should also be noted that the term "substantially crystalline" includes the descriptive term "crystalline," which refers to a material that is 100% crystalline.

[0117] As used herein, a crystal form is "substantially pure" when it constitutes, by weight, 90% or more of the total amount of all solid forms in a sample, as determined by methods according to this technique (such as quantitative XRPD). In some embodiments, a solid form is "substantially pure" when it constitutes, by weight, 95% or more of the total amount of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it constitutes, by weight, 99% or more of the total amount of all solid forms in a sample.

[0118] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD plot,” and “XRPD spectrum” interchangeably refer to an experimentally obtained plot of signal position (on the x-axis) versus signal intensity (on the y-axis).

[0119] As used herein, “signal” or “peak” refers to a point in an XRPD plot where the intensity, if measured in count, is at a local maximum. An XRPD peak is identified by the angle value measured in degrees 2θ (° 2θ) that it is plotted on the x-axis of the X-ray powder diffraction pattern, which may be expressed, for example, as “signal at ...° 2θ”, “signal at [one] 2θ value of ...” and / or “signal selected from at least ... 2θ values ​​of ...”.

[0120] The repeatability of the measured angle values ​​is within ±0.2° 2θ, that is, the angle values ​​can be at the listed angle values ​​+0.2° 2θ, the angle values ​​-0.2° 2θ, or any value between these two endpoints (angle values ​​+0.2° 2θ and angle values ​​-0.2° 2θ).

[0121] Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD plot may overlap and may not be apparent to the naked eye, for example. In fact, those skilled in the art will recognize that several industry-recognized methods are capable of and suitable for determining the presence of signals in the plot, such as Rietveld refinement.

[0122] The terms “signal intensity” and “peak intensity” are used interchangeably to refer to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that can affect the relative signal or peak intensity include sample thickness and preferred orientation (e.g., non-random distribution of crystalline particles).

[0123] As used herein, an X-ray powder diffraction pattern is “substantially similar to the pattern in [specific] pattern” when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the signal overlaps in two diffraction patterns. In determining “substantially similar,” those skilled in the art will understand that the intensity and / or signal position in an XRPD diffraction pattern can vary even for the same crystal form. Therefore, those skilled in the art will understand that the maximum signal value (in ° 2θ) in an XRPD diffraction pattern generally means that the value was identified as ± 0.2° 2θ of the reported value, which is an industry-recognized variance.

[0124] 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.

[0125] As used herein, the terms “melting temperature,” “melting point,” or “Tm” refer to the temperature at which the crystalline material and the liquid phase are in equilibrium.

[0126] As used herein, the term "dispersion" refers to a dispersion system in which one substance (i.e., the dispersed phase) is distributed in discrete units throughout a second substance (the continuous phase or mediator). The size of the dispersed phase can vary significantly (e.g., from nanometer-sized to several micrometer-sized colloidal particles). Typically, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In pharmaceutical applications, a solid dispersion may comprise a crystalline drug substance (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug substance (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion comprises a polymer constituting the dispersed phase and a drug substance constituting the continuous phase, or a solid dispersion comprises a drug substance constituting the dispersed phase and a polymer constituting the continuous phase.

[0127] Method for synthesizing compound I

[0128] Compound I can be prepared from known materials by the methods described herein (including examples), by other similar methods, and by other methods known to those skilled in the art. As will be understood by those skilled in the art, the functional groups of the intermediate compound may need to be protected by suitable protecting groups. Protecting groups can be added or removed according to standard techniques known to those skilled in the art. The use of protecting groups is described in detail in TGM Wuts et al. In "Protecting Groups in Organic Synthesis" (4th Edition, 2006).

[0129] In one embodiment, a technician can obtain from any form A1, A 1-1 A 1-2 A1-3 A 1-4 A 1-5 A2, A 2-1 A3, A 3-1 A 3-2 B1, B 1-1 B 1-2 B 1-3 Starting with compounds B2, C1, C2, and C3, compounds I or A1, A2, and A3 are prepared by following the reactions shown in schemes 1-11. 1-1 A 1-2 A 1-3 A 1-4 A 1-5 A2, A 2-1 A3, A 3-1 A 3-2 B1, B 1-1 B 1-2 B 1-3 Any one of the intermediate compounds B1, C2, C3, and C3.

[0130] The methods and steps described in this article can refer to formulas A1 and A. 1-1 A 1-2 A 1-3 A 1-4 A 1-5 A2, A 2-1 A3, A 3-1 A 3-2 B1, B 1-1 B 1-2 B 1-3 The transformation of starting compounds B2, C1, C2, and C3 into compound I. Those skilled in the art will understand that such methods can also be used to prepare any intermediate between any starting compound and compound I. For example, formula A... 1-2 The transformation of compound I to compound C2 involves the intermediate compound C2. Thus, those skilled in the art will understand that the description used for formula A... 1-2 The method for converting compound A into compound I can be used to convert compound A into compound I. 1-2 Compound preparation intermediate compound A 2-1 A2 and C2.

[0131] Similarly, Equation A 3-2 The transformation of compound I to compound A involves intermediate compound A. 3-1 The preparation of A3 and C3. Thus, those skilled in the art will understand that the described method for preparing formula A... 3-2 The method for converting compound A into compound I can be used to convert compound A into compound I. 3-2 Starting with compound A, prepare intermediate compound A. 3-1Any of A1, A3, and C3, or any intermediate compound, can be converted into the desired intermediate compound using the methods described herein. Therefore, this application contemplates the preparation of intermediate compounds A1, A2, and C3 from starting materials preceding any intermediate or intermediate being prepared. 1-1 A 1-2 A 1-3 A 1-4 A 1-5 A2, A 2-1 A3, A 3-1 A 3-2 B1, B 1-1 B 1-2 B 1-3 B2, C1, C2, and C3. For example, intermediate compound C2 can be derived from compound A. 1-2 A 1-3 A 1-4 A 1-5 A2, A 2-1 B1, B 1-1 B 1-2 B 1-3 Prepare starting with either B2 or B2. Similarly, compound A... 2-1 From compound A 1-2 A 1-3 A 1-4 and A 1-5 Prepare one of the following.

[0132] Option 1

[0133]

[0134] Option 2

[0135]

[0136] Option 3

[0137]

[0138] Option 4

[0139]

[0140] Option 5

[0141]

[0142] Option 6

[0143]

[0144] Option 7

[0145]

[0146] Option 8

[0147]

[0148] Option 9

[0149]

[0150] Option 10

[0151]

[0152] Option 11

[0153]

[0154] In one embodiment, this application provides a method for preparing compound I and its solvates:

[0155] ,

[0156] I

[0157] The method involves using a compound of formula (A1):

[0158]

[0159] (A1)

[0160] It is converted into compound I; where X 1 and X 2 Each of them is independently selected from halogens.

[0161] In some embodiments, X 1 and X 2 Same. In some embodiments, X 1 and X 2 Each of them is fluorine. In some embodiments, X 1 and X 2 Each of them is chlorine. In some embodiments, X 1 and X 2 Each of them is bromine. In some embodiments, X 1 and X 2 Each of them is iodine.

[0162] In some embodiments, X 1 and X 2 different.

[0163] In some embodiments, the step of converting a compound of formula (A1) to compound I includes converting a compound of formula (A1) to a compound of formula (C1):

[0164]

[0165] (C1).

[0166] In some embodiments, the step of converting the compound of formula (A1) into the compound of formula (C1) includes contacting the compound of formula (A1) with a compound of formula (B1) or (B2):

[0167] .

[0168] In some embodiments, the step of converting the compound of formula (A1) into the compound of formula (C1) includes contacting the compound of formula (A1) with the compound of formula (B1). In some embodiments, the step of converting the compound of formula (A1) into the compound of formula (C1) includes contacting the compound of formula (A1) with the compound of formula (B2).

[0169] In some embodiments, the step of contacting the compound of formula (A1) with the compound of formula (B1) or (B2) is carried out 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 hydroxide. In some embodiments, the first base is potassium carbonate.

[0172] In some embodiments, the step of converting compound (A1) to compound I further comprises converting compound (C1) to compound I. In some embodiments, the step of converting compound (C1) to compound I comprises treating compound (C1) with a first acid. In some embodiments, the first acid may be 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.

[0173] In some embodiments, the step of converting a compound of formula (C1) to compound I includes converting a compound of formula (C1) to a compound of formula (C4):

[0174] ;as well as

[0175] The compound of formula (C4) is converted into compound I. In some embodiments, the compound of formula (C4) is obtained in the form of a salt. In some embodiments, the salt is an HCl salt or a benzenesulfonate. In some embodiments, the compound of formula (C4) is obtained in the form of a solvate. In some embodiments, the solvate is an AcOH solvate. In some embodiments, the compound of formula (C4) is obtained in the form of an HCl salt (i.e., an AcOH solvate). In some embodiments, the compound of formula (C4) is obtained in the form of a hydrate.

[0176] In some embodiments, the step of converting the compound of formula (C1) to the compound of formula (C4) comprises treating the compound of formula (C1) with an acid to obtain 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, p-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 selected from dimethyl sulfoxide (DMSO), toluene, N The compound is treated with acid in a solvent of methylpyrrolidone (NMP) and 1,2-dichloroethane (DCE). In some embodiments, the compound of formula (C1) is treated with acid at a temperature of 60-100°C, for example, about 100°C. In some embodiments, the compound of formula (C1) is the limiting agent, and the acid is present in excess. In some embodiments, the compound of formula (C1) is the limiting agent, the acid is acetic acid (in excess), and the reaction is carried out at a temperature of 60-100°C, for example, about 100°C.

[0177] In some embodiments, the step of converting the compound of formula (C1) to the compound of formula (C4) comprises treating the compound of formula (C1) with a base to obtain the compound of formula (C4). In some embodiments, the base is potassium acetate. In some embodiments, the compound of formula (C1) is treated with a base in the presence of water. In some embodiments, the compound of formula (C1) is treated with a base as a solvent. N , N - Dimethylformamide is treated with a base. 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 agent, and the base is present in excess. In some embodiments, the compound of formula (C1) is the limiting agent, the base is potassium acetate (in excess), and the reaction is carried out at a temperature of 80-100°C.

[0178] In some embodiments, the compound of formula (C1) is the compound of formula (C2), i.e., X 2 It is chlorine:

[0179] .

[0180] Therefore, in these embodiments, the step of converting the compound of formula (C1) into compound I includes converting the compound of formula (C2) into compound I (see, for example, schemes 8 and 9).

[0181] In some embodiments, the step of converting compound (C2) into compound I comprises treating compound (C2) with a first acid to obtain 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.

[0182] In some embodiments, the step of converting compound (C2) into compound I includes converting compound (C2) into compound (C4):

[0183] ;as well as

[0184] The compound of formula (C4) is converted into compound I.

[0185] In some embodiments, the step of converting the compound of formula (C2) to the compound of formula (C4) comprises treating the compound of formula (C2) with an acid to obtain 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, p-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 selected from dimethyl sulfoxide (DMSO), toluene, ... N The compound (C2) is treated with acid in a solvent of methylpyrrolidone (NMP) and 1,2-dichloroethane (DCE). In some embodiments, the compound (C2) is treated with acid at a temperature of 60-100°C, for example, about 100°C. In some embodiments, the compound (C2) is the limiting agent, and the acid is present in excess. In some embodiments, the compound (C2) is the limiting agent, the acid is acetic acid (in excess), and the reaction is carried out at a temperature of 60-100°C, for example, about 100°C.

[0186] In some embodiments, the step of converting compound (C2) to compound (C4) comprises treating compound (C2) with a base to obtain compound (C4). In some embodiments, the base is potassium acetate. In some embodiments, compound (C2) is treated with a base in the presence of water. In some embodiments, compound (C2) is treated with a base as a solvent. N , N- Dimethylformamide is treated with a base. 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 agent, and the base is present in excess. In some embodiments, the compound of formula (C2) is the limiting agent, the base is potassium acetate (in excess), and the reaction is carried out at a temperature of 80-100°C.

[0187] In some embodiments, the step of converting compound (C4) to compound I comprises treating compound (C4) with an acid to obtain compound I. In some embodiments, the acid is a Brønsted acid. In some embodiments, the acid is selected from sulfuric acid, phosphoric acid, and oxalic acid. In some embodiments, compound (C4) is treated with an acid in the presence of water. In some embodiments, compound (C4) is treated with an acid in a solvent selected from toluene, acetic acid, anisole, γ-valerolactone, and sulfolane. In some embodiments, compound (C4) is treated with an acid at a temperature of 20-100°C, for example, about 60°C. In some embodiments, compound (C4) is the limiting agent, and the acid is present in excess. In some embodiments, compound (C4) is the limiting agent, the acid is sulfuric acid (in excess), and the reaction is carried out in toluene at a temperature of 20-100°C, for example, about 60°C. 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, WOCl4, VCl3, and Sc(OTf)3. In some embodiments, the compound of formula (C4) is treated with acid in the presence of water. In some embodiments, the compound of formula (C4) is treated with an acid selected from toluene, acetic acid, anisole, γ-valerolactone, sulfolane, 2-methyltetrahydrofuran, cyclopentyl methyl ether, N , N -Dimethylacetamide, isobutyl acetate, N The compound is treated with acid in a solvent or co-solvent of methylcaprolactam and water. In some embodiments, the compound of formula (C4) is treated with acid at a temperature of 20-100°C, for example, about 100°C. In some embodiments, the compound of formula (C4) is the limiting agent. In some embodiments, the compound of formula (C4) is the limiting agent, the acid is Cu(OTf)2, acetic acid is present in excess, and the reaction is carried out at a temperature of 20-100°C, for example, about 60°C.

[0188] In one embodiment, this application provides a method for preparing compound I:

[0189]

[0190] I

[0191] The method comprises using a compound of formula (A3):

[0192]

[0193] (A3)

[0194] It is converted into compound I.

[0195] In some embodiments, the step of converting compound (A3) into compound I includes converting compound (A3) into compound (C3):

[0196]

[0197] (C3).

[0198] In some embodiments, the step of converting the compound of formula (A3) into the compound of formula (C3) includes contacting the compound of formula (A3) with a compound of formula (B1) or (B2):

[0199] .

[0200] In some embodiments, the step of converting the compound of formula (A3) into the compound of formula (C3) includes contacting the compound of formula (A3) with the compound of formula (B1). In some embodiments, the step of converting the compound of formula (A3) into the compound of formula (C3) includes contacting the compound of formula (A3) with the compound of formula (B2).

[0201] In some embodiments, the step of contacting the compound of formula (A3) with the compound of formula (B1) or (B2) is carried out in the presence of a first palladium catalyst and a first base.

[0202] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the first palladium catalyst is PdCl2(dtbdpf).

[0203] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium hydroxide. In some embodiments, the first base is potassium carbonate.

[0204] In some embodiments, the step of converting compound (A3) into compound I further comprises converting compound (C3) into compound I.

[0205] In some embodiments, the step of converting compound (C3) to compound I comprises treating compound (C3) with a first acid. In some embodiments, the first acid may be 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.

[0206] On the other hand, the present invention relates to a method for preparing compound I according to scheme 12.

[0207] Option 12

[0208]

[0209] In one embodiment, the present invention relates to a method for preparing compound I:

[0210] ,

[0211] I

[0212] The method involves using a compound of formula (A2):

[0213]

[0214] (A2)

[0215] It is converted into compound I.

[0216] In some embodiments, the step of converting compound (A2) into compound I includes converting compound (A2) into compound (C2):

[0217] ;as well as

[0218] The compound of formula (C2) is converted into compound I. In some embodiments, converting the compound of formula (A2) into the compound of formula (C2) comprises treating the compound of formula (A2) with a compound of formula (B1) or (B2):

[0219] .

[0220] In some embodiments, the step of converting the compound of formula (A2) into the compound of formula (C2) includes treating the compound of formula (A2) with the compound of formula (B1). In some embodiments, the step of converting the compound of formula (A2) into the compound of formula (C2) includes treating the compound of formula (A2) with the compound of formula (B2).

[0221] In some embodiments, the step of treating compound (A2) with compound (B1) or (B2) is carried out in the presence of a first palladium catalyst and a first base.

[0222] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0223] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium hydroxide. In some embodiments, the first base is potassium carbonate.

[0224] In some embodiments, the step of converting compound (C2) into compound I includes converting compound (C2) into compound (C1). 3a Compounds:

[0225] ;

[0226] Where R is a C1-C6 alkyl group; and the formula (C 3a Compound (C2) is converted to compound I. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl. In some embodiments, compound (C2) is converted to compound (C3). 3a The compound comprises treating a compound of formula (C2) with NaOR to obtain a compound of formula (C2). 3a ) compounds. For example, in some embodiments where R is an ethyl group, compounds of formula (C2) are converted to compounds of formula (C3). 3a The compound comprises a compound of formula (C2) treated with NaOEt in ethanol at room temperature. In some embodiments, the compound of formula (C2) is converted to a compound of formula (C... 3a The compound contains compounds of formula (C2) that have been treated with ROH and acetic acid at high temperatures, such as 80-100°C.

[0227] In some embodiments, the step of converting compound (A2) into compound I includes converting compound (A2) into compound (A2). 3a Compounds:

[0228] ;

[0229] Where R is a C1-C6 alkyl group; and formula (A) 3a Compound (A2) is converted to compound I. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl. In some embodiments, compound (A2) is converted to compound (A... 3a The compound comprises treating a compound of formula (A2) with NaOR to obtain a compound of formula (A2). 3a ) compound. For example, in some embodiments where R is ethyl, the compound of formula (A2) is converted to the compound of formula (A) 3a The compound comprises a compound of formula (A2) treated with NaOEt in ethanol at room temperature. In some embodiments, the compound of formula (A2) is converted to a compound of formula (A... 3a The compound contains compounds of formula (A2) that have been treated with ROH and acetic acid at high temperatures, such as 80-100°C.

[0230] In some embodiments, formula (A) 3a The step of converting compound I to compound A involves converting compound A into compound I. 3a ) compounds are converted into formula (C 3a Compounds:

[0231] ;

[0232] Where R is a C1-C6 alkyl group; and the formula (C 3a Compound I is converted to compound A. In some embodiments, the compound of formula (A) is converted to compound I. 3a The compound is converted into the formula (C) 3a The compound contains compounds of formula (B1) or (B2) treated with formula (A). 3a Compounds:

[0233] .

[0234] In some embodiments, the formula (A) 3a The compound is converted into the formula (C) 3a The steps of compounding a compound include treating the compound of formula (A) with a compound of formula (B1). 3a ) compound. In some embodiments, the compound of formula (A) is used. 3a The compound is converted into the formula (C) 3a The steps of compounding a compound include treating the compound of formula (A) with a compound of formula (B2). 3a ) compounds.

[0235] In some embodiments, formula (A) is treated with a compound of formula (B1) or (B2). 3a The compounding process is carried out in the presence of a first palladium catalyst and a first base.

[0236] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0237] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium hydroxide. In some embodiments, the first base is potassium carbonate.

[0238] In some embodiments, formula (C) 3a The step of converting compound I to compound C involves converting compound I into compound C. 3a ) compounds are converted into formula (C 8a Compounds:

[0239] ;

[0240] Where R is a C1-C6 alkyl group; and the formula (C 8aCompound I is converted to compound C. In some embodiments, the compound of formula (C) is converted to compound I. 3a ) compounds are converted into formula (C 8a The compound contained in the presence of water was treated with trifluoroacetic acid of formula (C). 3a ) compound, to obtain formula (C 8a ) compounds.

[0241] In some embodiments, formula (C) 8a The step of converting compound I to compound C involves treating compound I with BBr3. 8a Compound I was obtained by reacting the compounds.

[0242] On the other hand, the present invention relates to a method for preparing compound I according to scheme 13.

[0243] Option 13

[0244]

[0245] In one embodiment, the present invention relates to a method for preparing compound I:

[0246] ,

[0247] I

[0248] The method includes formula (A) 2-1 Compounds:

[0249]

[0250] It is converted into compound I.

[0251] In some embodiments, formula (A) 2-1 The step of converting compound I to compound A involves converting compound A into compound I. 2-1 The compound is transformed into a compound of formula (C5):

[0252] ;as well as

[0253] The compound of formula (C5) is converted into compound I. In some embodiments, the compound of formula (A) is converted into compound I. 2-1 The conversion of a compound to the compound of formula (C5) comprises treating a compound of formula (B1) or (B2) with a compound of formula (A). 2-1 Compounds:

[0254] .

[0255] In some embodiments, the formula (A) 2-1 The step of converting compound A into compound B1 comprises treating compound C5 with compound B1.2-1 ) compound. In some embodiments, the compound of formula (A) is used. 2-1 The step of converting compound A into compound B2 comprises treating compound A with compound B2. 2-1 ) compounds.

[0256] In some embodiments, formula (A) is treated with a compound of formula (B1) or (B2). 2-1 The compounding process is carried out in the presence of a first palladium catalyst and a first base.

[0257] In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the palladium catalyst is PdCl2(PPh3)2.

[0258] In some embodiments, the first base is selected from potassium phosphate and potassium carbonate. In some embodiments, the first base is potassium hydroxide. In some embodiments, the first base is potassium carbonate.

[0259] In some embodiments, the step of converting compound (C5) to compound I includes converting compound (C5) to compound (C2):

[0260] ;as well as

[0261] The compound of formula (C2) is converted into compound I. In some embodiments, converting the compound of formula (C5) into the compound of formula (C2) comprises treating the compound of formula (C5) with a cyaniding agent (e.g., TMSCN) and a Lewis acid (e.g., Tf2O) to obtain the compound of formula (C2).

[0262] In some embodiments, the step of converting compound (C2) into compound I includes converting compound (C2) into compound (C7):

[0263] ;as well as

[0264] The compound of formula (C7) is converted into compound I. In some embodiments, the conversion of compound (C2) into compound (C7) comprises treating compound (C2) with an aqueous base (e.g., NaOH, KOH) to obtain compound (C7).

[0265] In some embodiments, the step of converting the compound of formula (C5) to compound I includes converting the compound of formula (C5) to compound (C6):

[0266] ;as well as

[0267] The compound of formula (C6) is converted into compound I.

[0268] In some embodiments, the step of converting the compound of formula (C5) to the compound of formula (C6) comprises treating the compound of formula (C5) with an acid to obtain 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, p-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 selected from dimethyl sulfoxide (DMSO), toluene, N The compound (C5) is treated with acid in a solvent of methylpyrrolidone (NMP) and 1,2-dichloroethane (DCE). In some embodiments, the compound (C5) is treated with acid at a temperature of 60-100°C, for example, about 100°C. In some embodiments, the compound (C5) is the limiting agent, and the acid is present in excess. In some embodiments, the compound (C5) is the limiting agent, the acid is acetic acid (in excess), and the reaction is carried out at a temperature of 60-100°C, for example, about 100°C.

[0269] In some embodiments, the step of converting the compound of formula (C5) to the compound of formula (C6) comprises treating the compound of formula (C5) with a base to obtain the compound of formula (C6). In some embodiments, the base is potassium acetate. In some embodiments, the compound of formula (C5) is treated with a base in the presence of water. In some embodiments, the compound of formula (C5) is treated with a base as a solvent. N , N - Dimethylformamide is treated with a base. 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 agent, and the base is present in excess. In some embodiments, the compound of formula (C5) is the limiting agent, the base is potassium acetate (in excess), and the reaction is carried out at a temperature of 80-100°C.

[0270] In some embodiments, the step of converting the compound of formula (C6) to compound I includes converting the compound of formula (C6) to the compound of formula (C4):

[0271] ;as well as

[0272] The compound of formula (C4) is converted into compound I. In some embodiments, converting the compound of formula (C6) into the compound of formula (C4) comprises treating the compound of formula (C6) with a cyaniding agent (e.g., TMSCN) and a Lewis acid (e.g., Tf2O) to obtain the compound of formula (C4).

[0273] In some embodiments, the step of converting compound (C4) to compound I includes converting compound (C4) to compound (C7):

[0274] ;as well as

[0275] The compound of formula (C7) is converted into compound I. In some embodiments, the conversion of the compound of formula (C4) into the compound of formula (C7) comprises treating the compound of formula (C4) with an aqueous base (e.g., NaOH, KOH) to obtain the compound of formula (C7).

[0276] In some embodiments, the step of converting a compound of formula (C7) into compound I comprises treating the compound of formula (C7) with a peptide coupling agent (e.g., T3P or CDI) and ammonia to obtain compound I.

[0277] Formula (A) 1 Preparation of compounds

[0278] In some embodiments, the method for preparing compound I further comprises taking (A) 1-1 Compounds:

[0279]

[0280] (A) 1-1 )

[0281] The step of converting into the compound of formula (A1).

[0282] In some embodiments, the step of converting a compound of formula (A1-1) into a compound of formula (A1) includes the following steps:

[0283] The compound of formula (A1-1) was treated with trifluoromethanesulfonic anhydride to form a trifluoromethanesulfonyl intermediate;

[0284] Treat the trifluoromethanesulfonyl intermediate with a cyaniding agent;

[0285] The cyanide intermediate is treated with a second base to form a cyanotrifluoromethanesulfonyl intermediate; and

[0286] The cyanotrifluoromethanesulfonyl intermediate was treated with an aqueous alkali to form a compound of formula (A1).

[0287] In some embodiments, the cyaniding agent is selected from trimethylcyanosilane, sodium cyanide, and potassium cyanide. In some embodiments, the cyaniding agent is trimethylcyanosilane. In some embodiments, the cyaniding agent is sodium cyanide. In some embodiments, the cyaniding agent is potassium cyanide.

[0288] 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.

[0289] In some embodiments, the aqueous alkali is an aqueous solution of sodium bicarbonate.

[0290] In some embodiments, a method for preparing compound I includes taking (A) 1-2 Compounds:

[0291]

[0292] (A) 1-2 )

[0293] Transformed into the aforementioned formula (A) 1-1 ) compounds.

[0294] In some embodiments, the formula (A) 1-2 The compound is converted into the formula (A) 1-1 The steps of compounding include treating the compound of formula (A) with a chlorinating agent. 1-2 The chlorinating agent is selected from HCl, oxaloyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphine dichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating agent is phosphorus oxychloride. In some embodiments, the chlorinating agent is selected from Cl2 (with / without an oxidizing agent), HCl / Cl- plus an oxidizing agent, N-chlorosuccinimide (NCS) / dichlorodimethylhydantoin (DCDMH) / trichloroisocyanuric acid (TCCA), sodium dichloroisocyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating agent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating agent is phosphorus oxychloride.

[0295] In some embodiments, a method for preparing compound I includes taking (A) 1-3 Compounds:

[0296]

[0297] (A) 1-3 )

[0298] Transformed into the aforementioned formula (A) 1-2 ) compounds.

[0299] In some embodiments, the formula (A) 1-3 The compound is converted into the formula (A) 1-2The steps of compounding include treating the compound of formula (A) with a second acid. 1-3 The second acid is a monocarboxylic acid selected from hydrochloric acid, acetic acid, nitric acid, and an aqueous solution of benzoic acid. In some embodiments, the second acid is a polycarboxylic acid. In some embodiments, the second acid is a dicarboxylic acid selected from sulfuric acid, carbonic acid, hydrogen sulfide, chromic acid, sulfurous acid, and oxalic acid. In some embodiments, the second acid is a tricarboxylic acid selected from phosphoric acid and citric acid. In some embodiments, the second acid is an aqueous solution of hydrochloric acid.

[0300] In some embodiments, the formula (A) 1-3 The compound is converted into the formula (A) 1-2 The compounding process includes heating (A) 1-3 ) compounds.

[0301] In some embodiments, formula (A) 1-3 ) compound is converted into formula (A 1-2 The steps involved in compounding the compound include treating it with an aqueous base (e.g., an aqueous solution of sodium hydroxide) of formula (A). 1-3 ) compound, to obtain formula (A) 1-2 ) compounds.

[0302] In some embodiments, a method for preparing compound I includes taking (A) 1-4 Compounds:

[0303]

[0304] (A) 1-4 )

[0305] Transformed into the aforementioned formula (A) 1-3 ) compounds.

[0306] In some embodiments, the formula (A) 1-4 The compound is converted into the formula (A) 1-3 The steps for compounding include treating the compound of formula (A) with diethyl malonate in the presence of a third base. 1-4The compound. In some embodiments, the third base is a basic alkoxide. In some embodiments, the third base is basic methanol. 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 a basic 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 basic tert-butanol. 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, the third base is basic tert-pentanol. In some embodiments, the third base is selected from lithium tert-pentanol, sodium tert-pentanol, and potassium tert-pentanol. In some embodiments, the third base is lithium tert-pentanol. In some embodiments, the third base is sodium tert-pentanol. In some embodiments, the third base is potassium tert-pentanol. 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.

[0307] In some embodiments, the method for preparing compound I comprises using compounds of formula (A1-5):

[0308]

[0309] (A) 1-5 )

[0310] Transformed into the aforementioned formula (A) 1-4 ) compounds.

[0311] In some embodiments, formula (A) 1-5 ) compound is converted into formula (A 1-4 The steps of compounding include treating the compound of formula (A) with carbon monoxide in the presence of a fourth base, a second palladium catalyst, and a first suitable ligand. 1-5 ) compounds.

[0312] In some embodiments, the fourth base is selected from triethylamine, juniper 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 juniper 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.

[0313] In some embodiments, the second palladium catalyst is Pd(OAc)2.

[0314] 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'-dinaphthalene (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.

[0315] Formula (A) 2 Preparation of compounds

[0316] On the other hand, the present invention relates to a method for preparing a compound of formula (A2) as described herein. Therefore, in some embodiments, the present invention relates to a method for preparing a compound of formula (A2) as described herein. In other embodiments, the present invention relates to a method for preparing compound I, wherein the compound of formula (A2) is prepared as described herein.

[0317] On the other hand, the present invention relates to a method for preparing compound (A2) according to scheme 14.

[0318] Option 14

[0319]

[0320] In one embodiment, the present invention relates to a method for preparing a compound of formula (A2):

[0321] ,

[0322] The method includes formula (A) 2-1 Compounds:

[0323]

[0324] It is converted into the compound of formula (A2). In some embodiments, formula (A2) is used to convert the compound of formula (A2) into a compound of formula (A2). 2-1 The steps for converting compound A to compound (A2) involve treating compound (A2) with trifluoromethanesulfonic anhydride, followed by treatment with a cyaniding agent. 2-1 The compound is used to form a cyanotrifluoromethanesulfonyl intermediate; and then the cyanotrifluoromethanesulfonyl intermediate is treated with an aqueous alkali to form a compound of formula (A2). In some embodiments, the compound of formula (A2) is used to form a cyanotrifluoromethanesulfonyl intermediate. 2-1 The steps for converting compound A to compound (A2) involve treating compound (A2) with a cyaniding agent followed by treatment with trifluoromethanesulfonic anhydride. 2-1 The compound is used to form a cyanotrifluoromethanesulfonyl intermediate; and then the cyanotrifluoromethanesulfonyl intermediate is treated with an aqueous alkali to form a compound of formula (A2).

[0325] In some embodiments, the cyaniding agent is selected from trimethylcyanosilane, sodium cyanide, and potassium cyanide. In some embodiments, the cyaniding agent is trimethylcyanosilane. In some embodiments, the cyaniding agent is sodium cyanide. In some embodiments, the cyaniding agent is potassium cyanide.

[0326] In some embodiments, the aqueous alkali is an aqueous solution of sodium bicarbonate and sodium thiosulfate.

[0327] In some embodiments, the method further includes formula (A) 1-2 Compounds:

[0328]

[0329] Transformed into the aforementioned formula (A) 2-1 The steps of compounding. In some embodiments, the compound of formula (A) is used. 1-2 The compound is converted into the formula (A) 2-1 The steps of compounding include treating the compound of formula (A) with a chlorinating agent. 1-2 The chlorinating agent is selected from HCl, oxaloyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphine dichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating agent is phosphorus oxychloride. In some embodiments, the chlorinating agent is selected from Cl2 (with / without an oxidizing agent), HCl / Cl- plus an oxidizing agent, N-chlorosuccinimide (NCS) / dichlorodimethylhydantoin (DCDMH) / trichloroisocyanuric acid (TCCA), sodium dichloroisocyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating agent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating agent is phosphorus oxychloride.

[0330] In some embodiments, the method further includes the following steps: (1) converting formula (A) 1-3 ) compound is converted into formula (A 1-2 (a) compounds; and / or (2) compounds of formula (A) 1-4 ) compound is converted into formula (A 1-3 ) compounds; and / or (3) compounds of formula (A 1-5 ) compound is converted into formula (A 1-4 Compounds, as described above in the preparation of compounds of formula (A1).

[0331] Formula (A) 3 Preparation of compounds

[0332] In some embodiments, a method for preparing compound I includes taking (A) 3-1 Compounds:

[0333]

[0334] (A) 3-1 )

[0335] It is converted into the compound of formula (A3).

[0336] In some embodiments, the formula (A) 3-1 The step of converting compound A to compound of formula (A3) includes treating compound of formula (A3) with a cyaniding agent and a second base. 3-1 ) compounds.

[0337] In some embodiments, the cyaniding agent is selected from trimethylcyanosilane, sodium cyanide, and potassium cyanide. In some embodiments, the cyaniding agent is trimethylcyanosilane. In some embodiments, the cyaniding agent is sodium cyanide. In some embodiments, the cyaniding agent is potassium cyanide.

[0338] In some embodiments, the second base is selected from triethylamine, 4-methylmorpholine, and juninge. In some embodiments, the second base is triethylamine. In some embodiments, the second base is 4-methylmorpholine. In some embodiments, the second base is juninge.

[0339] In some embodiments, a method for preparing compound I includes taking (A) 3-2 Compounds:

[0340]

[0341] (A) 3-2 )

[0342] Transformed into the aforementioned formula (A) 3-1 ) compounds.

[0343] In some embodiments, the formula (A) 3-2 The compound is converted into the formula (A) 3-1 The steps for compounding the compound include treating the compound of formula (A) with benzyl alcohol in the presence of a third base. 3-2 ( ) compound. In some embodiments, the third base is a basic alkoxide. In some embodiments, the third base is lithium tert-butoxide.

[0344] Formula (B) 1 Preparation of compounds

[0345] On the other hand, the present invention relates to a method for preparing a compound of formula (B1) as described herein. Therefore, in some embodiments, the present invention relates to a method for preparing a compound of formula (B1) as described herein. In other embodiments, the present invention relates to a method for preparing compound I, wherein the compound of formula (B1) is prepared as described herein.

[0346] In some embodiments, the method for preparing compound I includes taking (B) 1-1 Compounds:

[0347]

[0348] (B) 1-1 )

[0349] It is converted into the compound of formula (B1).

[0350] In some embodiments, formula (B) 1-1 The step of converting compound (B1) to compound (B2) involves treating compound (B1) with bis(pinacol)diboron in the presence of a third palladium catalyst and a fifth base. 1-1 ) compounds.

[0351] 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.

[0352] In some embodiments, the fifth base is selected from KOPh, triethylamine, juniper 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 juniper base. In some embodiments, the fifth base is KOEt. In some embodiments, the fifth base is KOAc.

[0353] In some embodiments, a method for preparing compound I includes using formula (B)1-2 Compounds:

[0354]

[0355] (B) 1-2 )

[0356] Transformed into the aforementioned formula (B) 1-1 ) compounds.

[0357] In some embodiments, formula (B) 1-2 ) compound is converted into formula (B 1-1 The steps of compounding include optionally making formula (B) in the presence of a sixth base. 1-2 The compound is contacted with trifluoromethanesulfonic anhydride. In some embodiments, the sixth base is pyridine.

[0358] In some embodiments, a method for preparing compound I includes using formula (B) 1-3 Compounds:

[0359]

[0360] (B) 1-3 )

[0361] Transformed into the aforementioned formula (B) 1-2 ) compounds.

[0362] In some embodiments, formula (B) 1-3 ) compound is converted into formula (B 1-2 The steps involved in compounding the compound included treating formula (B) with tert-butanol and a tertiary acid. 1-3 ( ) compound. In some embodiments, the third acid is sulfuric acid.

[0363] On the other hand, the present invention relates to a method for preparing compound (B1) according to scheme 15.

[0364] Option 15

[0365]

[0366] In one embodiment, the present invention relates to a method for preparing a compound of formula (B1):

[0367] ,

[0368] The method includes formula (B) 1-1a Compounds:

[0369]

[0370] It is converted into the compound of formula (B1). In some embodiments, formula (B1) is used to convert the compound of formula (B1) into a compound of formula (B1).1-1a The step of converting compound (B1) to compound (B2) involves treating compound (B1) with bis(pinacol)diboron in the presence of a palladium catalyst and a base. 1-1a ) compounds.

[0371] In some embodiments, the palladium catalyst is selected from Pd(OAc)₂ and dppf, Pd(dppf)Cl₂, Pd(PCy₃)₂, and Pd₂dba₃. In some embodiments, the palladium catalyst is Pd(OAc)₂ and 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.

[0372] In some embodiments, the base is selected from KOPh, triethylamine, juniper base, KOEt, and KOAc. In some embodiments, the base is KOPh. In some embodiments, the base is triethylamine. In some embodiments, the base is juniper base. In some embodiments, the base is KOEt. In some embodiments, the base is KOAc.

[0373] In some embodiments, the method further includes formula (B) 1-2 Compounds:

[0374]

[0375] Transformed into the aforementioned formula (B) 1-1a The steps of compounding (B) are described. In some embodiments, formula (B) is used. 1-2 ) compound is converted into formula (B 1-1a The steps of compounding involve treating the compound of formula (B) with sulfuryl fluoride (SO2F2) and a base (e.g., trimethylamine). 1-2 ) compound, to obtain formula (B 1-1a ) compounds.

[0376] In some embodiments, the method further includes formula (B) 1-3 Compounds:

[0377]

[0378] Transformed into the aforementioned formula (B) 1-2 The steps of compounding (B) are described. In some embodiments, formula (B) is used. 1-3 ) compound is converted into formula (B 1-2 The steps involved in compounding the compound included treating it with tert-butanol and an acid (B...). 1-3 (A compound. In some embodiments, the acid is sulfuric acid.)

[0379] In some embodiments, formula (B) 1-1a The compound can be used in the aforementioned method with formula (B)1-1b ), (B 1-1c ), (B 1-1d ), (B 1-1e ), (B 1-1f ) and (B 1-1g Any of the compounds in the formula (B) can be substituted, said compound may be similar to that in the formula (B) 1-1a The compounds are used together in the aforementioned method under the following conditions:

[0380] .

[0381] Preparation of compound I in solid form

[0382] In some embodiments, the method for preparing compound I further comprises converting compound I into a solvate of compound I.

[0383] In some embodiments, the step of converting compound I into a solvate of compound I comprises recrystallizing compound I from a suitable solvent. In some embodiments, a suitable solvent is 1-propanol.

[0384] In some embodiments, the solvate of compound I is a compound of formula (D):

[0385]

[0386] (D).

[0387] In some embodiments, the method for preparing compound I includes converting a solvate of compound I into form A of compound I.

[0388] In some embodiments, the step of converting the solvate of compound I into form A of compound I includes methanol solvent exchange and drying.

[0389] On one hand, this invention relates to a compound selected from:

[0390] , , , , , , , , and .

[0391] On the other hand, the present invention relates to a compound selected from:

[0392] , , , , , , and R is a C1-C6 alkyl group. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl.

[0393] On the other hand, the present invention relates to a compound selected from:

[0394] , , , , , , as well as .

[0395] In another aspect of this disclosure, a composition comprising one or more compounds selected from:

[0396] , , , , , , , , and .

[0397] In another aspect of this disclosure, a composition comprising compound I and compound (C2) is disclosed:

[0398] .

[0399] In some embodiments, the composition comprising compound I and compound (C2) further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0400] In another aspect of this disclosure, a composition comprising compound I and a compound of formula (C3) is disclosed:

[0401] .

[0402] In some embodiments, the composition comprising compound I and the compound of formula (C3) further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0403] In another aspect of this disclosure, a composition comprising a compound of formula (C2), a compound of formula (A1), and a compound of formula (B1) is disclosed:

[0404] .

[0405] In another aspect of this disclosure, a composition comprising a compound of formula (C3), a compound of formula (A3), and a compound of formula (B1) is disclosed:

[0406] .

[0407] In another aspect of this disclosure, a composition comprising a compound of formula (C2), a compound of formula (A2), and a compound of formula (B2) is disclosed:

[0408] .

[0409] In another aspect of this disclosure, a composition comprising a compound of formula (C3), a compound of formula (A3), and a compound of formula (B2) is disclosed:

[0410] .

[0411] In another aspect of this disclosure, a composition comprising compound I is disclosed:

[0412] ,

[0413] I

[0414] Or its solvates or pharmaceutically acceptable salts, prepared by any of the methods disclosed herein.

[0415] solid form of compound I

[0416] Another aspect of this disclosure provides solid forms of compound I (e.g., amorphous form, crystalline form, solvate, hydrate, and eutectic) that can be used in the therapeutic methods and pharmaceutical compositions described herein. In some embodiments, the invention provides a pure crystalline form of compound I. In some embodiments, the invention provides a solvate crystalline form of compound I. In some embodiments, the invention provides a hydrate crystalline form of compound I. In some embodiments, the invention provides a hemihydrate crystalline form of compound I. In some embodiments, the invention provides a eutectic crystalline form of compound I. In some embodiments, the invention provides an amorphous form of compound I.

[0417] A. Crystalline compound I, pure form A

[0418] In some embodiments, the present invention provides a pure crystalline form of compound I. In some embodiments, the present invention provides a pure form A of crystalline compound I.

[0419] In some embodiments, compound I in pure form A is substantially pure. In some embodiments, compound I in pure form A is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, compound I in pure form A is substantially 100% crystalline. In some embodiments, compound I in pure form A is 100% crystalline.

[0420] In some embodiments, compound I in its pure form A is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, and 10.4 ± 0.2° 2θ. In some embodiments, compound I in its pure form A is characterized by having an X-ray powder diffraction pattern with a signal of 5.5 ± 0.2° 2θ. In some embodiments, compound I in its pure form A is characterized by having an X-ray powder diffraction pattern with a signal of 9.0 ± 0.2° 2θ. In some embodiments, compound I in its pure form A is characterized by having an X-ray powder diffraction pattern with a signal of 10.4 ± 0.2° 2θ.

[0421] In some embodiments, compound I in pure form A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, and 10.4 ± 0.2° 2θ; and (b) one, two, or three signals selected from 12.8 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, and 20.4 ± 0.2° 2θ.

[0422] In some embodiments, compound I in pure form A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, and 10.4 ± 0.2° 2θ; (b) one, two, or three signals selected from 12.8 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, and 20.4 ± 0.2° 2θ; and (c) one, two, or three signals selected from 8.0 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, and 18.7 ± 0.2° 2θ.

[0423] In some embodiments, compound I in pure form A is characterized by an X-ray powder diffraction pattern having signals of: 5.5 ± 0.2° 2θ, 8.0 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 11.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 22.8 ± 0.2° 2θ, 23.9 ± 0.2° 2θ, 27.4 ± 0.2° 2θ, 27.7 ± 0.2° 2θ, 29.5 ± 0.2° 2θ, and 29.9 ± 0.2° 2θ.

[0424] In some embodiments, compound I in pure form A is characterized by being substantially similar to Figure 8 X-ray powder diffraction pattern.

[0425] In some embodiments, compound I in pure form A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 179.6 ± 0.2ppm, 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 ± 0.2ppm, 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 in pure form A is characterized by having peaks at the following locations.13 C SSNMR spectrum: 179.6 ± 0.2 ppm, 178.7 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0426] In some embodiments, compound I in pure form A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 178.8 ± 0.2ppm, 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 ± 0.2ppm, 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 in pure form A is characterized by having peaks at the following locations. 13 C SSNMR spectrum: 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 ± 0.2ppm and 20.5 ± 0.2 ppm.

[0427] In some embodiments, compound I in pure form A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 179.7 ± 0.2ppm, 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 ± 0.2ppm, 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 in pure form A is characterized by having peaks at the following locations. 13 C SSNMR spectrum: 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.

[0428] In some embodiments, compound I in pure form A is characterized by being substantially similar to Figure 9A of13 C SSNMR spectrum. In some embodiments, it is characterized by being substantially similar to Figure 9B bottom / lower trace 13 C SSNMR spectra are collected when a sample of compound I in its pure form A is maintained under ambient conditions. In some embodiments, it is characterized by being substantially similar to Figure 9B The middle trace 13 C SSNMR spectra were collected when a sample of compound I in pure form A was dried at 80°C for 3 hours. In some embodiments, the characteristics are substantially similar to... Figure 9B Top / upper trace 13 C16 SSNMR spectra were collected when the pure form A sample of compound I was dried at 80 °C for 3 hours and then rehumidified at 75% relative humidity for 12 hours at room temperature.

[0429] In some embodiments, compound I in pure form A is characterized by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell dimensions measured at 100 K for radiation (λ = 1.54178 Å):

[0430] .

[0431] In some embodiments, the diffractometer is a Brook diffractometer.

[0432] In some embodiments, the present invention provides a method for preparing compound I in pure form A, the method comprising (i) suspending an amorphous material of compound I in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solid, and (iv) drying under vacuum at 40°C to obtain compound I in pure form A.

[0433] B. Crystalline compound I, pure form B

[0434] In some embodiments, the present invention provides crystalline compound I in pure form B.

[0435] In some embodiments, compound I in pure form B is substantially pure. In some embodiments, compound I in pure form B is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, compound I in pure form B is substantially 100% crystalline. In some embodiments, compound I in pure form B is 100% crystalline.

[0436] In some embodiments, compound I in its pure form B is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.8 ± 0.2° 2θ, 9.5 ± 0.2° 2θ, and 9.8 ± 0.2° 2θ. In some embodiments, compound I in its pure form B is characterized by having an X-ray powder diffraction pattern with a signal of 5.8 ± 0.2° 2θ. In some embodiments, compound I in its pure form B is characterized by having an X-ray powder diffraction pattern with a signal of 9.5 ± 0.2° 2θ. In some embodiments, compound I in its pure form B is characterized by having an X-ray powder diffraction pattern with a signal of 9.8 ± 0.2° 2θ.

[0437] In some embodiments, compound I in pure form B is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.5 ± 0.2° 2θ, and 9.8 ± 0.2° 2θ; and (b) one, two, or three signals selected from 7.7 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, and 21.2 ± 0.2° 2θ.

[0438] In some embodiments, compound I in pure form B is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.5 ± 0.2° 2θ, and 9.8 ± 0.2° 2θ; (b) one, two, or three signals selected from 7.7 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 21.2 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, and 18.7 ± 0.2° 2θ; and (c) one, two, or three signals selected from 12.5 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, and 17.4 ± 0.2° 2θ.

[0439] In some embodiments, compound I in its pure form B is characterized by an X-ray powder diffraction pattern having signals of: 5.8 ± 0.2° 2θ, 7.7 ± 0.2° 2θ, 9.5 ± 0.2° 2θ, 12.5 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 16.8 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 18.4 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 21.2 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 23.8 ± 0.2° 2θ, 25.3 ± 0.2° 2θ, 25.6 ± 0.2° 2θ, and 27.7 ± 0.2° 2θ.

[0440] In some embodiments, compound I in pure form B is characterized by being substantially similar to Figure 10 X-ray powder diffraction pattern.

[0441] In some embodiments, compound I in pure form B is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 177.9 ± 0.2ppm, 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 ± 0.2ppm, 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 in pure form B is characterized by having peaks at the following locations. 13C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0442] In some embodiments, compound I in pure form B is characterized by being substantially similar to Figure 11 of 13 C SSNMR spectrum.

[0443] In some embodiments, compound I in pure form B is characterized by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell dimensions measured at 100 K for radiation (λ = 1.54178 Å):

[0444] .

[0445] In some embodiments, the diffractometer is a Brook diffractometer.

[0446] In some embodiments, the present invention provides a method for preparing compound I in pure form B, the method comprising (i) suspending amorphous compound I in nitromethane to form a mixture, (ii) stirring the mixture at room temperature for about 1 hour, (iii) separating a solid from the mixture, and (iv) drying the solid in an oven for about 72 hours.

[0447] C. Crystalline compound I, pure form C

[0448] In some embodiments, the present invention provides crystalline compound I in pure form C.

[0449] In some embodiments, compound I in pure form C is substantially pure. In some embodiments, compound I in pure form C is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, compound I in pure form C is substantially 100% crystalline. In some embodiments, compound I in pure form C is 100% crystalline.

[0450] In some embodiments, compound I in its pure form C is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 6.0 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ. In some embodiments, compound I in its pure form C is characterized by having an X-ray powder diffraction pattern with a signal of 6.0 ± 0.2° 2θ. In some embodiments, compound I in its pure form C is characterized by having an X-ray powder diffraction pattern with a signal of 13.9 ± 0.2° 2θ. In some embodiments, compound I in its pure form C is characterized by having an X-ray powder diffraction pattern with a signal of 19.7 ± 0.2° 2θ.

[0451] In some embodiments, compound I in its pure form C is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.0 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; and (b) one, two, or three signals selected from 15.4 ± 0.2° 2θ, 15.6 ± 0.2° 2θ, and 18.3 ± 0.2° 2θ.

[0452] In some embodiments, compound I in its pure form C is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.0 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; (b) one, two, or three signals selected from 15.4 ± 0.2° 2θ, 15.6 ± 0.2° 2θ, and 18.3 ± 0.2° 2θ; and (c) one, two, or three signals selected from 9.3 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, and 17.2 ± 0.2° 2θ.

[0453] In some embodiments, compound I in its pure form C is characterized by an X-ray powder diffraction pattern having one, two, three, four, five, six, seven, eight, nine, ten, or more signals selected from the following: 6.0 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 15.6 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 21.6 ± 0.2° 2θ, 22.3 ± 0.2°2θ, 22.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.4 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, 24.8 ±0.2° 2θ, 25.2 ± 0.2° 2θ, 26.4 ± 0.2° 2θ, 26.8 ± 0.2° 2θ and 28.8 ± 0.2° 2θ. In some embodiments, compound I in its pure form C is characterized by an X-ray powder diffraction pattern having signals of: 6.0 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 15.6 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 21.6 ± 0.2° 2θ, 22.3 ± 0.2° 2θ, 22.8 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 23.4 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 25.2 ± 0.2° 2θ, 26.4 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, and 28.8 ± 0.2° 2θ.

[0454] In some embodiments, compound I in its pure form C is characterized by being substantially similar to Figure 12 X-ray powder diffraction pattern.

[0455] In some embodiments, compound I in its pure form C is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 177.9 ± 0.2ppm, 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 ± 0.2ppm, 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 in its pure form C is characterized by having peaks at the following locations. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0456] In some embodiments, compound I in its pure form C is characterized by being substantially similar to Figure 13 of 13 C SSNMR spectrum.

[0457] In some embodiments, compound I in its pure form C is characterized by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell dimensions measured at 100 K for radiation (λ = 1.54178 Å):

[0458] .

[0459] In some embodiments, the diffractometer is a Brook diffractometer.

[0460] In some embodiments, compound I in its pure form C is characterized by using Cu K on a diffractometer. α Triclinic crystal system, space group P-1, and the following cell dimensions measured at 298 K for radiation (λ = 1.54178 Å):

[0461] .

[0462] In some embodiments, the diffractometer is a Brook diffractometer.

[0463] In some embodiments, the present invention provides a method for preparing pure form C of compound I, the method comprising (i) suspending pure form A of compound I in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20°C for about 1 hour, (iii) separating a solid from the mixture, and (iv) drying the solid in an oven for about 72 hours.

[0464] D. Crystalline compound I hemihydrate

[0465] In some embodiments, the present invention provides a compound I hemihydrate.

[0466] In some embodiments, the compound I hemihydrate is substantially pure. In some embodiments, the compound I hemihydrate is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the compound I hemihydrate is substantially 100% crystalline. In some embodiments, the compound I hemihydrate is 100% crystalline.

[0467] In some embodiments, the compound I hemihydrate is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 12.3 ± 0.2° 2θ. In some embodiments, the compound I hemihydrate is characterized by having an X-ray powder diffraction pattern with a signal of 5.1 ± 0.2° 2θ. In some embodiments, the compound I hemihydrate is characterized by having an X-ray powder diffraction pattern with a signal of 10.2 ± 0.2° 2θ. In some embodiments, the compound I hemihydrate is characterized by having an X-ray powder diffraction pattern with a signal of 12.3 ± 0.2° 2θ.

[0468] In some embodiments, the compound I hemihydrate is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 12.3 ± 0.2° 2θ; and (b) one, two, or three signals selected from 14.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, and 26.6 ± 0.2° 2θ.

[0469] In some embodiments, the compound I hemihydrate is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 12.3 ± 0.2° 2θ; (b) one, two, or three signals selected from 14.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, and 26.6 ± 0.2° 2θ; and (c) one or two signals selected from 11.1 ± 0.2° 2θ and 21.3 ± 0.2° 2θ.

[0470] In some embodiments, the compound I hemihydrate is characterized by an X-ray powder diffraction pattern having signals of: 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, and 26.6 ± 0.2° 2θ.

[0471] In some embodiments, the compound I hemihydrate is characterized by being substantially similar to Figure 14 X-ray powder diffraction pattern.

[0472] In some embodiments, the compound I hemihydrate is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectra: 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, the compound I hemihydrate is characterized by having peaks at the following locations. 13 C SSNMR spectrum: 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.

[0473] In some embodiments, the compound I hemihydrate is characterized by being substantially similar to Figure 15 of 13 C SSNMR spectrum.

[0474] In some embodiments, the present invention provides a method for preparing a hemihydrate of compound I, the method comprising (i) suspending compound I in water, (ii) shaking at 40°C for at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks, (iii) collecting the solid, and (iv) drying at 40°C under vacuum to obtain a hemihydrate of compound I.

[0475] E. Crystalline compound I-hydrate

[0476] In some embodiments, the present invention provides compound I hydrate.

[0477] In some embodiments, compound I monohydrate is substantially pure. In some embodiments, compound I monohydrate is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, 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 hemihydrate is 100% crystalline.

[0478] In some embodiments, compound I monohydrate is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 14.2 ± 0.2° 2θ. In some embodiments, compound I monohydrate is characterized by having an X-ray powder diffraction pattern with a signal of 5.0 ± 0.2° 2θ. In some embodiments, compound I monohydrate is characterized by having an X-ray powder diffraction pattern with a signal of 10.2 ± 0.2° 2θ.

[0479] In some embodiments, the compound I monohydrate is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 14.2 ± 0.2° 2θ; and (b) one, two, or three signals selected from 12.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, and 26.5 ± 0.2° 2θ.

[0480] In some embodiments, the compound I monohydrate is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 14.2 ± 0.2° 2θ; (b) one, two, or three signals selected from 12.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, and 26.5 ± 0.2° 2θ; and (c) one or two signals selected from 17.1 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, and 23.5 ± 0.2° 2θ.

[0481] In some embodiments, the compound I monohydrate is characterized by an X-ray powder diffraction pattern having signals of: 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.8 ± 0.2° 2θ, 18.1 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 26.5 ± 0.2° 2θ, 27.4 ± 0.2° 2θ, and 31.7 ± 0.2° 2θ.

[0482] In some embodiments, compound I monohydrate is characterized by being substantially similar to Figure 16 X-ray powder diffraction pattern.

[0483] In some embodiments, the present invention provides a method for preparing compound I monohydrate, the method comprising (i) suspending compound I in water, (ii) shaking at 40°C for no more than 48 hours, (iii) collecting the solid, and (iv) drying at 40°C under vacuum to obtain compound I monohydrate.

[0484] F. Crystalline compound I, methanol solvate

[0485] In some embodiments, the present invention provides a methanol solvate of compound I.

[0486] In some embodiments, the methanol solvate of compound I is substantially pure. In some embodiments, the methanol solvate of compound I is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the methanol solvate of compound I is substantially 100% crystalline. In some embodiments, the methanol solvate of compound I is 100% crystalline.

[0487] In some embodiments, the methanol solvate of compound I is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ. In some embodiments, the methanol solvate of compound I is characterized by an X-ray powder diffraction pattern with a signal of 6.6 ± 0.2° 2θ. In some embodiments, the methanol solvate of compound I is characterized by an X-ray powder diffraction pattern with a signal of 8.4 ± 0.2° 2θ. In some embodiments, the methanol solvate of compound I is characterized by an X-ray powder diffraction pattern with a signal of 10.6 ± 0.2° 2θ.

[0488] In some embodiments, the methanol solvate of compound I is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and (b) one, two, or three signals selected from 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, and 20.9 ± 0.2° 2θ.

[0489] In some embodiments, the methanol solvate of compound I is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; (b) one, two, or three signals selected from 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, and 20.9 ± 0.2° 2θ; and (c) one, two, or three signals selected from 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ.

[0490] In some embodiments, the methanol solvate of compound I is characterized by an X-ray powder diffraction pattern having signals of: 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.9 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ.

[0491] In some embodiments, the methanol solvate of compound I is characterized by being substantially similar to Figure 17 X-ray powder diffraction pattern.

[0492] In some embodiments, the methanol solvate of compound I is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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, the methanol solvate of compound I is characterized by having peaks at the following locations. 13C SSNMR spectrum: 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.

[0493] In some embodiments, the methanol solvate of compound I is characterized by being substantially similar to Figure 18 of 13 CSSNMR spectrum.

[0494] In some embodiments, the methanol solvate of compound I is characterized by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0495] .

[0496] In some embodiments, the diffractometer is a Brook diffractometer.

[0497] In some embodiments, the present invention provides a method for preparing a methanol solvate of compound I, the method comprising (i) suspending an amorphous material of compound I in methanol, (ii) shaking at 40°C for 1 hour, and (iii) collecting the solid to obtain a methanol solvate of compound I.

[0498] G. Crystalline compound InPA solvate mixture A

[0499] In some embodiments, the present invention provides a mixture A of compound InPA solvates.

[0500] In some embodiments, the compound InPA solvate mixture A is substantially pure. In some embodiments, the compound InPA solvate mixture A is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form). In some embodiments, the compound InPA solvate mixture A is substantially 100% crystalline. In some embodiments, the compound InPA solvate mixture A is 100% crystalline.

[0501] In some embodiments, the InPA solvate mixture A is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture A is characterized by an X-ray powder diffraction pattern with a signal of 5.3 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture A is characterized by an X-ray powder diffraction pattern with a signal of 8.8 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture A is characterized by an X-ray powder diffraction pattern with a signal of 10.6 ± 0.2° 2θ.

[0502] In some embodiments, the compound InPA solvate mixture A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and (b) one, two, or three signals selected from 10.1 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, and 18.8 ± 0.2° 2θ.

[0503] In some embodiments, the compound InPA solvate mixture A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; (b) one, two, or three signals selected from 10.1 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, and 18.8 ± 0.2° 2θ; and (c) one, two, or three signals selected from 13.5 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, and 25.5 ± 0.2° 2θ.

[0504] In some embodiments, the compound InPA solvate mixture A is characterized by an X-ray powder diffraction pattern having signals of: 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 18.4 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 22.8 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.5 ± 0.2° 2θ, and 26.1 ± 0.2° 2θ.

[0505] In some embodiments, the compound InPA solvate mixture A is characterized by being substantially similar to Figure 19 X-ray powder diffraction pattern.

[0506] In some embodiments, the compound InPA solvate mixture A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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, the compound InPA solvate mixture A is characterized by having peaks at the following locations: 13C SSNMR spectrum: 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 ± 0.2ppm, 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.

[0507] In some embodiments, the compound InPA solvate mixture A is characterized by being substantially similar to Figure 20 of 13 C SSNMR spectrum.

[0508] In some embodiments, the compound InPA solvate mixture A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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, the InPA solvate mixture A is characterized by having peaks at the following locations. 13C SSNMR spectrum: 176.5 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 13.4 ± 0.2 ppm and 11.7 ± 0.2 ppm.

[0509] In some embodiments, the compound InPA solvate mixture A is characterized by being substantially similar to Figure 21 of 13 C SSNMR spectrum.

[0510] In some embodiments, the compound InPA solvate mixture A is characterized by using CuK on a diffractometer. α The radiation (λ = 1.54178 Å) measured at 100 K in a monoclinic crystal system C2 / c Space group and the following cell sizes:

[0511] .

[0512] In some embodiments, the diffractometer is a Brook diffractometer.

[0513] In some embodiments, the present invention provides a method for preparing a mixture A of compound InPA solvates, the method comprising (i) suspending compound InPA solvate B and NaTFA in InPA, (ii) mixing at room temperature for 6-18 hours, (iii) collecting the solid, and (iv) air-drying for 15-45 minutes to obtain mixture A of compound InPA solvates.

[0514] H. Crystalline compound InPA solvate B

[0515] In some embodiments, the present invention provides a mixture B of compound InPA solvates.

[0516] In some embodiments, the compound InPA solvate mixture B is substantially pure. In some embodiments, the compound InPA solvate mixture B is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form). In some embodiments, the compound InPA solvate mixture B is substantially 100% crystalline. In some embodiments, the compound InPA solvate mixture B is 100% crystalline.

[0517] In some embodiments, the InPA solvate mixture B is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture B is characterized by an X-ray powder diffraction pattern with a signal of 5.3 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture B is characterized by an X-ray powder diffraction pattern with a signal of 8.8 ± 0.2° 2θ. In some embodiments, the InPA solvate mixture B is characterized by an X-ray powder diffraction pattern with a signal of 10.6 ± 0.2° 2θ.

[0518] In some embodiments, the compound InPA solvate mixture B is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and (b) one, two, or three signals selected from 9.9 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, and 14.8 ± 0.2° 2θ.

[0519] In some embodiments, the compound InPA solvate mixture B is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; (b) one, two, or three signals selected from 9.9 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, and 14.8 ± 0.2° 2θ; and (c) one or two signals selected from 18.9 ± 0.2° 2θ and 21.4 ± 0.2° 2θ.

[0520] In some embodiments, the inPA solvate mixture B is characterized by an X-ray powder diffraction pattern having signals of: 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 9.9 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 18.0 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 22.6 ± 0.2° 2θ, 22.9 ± 0.2° 2θ, 24.6 ± 0.2° 2θ, 25.7 ± 0.2° 2θ, 26.1 ± 0.2° 2θ, 26.5 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ.

[0521] In some embodiments, the compound InPA solvate mixture B is characterized by being substantially similar to Figure 22 X-ray powder diffraction pattern.

[0522] In some embodiments, the compound InPA solvate mixture B is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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, the compound InPA solvate mixture B is characterized by having peaks at the following locations: 13C SSNMR spectrum: 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 ± 0.2ppm, 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.

[0523] In some embodiments, the compound InPA solvate mixture B is characterized by being substantially similar to Figure 23 of 13 C SSNMR spectrum.

[0524] In some embodiments, the compound InPA solvate mixture B is characterized by using CuK on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0525] .

[0526] In some embodiments, the diffractometer is a Brook diffractometer.

[0527] In some embodiments, the present invention provides a method for preparing compound InPA solvate B, the method comprising (i) suspending an amorphous material of compound InPA in nPA, (ii) mixing at room temperature for 18-30 hours, (iii) collecting the solid, and (iv) drying under vacuum at 40°C to obtain compound InPA solvate B.

[0528] I. Crystalline compound InPA solvate C

[0529] In some embodiments, compound InPA solvate C.

[0530] In some embodiments, compound InPA solvate C is substantially pure. In some embodiments, compound InPA solvate C is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, compound InPA solvate C is substantially 100% crystalline. In some embodiments, compound InPA solvate C is 100% crystalline.

[0531] In some embodiments, the InPA solvate C is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 6.1 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, and 12.2 ± 0.2° 2θ. In some embodiments, the InPA solvate C is characterized by an X-ray powder diffraction pattern with a signal of 6.1 ± 0.2° 2θ. In some embodiments, the InPA solvate C is characterized by an X-ray powder diffraction pattern with a signal of 11.8 ± 0.2° 2θ. In some embodiments, the InPA solvate C is characterized by an X-ray powder diffraction pattern with a signal of 12.2 ± 0.2° 2θ.

[0532] In some embodiments, the compound InPA solvate C is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.1 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, and 12.2 ± 0.2° 2θ; and (b) one, two, or three signals selected from 7.2 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, and 15.8 ± 0.2° 2θ.

[0533] In some embodiments, the compound InPA solvate C is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.1 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, and 12.2 ± 0.2° 2θ; (b) one, two, or three signals selected from 7.2 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, and 15.8 ± 0.2° 2θ; and (c) one, two, or three signals selected from 5.4 ± 0.2° 2θ, 8.7 ± 0.2° 2θ, and 10.2 ± 0.2° 2θ.

[0534] In some embodiments, the compound InPA solvate C is characterized by an X-ray powder diffraction pattern having signals of: 5.3 ± 0.2° 2θ, 6.1 ± 0.2° 2θ, 7.2 ± 0.2° 2θ, 8.7 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, and 20.5 ± 0.2° 2θ.

[0535] In some embodiments, compound InPA solvate C is characterized by being substantially similar to Figure 24 X-ray powder diffraction pattern.

[0536] In some embodiments, the present invention provides a method for preparing compound I nPA solvate C, the method 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 solid to obtain compound I nPA solvate C.

[0537] J. Crystalline compound I Na hemisalt nPA solvate

[0538] In some embodiments, the present invention provides a solvate of compound I Na semi-salt nPA.

[0539] In some embodiments, the compound I Na hemisal nPA solvate is substantially pure. In some embodiments, the compound I Na hemisal nPA solvate is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the compound I Na hemisal nPA solvate is substantially 100% crystalline. In some embodiments, the compound I Na hemisal nPA solvate is 100% crystalline.

[0540] In some embodiments, the Na half-salt nPA solvate of compound I is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 6.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, and 14.9 ± 0.2° 2θ. In some embodiments, the Na half-salt nPA solvate of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 6.7 ± 0.2° 2θ. In some embodiments, the Na half-salt nPA solvate of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 14.1 ± 0.2° 2θ. In some embodiments, the Na half-salt nPA solvate of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 14.9 ± 0.2° 2θ.

[0541] In some embodiments, the solvate of compound I Na semi-salt nPA is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, and 14.9 ± 0.2° 2θ; and (b) one, two, or three signals selected from 13.4 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, and 18.7 ± 0.2° 2θ.

[0542] In some embodiments, the solvate of compound I Na semi-salt nPA is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, and 14.9 ± 0.2° 2θ; (b) one, two, or three signals selected from 13.4 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, and 18.7 ± 0.2° 2θ; and (c) one, two, or three signals selected from 5.2 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.3 ± 0.2° 2θ.

[0543] In some embodiments, the compound I Na hemisal nPA solvate is characterized by an X-ray powder diffraction pattern having signals of: 5.2 ± 0.2° 2θ, 6.7 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 9.8 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 13.6 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 20.6 ± 0.2° 2θ, 21.0 ± 0.2° 2θ, 24.6 ± 0.2° 2θ, 26.4 ± 0.2° 2θ, 26.6 ± 0.2° 2θ and 28.4 ± 0.2° 2θ.

[0544] In some embodiments, the compound I Na half-salt nPA solvate is characterized by being substantially similar to Figure 25 X-ray powder diffraction pattern.

[0545] In some embodiments, the compound I Na semi-salt nPA solvate is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 178.0± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2 ppm, 161.9 ± 0.2ppm, 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 ± 0.2ppm, 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, the compound I Na hemisal nPA solvate is characterized by having peaks at the following locations. 13C SSNMR spectrum: 178.0 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0546] In some embodiments, the compound I Na half-salt nPA solvate is characterized by being substantially similar to Figure 26 of 13 C SSNMR spectrum.

[0547] In some embodiments, the compound I Na semi-salt nPA solvate is characterized by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0548] .

[0549] In some embodiments, the diffractometer is a Brook diffractometer.

[0550] In some embodiments, the present invention provides a method for preparing a solvate of compound I Na hemisal nPA, the method comprising (i) treating 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6-naphthyl-5-carboxynitrile 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 an aqueous sodium chloride solution, (v) diluting the mixture with 2-MeTHF and subsequently concentrating it, (vi) treating the mixture with nPA and subsequently concentrating it, (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 solid, and (s) drying the mixture under vacuum at 40°C for 6-18 hours to obtain the solvate of compound I Na hemisal nPA.

[0551] K. Crystalline compound InPA solvate J

[0552] In some embodiments, the present invention provides compound InPA solvate J.

[0553] In some embodiments, compound InPA solvate J is substantially pure. In some embodiments, compound InPA solvate J is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, compound InPA solvate J is substantially 100% crystalline. In some embodiments, compound InPA solvate J is 100% crystalline.

[0554] In some embodiments, compound InPA solvate J is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.3 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, and 19.0 ± 0.2° 2θ. In some embodiments, compound InPA solvate J is characterized by having an X-ray powder diffraction pattern with a signal of 5.3 ± 0.2° 2θ. In some embodiments, compound InPA solvate J is characterized by having an X-ray powder diffraction pattern with a signal of 10.4 ± 0.2° 2θ. In some embodiments, compound InPA solvate J is characterized by having an X-ray powder diffraction pattern with a signal of 19.0 ± 0.2° 2θ.

[0555] In some embodiments, the compound InPA solvate J is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, and 19.0 ± 0.2° 2θ; and (b) one, two, or three signals selected from 8.8 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 13.4 ± 0.2° 2θ.

[0556] In some embodiments, the compound InPA solvate J is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.3 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, and 19.0 ± 0.2° 2θ; (b) one, two, or three signals selected from 8.8 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 13.4 ± 0.2° 2θ; and (c) one, two, or three signals selected from 14.1 ± 0.2° 2θ, 19.2 ± 0.2° 2θ, and 26.0 ± 0.2° 2θ.

[0557] In some embodiments, compound InPA solvate J is characterized by an X-ray powder diffraction pattern having signals of: 3.1 ± 0.2° 2θ, 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 19.0 ± 0.2° 2θ, 19.2 ± 0.2° 2θ, 26.0 ± 0.2° 2θ, and 26.4 ± 0.2° 2θ.

[0558] In some embodiments, compound InPA solvate J is characterized by being substantially similar to Figure 27 X-ray powder diffraction pattern.

[0559] In some embodiments, the present invention provides a method for preparing compound I nPA solvate J, the method 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 solid, and (vi) drying the solid under vacuum at 45°C to obtain compound I nPA solvate J.

[0560] L. Crystalline compound I 2-MeTHF solvate A

[0561] In some embodiments, the present invention provides compound I 2-MeTHF solvate A.

[0562] 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., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, 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.

[0563] In some embodiments, compound I 2-MeTHF solvate A is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ. In some embodiments, compound I 2-MeTHF solvate A is characterized by having an X-ray powder diffraction pattern with a signal of 5.8 ± 0.2° 2θ. In some embodiments, compound I 2-MeTHF solvate A is characterized by having an X-ray powder diffraction pattern with a signal of 9.4 ± 0.2° 2θ. In some embodiments, compound I 2-MeTHF solvate A is characterized by having an X-ray powder diffraction pattern with a signal of 14.0 ± 0.2° 2θ.

[0564] In some embodiments, compound I 2-MeTHF solvate A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ; and (b) one, two, or three signals selected from 9.8 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, and 15.4 ± 0.2° 2θ.

[0565] In some embodiments, compound I 2-MeTHF solvate A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ; (b) one, two, or three signals selected from 9.8 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, and 15.4 ± 0.2° 2θ; and (c) one, two, or three signals selected from 17.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, and 20.8 ± 0.2° 2θ.

[0566] In some embodiments, compound I 2-MeTHF solvate A is characterized by an X-ray powder diffraction pattern having signals of 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 9.8 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 14.0 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ.

[0567] In some embodiments, compound I 2-MeTHF solvate A is characterized by being substantially similar to Figure 28 X-ray powder diffraction pattern.

[0568] In some embodiments, the present invention provides a method for preparing compound I 2-MeTHF solvate A, the method comprising (i) treating compound I form A with 2-MeTHF, (ii) stirring the mixture at about 22°C for 24 hours, and (iii) separating the solid.

[0569] M. Crystalline compound I, 2-MeTHF solvate mixture A

[0570] In some embodiments, the present invention provides a mixture A of compound I 2-MeTHF solvates.

[0571] In some embodiments, the compound I 2-MeTHF solvate mixture A is substantially pure. In some embodiments, the compound I 2-MeTHF solvate mixture A is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form). In some embodiments, the compound I 2-MeTHF solvate mixture A is substantially 100% crystalline. In some embodiments, compound I 2-MeTHF solvate A is 100% crystalline.

[0572] In some embodiments, the compound I 2-MeTHF solvate mixture A is characterized by an X-ray powder diffraction pattern with a signal of 4.6 ± 0.2° 2θ.

[0573] In some embodiments, the compound I 2-MeTHF solvate mixture A is characterized by having an X-ray powder diffraction pattern having: (a) a signal at 4.6 ± 0.2° 2θ; and (b) one, two, or three signals selected from 15.8 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ.

[0574] In some embodiments, the compound I 2-MeTHF solvate mixture A is characterized by having an X-ray powder diffraction pattern having: (a) a signal at 4.6 ± 0.2° 2θ; (b) one, two, or three signals selected from 15.8 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ; and (c) one, two, or three signals selected from 12.4 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ.

[0575] In some embodiments, the compound I 2-MeTHF solvate mixture A is characterized by an X-ray powder diffraction pattern having signals of 4.6 ± 0.2° 2θ, 12.4 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ.

[0576] In some embodiments, the compound I 2-MeTHF solvate mixture A is characterized by being substantially similar to Figure 29 X-ray powder diffraction pattern.

[0577] In some embodiments, the present invention provides a method for preparing a compound I 2-MeTHF solvate mixture A, the method comprising (i) obtaining a solution of compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) collecting the solid, and (iv) drying under vacuum at 50°C to obtain compound I 2-MeTHF solvate mixture A.

[0578] N. Crystalline compound I 2-MeTHF mixture C

[0579] In some embodiments, the present invention provides a mixture C of compound I 2-MeTHF.

[0580] In some embodiments, the compound I 2-MeTHF mixture C is substantially pure. In some embodiments, the compound I 2-MeTHF mixture C is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the compound I 2-MeTHF mixture C is substantially 100% crystalline. In some embodiments, the compound I 2-MeTHF mixture C is 100% crystalline.

[0581] In some embodiments, the compound I 2-MeTHF mixture C is characterized by an X-ray powder diffraction pattern with a signal of 4.9 ± 0.2° 2θ.

[0582] In some embodiments, the compound I 2-MeTHF mixture C is characterized by having an X-ray powder diffraction pattern having: (a) a signal at 4.9 ± 0.2° 2θ; and (b) one, two, or three signals selected from 8.2 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, and 18.5 ± 0.2° 2θ.

[0583] In some embodiments, the compound I 2-MeTHF mixture C is characterized by having an X-ray powder diffraction pattern having: (a) a signal at 4.9 ± 0.2° 2θ; (b) one, two, or three signals selected from 8.2 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, and 18.5 ± 0.2° 2θ; and (c) one, two, or three signals selected from 15.3 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, and 23.1 ± 0.2° 2θ.

[0584] In some embodiments, the compound I 2-MeTHF mixture C is characterized by an X-ray powder diffraction pattern having signals of: 4.9 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 15.3 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 25.0 ± 0.2° 2θ, and 25.2 ± 0.2° 2θ.

[0585] In some embodiments, the compound I 2-MeTHF mixture C is characterized by being substantially similar to Figure 30 X-ray powder diffraction pattern.

[0586] In some embodiments, the present invention provides a method for preparing a compound I 2-MeTHF solvate mixture C, the method comprising (i) obtaining a solution of compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) heating the slurry to 90°C to dissolve a solid, (iv) cooling to 25°C, (v) collecting the solid, and (iv) drying at 50°C to obtain a compound I 2-MeTHF solvate mixture C.

[0587] O. Crystalline compound I mandelic acid eutectic

[0588] In some embodiments, the present invention provides a compound I mandelic acid eutectic.

[0589] In some embodiments, the compound I mandelic acid eutectic is substantially pure. In some embodiments, the compound I mandelic acid eutectic is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the compound I mandelic acid eutectic is substantially 100% crystalline. In some embodiments, the compound I mandelic acid eutectic is 100% crystalline.

[0590] In some embodiments, the compound I mandelic acid eutectic is characterized by having one, two, or three X-ray powder diffraction patterns selected from 6.6 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ. In some embodiments, the compound I mandelic acid eutectic is characterized by having an X-ray powder diffraction pattern with a signal of 6.6 ± 0.2° 2θ. In some embodiments, the compound I mandelic acid eutectic is characterized by having an X-ray powder diffraction pattern with a signal of 10.6 ± 0.2° 2θ. In some embodiments, the compound I mandelic acid eutectic is characterized by having an X-ray powder diffraction pattern with a signal of 21.1 ± 0.2° 2θ.

[0591] In some embodiments, the compound I mandelic acid eutectic is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.6 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ; and (b) one, two, or three signals selected from 8.4 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, and 18.8 ± 0.2° 2θ.

[0592] In some embodiments, the compound I mandelic acid eutectic is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 6.6 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ; (b) one, two, or three signals selected from 8.4 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, and 18.8 ± 0.2° 2θ; and (c) one, two, or three signals selected from 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, and 20.9 ± 0.2° 2θ.

[0593] In some embodiments, the compound I mandelic acid eutectic is characterized by an X-ray powder diffraction pattern having signals of: 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.9 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ.

[0594] In some embodiments, the compound I mandelic acid eutectic is characterized by being substantially similar to Figure 31 X-ray powder diffraction pattern.

[0595] In some embodiments, the present invention provides a method for preparing a mandelic acid eutectic of compound I, the method comprising (i) combining compound I and mandelic acid, (ii) diluting the mixture in DCM, (iii) stirring 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 obtain a mandelic acid eutectic of compound I. In some embodiments, stirring comprises ultrasonic treatment. In some embodiments, agitation comprises stirring. In some embodiments, the stirring process comprises ultrasonic treatment followed by stirring.

[0596] P. Crystalline compound I oxalic acid eutectic

[0597] In some embodiments, the present invention provides a eutectic of compound I oxalic acid.

[0598] In some embodiments, the oxalic acid eutectic of compound I is substantially pure. In some embodiments, the oxalic acid eutectic of compound I is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, less than 5% of compound I is in amorphous form). In some embodiments, the oxalic acid eutectic of compound I is substantially 100% crystalline. In some embodiments, the oxalic acid eutectic of compound I is 100% crystalline.

[0599] In some embodiments, the oxalic acid eutectic of compound I is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 8.9 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, and 14.5 ± 0.2° 2θ. In some embodiments, the oxalic acid eutectic of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 8.9 ± 0.2° 2θ. In some embodiments, the oxalic acid eutectic of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 11.6 ± 0.2° 2θ. In some embodiments, the oxalic acid eutectic of compound I is characterized by having an X-ray powder diffraction pattern with a signal of 14.5 ± 0.2° 2θ.

[0600] In some embodiments, the oxalic acid eutectic of compound I is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 8.9 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, and 14.5 ± 0.2° 2θ; and (b) one or two signals selected from 5.7 ± 0.2° 2θ and 20.1 ± 0.2° 2θ.

[0601] In some embodiments, the oxalic acid eutectic of compound I is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 8.9 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, and 14.5 ± 0.2° 2θ; (b) one or two signals selected from 5.7 ± 0.2° 2θ and 20.1 ± 0.2° 2θ; and (c) one, two, or three signals selected from 10.6 ± 0.2° 2θ, 13.8 ± 0.2° 2θ, and 22.9 ± 0.2° 2θ.

[0602] In some embodiments, the oxalic acid eutectic of compound I is characterized by an X-ray powder diffraction pattern having signals of: 5.7 ± 0.2° 2θ, 8.9 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, 13.8 ± 0.2° 2θ, 14.5 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, and 22.9 ± 0.2° 2θ.

[0603] In some embodiments, the oxalic acid eutectic of compound I is characterized by being substantially similar to Figure 32 X-ray powder diffraction pattern.

[0604] In some embodiments, the oxalic acid eutectic of compound I is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 177.5 ± 0.2ppm, 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 ± 0.2ppm, 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, the oxalic acid eutectic of compound I is characterized by having peaks at the following locations. 13C SSNMR spectrum: 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.

[0605] In some embodiments, the oxalic acid eutectic of compound I is characterized by being substantially similar to Figure 33 of 13 C SSNMR spectrum.

[0606] In some embodiments, the present invention provides a method for preparing oxalic acid cocrystal of compound I, the method comprising (i) suspending compound I and oxalic acid (1:1) in DCM, (ii) stirring the resulting slurry at room temperature, (iii) collecting the solid, and (iv) drying at 50°C under vacuum to obtain oxalic acid cocrystal of compound I.

[0607] Q. Crystalline compound I, TFA salt A

[0608] In some embodiments, the present invention provides compound I TFA salt A.

[0609] In some embodiments, compound I TFA salt A is substantially pure. In some embodiments, compound I TFA salt A is substantially crystalline (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, 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.

[0610] In some embodiments, compound I TFA salt A is characterized by having one, two, or three X-ray powder diffraction patterns with signals selected from 8.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ. In some embodiments, compound I TFA salt A is characterized by having an X-ray powder diffraction pattern with a signal of 8.4 ± 0.2° 2θ. In some embodiments, compound I TFA salt A is characterized by having an X-ray powder diffraction pattern with a signal of 15.1 ± 0.2° 2θ. In some embodiments, compound I TFA salt A is characterized by having an X-ray powder diffraction pattern with a signal of 19.7 ± 0.2° 2θ.

[0611] In some embodiments, the compound ITFA salt A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 8.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; and (b) one or two signals selected from 4.4 ± 0.2° 2θ and 11.4 ± 0.2° 2θ.

[0612] In some embodiments, compound I TFA salt A is characterized by having an X-ray powder diffraction pattern having: (a) one, two, or three signals selected from 8.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; (b) one or two signals selected from 4.4 ± 0.2° 2θ and 11.4 ± 0.2° 2θ; and (c) one, two, or three signals selected from 17.3 ± 0.2° 2θ, 23.8 ± 0.2° 2θ, and 26.3 ± 0.2° 2θ.

[0613] In some embodiments, compound ITFA salt A is characterized by an X-ray powder diffraction pattern having signals of the following: 4.4 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 11.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 23.8 ± 0.2° 2θ, and 26.3 ± 0.2° 2θ.

[0614] In some embodiments, compound I TFA salt A is characterized by being substantially similar to Figure 34 X-ray powder diffraction pattern.

[0615] In some embodiments, compound I TFA salt A is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectra: 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 having peaks at the following locations. 13 C SSNMR spectrum: 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.

[0616] In some embodiments, compound I TFA salt A is characterized by being substantially similar to Figure 35 of 13 C SSNMR spectrum.

[0617] In some embodiments, the present invention provides a method for preparing compound I TFA salt A, the method 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 solid, and (v) drying at room temperature to obtain compound I TFA salt A.

[0618] R. Amorphous compound I

[0619] In some embodiments, the present invention provides amorphous compound I.

[0620] In some embodiments, amorphous compound I is substantially pure. In some embodiments, amorphous compound I is substantially amorphous (i.e., less than 15% of compound I is crystalline, less than 10% of compound I is crystalline, less than 5% of compound I is crystalline). In some embodiments, amorphous compound I is substantially 100% amorphous. In some embodiments, amorphous compound I is 100% amorphous.

[0621] In some embodiments, amorphous compound I is characterized by being substantially similar to Figure 36 X-ray powder diffraction pattern.

[0622] In some embodiments, the amorphous I is characterized by having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C18 SSNMR spectra: 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 having peaks at the following locations. 13 CSSNMR spectrum: 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.

[0623] In some embodiments, amorphous compound I is characterized by being substantially similar to Figure 37 of 13C SSNMR spectrum.

[0624] In some embodiments, the present invention provides a method for preparing amorphous compound I, the method comprising (i) combining compound I and tert-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) separating the solid material.

[0625] Treatment

[0626] Compound I, in any 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 a Na+ channel. V 1.8. Therefore, in another aspect, this disclosure is characterized by a method for inhibiting a voltage-gated sodium channel in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. On the other hand, the voltage-gated sodium channel is Na... V 1.8.

[0627] On the other hand, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject compound I or a solvate thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0628] On the other hand, this disclosure relates to a method for treating pain in a subject or reducing the severity of pain, the method comprising administering compound I or a pharmaceutically acceptable salt thereof to the subject.

[0629] On the other hand, this disclosure relates to a method for treating pain in a subject or reducing the severity of pain, the method comprising administering to the subject a compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0630] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunion removal, hernia repair, or abdominoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0631] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, bunion removal pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or arrhythmia in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0632] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, erythrocytic ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0633] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of neuropathic pain in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy.

[0634] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced neuropathic pain, chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain, HIV-induced neuropathic pain; post-spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0635] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of musculoskeletal pain in a subject, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, musculoskeletal pain includes osteoarthritis pain.

[0636] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0637] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, ankylosing spondylitis, or vulvar pain, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0638] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0639] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0640] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes reflex sympathetic dystrophy pain, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0641] On the other hand, this disclosure is characterized by a method for treating a subject’s pathological cough or reducing its severity, wherein the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0642] On the other hand, this disclosure is characterized by a method for treating acute pain in a subject or reducing its severity, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, acute pain includes acute postoperative pain.

[0643] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of postoperative pain in a subject (e.g., pain from joint replacement surgery, soft tissue surgery, open-chest surgery, mastectomy, hemorrhoidectomy, hernia repair, bunionectomy, or abdominoplasty), said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0644] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of pain following a bunion excision in a subject, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0645] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of shoulder replacement pain or shoulder arthroscopy pain in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof, which is any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0646] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of pain during hernia repair in a subject, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0647] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of abdominal wall surgery pain in a subject, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0648] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of visceral pain in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, visceral pain includes visceral pain caused by abdominoplasty.

[0649] On the other hand, this disclosure is characterized by a method for treating or reducing the severity of a neurodegenerative disease in a subject, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, neurodegenerative diseases include multiple sclerosis. In some aspects, neurodegenerative diseases include Peter Hopkins syndrome (PTHS).

[0650] On the other hand, this disclosure is characterized by a method of treating a subject with one or more additional therapeutic agents, said additional therapeutic agents being administered simultaneously, before, or after treatment with an effective amount of Compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the additional therapeutic agents are sodium channel inhibitors.

[0651] On the other hand, this disclosure is characterized by a method for inhibiting voltage-gated sodium channels in a biological sample, the method comprising contacting the biological sample with an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. The voltage-gated sodium channel is, in this case, NaV1.8.

[0652] On the other hand, this disclosure is characterized by a treatment for acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive plasticity pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic symptoms, neurodegenerative diseases, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, central nervous system pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, and other conditions affecting the subject. Menstrual pain, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, thoracotomy pain, mastectomy pain, hernia repair pain, bunion removal pain, or abdominoplasty pain), cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., post-stroke central nervous system pain), whiplash-related syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, Raynaud's disease. Diseases, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteogenesis imperfecta, polymyalgia rheumatica, pyoderma gangrenosa, chronic widespread pain, diffuse idiopathic osteophyte formation, intervertebral disc degeneration / hernia, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry's disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, vertebral detachment, anterior spinal displacement, chemotherapy-induced stomatitis, Charcot neuropathic osteoarthritis. Methods for treating or reducing the severity of neuropathic angina, temporomandibular joint disorders, painful arthroplasty, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders, said methods comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0653] On the other hand, this disclosure is characterized by methods for treating or reducing the severity of pain in subjects for the following conditions: femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic lower back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tuss neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharge, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, postcardiac surgery). Postoperative pain, including pain following mastectomy, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after removal of the lower limb, upper limb, or breast), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical lower back pain, neck pain, tendinitis, injury pain, movement pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, lip pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depressive pain, leprosy pain, and Behcet's disease. Pain, painful obesity, phlebitis pain, Guillain-Barre pain, leg and toe pain, Haglund syndrome, erythromelalgia, Fabry's disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, type I complex regional pain syndrome (CRPS), type II complex regional pain syndrome (CRPS), widespread pain, paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0654] On the other hand, this disclosure is characterized by a method for treating a subject with trigeminal neuralgia, botulinum-treated migraine, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disease, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, paresthetoid femoral pain, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexus lesions, traumatic neuroma stump pain, or post-amputation pain, or for reducing its severity, said method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0655] In some embodiments, a method of treating a patient's pain, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of Compound I in any of the pharmaceutically acceptable crystalline (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is pure form A. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is pure form B. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is pure form C. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is a hemihydrate. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is a monohydrate. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is a methanol solvate of Compound I. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is a mixture A of Compound I nPA solvates. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate B. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is Compound I nPA solvate C. In some embodiments, a pharmaceutically acceptable crystalline form of Compound I is Compound I Na hemisalt nPA solvate. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I nPA solvate J. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I 2-Me THF solvate A. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I 2-Me THF solvate mixture A. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I 2-Me THF mixture C. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I mandelic acid cocrystal. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I DL-oxalate cocrystal. In some embodiments, a pharmaceutically acceptable crystalline form of compound I is compound I TFA salt A. In some embodiments, a method of treating a patient's pain or reducing its severity or treating its symptoms comprises administering to the patient an effective amount of amorphous compound I, as disclosed herein.

[0656] In some embodiments, a method of treating a patient's pain, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, a method of treating a patient's pain, or reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of amorphous compound I or a pharmaceutical composition thereof as disclosed herein.

[0657] In some embodiments, a method of treating a patient's pain, reducing its severity, or treating its symptoms comprises administering to the patient, in combination with at least one additional active pharmaceutical ingredient, an effective amount of Compound I in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, a method of treating a patient's pain, reducing its severity, or treating its symptoms comprises administering to the patient, in combination with at least one additional active pharmaceutical ingredient, an effective amount of Compound I in a solid form selected from: pure form A of Compound I, pure form B of Compound I, pure form C of Compound I, hemihydrate of Compound I, monohydrate of Compound I, methanol solvate of Compound I, mixture A of Compound I nPA solvates, compound I nPA solvates B, compound I nPA solvates C, compound I nPA hemisalt nPA solvate, compound I nPA solvate J, compound I 2-Me THF solvate A, mixture A of Compound I 2-Me THF solvates, mixture C of Compound I 2-Me THF, mandelic acid cocrystal, compound I DL-oxalate cocrystal, and compound I TFA salt A. In some embodiments, a method of treating a patient’s pain, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of an amorphous compound I as disclosed herein, in combination with at least one other active pharmaceutical ingredient.

[0658] In some embodiments, this disclosure is characterized in that compound I or a pharmaceutical composition thereof, in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, is used in any of the foregoing methods.

[0659] In some embodiments, this disclosure is characterized by the use of compound I or a pharmaceutical composition thereof in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein for the preparation of a medicament for use in any of the foregoing methods.

[0660] In some embodiments, this disclosure is characterized in that compound I or a pharmaceutical composition thereof, in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, is used as a medicament.

[0661] Other treatments

[0662] It should also be understood that the compound I and pharmaceutically acceptable compositions of any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein can be used in combination therapies, i.e., the compound and pharmaceutically acceptable composition of any of the pharmaceutically acceptable solid forms can be administered simultaneously, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapy employed may achieve the desired effect against the same condition (e.g., the compound of the present invention may be administered simultaneously with another agent for treating the same condition), or may achieve different effects (e.g., controlling any side effects). As used herein, other therapeutic agents commonly administered to treat or prevent a particular disease or symptom are referred to as “suitable for the treated disease or symptom.”For example, other exemplary therapeutic agents include (but are not limited to): non-opioid analgesics (indoles, such as etodolac, indomethacin, sulindac, tolmetin); naphthyl ketones, such as nabumetone; oxicams, such as piroxicam; para-aminophenol derivatives, such as acetaminophen; propionic acid, such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprazine; salicylates, such as aspirin, trisalicylate choline magnesium, diflunisal; and 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, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, drug-free analgesia can be achieved by combining the administration of one or more of the compounds of this invention. For example, anesthetic methods (spinal infusion, nerve block), neurosurgical methods (neurolysis of the CNS pathway), nerve stimulation methods (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy methods (physical therapy, orthopedic devices, diathermy) or psychotherapy methods (cognitive methods - hypnosis, biofeedback, or behavioral methods) can also be used.Other appropriate treatments or methods are generally described in The Merck Manual, 19th edition, edited by Robert S. Porter and Justin L. Kaplan, MerckSharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and on the website of the U.S. Food and Drug Administration (FDA) at www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0663] In another embodiment, the additional suitable therapeutic agent is selected from the following:

[0664] (1) Opioid analgesics, such as morphine, heroin, hydromorphone, hydroxymorphone, levolorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, tebuconazole or difelikefalin.

[0665] (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodoxacin, fenbufen, fenprofen, flufenisal, flurbiprofen, ibuprofen (including (but not limited to) intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketobuprofen, ketorolac (including (but not limited to) ketorolac thromboxane (e.g., Toradol®)). Meclofenamic acid, meloxicam, intravenous meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprazine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tometidine, or zomepirac.

[0666] (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methabarbital, methoexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental.

[0667] (4) Benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

[0668] (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine.

[0669] (6) Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone.

[0670] (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine.

[0671] (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphorane) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphorane), ketamine, memantine, pyrroloquinoline Quinine), cis-4-(phosphonomethyl)-2-piperidinic acid, budipine, EN-3231 (MorphiDex®, a combination of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel, which includes an NR2B antagonist such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0672] (9) α-Adrenergic, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline;

[0673] (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline.

[0674] (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate.

[0675] (12) Tachykinin (NK) antagonists, specifically NK-3, NK-2, or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacyclooctano[2,1-g][1,7]-naphthyl-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)- 1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0676] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium.

[0677] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib.

[0678] (15) Coal tar analgesics, especially paracetamol;

[0679] (16) Antipsychotic drugs, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, and sonapidazole. razole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, epilisarserin, osanetant, rimonabant, meclinertant, Miraxion®, or sarizotan.

[0680] (17) Vanillin receptor agonists (e.g., resinferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300).

[0681] (18) β-adrenergic, such as propranolol;

[0682] (19) Local anesthetics, such as mexiletine.

[0683] (20) Corticosteroids, such as dexamethasone;

[0684] (21) 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1DAgonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan.

[0685] (22) 5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907).

[0686] (23) Cholinergic (nicotine) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azacyclobutylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

[0687] (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER (Nucynta®);

[0688] (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-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)-pyrazolo[2',1':6,1]pyridolo[3,4-b] Indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azacyclobutane)-2,6-dihydro-7 H -pyrazolo[4,3- d Pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridyl)-3-ethyl-2-(1-isopropyl-3-azacyclobutane)-2,6-dihydro-7 H -pyrazolo[4,3- dPyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)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-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0689] (26) α-2-δ ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[α],3[α],5[α])(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, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-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;

[0690] (27) Cannabinoids, such as KHK-6188;

[0691] (28) Metabolic glutamate subtype 1 receptor (mGluR1) antagonists;

[0692] (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite demethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cerilamine, and trazodone;

[0693] (30) Norepinephrine (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), especially selective norepinephrine reuptake inhibitors, such as reboxetine, especially (S,S)-reboxetine;

[0694] (31) Bisserotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-demethylvenlafaxine, clomipramine, clomipramine metabolite demethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine.

[0695] (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarboxylate; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarboxylate S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolylbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarboxynitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-formamidinium, NXN-462 or guanidinoethyl disulfide;

[0696] (33) Acetylcholinesterase inhibitors, such as donepezil;

[0697] (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N -[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0698] (35) Leukotriene B4 antagonists; for example, 1-(3-biphenyl-4-ylmethyl-4-hydroxy-tryptane-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valerate (ONO-4057) or DPC-11870;

[0699] (36) 5-Lipooxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

[0700] (37) Sodium channel blockers, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate.

[0701] (38) Na V 1.7 Blockers, 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, for example, WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 (US2014) Those disclosed in 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 of which are hereby incorporated by reference;

[0702] (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl) ketone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-6-yl] ethyl ketone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl) ketone, 1-(4-diphenylmethylpiperidine-1-yl)-3- [2-(3,4-dimethylphenoxy)ethoxy]prop-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl] ketone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl) ketone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl] ketone, 5 -[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carboxylon, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1,4'-piperidine]-1'-yl]methyl ketone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-6-yl]ethyl ketone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-3-methyl-phenyl) ...-phenyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine] (propoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-6-yl] acetone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-6-yl] acetone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidine]-1'-yl] methyl ketone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-Dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]acetone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl]-2,2,2-trifluoro-acetone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin]-6-yl]-2,2,2-trifluoro-acetone, [1,4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl] ketone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridin-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-6-yl] acetone, 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-prop-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl] methyl ketone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1, [4'-piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl] ketone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidinyl)aminosulfonyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl] ketone;

[0703] (39) Na V1.8 Inhibitors, such as PF-04531083, PF-06372865, and those disclosed in the following applications: WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO201 4 / 120808 (US2014213616), WO2014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160 152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO202 0 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US2020140411), WO2020 / 261114, WO202 0 / 140959、WO2020 / 144375、WO2020 / 151728、WO2021 / 032074、WO2021 / 257490、WO2021 / 257420、WO2021 / 257418、WO2022 The blocking agents disclosed in / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, CN112479996 (WO2021 / 047622) and CN114591293, the entire contents of each of which are hereby incorporated by reference;

[0704] (39a)Na V1.8 Blockers, 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)benzamide, etc. 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 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)-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, dihydrogen phosphate [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridinyl]methyl ester, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, dihydrogen phosphate (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H) 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)pyridinecarboxylic acid, 2-(2,4-difluorophenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-3-carboxamide, 2-(4-fluoro-2-methoxy) 3-(2,4-difluorophenoxy)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-carboxamide, N-(3-aminosulfonylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-aminosulfonylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-aminosulfonylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)pyridinecarboxylic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1 H-Benz[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)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-carboxamide), N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-Dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)pyridinecarboxylic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)pyridinecarboxylic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)pyridinecarboxylic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl) 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)pyridinecarboxylic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-2-(4-fluoro-2-methoxyphenoxy)benzamido)pyridinecarboxylic 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)pyridinecarboxylic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyridinecarboxylic acid, 4-(4,5-dichloro-2-(4-) 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)pyridinecarboxylic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)pyridinecarboxylic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)pyridinecarboxylic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamido)pyridinecarboxylic acid, 2-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-aminosulfonylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N -(3-aminosulfonylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)-5-(trifluoromethyl)benzamide 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-aminosulfonylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)benzamide 4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-aminosulfonylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-aminosulfonylphenyl)-4-(trifluoromethyl)benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-aminosulfonylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-aminosulfonylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-aminosulfonylphenyl)benzamide, N-(3-aminosulfonylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl ...2-(4-(trifluoromethyl)benzamide)-2-(3-(trifluoromethoxy)phenoxy)-2-(4-(trifluoromethyl)benzamide)-2-(3-(trifluoromethoxy)phenoxy)-2-(4-(trifluoromethyl)benzamide)-2-(3-(trifluoromethoxy)phenoxy)-2-(4-(trifluoromethyl)benzamide)-2-(3-(trifluoromethoxy)phenoxy)-2-(4-(trifluoromethoxy)phenoxy)-2-(4-(trifluoromethyl)benzamide)-2-(3- N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteroxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteroxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteroxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoro... [[methoxy]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-(trideuteroxy)-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]benzene Formamide, 4-[[2-fluoro-6-[2-(trideuteroxy)-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)benz ... N-(3-aminocarbamoyl-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-(trideuteroxy)-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-(trideuteroxy)-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;

[0705] (40) Combinatorial Na V 1.7 and Na V 1.8 Blockers, such as DSP-2230, Lohocla201, or BL-1021;

[0706] (41) 5-HT3 antagonists, such as ondansetron.

[0707] (42) TPRV 1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®); and their pharmaceutically acceptable salts and solvates;

[0708] (43) Nicotine receptor antagonists, such as varenicline.

[0709] (44) N-type calcium channel antagonists, such as Z-160;

[0710] (45) Nerve growth factor antagonists, such as tanezumab.

[0711] (46) Endopeptidase stimulants, such as senrebotase.

[0712] (47) Angiotensin II antagonists, such as EMA-401;

[0713] (48) Acetaminophen (including (but not limited to) intravenous acetaminophen (e.g., Ofirmev®);

[0714] (49) Bupivacaine (including (but not limited to) bupivacaine liposome injectable suspensions (e.g., Expareel®, Bupivacaine ER (Posimir), Bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and

[0715] (50) Bupivacaine and meloxicam combination (e.g., HTX-011).

[0716] In one embodiment, other suitable 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.

[0717] In another embodiment, other suitable 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)oxetane-3-amine.

[0718] In another embodiment, other therapeutic agents are selected from GlyT2 / 5HT2 inhibitors, such as Operasenserin (VVZ149); TRPV modulators, such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652; EGR1 inhibitors, such as Brigoglide (AYX1); NGF inhibitors, such as tanizumab, fasinumab, ASP6294, or MEDI7352; µ-opioid agonists, such as cibupatol or NKTR181 (oxycodegol); CB-1 agonists, such as NEO1940 (AZN1940); imidazoline 12 agonists, such as CR4056; or p75NTR-Fc modulators, such as LEVI-04.

[0719] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0720] In another embodiment, the additional therapeutic agent is Na. V 1.7 Blockers, such as ST-2427 or 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 of which are hereby incorporated by reference.

[0721] In another embodiment, other therapeutic agents are 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, and Opiranserin (Unafra). TM), 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.

[0722] In another embodiment, other therapeutic agents are 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, LY3 556050, 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.

[0723] 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, and 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.

[0724] In another embodiment, the other therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na+ channel inhibitor identified above. V 1.7 and Na V 1.8 Blockers.

[0725] The amount of other therapeutic agents present in the compositions of the present invention may not exceed the amount typically applied in a composition containing the therapeutic agent as the sole active agent. The amount of other therapeutic agents in the compositions disclosed in the present invention may range from about 10% to 100% of the amount typically present in a composition containing the pharmaceutical agent as the sole active agent.

[0726] Compound I, or a pharmaceutically acceptable composition thereof, in any of the pharmaceutically acceptable solid forms disclosed herein, may also be incorporated into compositions for coating implantable medical devices (such as prostheses, artificial valves, artificial blood vessels, stents, and catheters). Therefore, in another aspect, the present invention includes compositions for coating implantable devices comprising any of the pharmaceutically acceptable solid forms as generally described above, as well as the classes and subclasses herein, and a carrier suitable for coating said implantable device. Still in another aspect, the present invention includes implantable devices coated with compositions comprising any of the pharmaceutically acceptable solid forms as generally described above, as well as the classes and subclasses herein, and a carrier suitable for coating said implantable device. General preparation of suitable coatings and coated implantable devices is described in U.S. Patents 6,099,562; 5,886,026 and 5,304,121. The coating is typically a biocompatible polymeric material, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further top-coated with a suitable fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combination thereof to impart controlled release characteristics to the composition.

[0727] Another aspect of the present invention relates to inhibiting Na in biological samples or subjects. V 1.8 Activity, wherein the method comprises administering to a subject any of Compound I or a pharmaceutical composition thereof in a pharmaceutically acceptable solid form disclosed herein, or contacting the biological sample therewith. As used herein, the term “biological sample” includes (but is not limited to) cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0728] Inhibiting Na in biological samples V 1.8 The activity is suitable for achieving a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying sodium channels in biological and pathological phenomena; and comparatively evaluating novel sodium channel inhibitors.

[0729] Pharmaceutical Composition

[0730] Another aspect of the invention provides a pharmaceutical composition comprising compound I in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical composition comprises compound I in solid form selected from: pure form A of compound I, pure form B of compound I, pure form C of compound I, amorphous compound I, hemihydrate of compound I, monohydrate of compound I, methanol solvate of compound I, mixture A of compound I nPA solvates, compound I nPA solvates B, compound I nPA solvates C, compound I Na hemisalt nPA solvate, compound I nPA solvate J, compound I 2-Me THF solvate A, mixture A of compound I 2-Me THF solvates, mixture C of compound I 2-Me THF, mandelic acid cocrystal, compound I DL-oxalic acid cocrystal, and compound I TFA salt A.

[0731] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) a compound I in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; and (b) at least one pharmaceutically acceptable carrier.

[0732] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) a compound I in solid form selected from the following: pure form A of compound I, pure form B of compound I, pure form C of compound I, amorphous compound I, hemihydrate of compound I, monohydrate of compound I, methanol solvate of compound I, mixture A of compound I nPA solvates, compound I nPA solvate B, compound I nPA solvate C, compound I Na hemisalt nPA solvate, compound I nPA solvate J, compound I 2-Me THF solvate A, mixture A of compound I 2-Me THF solvates, mixture C of compound I 2-Me THF, mandelic acid cocrystal, compound I DL-oxalate cocrystal, and compound I TFA salt A, and (b) at least one pharmaceutically acceptable carrier.

[0733] As described herein, pharmaceutically acceptable compositions of the present invention may further comprise pharmaceutically acceptable carriers, adjuvants, or mediators, as used herein, including any and all solvents, diluents or other liquid mediators, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit a particular desired dosage form. Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and their known preparation techniques. Unless any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effects or otherwise interacting in a harmful manner with any other component of the pharmaceutically acceptable composition, its use is considered to be within the scope of the present invention. Some examples of substances that 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; buffering substances, such as phosphates, glycine, sorbic acid, or potassium sorbate; mixtures of glycerides 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; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; lanolin; sugars, such as lactose, glucose... Sugars 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 gum; 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 as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic, compatible lubricants, such as sodium lauryl sulfate and magnesium stearate; as well as colorants, release agents, coating agents, sweeteners, flavoring agents and aromatizers, preservatives and antioxidants may also be present in the composition at the formulator's discretion.

[0734] Radiolabeled analogues of compound I

[0735] On the other hand, the present invention relates to radiolabeled analogues of compound I. The radiolabeled analogues 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.

[0736] As used herein, terminology " Compound I Radiolabeled analogues This refers to a compound that is the same as compound I as described in this article, except that one or more atoms have been replaced by radioactive isotopes of atoms present in compound I.

[0737] As used herein, terminology " radioactive isotopes ” Radioactive isotopes are isotopes of elements that are known to undergo spontaneous radioactive decay. Examples of radioactive isotopes include... 3 H, 14 C 32 P, 35 S, 18 F, 36 Cl, and isotopes whose decay patterns were identified in VS Shirley and CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0738] Radiolabeled analogues can be used in a variety of advantageous ways, including for various types of assays, such as substrate tissue distribution assays. For example, tritium (… 3 H) and / or carbon-14 ( 14 C) Labeled compounds are suitable for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0739] On the other hand, according to any of the embodiments described herein in conjunction with Compound I, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs.

[0740] On the other hand, according to any embodiment described herein in conjunction with Compound I, the present invention relates to pharmaceutical compositions comprising a radiolabeled analog or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or mediator.

[0741] On the other hand, according to any embodiment described herein in conjunction with Compound I, the present invention relates to a method for inhibiting voltage-gated sodium channels and a method for treating or reducing the severity of various diseases and conditions (including pain) in a subject, the method comprising administering an effective amount of a radiolabeled analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.

[0742] On the other hand, according to any of the embodiments described herein in conjunction with Compound I, the present invention relates to radiolabeled analogs for use, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

[0743] On the other hand, according to any embodiment described herein in conjunction with Compound I, the present invention relates to the use of radiolabeled analogues or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof for the preparation of pharmaceutical preparations.

[0744] On the other hand, according to any of the embodiments described herein in conjunction with Compound I, radiolabeled analogs, their pharmaceutically acceptable salts, and their pharmaceutical compositions may be used in combination therapies.

[0745] Non-limiting exemplary embodiments

[0746] Further embodiments of this disclosure are illustrated in the following numbered entries:

[0747] 1. A compound I in its pure form A.

[0748] 2. Compound I in pure form A according to Example 1, wherein compound I in pure 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, and wherein less than 5% of compound I is in amorphous form).

[0749] 3. Compound I in pure form A according to Example 1 or 2, wherein compound I in pure form A is substantially 100% crystalline.

[0750] 4. Compound I in pure form A according to any one of Examples 1 to 3, wherein compound I in pure form A is 100% crystalline.

[0751] 5. Compound I in pure form A according to any one of Examples 1 to 4, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ and 10.4 ± 0.2° 2θ.

[0752] 6. Compound I in pure form A according to Example 5, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 12.8 ± 0.2° 2θ, 16.0 ± 0.2° 2θ and 20.4 ± 0.2° 2θ.

[0753] 7. Compound I in pure form A according to Example 6, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 8.0 ± 0.2° 2θ, 17.3 ± 0.2° 2θ and 18.7 ± 0.2° 2θ.

[0754] 8. Compound I in pure form A according to any one of Examples 1 to 4, characterized by an X-ray powder diffraction pattern having the following signals: 5.5 ± 0.2° 2θ, 8.0 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 11.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 22.8 ± 0.2° 2θ, 23.9 ± 0.2° 2θ, 27.4 ± 0.2° 2θ, 27.7 ± 0.2° 2θ, 29.5 ± 0.2° 2θ and 29.9 ± 0.2° 2θ.

[0755] 9. Compound I in pure form A according to any one of Examples 1 to 4, characterized in that it is substantially similar to... Figure 8 X-ray powder diffraction pattern.

[0756] 10. Compound I in pure form A according to any one of Examples 1 to 9, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 36.2 ± 0.2 ppm, 30.3 ± 0.2 ppm, 29.5 ± 0.2 ppm and 20.4 ± 0.2 ppm.

[0757] 11. Compound I, pure form A, according to any one of Examples 1 to 9, characterized in that it has peaks at the following locations: 13C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0758] 12. Compound I in pure form A according to any one of Examples 1 to 9, characterized in that it is substantially similar to... Figure 9A of 13 C SSNMR spectrum.

[0759] 13. Compound I in pure form A according to any one of Examples 1 to 12, characterized in that it is prepared by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0760] .

[0761] 14. A compound I hemihydrate.

[0762] 15. The compound I hemihydrate according to Example 14, wherein the compound I hemihydrate 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, and wherein less than 5% of compound I is in amorphous form).

[0763] 16. The compound I hemihydrate according to Example 14 or 15, wherein the compound I hemihydrate is substantially 100% crystalline.

[0764] 17. The compound I hemihydrate according to any one of Examples 14 to 16, wherein the compound I hemihydrate is 100% crystalline.

[0765] 18. The compound I hemihydrate according to any one of Examples 14 to 17, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ and 12.3 ± 0.2° 2θ.

[0766] 19. The compound I hemihydrate according to Example 18, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 14.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ and 26.6 ± 0.2° 2θ.

[0767] 20. The compound I hemihydrate according to Example 19, characterized in that it has one or two X-ray powder diffraction patterns selected from 11.1 ± 0.2° 2θ and 21.3 ± 0.2° 2θ.

[0768] 21. The compound I hemihydrate according to any one of Examples 14 to 17, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ and 26.6 ± 0.2° 2θ.

[0769] 22. The compound I hemihydrate according to any one of Examples 14 to 17, characterized in that it is substantially similar to Figure 14 X-ray powder diffraction pattern.

[0770] 23. The compound I hemihydrate according to any one of Examples 14 to 22, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13CSSNMR spectrum: 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.

[0771] 24. The compound I hemihydrate according to any one of Examples 14 to 22, characterized in that it has peaks at the following locations: 13 C SSNMR spectrum: 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.

[0772] 25. The compound I hemihydrate according to any one of Examples 14 to 22, characterized in that it is substantially similar to Figure 15 of 13 C SSNMR spectrum.

[0773] 26. A compound I-hydrate.

[0774] 27. The compound I monohydrate according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0775] 28. The compound I monohydrate according to Example 26 or 27, wherein the compound I monohydrate is substantially 100% crystalline.

[0776] 29. The compound I monohydrate according to any one of Examples 26 to 28, wherein the compound I hemihydrate is 100% crystalline.

[0777] 30. The compound I monohydrate according to any one of Examples 26 to 29, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ and 14.2 ± 0.2° 2θ.

[0778] 31. The compound I monohydrate according to Example 30, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 12.2 ± 0.2° 2θ, 22.0 ± 0.2° 2θ and 26.5 ± 0.2° 2θ.

[0779] 32. The compound I monohydrate according to Example 31, characterized in that it has one or two X-ray powder diffraction patterns selected from signals of 17.1 ± 0.2° 2θ, 21.3 ± 0.2° 2θ and 23.5 ± 0.2° 2θ.

[0780] 33. The compound I monohydrate according to any one of Examples 26 to 29, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.8 ± 0.2° 2θ, 18.1 ± 0.2° 2θ, 20.3 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 22.0 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 26.5 ± 0.2° 2θ, 27.4 ± 0.2° 2θ, and 31.7 ± 0.2° 2θ.

[0781] 34. The compound I monohydrate according to any one of Examples 26 to 29, characterized in that it is substantially similar to Figure 16 X-ray powder diffraction pattern.

[0782] 35. A methanol solvate of compound I.

[0783] 36. The methanol solvate of compound I according to Example 35, wherein the methanol solvate of compound I 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, and wherein less than 5% of compound I is in amorphous form).

[0784] 37. The methanol solvate of compound I according to Example 35 or 36, wherein the methanol solvate of compound I is substantially 100% crystalline.

[0785] 38. The methanol solvate of compound I according to any one of Examples 35 to 37, wherein the methanol solvate of compound I is 100% crystalline.

[0786] 39. The methanol solvate of compound I according to any one of Examples 35 to 38, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ and 10.6 ± 0.2° 2θ.

[0787] 40. The methanol solvate of compound I according to Example 39, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ and 20.9 ± 0.2° 2θ.

[0788] 41. The methanol solvate of compound I according to Example 40, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ and 21.1 ± 0.2° 2θ.

[0789] 42. The methanol solvate of compound I according to any one of Examples 35 to 38, characterized in that it has an X-ray powder diffraction pattern having the following signals: 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.9 ± 0.2° 2θ and 21.1 ± 0.2° 2θ.

[0790] 43. The methanol solvate of compound I according to any one of Examples 35 to 38, characterized in that it is substantially similar to Figure 17 X-ray powder diffraction pattern.

[0791] 44. The methanol solvate of Compound I according to any one of Examples 35 to 43, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13CSSNMR spectrum: 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 ± 0.2ppm, 19.1 ± 0.2 ppm and 18.8 ± 0.2 ppm.

[0792] 45. The methanol solvate of compound I according to any one of Examples 35 to 43, characterized in that it has peaks at the following locations: 13C SSNMR spectrum: 178.3 ± 0.2 ppm, 177.4 ± 0.2 ppm, 172.8 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0793] 46. ​​The methanol solvate of compound I according to any one of Examples 35 to 43, characterized in that it is substantially similar to Figure 18 of 13 C SSNMR spectrum.

[0794] 47. The methanol solvate of compound I according to any one of Examples 35 to 46, characterized by a triclinic crystal system, space group P-1, and Cu K using the following... α Cell size measured at 100 K on a diffractometer for radiation (λ = 1.54178 Å):

[0795] .

[0796] 48. A compound I in pure form B according to any one of the embodiments, as set forth in section B above.

[0797] 49. A compound I in pure form C according to any one of the embodiments, as set forth in part C above.

[0798] 50. An amorphous compound I according to any one of the embodiments, as set forth in section R above.

[0799] 51. A mixture A of inPA solvates.

[0800] 52. The compound I nPA solvate mixture A according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0801] 53. The InPA solvate mixture A according to Example 51 or 52, wherein the InPA solvate mixture A is substantially 100% crystalline.

[0802] 54. The compound InPA solvate mixture A according to any one of Examples 51 to 53, wherein the compound InPA solvate mixture A is 100% crystalline.

[0803] 55. The compound InPA solvate mixture A according to any one of Examples 51 to 54, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ and 10.6 ± 0.2° 2θ.

[0804] 56. The compound InPA solvate mixture A according to Example 55, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 10.1 ± 0.2° 2θ, 13.7 ± 0.2° 2θ and 18.8 ± 0.2° 2θ.

[0805] 57. The compound InPA solvate mixture A according to Example 56, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 13.5 ± 0.2° 2θ, 14.3 ± 0.2° 2θ and 25.5 ± 0.2° 2θ.

[0806] 58. The compound InPA solvate mixture A according to any one of Examples 51 to 54, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 10.1 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 18.4 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 22.8 ± 0.2° 2θ, 23.3 ± 0.2° 2θ, 25.5 ± 0.2° 2θ, and 26.1 ± 0.2° 2θ.

[0807] 59. The compound InPA solvate mixture A according to any one of Examples 51 to 54, characterized in that it is substantially similar to Figure 19 X-ray powder diffraction pattern.

[0808] 60. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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.

[0809] 61. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it has peaks at the following locations: 13C SSNMR spectrum: 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.

[0810] 62. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it is substantially similar to Figure 20 of 13 C SSNMR spectrum.

[0811] 63. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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 ± 0.2ppm, 24.9 ± 0.2 ppm, 20.9 ± 0.2 ppm, 13.4 ± 0.2 ppm and 11.7 ± 0.2 ppm.

[0812] 64. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it has peaks at the following locations: 13 C SSNMR spectrum: 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 ± 0.2ppm, 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.

[0813] 65. The compound InPA solvate mixture A according to any one of Examples 51 to 59, characterized in that it is substantially similar to Figure 21 of 13 C SSNMR spectrum.

[0814] 66. The compound InPA solvate mixture A according to any one of Examples 51 to 65, characterized in that it is prepared by using Cu K on a diffractometer. α The radiation (λ = 1.54178 Å) measured at 100 K in a monoclinic crystal system C2 / c Space group and the following cell sizes:

[0815] .

[0816] 67. A mixture B of a compound InPA solvates.

[0817] 68. The compound I nPA solvate mixture B according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0818] 69. The InPA solvate mixture B according to Example 67 or 68, wherein the InPA solvate mixture B is substantially 100% crystalline.

[0819] 70. The compound InPA solvate mixture B according to any one of Examples 67 to 69, wherein the compound InPA solvate mixture B is 100% crystalline.

[0820] 71. The compound InPA solvate mixture B according to any one of Examples 67 to 70, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ and 10.6 ± 0.2° 2θ.

[0821] 72. The compound InPA solvate mixture B according to Example 71, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 9.9 ± 0.2° 2θ, 13.2 ± 0.2° 2θ and 14.8 ± 0.2° 2θ.

[0822] 73. The compound InPA solvate mixture B according to Example 72, characterized in that it has one or two X-ray powder diffraction patterns selected from signals of 18.9 ± 0.2° 2θ and 21.4 ± 0.2° 2θ.

[0823] 74. The compound InPA solvate mixture B according to any one of Examples 67 to 70, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 9.9 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 18.0 ± 0.2° 2θ, 18.9 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 22.6 ± 0.2° 2θ, 22.9 ± 0.2° 2θ, 24.6 ± 0.2° 2θ, 25.7 ± 0.2° 2θ, 26.1 ± 0.2° 2θ, 26.5 ± 0.2° 2θ, and 28.1 ± 0.2° 2θ.

[0824] 75. The compound InPA solvate mixture B according to any one of Examples 67 to 70, characterized in that it is substantially similar to Figure 22 X-ray powder diffraction pattern.

[0825] 76. The compound InPA solvate mixture B according to any one of Examples 67 to 75, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13 C SSNMR spectrum: 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.

[0826] 77. The compound InPA solvate mixture B according to any one of Examples 67 to 75, characterized in that it has peaks at the following locations: 13 C SSNMR spectrum: 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.

[0827] 78. The compound InPA solvate mixture B according to any one of Examples 67 to 75, characterized in that it is substantially similar to Figure 23 of 13 C SSNMR spectrum.

[0828] 79. The compound InPA solvate mixture B according to any one of Examples 67 to 78, characterized in that it is prepared by using Cu K on a diffractometer. αTriclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0829] .

[0830] 80. A compound InPA solvate C.

[0831] 81. The compound InPA solvate C according to Example 80, wherein the compound InPA 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, and wherein less than 5% of compound I is in amorphous form).

[0832] 82. The compound InPA solvate C according to Example 80 or 81, wherein the compound InPA solvate C is substantially 100% crystalline.

[0833] 83. The InPA solvate C of any one of Examples 80 to 82, wherein the InPA solvate C is 100% crystalline.

[0834] 84. The compound InPA solvate C according to any one of Examples 80 to 83, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 6.1 ± 0.2° 2θ, 11.8 ± 0.2° 2θ and 12.2 ± 0.2° 2θ.

[0835] 85. The compound InPA solvate C according to Example 84, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 7.2 ± 0.2° 2θ, 14.6 ± 0.2° 2θ and 15.8 ± 0.2° 2θ.

[0836] 86. The compound InPA solvate C according to Example 85, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.4 ± 0.2° 2θ, 8.7 ± 0.2° 2θ and 10.2 ± 0.2° 2θ.

[0837] 87. The compound InPA solvate C according to any one of Examples 80 to 83, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.3 ± 0.2° 2θ, 6.1 ± 0.2° 2θ, 7.2 ± 0.2° 2θ, 8.7 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, 12.2 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 17.5 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, and 20.5 ± 0.2° 2θ.

[0838] 88. Compound InPA solvate C according to any one of Examples 80 to 83, characterized in that it is substantially similar to Figure 24 X-ray powder diffraction pattern.

[0839] 89. A compound I Na semi-salt nPA solvate.

[0840] 90. The compound I Na hemi-salt nPA solvate according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0841] 91. The compound I Na semi-salt nPA solvate according to Example 89 or 90, wherein the compound I Na semi-salt nPA solvate is substantially 100% crystalline.

[0842] 92. The compound I Na semi-salt nPA solvate according to any one of Examples 89 to 91, wherein the compound I Na semi-salt nPA solvate is 100% crystalline.

[0843] 93. The compound I Na semi-salt nPA solvate according to any one of Examples 89 to 92, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 6.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ and 14.9 ± 0.2° 2θ.

[0844] 94. The compound I Na semi-salt nPA solvate according to Example 93, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 13.4 ± 0.2° 2θ, 17.3 ± 0.2° 2θ and 18.7 ± 0.2° 2θ.

[0845] 95. The compound I Na semi-salt nPA solvate according to Example 94, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 5.2 ± 0.2° 2θ, 8.8 ± 0.2° 2θ and 10.3 ± 0.2° 2θ.

[0846] 96. The compound I Na hemisal nPA solvate according to any one of Examples 89 to 92, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.2 ± 0.2° 2θ, 6.7 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 9.8 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 13.6 ± 0.2° 2θ, 13.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, 14.2 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 18.7 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 20.6 ± 0.2° 2θ, 21.0 ± 0.2° 2θ, 24.6 ± 0.2° 2θ, 26.4 ± 0.2° 2θ, 26.6 ± 0.2° 2θ and 28.4 ± 0.2° 2θ.

[0847] 97. The compound I Na half-salt nPA solvate according to any one of Examples 89 to 92, characterized in that it is substantially similar to Figure 25 X-ray powder diffraction pattern.

[0848] 98. The compound I Na half-salt nPA solvate according to any one of Examples 89 to 97, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13C SSNMR spectrum: 178.0 ± 0.2 ppm, 176.8 ± 0.2 ppm, 175.7 ± 0.2 ppm, 174.2 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0849] 99. The compound I Na half-salt nPA solvate according to any one of Examples 89 to 97, characterized in that it has peaks at the following locations: 13C SSNMR spectrum: 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.

[0850] 100. The compound I Na half-salt nPA solvate according to any one of Examples 89 to 97, characterized in that it is substantially similar to Figure 26 of 13 C SSNMR spectrum.

[0851] 101. The compound I Na half-salt nPA solvate according to any one of Examples 89 to 100, characterized in that it is prepared by using Cu K on a diffractometer. α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å):

[0852] .

[0853] 102. A compound InPA solvate J.

[0854] 103. The compound I inPA solvate J according to Example 102, wherein the compound I inPA 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, and wherein less than 5% of compound I is in amorphous form).

[0855] 104. The compound InPA solvate J according to Example 102 or 103, wherein the compound InPA solvate J is substantially 100% crystalline.

[0856] 105. The compound InPA solvate J according to any one of Examples 102 to 104, wherein the compound InPA solvate J is 100% crystalline.

[0857] 106. The compound InPA solvate J according to any one of Examples 102 to 105, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.3 ± 0.2° 2θ, 10.4 ± 0.2° 2θ and 19.0 ± 0.2° 2θ.

[0858] 107. The compound InPA solvate J according to Example 106, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 8.8 ± 0.2° 2θ, 10.6 ± 0.2° 2θ and 13.4 ± 0.2° 2θ.

[0859] 108. The compound InPA solvate J according to Example 107, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 14.1 ± 0.2° 2θ, 19.2 ± 0.2° 2θ and 26.0 ± 0.2° 2θ.

[0860] 109. The compound InPA solvate J according to any one of Examples 102 to 105, characterized in that it has an X-ray powder diffraction pattern having the following signals: 3.1 ± 0.2° 2θ, 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, 10.0 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 19.0 ± 0.2° 2θ, 19.2 ± 0.2° 2θ, 26.0 ± 0.2° 2θ, and 26.4 ± 0.2° 2θ.

[0861] 110. The compound InPA solvate J according to any one of Examples 102 to 105, characterized in that it is substantially similar to Figure 27 X-ray powder diffraction pattern.

[0862] 111. A compound I 2-MeTHF solvate A.

[0863] 112. The compound I 2-MeTHF solvate A according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0864] 113. Compound I2-MeTHF solvate A according to Example 111 or 112, wherein compound I2-MeTHF solvate A is substantially 100% crystalline.

[0865] 114. Compound I 2-MeTHF solvate A according to any one of Examples 111 to 113, wherein compound I 2-MeTHF solvate A is 100% crystalline.

[0866] 115. Compound I 2-MeTHF solvate A according to any one of Examples 111 to 114, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ and 14.0 ± 0.2° 2θ.

[0867] 116. The compound I 2-MeTHF solvate A according to Example 115, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 9.8 ± 0.2° 2θ, 10.3 ± 0.2° 2θ and 15.4 ± 0.2° 2θ.

[0868] 117. The compound I 2-MeTHF solvate A according to Example 116, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 17.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ and 20.8 ± 0.2° 2θ.

[0869] 118. Compound I 2-MeTHF solvate A according to any one of Examples 111 to 114, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 9.8 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 14.0 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 18.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 20.8 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, and 25.3 ± 0.2° 2θ.

[0870] 119. Compound I 2-MeTHF solvate A according to any one of Examples 111 to 114, characterized in that it is substantially similar to Figure 28 X-ray powder diffraction pattern.

[0871] 120. A mixture A of 2-MeTHF solvates of compound I.

[0872] 121. The compound I 2-MeTHF solvate mixture A according to Example 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, and wherein less than 5% of compound I is in amorphous form).

[0873] 122. The compound I 2-MeTHF solvate mixture A according to Example 120 or 121, wherein the compound I 2-MeTHF solvate mixture A is substantially 100% crystalline.

[0874] 123. The compound I 2-MeTHF solvate mixture A according to any one of Examples 120 to 122, wherein the compound I 2-MeTHF solvate A is 100% crystalline.

[0875] 124. The compound I 2-MeTHF solvate mixture A according to any one of Examples 120 to 123, characterized in that it has an X-ray powder diffraction pattern with a signal of 4.6 ± 0.2° 2θ.

[0876] 125. The compound I 2-MeTHF solvate mixture A according to Example 124, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 15.8 ± 0.2° 2θ, 18.8 ± 0.2° 2θ and 25.3 ± 0.2° 2θ.

[0877] 126. The compound I 2-MeTHF solvate mixture A according to Example 125, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 12.4 ± 0.2° 2θ, 14.8 ± 0.2° 2θ and 25.3 ± 0.2° 2θ.

[0878] 127. The compound I 2-MeTHF solvate mixture A according to any one of Examples 120 to 124, characterized in that it has an X-ray powder diffraction pattern having the following signals: 4.6 ± 0.2° 2θ, 12.4 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 19.4 ± 0.2° 2θ, 21.9 ± 0.2° 2θ and 25.3 ± 0.2° 2θ.

[0879] 128. The compound I 2-MeTHF solvate mixture A according to any one of Examples 120 to 124, characterized in that it is substantially similar to Figure 29 X-ray powder diffraction pattern.

[0880] 129. A mixture of compounds I 2-MeTHF C.

[0881] 130. The compound I 2-MeTHF mixture C according to Example 129, wherein the compound I 2-MeTHF solvate 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, and wherein less than 5% of compound I is in amorphous form).

[0882] 131. The compound I 2-MeTHF mixture C according to Example 129 or 130, wherein the compound I 2-MeTHF mixture C is substantially 100% crystalline.

[0883] 132. The compound I 2-MeTHF mixture C according to any one of Examples 129 to 131, wherein the compound I 2-MeTHF mixture C is 100% crystalline.

[0884] 133. The compound I 2-MeTHF mixture C according to any one of Examples 129 to 132, characterized in that it has an X-ray powder diffraction pattern with a signal of 4.9 ± 0.2° 2θ.

[0885] 134. The compound I 2-MeTHF mixture C according to Example 133, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 8.2 ± 0.2° 2θ, 17.2 ± 0.2° 2θ and 18.5 ± 0.2° 2θ.

[0886] 135. The compound I 2-MeTHF mixture C according to Example 134, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 15.3 ± 0.2° 2θ, 15.8 ± 0.2° 2θ and 23.1 ± 0.2° 2θ.

[0887] 136. The compound I 2-MeTHF mixture C according to any one of Examples 129 to 132, characterized in that it has an X-ray powder diffraction pattern having the following signals: 4.9 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 10.3 ± 0.2° 2θ, 11.3 ± 0.2° 2θ, 15.3 ± 0.2° 2θ, 15.7 ± 0.2° 2θ, 15.8 ± 0.2° 2θ, 17.2 ± 0.2° 2θ, 18.5 ± 0.2° 2θ, 19.6 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 25.0 ± 0.2° 2θ, and 25.2 ± 0.2° 2θ.

[0888] 137. The compound I 2-MeTHF mixture C according to any one of Examples 129 to 1329, characterized in that it is substantially similar to Figure 30 X-ray powder diffraction pattern.

[0889] 138. A compound I mandelic acid eutectic.

[0890] 139. The compound I mandelic acid eutectic according to Example 138, wherein the compound I mandelic acid eutectic 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, and wherein less than 5% of compound I is in amorphous form).

[0891] 140. The compound I mandelic acid eutectic according to Example 138 or 139, wherein the compound I mandelic acid eutectic is substantially 100% crystalline.

[0892] 141. The compound I mandelic acid eutectic according to any one of Examples 138 to 140, wherein the compound I mandelic acid eutectic is 100% crystalline.

[0893] 142. The compound I mandelic acid eutectic according to any one of Examples 138 to 141, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 6.6 ± 0.2° 2θ, 10.6 ± 0.2° 2θ and 21.1 ± 0.2° 2θ.

[0894] 143. The compound I mandelic acid eutectic according to Example 142, characterized in that it has one, two or three X-ray powder diffraction patterns selected from 8.4 ± 0.2° 2θ, 17.6 ± 0.2° 2θ and 18.8 ± 0.2° 2θ.

[0895] 144. The compound I mandelic acid eutectic according to Example 143, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ and 20.9 ± 0.2° 2θ.

[0896] 145. The compound I mandelic acid eutectic according to any one of Examples 138 to 141, characterized in that it has an X-ray powder diffraction pattern having the following signals: 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 13.3 ± 0.2° 2θ, 15.9 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 18.8 ± 0.2° 2θ, 20.9 ± 0.2° 2θ and 21.1 ± 0.2° 2θ.

[0897] 146. The compound I mandelic acid eutectic according to any one of Examples 138 to 141, characterized in that it is substantially similar to Figure 31 X-ray powder diffraction pattern.

[0898] 147. A compound I oxalic acid eutectic.

[0899] 148. The oxalic acid eutectic of compound I according to Example 147, wherein the oxalic acid eutectic of compound I 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, and wherein less than 5% of compound I is in amorphous form).

[0900] 149. The oxalic acid eutectic of compound I according to Example 147 or 148, wherein the oxalic acid eutectic of compound I is substantially 100% crystalline.

[0901] 150. The oxalic acid eutectic of compound I according to any one of Examples 147 to 149, wherein the oxalic acid eutectic of compound I is 100% crystalline.

[0902] 151. The oxalic acid eutectic of compound I according to any one of Examples 147 to 150, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 8.9 ± 0.2° 2θ, 11.6 ± 0.2° 2θ and 14.5 ± 0.2° 2θ.

[0903] 152. The oxalic acid eutectic of compound I according to Example 151, characterized in that it has one or two X-ray powder diffraction patterns selected from 5.7 ± 0.2° 2θ and 20.1 ± 0.2° 2θ.

[0904] 153. The oxalic acid eutectic of compound I according to Example 152, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 10.6 ± 0.2° 2θ, 13.8 ± 0.2° 2θ and 22.9 ± 0.2° 2θ.

[0905] 154. The oxalic acid eutectic of compound I according to any one of Examples 147 to 150, characterized in that it has an X-ray powder diffraction pattern having the following signals: 5.7 ± 0.2° 2θ, 8.9 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, 13.8 ± 0.2° 2θ, 14.5 ± 0.2° 2θ, 20.1 ± 0.2° 2θ and 22.9 ± 0.2° 2θ.

[0906] 155. The oxalic acid eutectic of compound I according to any one of Examples 147 to 150, characterized in that it is substantially similar to Figure 32 X-ray powder diffraction pattern.

[0907] 156. The oxalic acid eutectic of compound I according to any one of Examples 147 to 155, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following: 13CSSNMR spectrum: 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.

[0908] 157. The oxalic acid eutectic of compound I according to any one of Examples 147 to 155, characterized in that it has peaks at the following locations: 13 C SSNMR spectrum: 177.5 ± 0.2 ppm, 169.8 ± 0.2 ppm, 169.5 ± 0.2ppm, 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 ± 0.2ppm, 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.

[0909] 158. The oxalic acid eutectic of compound I according to any one of Examples 147 to 155, characterized in that it is substantially similar to Figure 33 of 13 C SSNMR spectrum.

[0910] 159. A compound I TFA salt A.

[0911] 160. Compound I TFA salt A according to Example 159, wherein 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, and wherein less than 5% of compound I is in amorphous form).

[0912] 161. The compound I TFA salt A according to Example 159 or 160, wherein the compound I TFA salt A is substantially 100% crystalline.

[0913] 162. The ITFA salt A of any one of Examples 159 to 161, wherein the ITFA salt A is 100% crystalline.

[0914] 163. The compound I TFA salt A according to any one of Examples 159 to 162, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 8.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ and 19.7 ± 0.2° 2θ.

[0915] 164. The compound I TFA salt A according to Example 163, characterized in that it has one or two X-ray powder diffraction patterns selected from 4.4 ± 0.2° 2θ and 11.4 ± 0.2° 2θ.

[0916] 165. The compound I TFA salt A according to Example 164, characterized in that it has one, two or three X-ray powder diffraction patterns selected from signals of 17.3 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.3 ± 0.2° 2θ.

[0917] 166. The compound I TFA salt A according to any one of Examples 159 to 162, characterized in that it has an X-ray powder diffraction pattern with the following signals: 4.4 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, 11.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, 17.3 ± 0.2° 2θ, 19.7 ± 0.2° 2θ, 20.4 ± 0.2° 2θ, 23.8 ± 0.2° 2θ and 26.3 ± 0.2° 2θ.

[0918] 167. The compound I TFA salt A according to any one of Examples 159 to 162, characterized in that it is substantially similar to Figure 34 X-ray powder diffraction pattern.

[0919] 168. Compound I TFA salt A according to any one of Examples 159 to 167, characterized in that it has one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 CSSNMR spectrum: 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.

[0920] 169. Compound I TFA salt A according to any one of Examples 159 to 167, characterized in that it has peaks at the following locations: 13 C SSNMR spectrum: 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.

[0921] 170. The compound I TFA salt A according to any one of Examples 159 to 167, characterized in that it is substantially similar to Figure 35 of 13 C SSNMR spectrum.

[0922] 171. A pharmaceutical composition comprising compound I according to any one of Examples 1 to 170.

[0923] 172. The pharmaceutical composition according to Example 171 further comprises one or more additional therapeutic agents.

[0924] 173. Compound I according to any one of Examples 1 to 170 or the pharmaceutical composition according to Examples 198 or 199, used to treat or reduce the severity of pain in a subject.

[0925] 174. The compound I or pharmaceutical composition for use according to Example 173, wherein the pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tuss syndrome, incontinence, pathological cough, or arrhythmia.

[0926] 175. The compound I or pharmaceutical composition for use according to Example 174, wherein the pain comprises neuropathic pain.

[0927] 176. The compound I or pharmaceutical composition for use according to Example 175, wherein the neuropathic pain comprises postherpetic neuralgia.

[0928] 177. The compound I or pharmaceutical composition for use according to Example 175, wherein the neuropathic pain comprises small fiber neuropathy.

[0929] 178. The compound I or pharmaceutical composition for use according to Example 175, wherein the neuropathic pain comprises idiopathic small fiber neuropathy.

[0930] 179. The compound I or pharmaceutical composition for use according to Example 175, wherein the neuropathic pain comprises diabetic neuropathy.

[0931] 180. The compound I or pharmaceutical composition for use according to Example 179, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.

[0932] 181. The compound I or pharmaceutical composition for use according to Example 173, wherein the pain comprises musculoskeletal pain.

[0933] 182. The compound I or pharmaceutical composition for use according to Example 181, wherein the musculoskeletal pain includes osteoarthritis pain.

[0934] 183. The compound I or pharmaceutical composition for use according to Example 173, wherein the pain comprises acute pain.

[0935] 184. The compound I or pharmaceutical composition for use according to Example 183, wherein the acute pain comprises acute postoperative pain.

[0936] 185. The compound I or pharmaceutical composition for use according to Example 173, wherein the pain comprises postoperative pain.

[0937] 186. The compound I or pharmaceutical composition for use according to Example 185, wherein the postoperative pain includes pain from bunion excision.

[0938] 187. The compound I or pharmaceutical composition for use according to Example 185, wherein the postoperative pain includes abdominoplasty pain.

[0939] 188. The compound I or pharmaceutical composition for use according to Example 185, wherein the postoperative pain includes pain from hernia repair surgery.

[0940] 189. The compound I or pharmaceutical composition for use according to Example 173, wherein the pain comprises visceral pain.

[0941] 190. The compound I or pharmaceutical composition for use according to any one of Examples 173 to 189, wherein the compound or pharmaceutical composition is to be administered in combination with one or more other therapeutic agents.

[0942] 191. The compound I or pharmaceutical composition for use according to Example 190, wherein the one or more additional therapeutic agents comprise one or more additional pain-modifying compounds.

[0943] 192. Use of compound I according to any one of Examples 1 to 170 or of the pharmaceutical composition according to Examples 171 or 172 for the preparation of a medicament for treating pain in a subject or reducing the severity of pain in a subject.

[0944] 193. The use according to Example 192, wherein the pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tuss syndrome, incontinence, pathological cough, or arrhythmia.

[0945] 194. The use according to Example 193, wherein the pain comprises neuropathic pain.

[0946] 195. The use according to Example 194, wherein the neuropathic pain includes postherpetic neuralgia.

[0947] 196. The use according to Example 194, wherein the neuropathic pain comprises small fiber neuropathy.

[0948] 197. The use according to Example 194, wherein the neuropathic pain comprises idiopathic small fiber neuropathy.

[0949] 198. The use according to Example 194, wherein the neuropathic pain includes diabetic neuropathy.

[0950] 199. The use according to Example 198, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.

[0951] 200. The use according to Example 193, wherein the pain includes musculoskeletal pain.

[0952] 201. The use according to Example 200, wherein the musculoskeletal pain includes osteoarthritis pain.

[0953] 202. The use according to Example 193, wherein the pain includes acute pain.

[0954] 203. The use according to Example 202, wherein the acute pain includes acute postoperative pain.

[0955] 204. The use according to Example 193, wherein the pain includes postoperative pain.

[0956] 205. The use according to Example 204, wherein the postoperative pain includes pain from bunion excision.

[0957] 206. The use according to Example 204, wherein the postoperative pain includes pain from abdominoplasty.

[0958] 207. The use according to Example 204, wherein the postoperative pain includes pain from hernia repair surgery.

[0959] 208. The use according to Example 193, wherein the pain includes visceral pain.

[0960] 209. The use according to any one of Examples 192 to 208, wherein the drug is used in combination with one or more other therapeutic agents.

[0961] 210. The use according to Example 209, wherein the one or more additional therapeutic agents comprise one or more additional pain-modifying compounds.

[0962] 211. A method for treating pain in a subject or reducing the severity of pain in a subject, the method comprising administering compound I according to any one of Examples 1 to 170 or the pharmaceutical composition according to Examples 171 or 172.

[0963] 212. The method according to Example 211, wherein the pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Toussaint syndrome, incontinence, pathological cough, or arrhythmia.

[0964] 213. The method according to Example 212, wherein the pain comprises neuropathic pain.

[0965] 214. The method according to Example 213, wherein the neuropathic pain includes postherpetic neuralgia.

[0966] 215. The method according to Example 213, wherein the neuropathic pain comprises small fiber neuropathy.

[0967] 216. The method according to Example 213, wherein the neuropathic pain includes idiopathic small fiber neuropathy.

[0968] 217. The method according to Example 213, wherein the neuropathic pain includes diabetic neuropathy.

[0969] 218. The method according to Example 217, wherein the diabetic neuropathy comprises diabetic peripheral neuropathy.

[0970] 219. The method according to Example 212, wherein the pain includes musculoskeletal pain.

[0971] 220. The method according to Example 219, wherein the musculoskeletal pain includes osteoarthritis pain.

[0972] 221. The method according to Example 212, wherein the pain includes acute pain.

[0973] 222. The method according to Example 221, wherein the acute pain includes acute postoperative pain.

[0974] 223. The method according to Example 212, wherein the pain includes postoperative pain.

[0975] 224. The method according to Example 223, wherein the postoperative pain includes pain from bunion excision.

[0976] 225. The method according to Example 223, wherein the postoperative pain includes pain from abdominoplasty.

[0977] 226. The method according to Example 223, wherein the postoperative pain includes pain from hernia repair surgery.

[0978] 227. The method according to Example 212, wherein the pain includes visceral pain.

[0979] 228. The method according to any one of Examples 211 to 227, wherein the drug is used in combination with one or more other therapeutic agents.

[0980] 229. The method according to Example 228, wherein the one or more additional therapeutic agents comprise one or more additional pain-modulating compounds.

[0981] 230. A method for preparing compound I in pure form A, the method comprising (i) suspending an amorphous material of compound I in methanol, (ii) shaking at room temperature for 1 hour, (iii) collecting the solid, and (iv) drying under vacuum at 40°C to obtain compound I in pure form A.

[0982] 231. A method for preparing compound I in pure form B, the method comprising (i) suspending amorphous compound I in nitromethane to form a mixture, (ii) stirring the mixture at room temperature for about 1 hour, (iii) separating a solid from the mixture, and (iv) drying the solid in an oven for about 72 hours to obtain compound I in pure form B.

[0983] 232. A method for preparing compound I pure form C, the method comprising (i) suspending compound I pure form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20°C for about 1 hour, (iii) separating a solid from the mixture, and (iv) drying the solid in an oven for about 72 hours to obtain compound I pure form C.

[0984] 233. A method for preparing a hemihydrate of compound I, the method comprising (i) suspending compound I in water, (ii) shaking at 40°C for at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks, (iii) collecting the solid, and (iv) drying at 40°C under vacuum to obtain a hemihydrate of compound I.

[0985] 234. A method for preparing compound I monohydrate, the method comprising (i) suspending compound I in water, (ii) shaking at 40°C for no more than 48 hours, (iii) collecting the solid, and (iv) drying at 40°C under vacuum to obtain compound I monohydrate.

[0986] 235. A method for preparing a methanol solvate of compound I, the method comprising (i) suspending an amorphous material of compound I in methanol, (ii) shaking at 40°C for 1 hour, and (iii) collecting the solid to obtain a methanol solvate of compound I.

[0987] 236. A method for preparing a mixture A of compound InPA solvates, the method comprising (i) suspending compound InPA solvate B and NaTFA in nPA, (ii) mixing at room temperature for 6-18 hours, (iii) collecting the solid, and (iv) air-drying for 15-45 minutes to obtain mixture A of compound InPA solvates.

[0988] 237. A method for preparing compound InPA solvate B, the method comprising (i) suspending an amorphous material of compound InPA in nPA, (ii) mixing at room temperature for 18-30 hours, (iii) collecting the solid, and (iv) drying under vacuum at 40°C to obtain compound InPA solvate B.

[0989] 238. A method for preparing compound I nPA solvate C, the method 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 solid to obtain compound I nPA solvate C.

[0990] 239. A method for preparing a solvate of compound I Na hemisal nPA, the method comprising (i) treating 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6-naphthidium-5-carboxynitrile 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 an aqueous sodium chloride solution, (v) diluting the mixture with 2-MeTHF and subsequently concentrating it, (vi) treating the mixture with nPA and subsequently concentrating it, (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 solid, and (s) drying at 40°C under vacuum for 6-18 hours to obtain the solvate of compound I Na hemisal nPA.

[0991] 240. A method for preparing compound I nPA solvate J, the method 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 solid, and (vi) drying the solid under vacuum at 45°C to obtain compound I nPA solvate J.

[0992] 241. A method for preparing compound I 2-MeTHF solvate A, the method comprising (i) treating compound I form A with 2-MeTHF, (ii) stirring the mixture at about 22°C for 24 hours, and (iii) separating the solid to obtain compound I 2-MeTHF solvate A.

[0993] 242. A method for preparing a mixture A of compound I 2-MeTHF solvates, the method comprising (i) obtaining a solution of compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) collecting the solid, and (iv) drying under vacuum at 50°C to obtain a mixture A of compound I 2-MeTHF solvates.

[0994] 243. A method for preparing a mixture C of compound I 2-MeTHF solvates, the method comprising (i) obtaining a solution of compound I in 2-MeTHF, (ii) concentrating the solution to obtain a slurry, (iii) heating the slurry to 90°C to dissolve a solid, (iv) cooling to 25°C, (v) collecting the solid, and (iv) drying at 50°C to obtain a mixture C of compound I 2-MeTHF solvates.

[0995] 244. A method for preparing a compound I mandelic acid eutectic, the method comprising (i) combining compound I and mandelic acid, (ii) diluting the mixture in DCM, (iii) stirring 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 obtain a compound I mandelic acid eutectic.

[0996] 245. A method for preparing oxalic acid cocrystal of compound I, the method comprising (i) suspending compound I and oxalic acid (1:1) in DCM, (ii) stirring the resulting slurry at room temperature, (iii) collecting the solid, and (iv) drying under vacuum at 50°C to obtain oxalic acid cocrystal of compound I.

[0997] 246. A method for preparing compound I TFA salt A, the method 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 solid, and (v) drying at room temperature to obtain compound I TFA salt A.

[0998] 247. A method for preparing amorphous compound I, the method comprising (i) combining compound I and tert-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) separating the solid material to obtain amorphous compound I.

[0999] Further embodiments of this disclosure are illustrated in the following numbered entries:

[1000] 1. A substantially crystalline compound I

[1001] I

[1002] The substantially crystalline compound I is selected from the following: pure form A of compound I, pure form B of compound I, pure form C of compound I, hemihydrate of compound I, monohydrate of compound I, methanol solvate of compound I, mixture A of compound I nPA solvates, compound I nPA solvate B, compound I nPA solvate C, Na hemisalt nPA solvate of compound I, compound I nPA solvate J, 2-Me THF solvate A of compound I, mixture A of compound I 2-Me THF solvates, mixture C of compound I 2-Me THF, mandelic acid eutectic of compound I, DL-oxalic acid eutectic of compound I, and ITFA salt A.

[1003] 2. The substantially crystalline compound I according to Example 1, wherein less than 15% of compound I is in an amorphous form.

[1004] 3. The substantially crystalline compound I according to Example 1, wherein less than 10% of compound I is in an amorphous form.

[1005] 4. The substantially crystalline compound I according to Example 1, wherein less than 5% of compound I is in an amorphous form.

[1006] 5. The substantially crystalline compound I according to Example 1, wherein 100% of compound I is crystalline.

[1007] 6. The substantially crystalline compound ...

Claims

1. A method for preparing compound I: ， I The method involves using a compound of formula (A1): （A1） It is converted into compound I; Where X 1 and X 2 Each of them is independently selected from halogens.

2. The method of claim 1, wherein converting the compound of formula (A1) to compound I comprises converting the compound of formula (A1) to compound (C1): （C1） And to convert the compound of formula (C1) into compound I.

3. The method of claim 2, wherein converting 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 method according to claim 2 or 3, wherein converting the compound of formula (C1) to compound I comprises converting the compound of formula (C1) to compound (C4): ;as well as The compound of formula (C4) is converted into compound I.

5. The method according to any one of claims 1 to 4, further comprising using formula (A) 1-1 Compounds: （A 1-1 ） It is converted into the compound of formula (A1).

6. The method of claim 5, further comprising using formula (A) 1-2 Compounds: （A 1-2 ） Transformed into the aforementioned formula (A) 1-1 ) compounds.

7. The method of claim 6, further comprising using formula (A) 1-3 Compounds: （A 1-3 ） Transformed into the aforementioned formula (A) 1-2 ) compounds.

8. The method of claim 7, further comprising using formula (A) 1-4 Compounds: （A 1-4 ） Transformed into the aforementioned formula (A) 1-3 ) compounds.

9. The method according to claim 8, further comprising a compound of formula (A1-5): （A 1-5 ） Transformed into the aforementioned formula (A) 1-4 ) compounds.

10. The method according to any one of claims 1 to 9, wherein both X1 and X2 are chlorine.

11. A method for preparing compound I: ， I The method involves using a compound of formula (A2): （A2） It is converted into compound I.

12. The method of claim 11, wherein the step of converting the compound of formula (A2) into compound I comprises converting the compound of formula (A2) into compound (C2): ;as well as The compound of formula (C2) is converted into compound I.

13. The method of claim 12, wherein the step of converting the compound of formula (C2) into compound I comprises converting the compound of formula (C2) into compound I. 3a Compounds: ； Where R is a C1-C6 alkyl group; and the formula (C 3a The compound is transformed into compound I.

14. The method of claim 11, wherein the step of converting the compound of formula (A2) into compound I comprises converting the compound of formula (A2) into compound I. 3a Compounds: ； Where R is a C1-C6 alkyl group; and the formula (A) is used to make the following formula (A) 3a The compound is transformed into compound I.

15. The method of claim 14, wherein the formula (A) is used to... 3a The step of converting compound I to compound A includes converting compound I into compound A. 3a ) compounds are converted into formula (C 3a Compounds: ； Where R is a C1-C6 alkyl group; and the formula (C 3a The compound is transformed into compound I.

16. The method according to claim 13 or 15, wherein the formula (C) 3a The step of converting compound I to compound C includes converting the compound of formula (C) into compound I. 3a ) compounds are converted into formula (C 8a Compounds: ； Where R is a C1-C6 alkyl group; and the formula (C 8a The compound is transformed into compound I.

17. A method for preparing compound I: I The method comprises using a compound of formula (A3): （A3） It is converted into compound I.

18. The method of claim 17, wherein converting the compound of formula (A3) to compound I comprises converting the compound of formula (A3) to compound (C3): （C3） And to convert the compound of formula (C3) into compound I.

19. The method of claim 18, wherein converting 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 method according to any one of claims 17 to 19, further comprising using formula (A) 3-1 Compounds: （A 3-1 ） It is converted into the compound of formula (A3).

21. The method of claim 20, further comprising using formula (A) 3-2 Compounds: （A 3-2 ） Transformed into the aforementioned formula (A) 3-1 ) compounds.

22. A method for preparing compound I: ， I The method includes formula (A) 2-1 Compounds: It is converted into compound I.

23. The method of claim 22, wherein the formula (A) is used to... 2-1 The step of converting compound I to compound A includes converting compound I into compound A. 2-1 The compound is transformed into a compound of formula (C5): ;as well as The compound of formula (C5) is converted into compound I.

24. The method of claim 23, wherein the formula (A) is used to... 2-1 The conversion of a compound into a compound of formula (C5) comprises treating the compound of formula (A) with a compound of formula (B1) or (B2). 2-1 Compounds: 。 25. The method according to claim 23 or 24, wherein the step of converting the compound of formula (C5) to compound I comprises converting the compound of formula (C5) to compound (C2): ;as well as The compound of formula (C2) is converted into compound I.

26. The method of claim 25, wherein the step of converting the compound of formula (C2) into compound I comprises converting the compound of formula (C2) into a compound of formula (C7): ;as well as The compound of formula (C7) is converted into compound I.

27. The method according to claim 23 or 24, wherein the step of converting the compound of formula (C5) into compound I comprises converting the compound of formula (C5) into compound (C6): ;as well as The compound of formula (C6) is converted into compound I.

28. The method of claim 27, wherein the step of converting the compound of formula (C6) to compound I comprises converting the compound of formula (C6) to compound of formula (C4): ;as well as The compound of formula (C4) is converted into compound I.

29. The method of claim 28, wherein the step of converting the compound of formula (C4) into compound I comprises converting the compound of formula (C4) into a compound of formula (C7): ;as well as The compound of formula (C7) is converted into compound I.

30. The method according to any one of claims 3 to 10, 19 to 21, and 24 to 29, further comprising using formula (B) 1-1 Compounds: （B 1-1 ） It is converted into the compound of formula (B1).

31. The method of claim 30, further comprising using formula (B) 1-2 Compounds: （B 1-2 ） Transformed into the aforementioned formula (B) 1-1 ) compounds.

32. The method according to any one of claims 3 to 10, 19 to 21, and 24 to 29, further comprising using formula (B) 1-1a ), (B 1-1b ), (B 1-1c ), (B 1-1d ), (B 1-1e ), (B 1-1f ) or (B 1-1g Compounds: , , , , , or It is converted into the compound of formula (B1).

33. The method of claim 32, further comprising using formula (B) 1-2 Compounds: Transformed into the aforementioned formula (B) 1-1a ), (B 1-1b ), (B 1-1c ), (B 1-1d ), (B 1-1e ), (B 1-1f ) or (B 1-1g ) compounds.

34. The method according to claim 31 or 33, further comprising using formula (B) 1-3 Compounds: （B 1-3 ） Transformed into the aforementioned formula (B) 1-2 ) compounds.

35. The method according to any one of claims 1 to 34, further comprising converting compound I into a solvate of compound I.

36. The method according to claim 35, wherein the solvate of the compound of formula (I) is a compound of formula (D): （D）。 37. The method according to claim 35 or 36, further comprising converting a solvate of compound I into form A of compound I.

38. A compound selected from: , , , , , , , , and .

39. A compound selected from: , , , , , , and R is a C1-C6 alkyl group. In some embodiments, R is ethyl, isopropyl, tert-amyl, or tert-butyl.

40. A compound selected from: , , , , , , as well as .

41. A compound I: ， I It is prepared by the method according to any one of claims 1 to 34.

42. A substantially crystalline compound I I The substantially crystalline compound I is selected from the following: pure form A of compound I, pure form B of compound I, pure form C of compound I, hemihydrate of compound I, monohydrate of compound I, methanol solvate of compound I, mixture A of compound I nPA solvates, compound I nPA solvate B, compound I nPA solvate C, compound I Na hemisalt nPA solvate, compound I nPA solvate J, compound I 2-Me THF solvate A, mixture A of compound I 2-Me THF solvates, mixture C of compound I 2-Me THF, mandelic acid eutectic of compound I, DL-oxalic acid eutectic of compound I, and TFA salt A of compound I.

43. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I in pure form A, optionally wherein compound I in pure form A is characterized by: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, and 10.4 ± 0.2° 2θ; and / or (b) A substantially similar X-ray powder diffraction pattern to Figure 8; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm, 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) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 129.6 ± 0.2 ppm, 116.3 ± and / or (e) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 135.0 ± 0.2 ppm, 132.8 ± and / or (f) substantially similar to Figure 9A 13 C SSNMR spectrum; and / or (g) Essentially similar to Figure 9B (bottom trace) 13 C SSNMR spectrum; and / or (h) Essentially similar to Figure 9B (intermediate trace) 13 C SSNMR spectrum; and / or (i) substantially similar to Figure 9B (top trace) 13 C SSNMR spectrum; and / or (j) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): 。 44. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I in its pure form B, optionally wherein compound I in its pure form B is characterized by: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.5 ± 0.2° 2θ, and 9.8 ± 0.2° 2θ; and / or (b) A substantially similar X-ray powder diffraction pattern to Figure 10; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 115.5 ± 0.2 ppm, 114.2 ± and / or (d) substantially similar to Figure 11 13 C SSNMR spectrum; and / or (e) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): 。 45. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I in its pure form C, optionally wherein compound I in its pure form C is characterized by: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 6.0 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 12; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 115.4 ± 0.2 ppm, 114.5 ± and / or (d) Essentially similar to Figure 13 13 C SSNMR spectrum; and / or (e) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): and / or (f) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell dimensions measured at 298 K for radiation (λ = 1.54178 Å): 。 46. ​​The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a compound I hemihydrate, optionally wherein the compound I hemihydrate is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.1 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 12.3 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 14; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 133.4 ± and / or (d) substantially similar to Figure 15 13 C SSNMR spectrum.

47. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I monohydrate, optionally wherein the compound I monohydrate is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.0 ± 0.2° 2θ, 10.2 ± 0.2° 2θ, and 14.2 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 16.

48. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a methanol solvate of compound I, optionally wherein the methanol solvate of compound I is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 6.6 ± 0.2° 2θ, 8.4 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 17; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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) substantially similar to Figure 18 13 C SSNMR spectrum; and / or (e) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): 。 49. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a solvate mixture A of compound I inPA, optionally wherein the solvate mixture A of compound I inPA is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 19; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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) substantially similar to Figure 20 13 C SSNMR spectrum; and / or (e) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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) substantially similar to Figure 21 13 C SSNMR spectrum; and / or (g) Using Cu K on a diffractometer α The radiation (λ = 1.54178 Å) measured at 100 K in a monoclinic crystal system C2 / c Space group and the following cell sizes: 。 50. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I inPA solvate B, optionally wherein compound I inPA solvate B is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.3 ± 0.2° 2θ, 8.8 ± 0.2° 2θ, and 10.6 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that of Figure 22; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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) Essentially similar to Figure 23 13 C SSNMR spectrum; and / or (e) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): 。 51. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I inPA solvate C, optionally wherein compound I inPA solvate C is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 6.1 ± 0.2° 2θ, 11.8 ± 0.2° 2θ, and 12.2 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 24.

52. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a solvate of compound I Na hemisal nPA, optionally wherein the solvate of compound I Na hemisal nPA is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 6.7 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, and 14.9 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 25; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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 ± 0.2ppm; and / or (d) Essentially similar to Figure 26 13 C SSNMR spectrum; and / or (e) Using Cu K on a diffractometer α Triclinic crystal system, P-1 space group, and the following cell sizes measured at 100 K for radiation (λ = 1.54178 Å): 。 53. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I inPA solvate J, optionally wherein compound I inPA solvate J is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.3 ± 0.2° 2θ, 10.4 ± 0.2° 2θ, and 19.0 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 27.

54. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I 2-Me THF solvate A, optionally wherein compound I 2-Me THF solvate A is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 5.8 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 28.

55. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a mixture A of compound I 2-Me THF solvates, optionally wherein compound I 2-Me THF solvate mixture A is characterized in that: (a) X-ray powder diffraction pattern with a signal of 4.6 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 29.

56. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I 2-Me THF mixture C, optionally wherein compound I 2-Me THF mixture C is characterized in that: (a) X-ray powder diffraction pattern with a signal of 4.9 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 30.

57. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a mandelic acid eutectic, optionally wherein the mandelic acid eutectic is characterized by: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 6.6 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, and 21.1 ± 0.2° 2θ; and / or (b) The X-ray powder diffraction pattern is substantially similar to that in Figure 31.

58. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is a compound I DL-oxalic acid cocrystal, optionally wherein the compound I DL-oxalic acid cocrystal is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 8.9 ± 0.2° 2θ, 11.6 ± 0.2° 2θ, and 14.5 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 32; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 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 ± 0.2ppm, 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) Essentially similar to Figure 33 13 C SSNMR spectrum.

59. The substantially crystalline compound according to claim 42, wherein the substantially crystalline compound I is compound I TFA salt A, optionally wherein compound I TFA salt A is characterized in that: (a) An X-ray powder diffraction pattern having one, two, or three signals selected from 8.4 ± 0.2° 2θ, 15.1 ± 0.2° 2θ, and 19.7 ± 0.2° 2θ; and / or (b) An X-ray powder diffraction pattern substantially similar to that in Figure 34; and / or (c) Having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from the following. 13 C SSNMR spectrum: 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 ± 0.2ppm, 133.7 ± and / or (d) substantially similar to Figure 35 13 C SSNMR spectrum.

60. An amorphous compound I I。 61. A pharmaceutical composition comprising a substantially crystalline compound I according to any one of claims 42 to 59 or an 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 treating pain in a subject or reducing the severity of pain in a subject, optionally wherein said pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.

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

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

65. A method for preparing compound I in solid form, the method comprising: (a) (i) The amorphous material of compound I was suspended in methanol, (ii) shaken at room temperature for 1 hour, (iii) the solid was collected, and (iv) dried under vacuum at 40 °C to obtain compound I in pure form A; (b) (i) suspending amorphous compound I in nitromethane to form a mixture, (ii) stirring the mixture at room temperature for about 1 hour, (iii) separating the solid from the mixture, and (iv) drying the solid in an oven for about 72 hours to obtain compound I in pure form B; (c) (i) suspending compound I in pure form A in 2-MeTHF to form a mixture, (ii) stirring the mixture at about 20°C for about 1 hour, (iii) separating the solid from the mixture, and (iv) drying the solid in an oven for about 72 hours to obtain compound I in pure 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 3 weeks or at least 4 weeks, (iii) collecting the solid, and (iv) drying at 40°C under vacuum to obtain compound I hemihydrate; (e) (i) Suspend compound I in water, (ii) shake at 40°C for no more than 48 hours, (iii) collect the solid, and (iv) dry at 40°C under vacuum to obtain compound I monohydrate; (f) (i) Suspend the amorphous material of compound I in methanol, (ii) shake at 40°C for 1 hour, and (iii) collect the solid to obtain the methanol solvate of compound I; (g) (i) Suspend compound I nPA solvate B and NaTFA in nPA, (ii) mix at room temperature for 6-18 hours, (iii) collect the solid, and (iv) air dry for 15-45 minutes to obtain compound I nPA solvate mixture A; (h)(i) The amorphous material of compound I nPA is suspended in nPA, (ii) it is mixed at room temperature for 18-30 hours, (iii) the solid is collected, and (iv) it is dried under vacuum at 40°C to obtain compound I nPA solvate B; (i) Dissolve compound I in nPA, (ii) mix at 90-100°C for 1-2 hours, (iii) mix at room temperature for 6-30 hours, and (iv) collect the solid to obtain compound I nPA solvate C; (j) (i) treating 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-chloro-1,6-naphthyl-5-carboxynitrile 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 an aqueous sodium chloride solution, (v) diluting the mixture with 2-MeTHF and then concentrating it, (vi) treating the mixture with nPA and then concentrating it, (vii) heating the mixture to 90°C and then holding it at 50°C for 6-18 hours, (viii) cooling the mixture to room temperature, (ix) collecting the solid, and (s) drying it under vacuum at 40°C for 6-18 hours to give compound I Na hemisal 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 then 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 solid, and (vi) drying the solid under vacuum at 45°C to give compound I nPA solvate J; (l) (i) treating compound I form A with 2-MeTHF, (ii) stirring the mixture at about 22°C for 24 hours, and (iii) separating the solid to obtain compound I 2-MeTHF solvate A; (m) (i) Obtain a solution of compound I in 2-MeTHF, (ii) concentrate the solution to obtain a slurry, (iii) collect the solid, and (iv) dry it under vacuum at 50°C to obtain a mixture A of compound I 2-MeTHF solvates; (n) (i) Obtain a solution of compound I in 2-MeTHF, (ii) concentrate the solution to obtain a slurry, (iii) heat the slurry to 90°C to dissolve the solid, (iv) cool to 25°C, (v) collect the solid, and (iv) dry at 50°C to obtain a mixture C of compound I 2-MeTHF solvates; (o) (i) Combining compound I and mandelic acid, (ii) diluting the mixture in DCM, (iii) stirring 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 obtain a eutectic of compound I and mandelic acid. (p) (i) Compound I and oxalic acid (1:1) were suspended in DCM, (ii) the resulting slurry was stirred at room temperature, (iii) the solid was collected, and (iv) the solid was dried under vacuum at 50 °C to obtain compound I oxalic acid eutectic. (q) (i) Suspend compound I in DCM, (ii) Treat the suspension with TFA, (iii) Stir at room temperature for 15-45 minutes, (iv) Collect the solid, and (v) Dry at room temperature to obtain TFA salt A of compound I; or (r) (i) Combining compound I and tert-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) separating the solid material to obtain amorphous compound I.

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