Method for preparing a sodium channel modulator and its solid form for the treatment of pain.

Abstract

Processes and methods for preparing compound (I) are disclosed. The crystalline form of compound (I), its pharmaceutically acceptable salts, solvates, hydrates, and cocrystals, pharmaceutical compositions containing them, methods for pain relief using them, and methods for producing them are also disclosed. Also disclosed are voltage-gated sodium channels (Na V Processes and methods for inhibiting (Na), and (Na v )The crystalline and amorphous solid forms of inhibitors, pharmaceutical compositions thereof, methods for treating pain using any of the foregoing, and processes for producing the crystalline and amorphous forms are also disclosed herein. TIFF2026536597000171.tif4342

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 592,530, filed on 23 October 2023, and U.S. Provisional Patent Application No. 63 / 592,494, filed on 23 October 2023, each of which is incorporated herein by reference in whole.

[0002] Technical field Voltage-gated sodium channels (Na V Processes and methods for producing compounds that inhibit ) are disclosed herein.

[0003] Also, voltage-gated sodium channels (Na V Processes and methods for inhibiting (Na), and (Na v )The crystalline and amorphous solid forms of inhibitors, pharmaceutical compositions thereof, methods for treating pain using any of the foregoing, and processes for producing the crystalline and amorphous forms are also disclosed herein. [Background technology]

[0004] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which the patient would benefit from pain suppression. Acute and chronic pain are two common pain conditions that can be distinguished by the duration of the pain. Acute pain can occur for many reasons (e.g., hospital procedures), and treatment options are generally limited by insufficient efficacy and / or adverse events. Similar to acute pain, chronic pain can occur for many reasons, and treatment options are limited by insufficient efficacy 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, 2008. 137(3): p.681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves, and pain caused by discrete nerve damage. Metabolic neuropathy includes post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include post-amputation pain, postoperative nerve injury pain, and nerve compression injuries such as neuropathic back pain.

[0006] Voltage-gated sodium channels (Na V ) is involved in pain signaling. V Sodium channels are biological mediators of electrical signaling, as they mediate the rapid increase in action potentials in many excitable cell types, such as neurons, skeletal muscle cells, and cardiomyocytes (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Evidence for the role of these channels in normal physiological function, pathological conditions arising from mutations in sodium channel genes, preclinical studies in animal models, and the clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V This suggests a central role (Rush, A.M. and TRCummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na). V1.8 Sodium Channels. Mol. Interv., 2007, 7(4): p.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64(2008), Krafte, D.S. and Bannon, A.W., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p.50-56(2008)). In the initiation and propagation of neuronal signals, Na V Due to the role that Na V Antagonists that reduce currents can prevent or reduce neural signal transmission, and Na V Channels have long been considered to have high potential for reducing pain under conditions where high excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J.J., Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7(2), p.144-58(2008)). Several clinically useful analgesics have been identified as inhibitors of Na V Channels. Local anesthetics such as lidocaine block pain by inhibiting Na V Other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been proven to be effective in reducing pain by blocking channels, have also been suggested to act via sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p.3-9(2002), Wang, G.K., Mitchell, J., and Wang, S.Y., Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008)).

[0007] Na V It forms a subfamily of voltage-gated ion channel superfamily, Na V 1.1~Na V It has nine isoforms, referred to as 1.9. The tissue localization of these nine isoforms differs. V 1.4 is the primary sodium channel of skeletal muscle, Na V 1.5 is the primary sodium channel in cardiomyocytes. V 1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. While the functional behavior of the nine isoforms is similar, they are distinct in the details of their voltage-gated and dynamic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005)).

[0008] When they were discovered, Na V Channel 1.8 was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p.257-62). Subsequently, Na V1.8 has been shown to be the carrier of sodium current that maintains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is involved in spontaneous firing in damaged neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na V1.8 in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82、Lai,J.,et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8.Pain,2002.95(1-2):p.143-52、Dong,X.W.,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.Neuroscience,2007.146(2):p.812-21、Huang,H.L.,et al.,Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.Mol.Pain,2008.4:p.33、Black,J.A.,et al.,Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas.Ann.Neurol.,2008.64(6):p.644-53、Coward,K.,et al.,Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain,2000.85(1-2):p.41-50、Yiangou,Y.,et al.,SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves.FEBS Lett.,2000.467(2-3):p.249-52、Ruangsri,S.,et al.,Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8)mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.J.Biol.Chem.286(46):p.39836-47)。Na VSmall DRG neurons expressing 1.8 include nociceptors involved (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is necessary for rapid, repetitive action potentials in nociceptors and for spontaneous activity in damaged neurons. (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons.J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V1.8 appears to be a driving factor for hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na V 1.8 mRNA expression levels indicate an increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135 (Pt 2): p.359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6).

[0009] The inventors of this invention believe that some voltage-gated sodium channel inhibitors may have an insufficient therapeutic window (e.g., Na VIt was discovered that it has limitations as a therapeutic agent due to a lack of isoform selectivity, low potency, and / or other reasons. Therefore, selective Na V 1.8 The need remains to develop selective voltage-gated sodium channel inhibitors, such as inhibitors, and methods for producing them.

[0010] Compound I, 2-[2-(3,4-difluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]-4-oxo-1H-1,6-naphthyridine-5-carboxamide, Na v It is an inhibitor and therefore useful in the treatment of pain. Compound I has the following structure: [ka]

[0011] Compound I is disclosed in PCT International Application No. PCT / US2023 / 019469. Crystalline form is of interest in the pharmaceutical industry, where control of the crystalline form of the active ingredient is desirable or even required. Since different crystalline forms can have different properties, a reproducible process for producing compounds with a specific crystalline form in high purity may be desirable for compounds intended for use in pharmaceuticals. For example, different crystalline forms may have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit higher levels of purity, chemical stability, and / or physical stability compared to the form produced in PCT US / 2023 / 019469. Certain crystalline forms (e.g., the crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate forms of compound I, collectively referred to as “crystalline forms”) may exhibit lower hygroscopicity than any existing form. Therefore, the crystalline forms of this disclosure may offer advantages in the manufacture, storage, and handling of the active pharmaceutical ingredient compared to the amorphous form produced in PCT US / 2023 / 019469. Thus, pharmaceutically acceptable crystalline forms of compound I may be particularly useful in the manufacture of drugs for the treatment of pain. Furthermore, there remains a need for more efficient processes for the synthesis of compound I, for example, that yield this compound or a pharmaceutically acceptable salt thereof in higher yield, with higher selectivity, and / or higher purity compared to known processes. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-Patent Document 2] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-Patent Document 3] Rush, AMand TRCummins, Painful Research:Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5) [Non-Patent Document 4] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin.Investig.Drugs 17(12), p.1849-64(2008) [Non-Patent Document 5] Krafte, DSand Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56 (2008) [Non-Patent Document 6] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders.CNS Neurol.Disord.Drug Targets 7(2), p.144-58(2008) [Non-Patent Document 7] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-Patent Document 8] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008) [Non-Patent Document 9] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology.XLVII.Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol.Rev.57(4), p.397(2005) [Non-Patent Document 10] Akopian, AN, L. Sivilotti, and JNWood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.Nature, 1996.379(6562):p.257-62 [Non-Patent Document 11] Blair, NTand BPBean, Roles of tetrodotoxin (TTX)-sensitive Na+ current,TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90 [Non-Patent Document 12] Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6 Non-Patent Document 13 Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5 Non-Patent Document 14 Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82 Non-Patent Document 15 Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain, 2002. 95(1-2): p. 143-52 Non-Patent Document 16 Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007, 146(2): p.812-21 Non-Patent Document 17 Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol. Pain, 2008, 4: p.33 Non-Patent Document 18 Black, J.A., et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann. Neurol., 2008, 64(6): p.644-53 Non-Patent Document 19 Coward, K., et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000, 85(1-2): p.41-50 Non-Patent Document 20 Yiangou, Y., et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 2000, 467(2-3): p.249-52 Non-Patent Document 21 Ruangsri, S., et al., Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286(46): p. 39836-47 Non-Patent Document 22 Blair, N.T. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90 Non-Patent Document 23 Choi, J.S. and S.G. Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): p. 3173-84 Non-Patent Document 24 Renganathan, M., T.R. Cummins, and S.G. Waxman, Contribution of Na(V)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 2001. 86(2): p. 629-40 Non-Patent Document 25 Roza,C.,et al.,The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6 Non-Patent Document 26 Rush,A.M.,et al.,A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons.Proc.Natl.Acad.Sci.USA,2006.103(21):p.8245-50 Non-Patent Document 27 Sun,W.,et al.,Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats.Brain,135(Pt 2):p.359-75 Non-Patent Document 28 Strickland,I.T.,et al.,Changes in the expression of NaV1.7,NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72 Non-Patent Document 29 Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodium channels NaV1.8 and NaV1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6 [Overview of the project]

[0013] In one embodiment, the present invention relates to a compound of formula I: [ka] The present invention relates to a method for preparing a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the method is carried out according to the reaction steps described herein, formulas A1, 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 This includes converting any of the compounds B-1, B-2, B-3, B-4, B-5, C-1, C-2, C-3, C-4, D-1, D-2, E-A1, E-A2, and E-A3 to a compound of formula I, or its solvate, or tautomer, or a pharmaceutically acceptable salt thereof.

[0015] In another embodiment, the present invention is [ka] A compound selected from, Or relating to pharmaceutically acceptable salts thereof, their tautomers, or combinations thereof.

[0016] In another embodiment, the disclosure relates to a substantially crystalline compound I, wherein the crystalline compound I is selected from a neat form A of substantially pure compound I, a neat form B of compound I, a neat form E of compound I, an acetone solvate hydrate form A of compound I, an ethanol solvate form A of compound I, a hydrate form A of compound I, and a dehydrated hydrate form A of compound I.

[0017] In some embodiments, this disclosure relates to an amorphous form of a substantially amorphous compound I. [Brief explanation of the drawing]

[0018] [Figure 1] This provides an X-ray powder diffraction (XRPD) pattern of the amorphous form of compound I. [Figure 2] This provides the 13C solid-state NMR (SSNMR) spectrum of compound I in its amorphous form. [Figure 3] The 19F NMR spectrum of the amorphous form of compound I is provided. [Figure 4] This provides an XRPD pattern of neat form A of crystalline compound I. [Figure 5] This provides the 13C SSNMR spectrum of neat form A of crystalline compound I. [Figure 6] This provides the 19F NMR spectrum of neat form A of crystalline compound I. [Figure 7] This provides an XRPD pattern of neat form B of crystalline compound I. [Figure 8] This provides the 13C SSNMR spectrum of neat form B of crystalline compound I. [Figure 9] This provides the 19F NMR spectrum of neat form B of crystalline compound I. [Figure 10] This provides an XRPD pattern of the neat form E of crystalline compound I. [Figure 11] This provides the 13C SSNMR spectrum of neat form E of crystalline compound I. [Figure 12]Providing a 19F NMR spectrum of neat Form E of crystalline Compound I. [Figure 13] Providing an XRPD pattern of acetone solvate hydrate Form A of crystalline Compound I. [Figure 14] Providing a 13C SSNMR spectrum of acetone solvate hydrate Form A of crystalline Compound I. [Figure 15] Providing a 19F NMR spectrum of acetone solvate hydrate Form A of crystalline Compound I. [Figure 16] Providing an XRPD pattern of ethanol solvate Form A of crystalline Compound I. [Figure 17] Providing a 13C SSNMR spectrum of ethanol solvate Form A of crystalline Compound I. [Figure 18] Providing a 19F NMR spectrum of ethanol solvate Form A of crystalline Compound I. [Figure 19] Providing an XRPD pattern of hydrate Form A (wet form) of crystalline Compound I. [Figure 20] Providing an XRPD pattern of dehydrated hydrate Form A (dry form) of crystalline Compound I. [Figure 21] Providing an overlay of the XRPD pattern of crystalline Compound I hydrate Form A with crystalline Compound I dehydrated hydrate Form A. The dry form is shown as a dashed line. [Figure 22] Providing a 13C SSNMR spectrum of hydrate Form A of crystalline Compound I. [Figure 23] Providing a 19F NMR spectrum of hydrate Form A of crystalline Compound I. MODE FOR CARRYING OUT THE INVENTION

[0019] Definitions The following definitions are intended to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered ambiguous. Rather, the term is to be used within its accepted meaning.

[0020] "Compound I", as used throughout the present disclosure, refers to 2-[2-(3,4-difluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)-3-pyridyl]-4-oxo-1H-1,6-naphthyridine-5-carboxamide, which has the following structure. ##STR##

[0021] Compound I may be in the form of a pharmaceutically acceptable salt, solvate, and / or hydrate. Compound I, as well as methods of making and using Compound I, tautomers of Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of any of the foregoing, are disclosed in PCT / US2023 / 019469, which is incorporated herein by reference.

[0022] As used herein, the term "compound", when referring to a compound described in the present application, refers to a collection of molecules having the same chemical structure, except that isotopic variations may exist between the constituent atoms of the molecules. The term "compound" includes such collections of molecules regardless of the purity of a given sample containing the collection of molecules. Accordingly, the term "compound" includes such collections of molecules in pure form, in admixture with one or more other substances (for example, as a solution, suspension, colloid, or pharmaceutical composition, or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0023] In this specification and in the claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the present invention is intended to represent any stable isotope of the specified element. In the examples, if an atom is not specifically designated as a particular isotope of any compound of the present invention, no effort is made to enrich that atom in a particular isotope, and therefore, a person skilled in the art will understand that such an atom likely existed in the isotopic composition of the specified element at approximately its natural abundance.

[0024] As used herein and in the claims, "H" refers to hydrogen, any stable isotope of hydrogen, i.e., 1 Includes H and D.

[0025] In some embodiments, the compounds described in this application contain each constituent atom in an isotopic composition that approximates the natural abundance of the specified element.

[0026] In some embodiments, the compounds described in this application, and their pharmaceutically acceptable salts, contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("isotope-labeled" compound and salt). Examples of commercially available and suitable stable isotopes for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example, respectively. 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P is one example, but is not limited to these. For example, as used herein and in the claims, "H" refers to hydrogen, any stable isotope of hydrogen, i.e., 1 Includes H and D.

[0027] The terms “compound of formula” followed by a number (typically a Roman numeral) and “compound” followed by the same number (Roman numeral or otherwise) may be used interchangeably. For example, “compound of formula V” and “compound V” refer to the same compound.

[0028] When referring to a chemical reaction, the term "reaction" means adding or mixing two or more reagents under appropriate conditions to produce a specified product and / or a desired product. Naturally, a reaction that produces a specified product and / or a desired product does not necessarily arise directly from the combination of the two reagents initially added; that is, there may be one or more intermediates formed in the mixture that ultimately lead to the formation of the specified product and / or the desired product.

[0029] When referring to a reaction, the term "conducted in a solvent" means that the substrate and reagents are dissolved or suspended in a specified solvent, or in a mixture of solvents containing the specified solvent.

[0030] The term "chromatographic purification" refers to any method of purification based on differential retention by a stationary phase. Methods of chromatographic purification include flash chromatography, medium-pressure liquid chromatography, preparative thin-layer chromatography, and high-performance liquid chromatography.

[0031] As used herein, the terms “convert” and “transform” refer to the process of converting a first compound or salt into a second compound or salt, and to the process of converting a first compound or salt into a second compound or salt in one or more chemical steps.

[0032] The term "acid" refers to a chemical species with a pKa (in water) of less than 7. This term includes inorganic (mineral) acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid. This term also includes organic acids, such as acetic acid, propionic acid, n-butyric acid, i-butyric acid, n-valeric acid, i-valeric acid, n-hexanoic acid, succinic acid, glutaric acid, adipic acid, aspartic acid, formic acid, citric acid, o-chlorobenzoic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, nicotinic acid, lactic acid, oxalic acid, picric acid, picolinic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, phthalic acid, isophthalic acid, terephthalic acid, maleic acid, and malonic acid.

[0033] The term "base" refers to a chemical species whose conjugate acid has a pKa (in water) greater than 7. This term includes "inorganic bases" such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monobasic, dibasic, or tribasic), sodium hydride, and potassium hydride. This term also includes "anionic organic bases" such as methyllithium, butyllithium, lithium diisopropylamide, and sodium acetate. This term also includes 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), di It contains "neutral organic bases" such as methylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[0034] The term "alcohol protecting group" refers to a chemical moiety suitable for protecting an alcohol group from undesirable side reactions during a synthetic procedure. Common alcohol protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl, or triarylsilyl. Other alcohol protecting groups are also well known in the art. See, for example, PGMWuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0035] The term "deprotection" refers to the process of reacting a compound or salt containing a protecting group, such as an alcohol protecting group, under conditions suitable for removing the protecting group and exposing the protected portion. For example, if a compound or salt contains an alcohol protecting group, the term "deprotection" refers to reacting the compound or salt under conditions suitable for removing the alcohol protecting group and exposing the alcohol. Conditions for removing various protecting groups are well known in the art. See, for example, PGMWuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0036] The term "hydrogenation catalyst" refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of benzyl carbon-oxygen single bonds. Suitable hydrogenation catalysts are well known in the art and include, for example, palladium on activated carbon, platinum oxide, and Raney nickel.

[0037] The term "coupling", when referring to the reaction between a carboxylic acid or acid halide and an amine, refers to the final transformation that combines the carboxylic acid or acid halide and the amine to form an amide. This term includes the direct reaction between a carboxylic acid and an amine, as well as the reaction between an activated derivative of a carboxylic acid (such as a derivative formed by the reaction between a carboxylic acid and a coupling reagent) and an amine.

[0038] The term "coupling reagent" refers to a reagent suitable for reacting with a carboxylic acid to activate the carboxylic acid for coupling with an amine to form an amide bond. Coupling reagents are well known in the art. Coupling reagents include, but are not limited to, thionyl chloride, oxalyl chloride, 1,1'-carbonylbis-(4,5-dicyanoimidazole) (CBDCI), 1,1'-carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0039] The term "monovalent cation" refers to alkali metal cations, NH + , and any cation with a +1 charge, such as tetraalkylammonium.

[0040] The term "alkali metal cation" refers to lithium (Li + ), sodium (Na+), potassium (K + ), rubidium (Rb + ), and cesium (Cs + ), refers to a cation derived from a Group I metal atom, including but not limited to the above-listed species.

[0041] The term "substituted benzyl" refers to a benzyl group substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, and cyano.

[0042] The term "ketone solvent" refers to a compound of formula C n H 2n+1 C(O)C m H 2m+1 wherein n and m are each independently an integer from 1 to 6. The C n H 2n+1 and C m H 2m+1 groups may be linear or branched, and each may be substituted with up to 3 halogens. Ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, 3-pentanone, and methyl tert-butyl ketone.

[0043] The term "ether-based solvent" refers to an organic solvent having at least one ether moiety. Examples of ether-based solvents include, but are not limited to, tetrahydrofuran, dimethoxyethane, dioxane, and dialkyl ethers such as diethyl ether and methyl isobutyl ether.

[0044] The term "ester solvent" refers to a compound of formula C n H 2n+1 OC(O)C m H 2m+1 wherein n and m are each independently an integer from 1 to 6. The C n H 2n+1 and C m H 2m+1 groups may be linear or branched, and each may be substituted with up to 3 halogens. Ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, butyl acetate, and ethyl propionate.

[0045] The term "halogenated solvent" refers to C1-C6 alkanes or C2-C6 alkenes substituted with up to six halogens. Halogenated solvents include, but are not limited to, dichloromethane, dichloroethane, chloroform, tetrachloroethylene, and carbon tetrachloride.

[0046] The term "aromatic solvent" is C 6~10 This refers to aromatic hydrocarbons. Aromatic hydrocarbons may be substituted with up to six halogens. Examples of aromatic solvents include, but are not limited to, benzene, trifluoromethylbenzene, xylene, and toluene.

[0047] The term "approximately" means that the stated number may vary by ±10% from its value. If the term defines temperature, the stated temperature may vary by ±10%. For example, approximately 80°C means 72°C to 88°C. If the term defines pressure, the term "approximately" means that the pressure may vary by ±10%. Therefore, approximately 100 bar means 90 to 110 bar. If the term defines quantity (such as equivalent or weight), the term means that the quantity may vary by ±10%. For example, approximately 1 equivalent means 0.9 to 1.1 equivalents. If the term defines time, the term means that the stated time may vary by ±10%. For example, approximately 1 hour means 0.9 to 1.1 hours.

[0048] The term "leaving group" refers to a chemical group that is readily replaced by a desired incoming chemical moiety. Therefore, the selection of a particular suitable leaving group is determined based on its ability to be readily replaced by an incoming chemical moiety, such as a CN group. Suitable leaving groups are well known in the art; see, for example, “Advanced Organic Chemistry,” Jerry March, 5th sup.th Ed., pp. 351–357, John Wiley and Sons, NY.

[0049] As used herein, the term “cyanating agent” refers to reagents useful in the synthesis of the compounds disclosed herein, such as trimethylsilyl cyanide (TMSCN), diethylaluminum cyanide, KCN, NaCN, TBACN, and HCN. 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), ethyl boron trifluoride etherate (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, SnCl4, etc. In further embodiments, the Lewis acid is trifluoromethanesulfonic anhydride (Tf2O). The cyanation reaction may be carried out in an organic solvent, such as toluene, dichloromethane, 2-methyl THF, acetonitrile, methanol, 1,2-dichloroethane, or nitromethane.

[0050] As used herein, the terms “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refer to a bioactive compound.

[0051] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0052] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound administered that produces the desired effect (e.g., improvement of pain or symptoms of pain, or reduction of the severity of pain or symptoms of pain). The exact amount of the effective dose depends on the therapeutic purpose and may be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0053] As used herein, terms such as “treatment” and “to treat” generally mean an improvement in pain or one or more of its symptoms in the subject, or a reduction in the severity of pain or one or more of its symptoms. “Treatment” as used herein includes, but is not limited to, chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, pain from hernia repair, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. The improvement in any of these symptoms or the reduction in their severity can be readily assessed according to standard methods and techniques known in the art.

[0054] As used herein, the term “in combination with ~” means that, when referring to two or more compounds, drugs, or additional active pharmaceutical ingredients, the two or more compounds, drugs, or active pharmaceutical ingredients are administered to the patient before each other, simultaneously with each other, or after each other.

[0055] The terms "selected from" and "chosen from" are used interchangeably in this specification.

[0056] As used herein, the term “ambient conditions” means room temperature, ambient conditions, and uncontrolled humidity conditions. As used herein, the terms “room temperature” and “ambient temperature” mean 15°C to 30°C.

[0057] As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of the product greater than 1 g / L).

[0058] As used herein, the term “stable” means a compound or solid form that remains substantially unchanged when subjected to conditions that enable their generation, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0059] The term "chemically stable," as used herein, means that the solid form of compound I does not decompose into one or more different compounds when exposed to specific conditions, such as 40°C / 75% relative humidity, for a specified period of time, e.g., one day, two days, three days, one week, two 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%, or less than 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.

[0060] The term "physically stable," as used herein, means that the solid form of compound I does not change into one or more different physical forms of compound I (e.g., different solid forms as measured by XRPD, DSC, etc.) when exposed to specific conditions, e.g., 40°C / 75% relative humidity, for a specific period of time, e.g., one day, two days, three days, one week, two weeks, or longer. In some embodiments, less than 25% of the solid form of compound I changes into one or more different physical forms when exposed to specific 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%, or less than about 0.5% of the solid form of compound I changes into one or more different physical forms of compound I when exposed 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.

[0061] As used herein, the term “hydrate” refers to any crystalline compound I that contains water in its crystal lattice. The stoichiometry of the hydrate of compound I may vary. For example, the hydrate of compound I may be a quarter-hydrate, hemihydrate, monohydrate, dihydrate, or partially dehydrated form.

[0062] As used herein, the term “pharmaceutically acceptable solid form” refers to the solid form of Compound I of this disclosure, and the solid forms of Compound I (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) are nontoxic and suitable for use in pharmaceutical compositions.

[0063] As used herein, the term “amorphous” refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally rather isotropic, that is, they exhibit similar properties in all directions. Amorphous solids do not have a distinct melting point. Amorphous solids are generally glasses or supercooled liquids in which molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., no molecular packing and no long-range order. For example, an amorphous material is a solid material that does not have a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline when determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, the solid material may contain amorphous compounds, and for example, the solid material may be characterized by the absence of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the material is amorphous but not crystalline, as determined by XRPD). Instead, one or more broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. Solid materials containing amorphous compounds may be characterized, for example, by a broader melting temperature range of the solid material compared to the melting temperature range of a pure crystalline solid. Other techniques, such as solid-state NMR, may also be used to characterize the crystalline or amorphous form.

[0064] As used herein, the terms “crystal morphology,” “crystalline form,” and “morphology” are interchangeable to refer to a crystal structure (or polymorph) having a specific molecular packing arrangement in the crystal lattice. Crystalline forms are, for example, determined by X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, and 13 C solid-state nuclear magnetic resonance ( 13 They can be identified and distinguished from one another by one or more feature analysis techniques, including C SSNMR. Therefore, as used herein, the terms “crystalline form [X] of compound (I)” and “potassium salt of crystalline form [C] of compound (I)” mean, for example, XRPD, single-crystal X-ray diffraction, and 13 This refers to unique crystalline morphologies that can be identified and distinguished from one another by one or more feature analysis techniques, including C SSNMR. In some embodiments, novel crystalline morphologies are characterized by X-ray powder diffractograms having one or more signals at one or more specified degree 2-theta values ​​(°2θ).

[0065] As used herein, the term “free form” refers to the non-ionized form of a compound in the solid state. Examples of free forms include free bases and free acids.

[0066] As used herein, the term “neat form” refers to the non-solvated and unhydrated free form of a compound in the solid state.

[0067] As used herein, the term “solvate” refers to a crystalline form comprising one or more molecules of the compounds herein and one or more molecules of the solvent, in stoichiometric or non-stoichiometric quantities, incorporated into a crystal lattice. When the solvent is water, the solvate is referred to as a “hydrate.”

[0068] As used herein, the term “hydrate” refers to any crystalline compound I that contains water in its crystal lattice. The stoichiometry of the hydrate of compound I may vary; that is, compound I can be a variable hydrate. For example, the hydrate of compound I may be a quarter-hydrate, hemihydrate, monohydrate, dihydrate, or partially dehydrated form.

[0069] In some embodiments, the solid material may comprise a mixture of crystalline and amorphous solids. The solid material comprising the amorphous compound may also comprise, for example, up to 30% crystalline solid. In some embodiments, the solid material prepared to comprise the amorphous compound may also comprise, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solid. In embodiments in which the solid material comprises a mixture of crystalline and amorphous solids, feature analysis data such as XRPD may include indices for both crystalline and amorphous solids. In some embodiments, the crystalline form of the disclosure may contain up to 30% amorphous compound. In some embodiments, the crystalline preparation of compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solid.

[0070] As used herein, the term “substantially amorphous” refers to a solid material that has little or no long-range order at the molecular level. For example, a substantially amorphous substance has a degree of crystallinity of less than 15% (e.g., less than 10%, or 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 substance with no crystallinity at all (0%).

[0071] As used herein, the term “substantially crystalline” refers to a solid material that contains little to no amorphous molecules. For example, a substantially crystalline substance 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 substance that is in a 100% crystalline form.

[0072] As used herein, a crystalline form is "substantially pure" if, as determined by a method in the Art, such as quantitative XRPD, it accounts for 90% by weight or more of the total amount of all solid forms in the sample. In some embodiments, a solid form is "substantially pure" if it accounts for 95% by weight or more of the total amount of all solid forms in the sample. In some embodiments, a solid form is "substantially pure" if it accounts for 99% by weight or more of the total amount of all solid forms in the sample.

[0073] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern,” and “XRPD spectrum” are interchangeable in referring to experimentally obtained patterns plotting signal position (on the horizontal coordinate) against signal intensity (on the vertical coordinate).

[0074] As used herein, “signal” or “peak” refers to a point on the XRPD pattern where the intensity, measured in counts, is locally maximum. An XRPD peak is identified by its angular value, measured at degrees 2θ (°2θ), shown on the transverse coordinate of the X-ray powder diffractogram, which may be expressed, for example, as “...signal at degrees 2theta”, “[a]...signal at 2theta value”, and / or “...signal at 2theta value of at least... selected from”.

[0075] The repeatability of the measured angle values ​​is within ±0.2°²θ, meaning that the angle values ​​can be any value between the enumerated angle value +0.2°²theta, the angle value -0.2°²theta, or any value between the two endpoints (angle value +0.2°²theta and angle value -0.2°²theta).

[0076] Those skilled in the art will recognize that one or more signals (or peaks) may overlap in an XRPD pattern, and that these may not be apparent to the naked eye, for example. In practice, those skilled in the art will recognize that certain methods known in the art are capable of and suitable for determining whether a signal is present by pattern analysis, such as the Rietveld method (Rietveld refinement).

[0077] The terms "signal intensity" and "peak intensity" are interchangeable in referring to the relative signal intensity within a given X-ray powder diffractogram. Factors that may affect the relative signal intensity or peak intensity include the thickness of the sample and the preferred orientation (e.g., crystalline particles are not randomly distributed).

[0078] As used herein, an X-ray powder diffractogram is "substantially similar to that in the [specific] figure" if at least 90% of the signals, e.g., at least 95%, at least 98%, or at least 99%, overlap in two diffractograms. In determining "substantially similar," a person skilled in the art will understand that variations in intensity and / or signal position can exist in an XRPD diffractogram even for the same crystalline form. Thus, a person skilled in the art will understand that, generally, the maximum value of the signal in an XRPD diffractogram (in degrees in 2-theta units) means that the value is identified as ±0.2 degrees 2-theta of its reported value, which is the dispersion recognized in the art.

[0079] As used herein, the term “glass transition temperature” or “Tg” refers to the temperature at which a “glassy” amorphous solid, which is hard and brittle above, becomes a viscous or rubbery supercooled liquid.

[0080] As used herein, the terms “melting temperature,” “melting point,” or “Tm” refer to the temperature at which a crystalline substance is in equilibrium with the liquid phase.

[0081] As used herein, the term "dispersion" refers to a dispersion system in which the dispersed phase, which is one entity, is distributed as constituent units throughout the second entity (continuous phase or vehicle). The size of the dispersed phase can vary significantly (for example, colloidal particles ranging from nanometer dimensions to several microns in size). In general, 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 can comprise a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, can comprise an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, the solid dispersion comprises a polymer that constitutes the dispersed phase, and the drug constitutes the continuous phase, or the solid dispersion comprises a drug that constitutes the dispersed phase and a polymer that constitutes the continuous phase.

[0082] Mode for Carrying Out the Invention One aspect of the present disclosure provides a compound of Formula I: [Chem.] or a solvate, or tautomer, or pharmaceutically acceptable salt thereof.

[0083] Another aspect of the present disclosure provides solid forms of Compound I (e.g., crystalline forms, amorphous forms, solvates, hydrates, co-crystals) that can be used in the therapeutic methods and pharmaceutical compositions described herein. In some embodiments, the present invention provides a neat amorphous form of Compound I. In some embodiments, the present invention provides a neat crystalline form of Compound I. In some embodiments, the present invention provides a solvate crystalline form of Compound I. In some embodiments, the present invention provides a hydrate crystalline form of Compound I.

[0084] A. Methods of Preparing Compound I In one embodiment, a person skilled in the art will use Formula A1, A 1-1 , A 1-2 , A 1-3 , A 1-4 , A 1-5 , A2, A 2-1A3, A 3-1 , A 3-2 Starting with any compound from B-1, B-2, B-3, B-4, B-5, C-1, C-2, C-3, C-4, D-1, D-2, E-A1, E-A2, and E-A3, a compound of formula I, or formulas A1, 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 It is possible to prepare any of the intermediate compounds of B-1, B-2, B-3, B-4, B-5, C-1, C-2, C-3, C-4, D-1, D-2, E-A1, E-A2, and E-A3.

[0085] The method steps described herein are based on formulas A1, 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 , B-1, B-2, B-3, B-4, B-5, C-1, C-2, C-3, The conversion of the starting compounds C-4, D-1, D-2, E-A1, E-A2, E-A3, and F-A2 to compounds of formula I can be mentioned. Those skilled in the art will understand that such methods can also be used to prepare any intermediate between any starting compound and a compound of formula I. For example, formula A 1-2 The conversion of compound A to compound I is via intermediate compound E-A1. Therefore, a person skilled in the art would know that compound A 1-2 To convert the compound of formula A to the compound of formula I, use the method described below. 1-2 You will understand that intermediate compounds E-A1, A1, and D1 can be prepared from the compound.

[0086] Similarly, equation A 3-2 The conversion of compound I to intermediate compound A 3-1The preparation of A3, D-1, and E-A3 is carried out. Therefore, a person skilled in the art will know that formula A 3-2 To convert the compound of formula A to the compound of formula I, use the method described below. 3-2 Starting with compound A, 3-1 , A3, and D-1, and It will be understood that any of E-A3 can be prepared, or any intermediate compound can be converted to a desired intermediate compound using the method described herein. Thus, this application will start from any intermediate or starting material preceding the intermediate being prepared, to prepare intermediate compounds A1, 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 , The aim is to prepare B-1, B-2, B-3, B-4, B-5, C-1, C-2, C-3, C-4, D-1, D-2, E-A1, E-A2, E-A3, and F-A2.

[0087] Scheme 1 [ka]

[0088] Scheme 2 [ka]

[0089] Scheme 3 [ka]

[0090] Scheme 4 [ka]

[0091] Scheme 5 [ka]

[0092] Scheme 6 [ka]

[0093] Scheme 7 [ka]

[0094] Scheme 8 [ka]

[0095] Scheme 9 [ka]

[0096] In one embodiment, the present application relates to a process for preparing a compound of formula (I), its solvate, and a pharmaceutically acceptable salt thereof, [ka] Compound of formula (A1): [ka] This includes converting to the compound of formula (I), where X 1 and X 2 Each of these independently provides a process selected from halogens.

[0097] In some embodiments, X 1 and X 2 They are the same. In some embodiments, X 1 and X 2 Each of them is fluoro. In some embodiments, X1 and X 2 Each of them is chloro. In some embodiments, X 1 and X 2 Each of them is a bromo. In some embodiments, X 1 and X 2 Each of them is iodine.

[0098] In some embodiments, X 1 and X 2 They are different.

[0099] In some embodiments, the step of converting the compound of formula (A1) to the compound of formula (I) is: [ka] This includes converting to [a specific format].

[0100] In some embodiments, the step of converting the compound of formula (A1) to the compound of formula (E-A1) is performed by converting the compound of formula (A1) to the compound of formula (D-1): [ka] This includes making contact with it.

[0101] In some embodiments, the step of contacting the compound of formula (A1) with the compound of formula (D-1) is carried out in the presence of a first palladium catalyst and a first base. In some embodiments, the first palladium catalyst is a palladium-phosphine complex. In some embodiments, the first palladium catalyst is PdCl2(dtbdpf).

[0102] In some embodiments, the step of contacting the compound of formula (A1) with the compound of formula (D-1) is carried out in the presence of a first palladium catalyst, a first ligand, and a first base. In some embodiments, the first palladium catalyst is PdCl2.

[0103] In some embodiments, the first ligand is selected from 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf), bis[(2-diphenylphosphino)phenyl]ether (DPEPhos), 1,2-bis(diphenylphosphino)ethane (dppe), triphenylphosphine (PPh3), cyclohexyldiphenylphosphine (CyPh2P), tri(o-tolyl)phosphine (P(o-tol)3), and di(1-adamantyl)-n-butylphosphine (CataCXium A). In other embodiments, the first ligand is 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf). In other embodiments, the first ligand is 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf). In other embodiments, the first ligand is bis[(2-diphenylphosphino)phenyl] ether (DPEPhos). In other embodiments, the first ligand is 1,2-bis(diphenylphosphino)ethane (dppe). In other embodiments, the first ligand is triphenylphosphine (PPh3). In other embodiments, the first ligand is cyclohexyldiphenylphosphine (CyPh2P). In other embodiments, the first ligand is tri(o-tolyl)phosphine (P(o-tol)3). In other embodiments, the first ligand is di(1-adamantyl)-n-butylphosphine (CataCXium A).

[0104] In some embodiments, the first base is selected from potassium carbonate, potassium phosphate, and potassium fluoride. In some embodiments, the first base is selected from potassium carbonate, potassium phosphate, potassium fluoride, potassium bicarbonate, tripotassium phosphate, dipotassium phosphate, potassium acetate, potassium pivalate, potassium hydroxide, potassium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylamine. In other embodiments, the first base is potassium carbonate. In other embodiments, the first base is potassium phosphate. In other embodiments, the first base is potassium fluoride. In other embodiments, the first base is potassium bicarbonate. In other embodiments, the first base is tripotassium phosphate. In other embodiments, the first base is dipotassium phosphate. In other embodiments, the first base is potassium acetate. In other embodiments, the first base is potassium pivalate. In other embodiments, the first base is potassium hydroxide. In other embodiments, the first base is potassium hexamethyldisilazide. In other embodiments, the first base is 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In other embodiments, the first base is triethylamine.

[0105] In some embodiments, the step of converting a compound of formula (A1) to a compound of formula (I) further includes converting a compound of formula (E-A1) to a compound of formula (I).

[0106] In some embodiments, the step of converting a compound of formula (E-A1) to a compound of formula (I) includes treating the compound of formula (E-A1) with a first acid. In some embodiments, the first acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, and trifluoroacetic 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.

[0107] In some embodiments, the step of converting a compound of formula (A1) to a compound of formula (I) is performed on a compound of formula (E-A2): [ka] This further includes converting to the compound of formula I.

[0108] In some embodiments, the step of converting the compound of formula (E-A2) to the compound of formula (I) involves treating the compound of formula (E-A2) with a first acid in the presence of water and heat to obtain the compound of formula (F-A2): [ka] This includes preparing [the product / service]. In some embodiments, the first 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 other embodiments, the first acid is acetic acid. In other embodiments, the first acid is formic acid. In other embodiments, the first acid is sulfuric acid. In other embodiments, the first acid is phosphoric acid. In other embodiments, the first acid is hydrochloric acid. In other embodiments, the first acid is methanesulfonic acid. In other embodiments, the first acid is oxalic acid. In other embodiments, the first acid is p-toluenesulfonic acid. In other embodiments, the first acid is trifluoroacetic acid. In some embodiments, the step of preparing the compound of formula (F-A2) by treating the compound of formula (E-A2) with the first acid in the presence of water and heat is carried out at a temperature of about 60°C to about 100°C. In other embodiments, the step of preparing the compound of formula (F-A2) by treating the compound of formula (E-A2) with a first acid in the presence of water and heat is carried out at a temperature of approximately 100°C.

[0109] In some embodiments, the step of converting a compound of formula (E-A2) to a compound of formula (I) includes treating the compound of formula (E-A2) with a first Lewis acid in the presence of acetic acid to prepare a compound of formula (F-A2). In some embodiments, the first Lewis acid is selected from MoCl2O2, MoCl5, CuOTf2, VCl3, WOCl4, and WCl6. In other embodiments, the first Lewis acid is MoCl2O2. In other embodiments, the first Lewis acid is MoCl5. In other embodiments, the first Lewis acid is CuOTf2. In other embodiments, the first Lewis acid is VCl3. In other embodiments, the first Lewis acid is WOCl4. In other embodiments, the first Lewis acid is WCl6.

[0110] In some embodiments, the step of converting a compound of formula (E-A2) to a compound of formula (I) includes treating the compound of formula (E-A2) with a first base in the presence of water and heat to prepare a compound of formula (F-A2). In some embodiments, the first base is potassium acetate. In some embodiments, the step of treating the compound of formula (E-A2) with a first base in the presence of water and heat to prepare a compound of formula (F-A2) is carried out at a temperature of about 80°C to about 100°C.

[0111] In some embodiments, the step of converting a compound of formula (A1) to a compound of formula (I) further includes converting a compound of formula (F-A2) to a compound of formula (I).

[0112] In some embodiments, the step of converting a compound of formula (F-A2) to a compound of formula (I) includes treating the compound of formula (F-A2) with an acid. In some embodiments, the acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, oxalic acid, and trifluoroacetic acid. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the acid is methanesulfonic acid. In some embodiments, the acid is phosphoric acid. In some embodiments, the first acid is oxalic acid.

[0113] In some embodiments for preparing the compound of formula I, the process is as follows: 1-1 ) compounds: [ka] This includes converting to the compound of formula (A1).

[0114] In some embodiments, formula (A 1-1 The step of converting the compound of formula (A1) to the compound of formula (A1) is: Formula (A 1-1 The process involves treating the compound with trifluoromethanesulfonic acid anhydride to form a trifuryl intermediate, A step of treating the trifuryl intermediate with a cyanation reagent, A step of treating the cyanation intermediate with a second base to form a cyanated trifuryl intermediate, The process includes the step of treating a cyanated trifuryl intermediate with an aqueous base to form a compound of formula (A1).

[0115] In some embodiments, the cyanating agent is trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. In some embodiments, the cyanating agent is trimethylsilyl cyanide. In some embodiments, the cyanating agent is sodium cyanide. In some embodiments, the cyanating agent is potassium cyanide.

[0116] In some embodiments, the second base is selected from 4-methylmorpholine, trimethylamine, and a Hünig base. In some embodiments, the second base is 4-methylmorpholine. In some embodiments, the second base is trimethylamine. In some embodiments, the second base is a Hünig base.

[0117] In some embodiments, the aqueous base is an aqueous solution of sodium bicarbonate.

[0118] In some embodiments, the process for preparing the compound of formula I is as follows: 1-2 ) compounds: [ka] Formula (A 1-1 This includes converting to a compound of ).

[0119] In some embodiments, formula (A 1-2 The compound of formula (A 1-1 The step of converting to the compound of formula (A 1-2 The process involves treating a compound with a halogenating reagent. In some embodiments, the halogenating reagent is a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from HCl, oxalyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphonic acid dichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating reagent is phosphorus oxychloride. In some embodiments, the chlorinating reagent is selected from Cl2 (with / without oxidizing agent), HCl / Cl (with oxidizing agent), N-chlorosuccinimide (NCS) / dichlorodimethylhydantoin (DCDMH) / trichloroisocyanuric acid (TCCA) sodium dichloroisocyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating reagent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating reagent is phosphorus oxychloride.

[0120] In some embodiments, the process for preparing the compound of formula I is as follows: 1-3 ) compounds: [ka] Formula (A 1-2 This includes converting to a compound of ).

[0121] In some embodiments, formula (A 1-3 The compound of formula (A 1-3 The step of converting to the compound of formula (A 1-3This involves treating the compound with a second acid. In some embodiments, the second acid is aqueous hydrochloric acid.

[0122] In some embodiments, the process for preparing the compound of formula I is as follows: 1-4 ) compounds: [ka] Formula (A 1-3 This includes converting to a compound of ).

[0123] In some embodiments, formula (A 1-4 The compound of formula (A 1-3 The step of converting to a compound of formula (A) is performed in the presence of a third base. 1-4 This involves treating the compound with diethyl malonate. In some embodiments, the third base is an alkali alkoxide. In some embodiments, the third base is a sodium ethoxide.

[0124] In some embodiments, the process for preparing the compound of formula I is as follows: 1-5 ) compounds: [ka] Formula (A 1-4 This includes converting to a compound of ).

[0125] In some embodiments, formula (A 1-5 The compound of formula (A 1-4 The step of converting to a compound of formula (A) is performed in the presence of a fourth base, a second palladium catalyst, and a first preferred ligand. 1-5 This includes treating the compound with carbon monoxide.

[0126] In some embodiments, the fourth base is selected from triethylamine, Hünig base, 4-methylmorpholine, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). In some embodiments, the fourth base is triethylamine.

[0127] In some embodiments, the second palladium catalyst is Pd(OAc)2.

[0128] In some embodiments, the first preferred ligand is selected from 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), triphenylphosphine (PPh3), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP). In some embodiments, the first preferred ligand is 1,1'-bis(diphenylphosphino)ferrocene (DPPF).

[0129] In some embodiments, X 1 and X 2 Each of them is chloroform.

[0130] In some embodiments, the process for preparing the compound of formula (I) is as follows: [ka] Compound of formula (A3): [ka] This includes converting to the compound of formula (I).

[0131] In some embodiments, the step of converting the compound of formula (A3) to the compound of formula (I) is to convert the compound of formula (A3) to the compound of formula (E-A3): [ka] This includes converting to [a specific format].

[0132] In some embodiments, the step of converting the compound of formula (A3) to the compound of formula (E-A3) is performed by converting the compound of formula (A3) to the compound of formula (D-1): [ka] This includes making contact with it.

[0133] In some embodiments, the process for preparing the compound of formula I includes contacting the compound of formula (A3) with the compound of formula (D-1) in the presence of a first palladium catalyst and a first base. In some embodiments, the first palladium catalyst is PdCl2(dtbdpf). In some embodiments, the first base is potassium phosphate.

[0134] In some embodiments, the step of contacting the compound of formula (A3) with the compound of formula (D-1) is carried out in the presence of a first palladium catalyst, a first ligand, and a first base. In some embodiments, the first palladium catalyst is PdCl2.

[0135] In some embodiments, the first ligand is selected from 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf), bis[(2-diphenylphosphino)phenyl]ether (DPEPhos), 1,2-bis(diphenylphosphino)ethane (dppe), triphenylphosphine (PPh3), cyclohexyldiphenylphosphine (CyPh2P), tri(o-tolyl)phosphine (P(o-tol)3), and di(1-adamantyl)-n-butylphosphine (CataCXium A). In other embodiments, the first ligand is 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf). In other embodiments, the first ligand is 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf). In other embodiments, the first ligand is bis[(2-diphenylphosphino)phenyl] ether (DPEPhos). In other embodiments, the first ligand is 1,2-bis(diphenylphosphino)ethane (dppe). In other embodiments, the first ligand is triphenylphosphine (PPh3). In other embodiments, the first ligand is cyclohexyldiphenylphosphine (CyPh2P). In other embodiments, the first ligand is tri(o-tolyl)phosphine (P(o-tol)3). In other embodiments, the first ligand is di(1-adamantyl)-n-butylphosphine (CataCXium A).

[0136] In some embodiments, the first base is selected from potassium carbonate, potassium phosphate, potassium fluoride, potassium bicarbonate, tripotassium phosphate, dipotassium phosphate, potassium acetate, potassium pivalate, potassium hydroxide, potassium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and triethylamine. In other embodiments, the first base is potassium carbonate. In other embodiments, the first base is potassium phosphate. In other embodiments, the first base is potassium fluoride. In other embodiments, the first base is potassium bicarbonate. In other embodiments, the first base is tripotassium phosphate. In other embodiments, the first base is dipotassium phosphate. In other embodiments, the first base is potassium acetate. In other embodiments, the first base is potassium pivalate. In other embodiments, the first base is potassium hydroxide. In other embodiments, the first base is potassium hexamethyldisilazide. In other embodiments, the first base is 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In other embodiments, the first base is triethylamine.

[0137] In some embodiments, the step of converting a compound of formula (A3) to a compound of formula (I) further includes converting a compound of formula (E-A3) to a compound of formula (I).

[0138] In some embodiments, the step of converting a compound of formula (E-A3) to a compound of formula (I) includes treating the compound of formula (E-A3) with a first acid. In some embodiments, the first acid is 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.

[0139] In some embodiments, the process for preparing the compound of formula I is as follows: 3-1 ) compounds: [ka] This includes converting to the compound of formula (A3).

[0140] In some embodiments, formula (A 3-1 The step of converting the compound of formula (A) to the compound of formula (A) is the step of converting the compound of formula (A 3-1 This involves treating the compound with a cyanating reagent and a second base.

[0141] In some embodiments, the cyanating agent is trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. In some embodiments, the cyanating agent is trimethylsilyl cyanide. In some embodiments, the cyanating agent is sodium cyanide. In some embodiments, the cyanating agent is potassium cyanide.

[0142] In some embodiments, the second base is triethylamine.

[0143] In some embodiments, the process for preparing the compound of formula I is as follows: 3-2 ) compounds: [ka] Formula (A 3-1 This includes converting to a compound of ).

[0144] In some embodiments, formula (A 3-2 The compound of formula (A 3-1 The step of converting to a compound of formula (A) is performed in the presence of a third base. 3-2 This includes treating the compound with benzyl alcohol.

[0145] In some embodiments, the third base is selected from carbonate bases, phosphate bases, hexamethyldisilizanone sodium, alkyllithium reagents, hydride reagents, alkali alkoxides, and alkali hydroxides. In some embodiments, the third base is an alkali alkoxide. In some embodiments, the third base is an alkali methoxide. In some embodiments, the third base is selected from lithium methoxide, sodium methoxide, and potassium methoxide. In some embodiments, the third base is lithium methoxide. In some embodiments, the third base is sodium methoxide. In some embodiments, the third base is potassium methoxide. In some embodiments, the third base is an alkali ethoxide. In some embodiments, the third base is selected from lithium ethoxide, sodium ethoxide, and potassium ethoxide. In some embodiments, the third base is lithium ethoxide. In some embodiments, the third base is sodium ethoxide. In some embodiments, the third base is potassium ethoxide. In some embodiments, the third base is an alkali tert-butoxide. In some embodiments, the third base is selected from lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. In some embodiments, the third base is lithium tert-butoxide. In some embodiments, the third base is sodium tert-butoxide. In some embodiments, the third base is potassium tert-butoxide. In some embodiments, the third base is an alkali tert-pentoxide. In some embodiments, the third base is selected from lithium tert-pentoxide, sodium tert-pentoxide, and potassium tert-pentoxide. In some embodiments, the third base is lithium tert-pentoxide. In some embodiments, the third base is sodium tert-pentoxide. In some embodiments, the third base is potassium tert-pentoxide. In some embodiments, the third base is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.In some embodiments, the third base is lithium bis(trimethylsilyl)amide. In some embodiments, the third base is sodium bis(trimethylsilyl)amide. In some embodiments, the third base is potassium bis(trimethylsilyl)amide. In some embodiments, the third base is an alkali 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.

[0146] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (D-1).

[0147] In some embodiments, the step of converting a compound of formula (D-2) to a compound of formula (D-1) includes treating the compound of formula (D-2) with tetrahydroxydiborone (diboronic acid) in the presence of a third palladium catalyst, a second preferred ligand, and a fifth base.

[0148] In some embodiments, the third palladium catalyst is selected from Pd(OAc)2, Pd(dppf)Cl2, Pd(PCy3)2, and Pd2dba3. In some embodiments, the third palladium catalyst is Pd(OAc)2. In some embodiments, the second preferred ligand is cyclohexyldiphenylphosphine.

[0149] In some embodiments, the fifth base is selected from KOPh, triethylamine, Hünig base, KOEt, and potassium acetate (KOAc). In some embodiments, the fifth base is potassium acetate.

[0150] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (D-2).

[0151] In some embodiments, the step of converting the compound of formula (B-1) to the compound of formula (D-2) is performed in the presence of a sixth base, converting the compound of formula (B-1) to the compound of formula (C-1): [ka] This includes making contact with it.

[0152] In some embodiments, the step of converting the compound of formula (B-1) to the compound of formula (D-2) includes contacting the compound of formula (B-2) with the compound of formula (C-1) in the presence of a sixth base and a phase transfer catalyst.

[0153] In some embodiments, the sixth base is potassium carbonate.

[0154] In some embodiments, the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylphosphonium bromide (TBPB), tetrabutylammonium bisulfate (TBA HSO4), and tetraoctylammonium chloride (TOAC). In other embodiments, the phase transfer catalyst is tetrabutylammonium bromide (TBAB). In other embodiments, the phase transfer catalyst is tetrabutylammonium chloride (TBAC). In other embodiments, the phase transfer catalyst is tetrabutylphosphonium bromide (TBPB). In other embodiments, the phase transfer catalyst is tetrabutylammonium bisulfate (TBA HSO4). In other embodiments, the phase transfer catalyst is tetraoctylammonium chloride (TOAC).

[0155] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (B-1).

[0156] In some embodiments, the step of converting a compound of formula (B-2) to a compound of formula (B-1) includes treating the compound of formula (B-2) with a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from HCl, oxalyl chloride, trichloroacetic anhydride / phosgene, triphenylphosphine dichloride, phenylphosphonic acid dichloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the chlorinating reagent is phosphorus oxychloride. In some embodiments, the chlorinating reagent is selected from Cl2 (with / without oxidizing agent), HCl / Cl (with oxidizing agent), N-chlorosuccinimide (NCS) / dichlorodimethyl hydantoin (DCDMH) / trichloroisocyanuric acid (TCCA) sodium dichloroisocyanurate NaDCC, NaOCl, SO2Cl2, and CCl4 / C2Cl6. In some embodiments, the chlorinating reagent is selected from phosphorus oxychloride and phosphorus pentachloride. In some embodiments, the chlorinating agent is phosphorus oxychloride.

[0157] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (B-2).

[0158] In some embodiments, the step of converting the compound of formula (B-3) to the compound of formula (B-2) includes treating the compound of formula (B-3) with a brominating reagent in the presence of a third acid.

[0159] In some embodiments, the brominating agent is molecular bromine. In some embodiments, the third acid is acetic acid.

[0160] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (B-3).

[0161] In some embodiments, the step of converting a compound of formula (B-4) to a compound of formula (B-3) includes treating the compound of formula (B-4) with a fourth acid in the presence of a first preferred solvent.

[0162] In some embodiments, the fourth acid is an inorganic acid. In some embodiments, the fourth acid is an aqueous solution of concentrated hydrochloric acid. In some embodiments, the first preferred solvent includes dioxane and water.

[0163] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (B-4).

[0164] In some embodiments, the step of converting the compound of formula (B-5) to the compound of formula (B-4) includes treating the compound of formula (B-5) with a methylation reagent in the presence of a fourth palladium catalyst and a seventh base.

[0165] In some embodiments, the first methylating agent is methylboronic acid. In some embodiments, the fourth palladium catalyst is Pd(dppf)Cl2·DCM. In some embodiments, the seventh base is potassium carbonate.

[0166] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This involves converting to a compound of formula (C-1), and PG is a suitable protecting group.

[0167] In some embodiments, the step of converting a compound of formula (C-2) to a compound of formula (C-1) includes deprotecting the compound of formula (C-1) to obtain the compound of formula (C-2).

[0168] In some embodiments, PG is tetrahydropyranyl.

[0169] In some embodiments, the step of converting a compound of formula (C-2) to a compound of formula (C-1) includes treating the compound of formula (C-2) with a first acid catalyst. In some embodiments, the first acid catalyst is pyridinium p-toluenesulfonate.

[0170] In some embodiments, the compound of formula (C-3): [ka] In the step of converting to a (C-2) compound, PG is a suitable protecting group. In some embodiments, PG is tetrahydropyranyl.

[0171] In some embodiments, the step of converting the compound of formula (C-3) to the compound of formula (C-2) includes treating the compound of formula (C-3) with a second methylation reagent in the presence of an eighth base.

[0172] In some embodiments, the second methylating agent is methyl iodide. In some embodiments, the eighth base is butyllithium. In some embodiments, the eighth base is n-butyllithium.

[0173] In some embodiments, the process for preparing the compound of formula I is as follows: [ka] This includes converting to the compound of formula (C-3).

[0174] In some embodiments, the step of converting a compound of formula (C-4) to a compound of C-3 includes treating the compound of (C-4) with a suitable protecting group in the presence of a second acid catalyst. In some embodiments, the suitable protecting group is 3,4-dihydropyran. In some embodiments, the second acid catalyst is pyridinium p-toluenesulfonate.

[0175] In some embodiments, the process for preparing the compound of formula I includes converting the compound of formula (I) into a solvate of the compound of formula (I).

[0176] In some embodiments, the step of converting a compound of formula (I) to a solvate of a compound of formula (I) includes recrystallizing the compound of formula (I) from a suitable solvent. In some embodiments, the suitable solvent is ethanol.

[0177] In some embodiments, the solvate of the compound of formula (I) is the compound of formula (F): [ka] That is the case.

[0178] In some embodiments, the process for preparing the compound of formula I includes the step of converting the solvate of the compound of formula (I) into form A of the compound of formula (I).

[0179] In some embodiments, the present invention [ka] Regarding compounds selected from.

[0180] In some embodiments, the present invention [ka] The present invention relates to a composition comprising one or more compounds selected from the following.

[0181] In some embodiments, the present invention relates to compounds of formula (I) and compounds of formula (E-A2): [ka] This relates to compositions containing the following:

[0182] In some embodiments, the composition further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0183] In some embodiments, the present invention relates to compounds of formula (I) and compounds of formula (E-A3): [ka] This relates to compositions containing the following:

[0184] In some embodiments, the composition further comprises an acid. In some embodiments, the acid is trifluoroacetic acid.

[0185] In some embodiments, the composition comprises a compound of formula (E-A2), a compound of formula (A2), and a compound of formula (D-1): [ka] Includes.

[0186] In some embodiments, the composition comprises a compound of formula (E-A3), a compound of formula (A3), and a compound of formula (D-1): [ka] Includes.

[0187] In some embodiments, the compound of formula (I): [ka] Or a pharmaceutically acceptable salt thereof, or a solvate thereof, may be prepared by any one or more of the processes disclosed herein.

[0188] B. Amorphous form of compound I In some embodiments, the disclosure provides a neat amorphous form of compound I. In some embodiments, the disclosure provides an amorphous form of compound I. Figure 1 provides an X-ray powder diffractogram of the amorphous form of compound I at room temperature.

[0189] In some embodiments, the amorphous form of compound I is substantially pure. In some embodiments, the amorphous form of compound I is substantially amorphous. In some embodiments, the amorphous form of compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0190] In some embodiments, the amorphous form of compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 1.

[0191] In some embodiments, the amorphous form of compound I has a peak at 177.6 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 172.0 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 162.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 155.2 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 149.9 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 147.0 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 121.0 ± 0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 120.1 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 119.1 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 116.0 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 114.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 113.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 15.5 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at 7.7 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0192] In some embodiments, the amorphous form of compound I has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 177.6±0.2 ppm, 172.0±0.2 ppm, 162.6±0.2 ppm, 155.2±0.2 ppm, 149.9±0.2 ppm, 147.0±0.2 ppm, 121.0±0.2 ppm, 120.1±0.2 ppm, 119.1±0.2 ppm, 116.0±0.2 ppm, 114.6±0.2 ppm, 113.8±0.2 ppm, 15.5±0.2 ppm, and 7.7±0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the amorphous form of compound I has peaks at 177.6±0.2 ppm, 172.0±0.2 ppm, 162.6±0.2 ppm, 155.2±0.2 ppm, 149.9±0.2 ppm, 147.0±0.2 ppm, 121.0±0.2 ppm, 120.1±0.2 ppm, 119.1±0.2 ppm, 116.0±0.2 ppm, 114.6±0.2 ppm, 113.8±0.2 ppm, 15.5±0.2 ppm, and 7.7±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0193] In some embodiments, the amorphous form of compound I is substantially the same as that shown in Figure 2. 13 Characterized by C SSNMR spectra.

[0194] In some embodiments, the amorphous form of compound I has a peak at -61.9 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the amorphous form of compound I has a peak at -142.1 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0195] In some embodiments, the amorphous form of compound I has one or two peaks selected from -61.9 ± 0.2 ppm and -142.1 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0196] In some embodiments, the amorphous form of compound I is substantially the same as that shown in Figure 3. 19 Characterized by F SSNMR spectra.

[0197] Another aspect of the present disclosure provides a method for preparing an amorphous form of compound I. In some embodiments, the method for preparing an amorphous form of compound I includes (i) dissolving compound I, (ii) filtering and evaporating the solvent by centrifugal evaporation at 50°C and 12 mbar for 1 hour, and (iii) drying overnight in a vacuum oven at 50°C to obtain an amorphous form of compound I.

[0198] C. Neat form of crystalline compound I A In some embodiments, the disclosure provides a neat crystalline form of compound I. In some embodiments, the disclosure provides a neat form A of crystalline compound I. Figure 4 provides an X-ray powder diffractogram of neat form A of crystalline compound I.

[0199] In some embodiments, neat form A of crystalline compound I is substantially pure. In some embodiments, neat form A of crystalline compound I is substantially crystalline. In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0200] In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.5 ± 0.2 degrees 2 theta. In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.3 ± 0.2 degrees 2 theta. In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.5 ± 0.2 degrees 2 theta.

[0201] In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 7.4 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.3 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 11.3 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.4 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.9 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.9 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.6 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.6 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.0 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.7 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.9 ± 0.2 degrees 2-theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.2 ± 0.2 degrees 2-theta.In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.8 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.4 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.9 ± 0.2 degrees 2 theta. In some embodiments, the neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.5 ± 0.2 degrees 2 theta. In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.5 ± 0.2 degrees 2 theta. In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.1 ± 0.2 degrees 2 theta.

[0202] In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals from 9.5±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, and 13.5±0.2 degrees 2-theta.

[0203] In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 9.5±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, and 13.5±0.2 degrees 2-theta, and (b) one or two signals selected from 11.3±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, and 20.5±0.2 degrees 2-theta.

[0204] In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 11.3±0.2° 2-theta, 15.9±0.2° 2-theta, 20.5±0.2° 2-theta, 14.9±0.2° 2-theta, 16.6±0.2° 2-theta, and 23.5±0.2° 2-theta.

[0205] In some embodiments, neat form A of crystalline compound I is 7.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, 13.5±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.6±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.0±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from theta, 19.2±0.2° 2-theta, 19.5±0.2° 2-theta, 19.8±0.2° 2-theta, 20.5±0.2° 2-theta, 21.4±0.2° 2-theta, 21.9±0.2° 2-theta, 22.5±0.2° 2-theta, 23.5±0.2° 2-theta, and 24.1±0.2° 2-theta.

[0206] In some embodiments, the neat form A of crystalline compound I is 7.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, 13.5±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.6±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.0± Characterized by X-ray powder diffractograms with signals at 0.2° 2-theta, 18.7±0.2° 2-theta, 18.9±0.2° 2-theta, 19.2±0.2° 2-theta, 19.5±0.2° 2-theta, 19.8±0.2° 2-theta, 20.5±0.2° 2-theta, 21.4±0.2° 2-theta, 21.9±0.2° 2-theta, 22.5±0.2° 2-theta, 23.5±0.2° 2-theta, and 24.1±0.2° 2-theta.

[0207] In some embodiments, neat form A of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 4.

[0208] In some embodiments, neat form A of crystalline compound I has a peak at 170.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 163.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 162.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 160.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 158.6 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 158.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 154.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 154.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 148.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 147.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 146.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 145.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 143.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 143.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 141.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 127.4 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 125.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 123.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 122.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 121.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 120.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 117.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 117.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 116.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 115.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 114.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 113.6 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 112.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 15.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at 8.2 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0209] In some embodiments, the neat form A of crystalline compound I is 170.4±0.2 ppm, 163.8±0.2 ppm, 162.4±0.2 ppm, 160.9±0.2 ppm, 158.6±0.2 ppm, 158.3±0.2 ppm, 154.6±0.2 ppm, 154.0±0.2 ppm, 148.3±0.2 ppm, 147.6±0.2 ppm, 146.9±0.2 ppm, 145.9±0.2 ppm, 143.5±0.2 ppm, 143.1±0.2 ppm, 141.9±0.2 ppm, and 127.4±0. It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 2 ppm, 125.3±0.2 ppm, 123.6±0.2 ppm, 122.2±0.2 ppm, 121.3±0.2 ppm, 120.7±0.2 ppm, 117.9±0.2 ppm, 117.3±0.2 ppm, 116.3±0.2 ppm, 115.8±0.2 ppm, 114.2±0.2 ppm, 113.6±0.2 ppm, 112.8±0.2 ppm, 15.4±0.2 ppm, and 8.2±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0210] In some embodiments, the neat form A of crystalline compound I is 170.4±0.2 ppm, 163.8±0.2 ppm, 162.4±0.2 ppm, 160.9±0.2 ppm, 158.6±0.2 ppm, 158.3±0.2 ppm, 154.6±0.2 ppm, 154.0±0.2 ppm, 148.3±0.2 ppm, 147.6±0.2 ppm, 146.9±0.2 ppm, 145.9±0.2 ppm, 143.5±0.2 ppm, 143.1±0.2 ppm, 14 It has peaks at 1.9±0.2 ppm, 127.4±0.2 ppm, 125.3±0.2 ppm, 123.6±0.2 ppm, 122.2±0.2 ppm, 121.3±0.2 ppm, 120.7±0.2 ppm, 117.9±0.2 ppm, 117.3±0.2 ppm, 116.3±0.2 ppm, 115.8±0.2 ppm, 114.2±0.2 ppm, 113.6±0.2 ppm, 112.8±0.2 ppm, 15.4±0.2 ppm, and 8.2±0.2 ppm. 13 It has a CSSNMR spectrum. 13 It is characterized by having CSSNMR.

[0211] In some embodiments, neat form A of crystalline compound I is substantially similar to that shown in Figure 5. 13 Characterized by C SSNMR spectra.

[0212] In some embodiments, neat form A of crystalline compound I has a peak at -61.2 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at -61.6 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at -138.6 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at -140.3 ± 0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at -142.0 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has a peak at -146.0 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0213] In some embodiments, neat form A of crystalline compound I has one or two peaks selected from -61.2±0.2 ppm, -61.6±0.2 ppm, -138.6±0.2 ppm, -140.3±0.2 ppm, -142.0±0.2 ppm, and -146.0±0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form A of crystalline compound I has peaks at -61.2±0.2 ppm, -61.6±0.2 ppm, -138.6±0.2 ppm, -140.3±0.2 ppm, -142.0±0.2 ppm, and -146.0±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0214] In some embodiments, neat form A of crystalline compound I is substantially similar to that shown in Figure 6. 19 Characterized by F SSNMR spectra.

[0215] In some embodiments, the neat form A of crystalline compound I is triclinic, P-1 space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 9.6 ± 0.1 Å α 94.3 ± 0.1° b 12.6 ± 0.1 Å β 97.3 ± 0.1° c 18.7 ± 0.1 Å γ 107.3 ± 0.1°. It is characterized by: In some embodiments, the diffractometer is a Bruker diffractometer.

[0216] Another aspect of the present invention provides a method for producing neat form A of crystalline compound I. In some embodiments, the method for producing neat form A of crystalline compound I includes (i) combining compound I and ethyl acetate, (ii) distilling under vacuum at 50°C, (iii) adding ethyl acetate, (iv) distilling under vacuum at 50°C, (v) heating to 75°C, (vi) adding heptane, (vii) cooling to 40°C, (viii) adding a seed of form A of crystalline compound I, (ix) holding at 40°C for 1.5 hours, (x) adding heptane over 5 hours, (xi) cooling the slurry to 20°C over 5 hours, (xii) holding at 20°C for 11 hours, (xiii) collecting the solid, and (xiv) drying the solid in a vacuum oven at 45°C for 46 hours with a small nitrogen bleed to obtain neat form A of crystalline compound I.

[0217] D. Neat form of crystalline compound I B In some embodiments, the present disclosure provides a neat form B of crystalline compound I. Figure 7 provides an X-ray powder diffractogram of neat form B of crystalline compound I.

[0218] In some embodiments, neat form B of crystalline compound I is substantially pure. In some embodiments, neat form B of crystalline compound I is substantially crystalline. In some embodiments, neat form B of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0219] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 4.8 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.3 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.5 ± 0.2 degrees 2 theta.

[0220] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 6.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 7.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.8 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 10.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.8 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.7 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.2 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.9 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.9 ± 0.2 degrees 2-theta.In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.9 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.2 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.9 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.7 ± 0.2 degrees 2 theta. In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.0 ± 0.2 degrees 2-theta.

[0221] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals of 4.8±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, and 18.5±0.2 degrees 2-theta.

[0222] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 4.8±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, and 18.5±0.2 degrees 2-theta, and (b) one or two signals selected from 6.0±0.2 degrees 2-theta, 16.5±0.2 degrees 2-theta, and 16.9±0.2 degrees 2-theta.

[0223] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 4.8±0.2° 2-theta, 13.3±0.2° 2-theta, 18.5±0.2° 2-theta, 6.0±0.2° 2-theta, 16.5±0.2° 2-theta, 16.9±0.2° 2-theta, 14.1±0.2° 2-theta, 14.7±0.2° 2-theta, and 15.2±0.2° 2-theta.

[0224] In some embodiments, neat form B of crystalline compound I is 4.8±0.2 degrees 2-theta, 6.0±0.2 degrees 2-theta, 7.0±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 12.1±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 15.2±0.2 degrees 2-theta, 16.5±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from 17.9±0.2° 2-theta, 18.5±0.2° 2-theta, 18.9±0.2° 2-theta, 19.2±0.2° 2-theta, 19.5±0.2° 2-theta, 20.9±0.2° 2-theta, 21.7±0.2° 2-theta, and 23.0±0.2° 2-theta.

[0225] In some embodiments, the neat form B of crystalline compound I is 4.8±0.2 degrees 2-theta, 6.0±0.2 degrees 2-theta, 7.0±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 12.1±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 15.2±0.2 degrees 2-theta, 16.5±0 Characterized by X-ray powder diffractograms having signals at 0.2° 2-theta, 16.9±0.2° 2-theta, 17.5±0.2° 2-theta, 17.9±0.2° 2-theta, 18.5±0.2° 2-theta, 18.9±0.2° 2-theta, 19.2±0.2° 2-theta, 19.5±0.2° 2-theta, 20.9±0.2° 2-theta, 21.7±0.2° 2-theta, and 23.0±0.2° 2-theta.

[0226] In some embodiments, the neat form B of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 7.

[0227] In some embodiments, neat form B of crystalline compound I has a peak at 176.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 171.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 164.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 161.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 160.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 155.3 ± 0.2 ppm.13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 154.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 148.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 147.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 146.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 145.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 144.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 127.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 125.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 122.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 121.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 118.4 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 116.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 114.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 113.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 112.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 17.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 15.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 10.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 9.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at 8.8 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0228] In some embodiments, the neat form B of crystalline compound I is 176.9±0.2 ppm, 171.7±0.2 ppm, 164.0±0.2 ppm, 161.4±0.2 ppm, 160.7±0.2 ppm, 155.3±0.2 ppm, 154.8±0.2 ppm, 148.6±0.2 ppm, 147.6±0.2 ppm, 146.4±0.2 ppm, 145.7±0.2 ppm, 144.8±0.2 ppm, 127.7±0.2 ppm, 125.4± It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 0.2 ppm, 122.0 ± 0.2 ppm, 121.5 ± 0.2 ppm, 118.4 ± 0.2 ppm, 116.3 ± 0.2 ppm, 114.8 ± 0.2 ppm, 113.8 ± 0.2 ppm, 112.6 ± 0.2 ppm, 17.8 ± 0.2 ppm, 15.0 ± 0.2 ppm, 10.7 ± 0.2 ppm, 9.6 ± 0.2 ppm, and 8.8 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0229] In some embodiments, the neat form B of crystalline compound I is 176.9±0.2 ppm, 171.7±0.2 ppm, 164.0±0.2 ppm, 161.4±0.2 ppm, 160.7±0.2 ppm, 155.3±0.2 ppm, 154.8±0.2 ppm, 148.6±0.2 ppm, 147.6±0.2 ppm, 146.4±0.2 ppm, 145.7±0.2 ppm, 144.8±0.2 ppm, It has peaks at 127.7±0.2 ppm, 125.4±0.2 ppm, 122.0±0.2 ppm, 121.5±0.2 ppm, 118.4±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 112.6±0.2 ppm, 17.8±0.2 ppm, 15.0±0.2 ppm, 10.7±0.2 ppm, 9.6±0.2 ppm, and 8.8±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0230] In some embodiments, neat form B of crystalline compound I is substantially similar to that shown in Figure 8. 13Characterized by C SSNMR spectra.

[0231] In some embodiments, neat form B of crystalline compound I has a peak at -61.6 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at -138.0 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at -139.7 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at -143.4 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has a peak at -144.9 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0232] In some embodiments, neat form B of crystalline compound I has one or two peaks selected from -61.6±0.2 ppm, -138.0±0.2 ppm, -139.7±0.2 ppm, -143.4±0.2 ppm, and -144.9±0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, neat form B of crystalline compound I has peaks at -61.6±0.2 ppm, -138.0±0.2 ppm, -139.7±0.2 ppm, -143.4±0.2 ppm, and -144.9±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0233] In some embodiments, neat form B of crystalline compound I is substantially similar to that shown in Figure 9. 19 Characterized by F SSNMR spectra.

[0234] Another aspect of the present disclosure provides a method for obtaining neat form B of crystalline compound I. In some embodiments, the method for obtaining neat form B of crystalline compound I includes (i) adding hydrate form A of compound I to an oven set to 180°C, and (ii) cooling under ambient conditions to obtain neat form B of crystalline compound I.

[0235] E. Neat form of crystalline compound I E In some embodiments, the present disclosure provides a neat form E of crystalline compound I. Figure 10 provides an X-ray powder diffractogram of neat form E of crystalline compound I.

[0236] In some embodiments, the neat form E of crystalline compound I is substantially pure. In some embodiments, the neat form E of crystalline compound I is substantially crystalline. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0237] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.6 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 10.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.6 ± 0.2 degrees 2 theta.

[0238] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.7 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 11.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.2 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.4 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.3 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.6 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.4 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.1 ± 0.2 degrees 2-theta.In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.5 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.0 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.2 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.1 ± 0.2 degrees 2 theta. In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.7 ± 0.2 degrees 2 theta.

[0239] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals selected from 8.6±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 12.6±0.2 degrees 2-theta.

[0240] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 8.6±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 12.6±0.2 degrees 2-theta, and (b) one or two signals selected from 14.1±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta.

[0241] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 8.6±0.2° 2-theta, 10.1±0.2° 2-theta, 12.6±0.2° 2-theta, 14.1±0.2° 2-theta, 20.3±0.2° 2-theta, 23.2±0.2° 2-theta, 11.5±0.2° 2-theta, 14.2±0.2° 2-theta, and 15.1±0.2° 2-theta.

[0242] In some embodiments, the neat form E of crystalline compound I is 8.5±0.2 degrees 2-theta, 8.6±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 12.0±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 20.6±0.2 degrees 2-theta, 21. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from 0±0.2° 2-theta, 21.4±0.2° 2-theta, 22.1±0.2° 2-theta, 22.5±0.2° 2-theta, 23.0±0.2° 2-theta, 23.2±0.2° 2-theta, 24.1±0.2° 2-theta, and 24.7±0.2° 2-theta.

[0243] In some embodiments, the neat form E of crystalline compound I is 8.5±0.2 degrees 2-theta, 8.6±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 12.0±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta Characterized by X-ray powder diffractograms having signals at 20.3±0.2° 2-theta, 20.6±0.2° 2-theta, 21.0±0.2° 2-theta, 21.4±0.2° 2-theta, 22.1±0.2° 2-theta, 22.5±0.2° 2-theta, 23.0±0.2° 2-theta, 23.2±0.2° 2-theta, 24.1±0.2° 2-theta, and 24.7±0.2° 2-theta.

[0244] In some embodiments, the neat form E of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 10.

[0245] In some embodiments, the neat form E of crystalline compound I has a peak at 170.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 163.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 162.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 161.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 159.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 154.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 150.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 149.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 148.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 148.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 147.1 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 144.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 143.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 143.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 126.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 126.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 124.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 122.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 120.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 117.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 116.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 115.2 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 114.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 113.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 15.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 15.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at 8.4 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0246] In some embodiments, the neat form E of crystalline compound I is 170.0±0.2 ppm, 163.0±0.2 ppm, 162.3±0.2 ppm, 161.3±0.2 ppm, 159.3±0.2 ppm, 154.7±0.2 ppm, 150.6±0.2 ppm, 149.8±0.2 ppm, 148.6±0.2 ppm, 148.3±0.2 ppm, 147.1±0.2 ppm, 144.9±0.2 ppm, 143.9±0.2 ppm, 143.5±0.2 ppm, 1 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 26.9±0.2ppm, 126.0±0.2ppm, 124.1±0.2ppm, 122.6±0.2ppm, 120.8±0.2ppm, 117.8±0.2ppm, 116.7±0.2ppm, 115.2±0.2ppm, 114.1±0.2ppm, 113.1±0.2ppm, 15.9±0.2ppm, 15.3±0.2ppm, and 8.4±0.2ppm. 13 It is characterized by having a C SSNMR spectrum.

[0247] In some embodiments, the neat form E of crystalline compound I is 170.0±0.2 ppm, 163.0±0.2 ppm, 162.3±0.2 ppm, 161.3±0.2 ppm, 159.3±0.2 ppm, 154.7±0.2 ppm, 150.6±0.2 ppm, 149.8±0.2 ppm, 148.6±0.2 ppm, 148.3±0.2 ppm, 147.1±0.2 ppm, 144.9±0.2 ppm, 143.9±0.2 ppm. It is characterized by peaks at m, 143.5±0.2 ppm, 126.9±0.2 ppm, 126.0±0.2 ppm, 124.1±0.2 ppm, 122.6±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 116.7±0.2 ppm, 115.2±0.2 ppm, 114.1±0.2 ppm, 113.1±0.2 ppm, 15.9±0.2 ppm, 15.3±0.2 ppm, and 8.4±0.2 ppm.

[0248] In some embodiments, the neat form E of crystalline compound I is substantially similar to that shown in Figure 11. 13 Characterized by C SSNMR spectra.

[0249] In some embodiments, the neat form E of crystalline compound I has a peak at -60.9 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -62.5 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -63.1 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -135.1 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -137.1 ± 0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -140.7 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has a peak at -141.9 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0250] In some embodiments, the neat form E of crystalline compound I has one or two peaks selected from -60.9±0.2 ppm, -62.5±0.2 ppm, -63.1±0.2 ppm, -135.1±0.2 ppm, -137.1±0.2 ppm, -140.7±0.2 ppm, and -141.9±0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the neat form E of crystalline compound I has peaks at -60.9±0.2 ppm, -62.5±0.2 ppm, -63.1±0.2 ppm, -135.1±0.2 ppm, -137.1±0.2 ppm, -140.7±0.2 ppm, and -141.9±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0251] In some embodiments, the neat form E of crystalline compound I is substantially similar to that shown in Figure 12. 19 Characterized by F SSNMR spectra.

[0252] In some embodiments, the neat form E of crystalline compound I is triclinic, P-1 space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 8.7 ± 0.1 Å α 92.7 ± 0.1° b 12.2 ± 0.1 Å β 96.3 ± 0.1° c 20.9 ± 0.1 Å γ 98.6 ± 0.1°. It is characterized by: In some embodiments, the diffractometer is a Rigaku diffractometer.

[0253] In some embodiments, the neat form E of crystalline compound I is triclinic, P-1 space group, and has the following unit cell dimensions measured at 298 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 8.9 ± 0.1 Å α 92.6 ± 0.1° b 12.3 ± 0.1 Å β 97.1 ± 0.1° c 21.1 ± 0.1 Å γ 98.5 ± 0.1°. It is characterized by: In some embodiments, the diffractometer is a Rigaku diffractometer.

[0254] Another aspect of the present disclosure provides a method for obtaining neat form E of crystalline compound I. In some embodiments, the method for obtaining neat form E of crystalline compound I includes (i) combining hydrate form A of compound I with trifluorotoluene, (ii) heating the slurry to 80°C, and (iii) cooling to room temperature to obtain neat form E of crystalline compound I.

[0255] F. Acetone solvate hydrate of crystalline compound I, form A In some embodiments, the present disclosure provides an acetone solvate hydrate form A of crystalline compound I. Figure 13 provides an X-ray powder diffractogram of the acetone solvate hydrate form A of crystalline compound I.

[0256] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is substantially pure. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is substantially crystalline. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0257] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.2 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.1 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 25.9 ± 0.2 degrees 2 theta.

[0258] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 7.2 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.1 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.4 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.7 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 11.2 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 11.5 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.3 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.5 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.9 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.1 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.9 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.4 ± 0.2 degrees 2 theta.In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.8 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.1 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.6 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.2 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.5 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.6 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.7 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.7 ± 0.2 degrees 2 theta. In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.8 ± 0.2 degrees 2 theta.

[0259] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals from among 17.2±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 25.9±0.2 degrees 2-theta.

[0260] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 17.2±0.2° 2-theta, 18.1±0.2° 2-theta, and 25.9±0.2° 2-theta, and (b) one or two signals selected from 12.9±0.2° 2-theta, 15.6±0.2° 2-theta, and 24.8±0.2° 2-theta.

[0261] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 12.9±0.2° 2-theta, 15.6±0.2° 2-theta, 24.8±0.2° 2-theta, 8.1±0.2° 2-theta, 12.3±0.2° 2-theta, and 17.6±0.2° 2-theta.

[0262] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is 7.2±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 9.7±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 12.9±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.9±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 15.5±0.2 degrees 2-theta. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from 16.2±0.2° 2-theta, 16.5±0.2° 2-theta, 17.2±0.2° 2-theta, 17.6±0.2° 2-theta, 17.7±0.2° 2-theta, 18.1±0.2° 2-theta, 22.7±0.2° 2-theta, 24.8±0.2° 2-theta, and 25.9±0.2° 2-theta.

[0263] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is 7.2±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 9.7±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 12.9±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.9±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.8±0.2 Characterized by X-ray powder diffractograms having signals at degrees 2-theta, 15.1±0.2 degrees 2-theta, 15.5±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 16.5±0.2 degrees 2-theta, 17.2±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 17.7±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 22.7±0.2 degrees 2-theta, 24.8±0.2 degrees 2-theta, and 25.9±0.2 degrees 2-theta.

[0264] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 13.

[0265] In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 212.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 211.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 179.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 178.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 178.4 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 174.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 174.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 172.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 172.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 163.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 156.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 155.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 152.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 150.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 148.7 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 147.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 147.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 145.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 125.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 124.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 122.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 121.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 121.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 118.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 118.1 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 117.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 116.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 115.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 115.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 113.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 113.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 112.4 ± 0.2 ppm. 13 It is characterized as having a 3C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 30.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 29.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 18.4 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 17.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 8.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at 8.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0266] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is 212.9±0.2 ppm, 211.6±0.2 ppm, 179.2±0.2 ppm, 178.9±0.2 ppm, 178.4±0.2 ppm, 174.7±0.2 ppm, 174.1±0.2 ppm, 172.7±0.2 ppm, and 17 2.2±0.2ppm, 163.1±0.2ppm, 156.7±0.2ppm, 155.6±0.2ppm, 152.3±0.2ppm, 150.1±0. 2ppm, 148.7±0.2ppm, 147.9±0.2ppm, 147.0±0.2ppm, 145.1±0.2ppm, 125.5±0.2ppm, 1 24.5±0.2ppm, 122.5±0.2ppm, 121.6±0.2ppm, 121.1±0.2ppm, 118.5±0.2ppm, 118.1±0 .2ppm, 117.4±0.2ppm, 116.8±0.2ppm, 115.7±0.2ppm, 115.3±0.2ppm, 113.9±0.2ppm, It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 113.2±0.2 ppm, 112.4±0.2 ppm, 30.0±0.2 ppm, 29.5±0.2 ppm, 18.4±0.2 ppm, 17.6±0.2 ppm, 8.8±0.2 ppm, and 8.1±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0267] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is 212.9±0.2 ppm, 211.6±0.2 ppm, 179.2±0.2 ppm, 178.9±0.2 ppm, 178.4±0.2 ppm, 174.7±0.2 ppm, 174.1±0.2 ppm, 172.7±0.2 ppm, 172.2±0.2 ppm, 163.1±0.2 ppm, 156.7±0.2 ppm, 155.6±0.2 ppm, 152.3±0.2 ppm, 150.1±0.2 ppm, 148.7±0.2 ppm, 147.9±0.2 ppm, 147.0±0.2 ppm, and 145.1±0.2 It has peaks at ppm, 125.5±0.2 ppm, 124.5±0.2 ppm, 122.5±0.2 ppm, 121.6±0.2 ppm, 121.1±0.2 ppm, 118.5±0.2 ppm, 118.1±0.2 ppm, 117.4±0.2 ppm, 116.8±0.2 ppm, 115.7±0.2 ppm, 115.3±0.2 ppm, 113.9±0.2 ppm, 113.2±0.2 ppm, 112.4±0.2 ppm, 30.0±0.2 ppm, 29.5±0.2 ppm, 18.4±0.2 ppm, 17.6±0.2 ppm, 8.8±0.2 ppm, and 8.1±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0268] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is substantially similar to that shown in Figure 14. 13 Characterized by C SSNMR spectra.

[0269] In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -60.4 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -61.2 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -61.6 ± 0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -62.7 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -135.9 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -136.1 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -139.6 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -140.6 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -141.7 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -145.2 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has a peak at -145.7 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0270] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is -60.4±0.2 ppm, -61.2±0.2 ppm, -61.6±0.2 ppm, -62.7±0.2 ppm, -135.9±0.2 ppm, -136.1±0.2 ppm, It has one or two peaks selected from -139.6±0.2ppm, -140.6±0.2ppm, -141.7±0.2ppm, -145.2±0.2ppm, and -145.7±0.2ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the acetone solvate hydrate form A of crystalline compound I has peaks at -60.4±0.2 ppm, -61.2±0.2 ppm, -61.6±0.2 ppm, -62.7±0.2 ppm, -135.9±0.2 ppm, -136.1±0.2 ppm, -139.6±0.2 ppm, -140.6±0.2 ppm, -141.7±0.2 ppm, -145.2±0.2 ppm, and -145.7±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0271] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is substantially similar to that shown in Figure 15. 19 Characterized by F SSNMR spectra.

[0272] In some embodiments, the acetone solvate hydrate form A of crystalline compound I is monoclinic, P21 space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 9.2 ± 0.1 Å α 90° b 39.8 ± 0.1 Å β 96.3 ± 0.1° c 12.9 ± 0.1 Å γ 90°. It is characterized by: In some embodiments, the diffractometer is a Rigaku diffractometer.

[0273] Another aspect of the present disclosure provides a method for obtaining a crystalline compound I acetone solvate hydrate in form A. In some embodiments, a method for producing a crystalline compound I acetone solvate hydrate in form A comprises (i) saturating acetone with compound I, (ii) adding water dropwise until it reaches 20% of the final volume, and (iii) holding overnight at room temperature to obtain a crystalline compound I acetone solvate hydrate in form A.

[0274] G. Ethanol solvate form of crystalline compounds A In some embodiments, this disclosure provides an ethanol solvate form A of crystalline compound I. Figure 16 provides an X-ray powder diffractogram of ethanol solvate form A of crystalline compound I.

[0275] In some embodiments, the ethanol solvate form A of crystalline compound I is substantially pure. In some embodiments, the ethanol solvate form A of crystalline compound I is substantially crystalline. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0276] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.4 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.1 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 26.0 ± 0.2 degrees 2 theta.

[0277] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 10.7 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.2 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.6 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.8 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.1 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.9 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.0 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.9 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.3 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.4 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.1 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.9 ± 0.2 degrees 2 theta.In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.8 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.2 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.4 ± 0.2 degrees 2 theta. In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.1 ± 0.2 degrees 2 theta.

[0278] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals from among 9.4±0.2 degrees 2-theta, 16.1±0.2 degrees 2-theta, and 26.0±0.2 degrees 2-theta.

[0279] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 9.4±0.2° 2-theta, 16.1±0.2° 2-theta, and 26.0±0.2° 2-theta, and (b) one or two signals selected from 15.1±0.2° 2-theta, 17.0±0.2° 2-theta, and 22.4±0.2° 2-theta.

[0280] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 9.4±0.2° 2-theta, 16.1±0.2° 2-theta, 26.0±0.2° 2-theta, 15.1±0.2° 2-theta, 17.0±0.2° 2-theta, 22.4±0.2° 2-theta, 13.2±0.2° 2-theta, 13.6±0.2° 2-theta, and 13.8±0.2° 2-theta.

[0281] In some embodiments, the ethanol solvate form A of crystalline compound I is 9.4±0.2 degrees 2-theta, 10.7±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.6±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.1±0.2 degrees 2-theta, 17.0±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from 19.1±0.2° 2-theta, 19.9±0.2° 2-theta, 21.8±0.2° 2-theta, 22.2±0.2° 2-theta, 22.4±0.2° 2-theta, 24.1±0.2° 2-theta, and 26.0±0.2° 2-theta.

[0282] In some embodiments, the ethanol solvate form A of crystalline compound I is 9.4±0.2 degrees 2-theta, 10.7±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.6±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.1±0.2 degrees 2-theta, 17.0±0.2 degrees 2-theta, 17.9±0.2 Characterized by X-ray powder diffractograms having signals at degrees 2-theta, 18.3±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.1±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 21.8±0.2 degrees 2-theta, 22.2±0.2 degrees 2-theta, 22.4±0.2 degrees 2-theta, 24.1±0.2 degrees 2-theta, and 26.0±0.2 degrees 2-theta.

[0283] In some embodiments, the ethanol solvate form A of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 16.

[0284] In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 178.2 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 175.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 163.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 163.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 162.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 154.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 148.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 146.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 145.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 125.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 123.1 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 121.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 120.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 119.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 116.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 116.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 114.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 113.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 56.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 18.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 17.2 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 9.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at 7.9 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0285] In some embodiments, the ethanol solvate form A of crystalline compound I is 178.2±0.2 ppm, 175.7±0.2 ppm, 163.9±0.2 ppm, 163.4±0.2 ppm, 162.8±0.2 ppm, 154.9±0.2 ppm, 148.1±0.2 ppm, 146.0±0.2 ppm, 145.2±0.2 ppm, 125.9±0.2 ppm, 123.1±0.2 ppm, and 121.8±0.2 ppm. It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from ppm, 120.4±0.2 ppm, 119.5±0.2 ppm, 116.9±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 56.5±0.2 ppm, 18.4±0.2 ppm, 17.2±0.2 ppm, 9.2±0.2 ppm, and 7.9±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0286] In some embodiments, the ethanol solvate form A of crystalline compound I is 178.2±0.2 ppm, 175.7±0.2 ppm, 163.9±0.2 ppm, 163.4±0.2 ppm, 162.8±0.2 ppm, 154.9±0.2 ppm, 148.1±0.2 ppm, 146.0±0.2 ppm, 145.2±0.2 ppm, 125.9±0.2 ppm, and 123. It has peaks at 1±0.2 ppm, 121.8±0.2 ppm, 120.4±0.2 ppm, 119.5±0.2 ppm, 116.9±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 56.5±0.2 ppm, 18.4±0.2 ppm, 17.2±0.2 ppm, 9.2±0.2 ppm, and 7.9±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0287] In some embodiments, the ethanol solvate form A of crystalline compound I is substantially similar to that shown in Figure 17. 13 Characterized by C SSNMR spectra.

[0288] In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at -61.1 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at -138.1 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has a peak at -141.2 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0289] In some embodiments, the ethanol solvate form A of crystalline compound I has one or two peaks selected from -61.1±0.2 ppm, -138.1±0.2 ppm, and -141.2±0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, the ethanol solvate form A of crystalline compound I has peaks at -61.1±0.2 ppm, -138.1±0.2 ppm, and -141.2±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0290] In some embodiments, the ethanol solvate form A of crystalline compound I is substantially similar to that shown in Figure 18. 19 Characterized by F SSNMR spectra.

[0291] In some embodiments, the ethanol solvate form A of crystalline compound I is monoclinic, P21 / c space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 17.0 ± 0.1 Å α 90° b 11.1 ± 0.1 Å β 105.9 ± 0.1° c 13.2 ± 0.1 Å γ 90°. It is characterized by: In some embodiments, the diffractometer is a Bruker diffractometer.

[0292] Another aspect of the present disclosure provides a method for obtaining ethanol solvate form A of crystalline compound I. In some embodiments, the method for producing ethanol solvate form A of crystalline compound I includes (i) combining compound I and ethyl acetate, (ii) heating the slurry to 50°C, (iii) adding ethanol and distilling under vacuum at 50°C, (iv) adding ethanol and distilling under vacuum at 50°C, (v) adding ethanol and distilling to a minimum volume under vacuum at 50°C, (vi) adding ethanol and distilling under vacuum at 50°C, and (vii) drying the solid in a vacuum oven at 45°C for 42 hours with a small nitrogen bleed to obtain ethanol solvate form A of crystalline compound I.

[0293] H. Hydrate form A of crystalline compound I In some embodiments, the present disclosure provides a hydrated form A of crystalline compound I. Figure 19 provides an X-ray powder diffractogram of hydrated form A of crystalline compound I.

[0294] In some embodiments, the hydrate form A of crystalline compound I is substantially pure. In some embodiments, the hydrate form A of crystalline compound I is substantially crystalline. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0295] In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.7 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.4 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.8 ± 0.2 degrees 2-theta.

[0296] In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 4.7 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.5 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 11.0 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.7 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.1 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.4 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.8 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.3 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.5 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.8 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.2 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.1 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.4 ± 0.2 degrees 2-theta.In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.2 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.9 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.9 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.4 ± 0.2 degrees 2-theta. In some embodiments, the hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.7 ± 0.2 degrees 2-theta. In some embodiments, hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 25.4 ± 0.2 degrees 2-theta.

[0297] In some embodiments, hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals from among 8.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, and 18.8±0.2 degrees 2-theta.

[0298] In some embodiments, hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram (a) one or two signals selected from 8.7±0.2° 2-theta, 12.4±0.2° 2-theta, and 18.8±0.2° 2-theta, and (b) one or two signals selected from 12.7±0.2° 2-theta, 17.5±0.2° 2-theta, and 19.8±0.2° 2-theta.

[0299] In some embodiments, hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 8.7±0.2° 2-theta, 12.4±0.2° 2-theta, 18.8±0.2° 2-theta, 12.7±0.2° 2-theta, 17.5±0.2° 2-theta, 19.8±0.2° 2-theta, 13.1±0.2° 2-theta, 16.3±0.2° 2-theta, and 21.1±0.2° 2-theta.

[0300] In some embodiments, the hydrate form A of crystalline compound I is 8.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 4.7±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 11.0±0.2 degrees 2-theta, 12.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 15.8±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, and 20.2±0.2 degrees 2-theta. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from theta, 21.1±0.2° 2-theta, 21.4±0.2° 2-theta, 22.2±0.2° 2-theta, 22.9±0.2° 2-theta, 23.9±0.2° 2-theta, 24.4±0.2° 2-theta, 24.7±0.2° 2-theta, and 25.4±0.2° 2-theta.

[0301] In some embodiments, the hydrate form A of crystalline compound I is 8.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 4.7±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 11.0±0.2 degrees 2-theta, 12.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 15.8±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, 17.5± Characterized by X-ray powder diffractograms having signals at 0.2° 2-theta, 19.8±0.2° 2-theta, 20.2±0.2° 2-theta, 21.1±0.2° 2-theta, 21.4±0.2° 2-theta, 22.2±0.2° 2-theta, 22.9±0.2° 2-theta, 23.9±0.2° 2-theta, 24.4±0.2° 2-theta, 24.7±0.2° 2-theta, and 25.4±0.2° 2-theta.

[0302] In some embodiments, hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 19.

[0303] In some embodiments, hydrate form A of crystalline compound I has a peak at 177.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 172.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 170.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 162.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 154.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 154.0 ± 0.2 ppm.13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 150.2 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 148.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 147.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 146.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 145.5 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 126.3 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 125.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 123.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 122.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 121.6 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 120.6 ± 0.2 ppm. 13It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 118.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 117.9 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 117.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 116.0 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 114.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 114.4 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 112.8 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 17.7 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 17.1 ± 0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at 8.7 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0304] In some embodiments, the hydrate form A of crystalline compound I is 177.3±0.2 ppm, 172.8±0.2 ppm, 170.5±0.2 ppm, 162.0±0.2 ppm, 154.3±0.2 ppm, 154.0±0.2 ppm, 150.2±0.2 ppm, 148.7±0.2 ppm, 147.6±0.2 ppm, 146.6±0.2 ppm, 145.5±0.2 ppm, 126.3±0.2 ppm, 125.0±0.2 ppm, 123.8±0.2 ppm, 1 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 22.4±0.2ppm, 121.6±0.2ppm, 120.6±0.2ppm, 118.4±0.2ppm, 117.9±0.2ppm, 117.0±0.2ppm, 116.0±0.2ppm, 114.7±0.2ppm, 114.4±0.2ppm, 112.8±0.2ppm, 17.7±0.2ppm, 17.1±0.2ppm, and 8.7±0.2ppm. 13 It is characterized by having a C SSNMR spectrum.

[0305] In some embodiments, the hydrate form A of crystalline compound I is 177.3±0.2 ppm, 172.8±0.2 ppm, 170.5±0.2 ppm, 162.0±0.2 ppm, 154.3±0.2 ppm, 154.0±0.2 ppm, 150.2±0.2 ppm, 148.7±0.2 ppm, 147.6±0.2 ppm, 146.6±0.2 ppm, 145.5±0.2 ppm, 126.3±0.2 ppm, and 125.0±0. It has peaks at 2 ppm, 123.8±0.2 ppm, 122.4±0.2 ppm, 121.6±0.2 ppm, 120.6±0.2 ppm, 118.4±0.2 ppm, 117.9±0.2 ppm, 117.0±0.2 ppm, 116.0±0.2 ppm, 114.7±0.2 ppm, 114.4±0.2 ppm, 112.8±0.2 ppm, 17.7±0.2 ppm, 17.1±0.2 ppm, and 8.7±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0306] In some embodiments, hydrate form A of crystalline compound I is substantially similar to that shown in Figure 22. 13 Characterized by C SSNMR spectra.

[0307] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 6% relative humidity (RH), exhibiting a peak of 171.5±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH), with a peak at 171.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 33% relative humidity (RH) with a peak at 170.7±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0308] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 6% relative humidity (RH), exhibiting a peak of 155.0±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH) with a peak at 155.0±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 22% relative humidity (RH) with a peak at 154.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 33% relative humidity (RH), with a peak at 154.4±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0309] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 6% relative humidity (RH), exhibiting a peak of 149.5±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH) with a peak at 149.4±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 22% relative humidity (RH) with a peak at 148.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 33% relative humidity (RH), with a peak at 148.6±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0310] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 6% relative humidity (RH), exhibiting a peak of 145.8±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH) with a peak at 145.8±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 22% relative humidity (RH) with a peak at 145.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 33% relative humidity (RH), with a peak at 145.5±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0311] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 6% relative humidity (RH), exhibiting a peak of 8.5±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH), with a peak at 8.5±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 22% relative humidity (RH) with a peak at 8.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 33% relative humidity (RH), with a peak at 8.6±0.2 ppm. 13 It is characterized as having a 13C SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 43% relative humidity (RH), with a peak at 8.6±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0312] In some embodiments, hydrate form A of crystalline compound I has a peak at -59.4 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at -60.2 ± 0.2 ppm. 19 Characterized as having an F SSNMR spectrum. In some embodiments, the hydrate form A of crystalline compound I has a peak at -135.0 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at -138.4 ± 0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at -141.7 ± 0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has a peak at -144 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0313] In some embodiments, hydrate form A of crystalline compound I has one or two peaks selected from -59.4±0.2 ppm, -60.2±0.2 ppm, -135.0±0.2 ppm, -138.4±0.2 ppm, -141.7±0.2 ppm, and -144.0±0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I has peaks at -59.4±0.2 ppm, -60.2±0.2 ppm, -135.0±0.2 ppm, -138.4±0.2 ppm, -141.7±0.2 ppm, and -144.0±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0314] In some embodiments, hydrate form A of crystalline compound I is substantially similar to that shown in Figure 23. 19 Characterized by F SSNMR spectra.

[0315] In some embodiments, hydrate form A of crystalline compound I is measured at 25±2°C and 11% relative humidity (RH), exhibiting a peak at -142.4±0.2 ppm. 19 It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25 ± 2°C and 22% relative humidity (RH) with a peak at -141.9 ± 0.2 ppm. 19It is characterized as having an F SSNMR spectrum. In some embodiments, hydrate form A of crystalline compound I is measured at 25 ± 2 °C and 33% relative humidity (RH), with a peak at -141.8 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0316] In some embodiments, hydrate form A of crystalline compound I is triclinic, P-1 space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 10.5 ± 0.1 Å α 91.3 ± 0.1° b 11.2 ± 0.1 Å β 103.9 ± 0.1° c 19.2 ± 0.1 Å γ 98.4 ± 0.1°. It is characterized by: In some embodiments, the diffractometer is a Bruker diffractometer.

[0317] Another aspect of the present disclosure provides a method for producing crystalline compound I hydrate form A. In some embodiments, a method for producing crystalline compound I hydrate form A comprises (i) combining compound I ethanol solvate form A and acetone, (ii) stirring the slurry while heating to 50°C, (iii) adding water over 1 hour, (iv) adding the seed of crystalline compound I hydrate form A, (v) stirring for 30 minutes, (vi) adding water over 8 hours, (vii) stirring at 50°C for 5 hours, (viii) cooling the slurry to 20°C over 3 hours, (ix) stirring for 2 hours, and (x) collecting the solid and washing it with 1:2 acetone:water to obtain crystalline compound I hydrate form A.

[0318] I. Dehydrated hydrate form A of crystalline compound I In some embodiments, the present disclosure provides a dehydrated hydrate form A of crystalline compound I. Figure 20 provides an X-ray powder diffractogram of the dehydrated hydrate form A of crystalline compound I.

[0319] In some embodiments, the dehydrated hydrate form A of crystalline compound I is substantially pure. In some embodiments, the dehydrated hydrate form A of crystalline compound I is substantially crystalline. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0320] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 8.7 ± 0.2 degrees 2 theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 15.9 ± 0.2 degrees 2 theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 18.7 ± 0.2 degrees 2 theta.

[0321] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 4.7 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 9.5 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 10.9 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.4 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 12.6 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 13.1 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 14.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 16.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 17.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 19.8 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 20.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.1 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 21.4 ± 0.2 degrees 2-theta.In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 22.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.0 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 23.9 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.3 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 24.7 ± 0.2 degrees 2-theta. In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having a signal of 25.3 ± 0.2 degrees 2-theta.

[0322] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having one or two signals from among 8.7±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, and 18.7±0.2 degrees 2-theta.

[0323] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having (a) one or two signals selected from 8.7±0.2° 2-theta, 15.9±0.2° 2-theta, and 18.7±0.2° 2-theta, and (b) one or two signals selected from 12.4±0.2° 2-theta, 12.6±0.2° 2-theta, 17.3±0.2° 2-theta, and 19.8±0.2° 2-theta.

[0324] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 8.7±0.2° 2-theta, 15.9±0.2° 2-theta, 18.7±0.2° 2-theta, 12.4±0.2° 2-theta, 12.6±0.2° 2-theta, 17.3±0.2° 2-theta, 19.8±0.2° 2-theta, 13.1±0.2° 2-theta, 16.3±0.2° 2-theta, and 21.1±0.2° 2-theta.

[0325] In some embodiments, the hydrate form A of crystalline compound I is 4.7±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, 17.3±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, and 20.3±0.2 degrees 2-theta. Characterized by an X-ray powder diffractogram having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 signals selected from theta, 21.1±0.2° 2-theta, 21.4±0.2° 2-theta, 22.3±0.2° 2-theta, 23.0±0.2° 2-theta, 23.9±0.2° 2-theta, 24.3±0.2° 2-theta, 24.7±0.2° 2-theta, and 25.3±0.2° 2-theta.

[0326] In some embodiments, the hydrate form A of crystalline compound I is 4.7±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, 17.3±0.2 degrees 2-theta, 18.7± Characterized by X-ray powder diffractograms with signals at 0.2° 2-theta, 19.8±0.2° 2-theta, 20.3±0.2° 2-theta, 21.1±0.2° 2-theta, 21.4±0.2° 2-theta, 22.3±0.2° 2-theta, 23.0±0.2° 2-theta, 23.9±0.2° 2-theta, 24.3±0.2° 2-theta, 24.7±0.2° 2-theta, and 25.3±0.2° 2-theta.

[0327] In some embodiments, the dehydrated hydrate form A of crystalline compound I is characterized by an X-ray powder diffractogram substantially similar to that in Figure 20.

[0328] In some embodiments, the dehydrated hydrate form A of crystalline compound I is triclinic, P-1 space group, and has the following unit cell dimensions measured at 100 K using a diffractometer with Cu Kα radiation (λ=1.54178 Å): a 10.4 ± 0.1 Å α 90.7 ± 0.1° b 11.2 ± 0.1 Å β 104.7 ± 0.1° c 19.3 ± 0.1 Å γ 98.0 ± 0.1°. It is characterized by: In some embodiments, the diffractometer is a Bruker diffractometer.

[0329] Another aspect of the present disclosure provides a method for producing a dehydrated form A of crystalline compound I. In some embodiments, a method for producing a dehydrated form A of crystalline compound I includes: (i) combining the ethanol solvate form A of compound I with acetone; (ii) stirring the slurry while heating to 50°C; (iii) adding water over 1 hour; (iv) adding the seed of a dehydrated form A of crystalline compound I; (v) stirring for 30 minutes; (vi) adding water over 8 hours; (vii) stirring at 50°C for 5 hours; (viii) cooling the slurry to 20°C over 3 hours; (ix) stirring for 2 hours; (x) collecting the solid and washing it with 1:2 acetone:water; and (xi) drying the solid at 50°C in a vacuum oven with a small nitrogen bleed to obtain a dehydrated form A of crystalline compound I.

[0330] J. Treatment method Compound I acts as a voltage-gated sodium channel inhibitor in any one of the pharmaceutically acceptable solid forms disclosed herein. In some embodiments, the voltage-gated sodium channel is Na V 1.8. Therefore, in another embodiment, the present disclosure is characterized by a method for inhibiting voltage-gated sodium channels in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In another embodiment, voltage-gated sodium channels are Na V 1.8. In another embodiment, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a subject, comprising administering a compound of formula I, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0331] In one embodiment, the present disclosure relates to a method for treating or reducing the severity of pain in a subject, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the subject.

[0332] In another aspect, the Disclosure relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in a method for treating or reducing the severity of pain in a subject, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the subject.

[0333] In another aspect, the disclosure relates to a composition comprising a compound of formula I, or a solvate I thereof, or a pharmaceutically acceptable salt thereof, for use in a manner for treating or reducing the severity of pain in a subject, wherein the composition is prepared for administration to a subject of a compound of formula I, or a solvate I thereof, or a pharmaceutically acceptable salt thereof.

[0334] In yet another aspect, the Disclosure provides a method for treating or reducing the severity of chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0335] In yet another aspect, the Disclosure provides 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, aponeurosis resection pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0336] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain includes pain from inflammatory bowel disease, pain from Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0337] Further embodiments of this disclosure feature a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, neuropathic pain includes postherpetic neuralgia, small-diameter fiber neuropathy, diabetic neuropathy, or idiopathic small-diameter fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the term "idiopathic small-diameter fiber neuropathy" shall be understood to include any small-diameter fiber neuropathy.

[0338] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of neuropathic pain in subjects, wherein the neuropathic pain is postherpetic neuralgia, diabetic neuropathy, painful HIV-related 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, radiculopathy, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug-induced nerve pain The method comprises administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0339] In yet another embodiment, the present disclosure is characterized by a method for treating or reducing the severity of musculoskeletal pain in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0340] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or toothache, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0341] In yet another aspect, the Disclosure relates to 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 vulvodynia, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0342] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes pain of rheumatoid arthritis, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0343] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0344] In yet another aspect, the Disclosure relates to a method for treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes pain of reflex sympathetic dystrophy, and the method comprises administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0345] In yet another aspect, the present disclosure is characterized by a method for treating or reducing the severity of a pathological cough in a subject, the method comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0346] In yet another aspect, the present disclosure is characterized by a method for treating or reducing the severity of acute pain in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some aspects, acute pain includes acute postoperative pain.

[0347] In yet another aspect, the Disclosure provides a method for treating or reducing the severity of postoperative pain in a subject (e.g., pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hemorrhoidectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0348] Another aspect of the disclosure is a method for treating or reducing the severity of pain associated with aponeurosis resection in a subject, comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0349] Another aspect of the present disclosure is a method for treating or reducing the severity of pain associated with shoulder arthroplasty or arthroscopic surgery in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0350] Another aspect of the disclosure is a method for treating or reducing the severity of pain associated with hernia repair in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0351] Another aspect of the disclosure is a method for treating or reducing the severity of pain associated with abdominal wall reconstruction in a subject, comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0352] In yet another embodiment, the present disclosure is characterized by a method for treating or reducing the severity of visceral pain in a subject, comprising administering an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0353] Further embodiments of the Disclosure feature a method for treating or reducing the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the neurodegenerative disease includes multiple sclerosis. In some embodiments, the neurodegenerative disease includes Pitt-Hopkins syndrome (PTHS).

[0354] In yet another embodiment, the disclosure features a method in which a subject is treated simultaneously with one or more additional therapeutic agents administered before or after treatment with an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0355] In another embodiment, the present disclosure is characterized by a method for inhibiting voltage-gated sodium channels in a biological sample, comprising contacting the biological sample with an effective amount of compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0356] In another aspect, this disclosure covers acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, tension headache, all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, diabetic neuropathy. - Pyromopathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain after thoracotomy, pain after mastectomy, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus Epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoproliferative disorder, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthritis, temporomandibular joint A method for treating or reducing the severity of joint pain, painful total knee arthroplasty, noncardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular lower extremity ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0357] In another aspect, this disclosure relates to the following conditions: femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, and 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, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom pain (e.g., after lower limb, upper limb, or breast removal), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tendinitis, injury pain, motor pain, acute visceral pain, nephritis, pyelonephritis, appendicitis, cholecystitis, bowel obstruction Obstruction, hernia, chest pain, cardiac pain, pelvic pain, kidney stone pain, acute obstetric pain, labor pains, 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, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, pain in depression, leprosy pain, Behçet's disease pain, color blindness, venous pain, Guillain-Barré pain, painful leg and toe movements, Haglund syndrome, polycythemia pain, Fabry disease pain, bladder and urinary tract pain A method for treating or reducing the severity of genital disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS), type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain, comprising administering an effective amount of compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0358] In another aspect, the present disclosure is characterized by a method for treating or reducing the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus disorder, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia of femoral pain, saphenous neuropathy, sciatic neuropathy, fibular neuropathy, tibial neuropathy, lumbosacral plexus disorder, stump pain of traumatic neuroma, or post-amputation pain in a subject, comprising administering an effective amount of Compound I or a pharmaceutical composition thereof in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein.

[0359] In some embodiments, a method for treating pain in a patient, or reducing its severity, or treating it symptomatically, involves administering an effective amount of compound I to the patient in any one of the pharmaceutically acceptable crystalline forms disclosed herein. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is neat form A of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is neat form B of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is neat form E of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is acetone solvate hydrate form A of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is ethanol solvate form A of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is hydrate form A of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is hydrate form A of compound I. In some embodiments, the pharmaceutically acceptable crystalline form of compound I is the dehydrated hydrate form A of compound I.

[0360] In some embodiments, a method for treating a patient's head size, reducing its severity, or treating it symptomatically involves administering an effective amount of compound I in a pharmaceutically acceptable amorphous form as disclosed herein to the patient. In some embodiments, the pharmaceutically acceptable form of compound I is the amorphous form of compound I.

[0361] In some embodiments, a method for treating, reducing the severity of, or symptomatically treating pain in a patient involves administering to the patient an effective amount of compound I as one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, in combination with at least one additional pharmaceutically active ingredient. In some embodiments, a method for treating, reducing the severity of, or symptomatically treating pain in a patient involves administering to the patient an effective amount of compound I as a solid form selected from neat form A, neat form B, neat form E, acetone solvate hydrate form A, ethanol solvate form A, hydrate form A, dehydrated hydrate form A, and amorphous form of compound I, in combination with at least one additional pharmaceutically active ingredient.

[0362] In some embodiments, the Disclosure features Compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, for use in any of the methods described above.

[0363] In some embodiments, the Disclosure features the use of Compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, for the manufacture of a pharmacopoeia for use in any of the methods described above.

[0364] In some embodiments, the Disclosure features Compound I, or a pharmaceutical composition thereof, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, for use as a pharmaceutical agent.

[0365] The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, and it will also be understood that the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (treatments or procedures) used in a combination regimen will take into account the suitability of the desired therapeutic agent and / or procedure, as well as the desired therapeutic effect to be achieved. Naturally, the therapies used may achieve the desired effect for the same disorder (for example, the compounds of the present invention may be administered simultaneously with another agent used to treat the same disorder) or they may achieve a different effect (for example, control of any adverse effect). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known to be "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include non-opioid analgesics (indoles, e.g., etodolac, indomethac, sulindac, tolmetine; naphthyl alkanones, e.g., nabumetone; oxicam, e.g., piroxicam; para-aminophenol derivatives, e.g., acetaminophen; propionic acid, e.g., fenoprofen, fluviprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozine; salicylates, e.g., aspirin) Examples include, but are not limited to, magnesium choline trisalicylate, diflunisal; fenamet (e.g., meclofenamic acid, mefenamic acid; and pyrazoles (e.g., phenylbutazone)); or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, buprenorphine, butorphanol, dezosin, nalbufine, and pentazocine). Furthermore, non-pharmacological analgesic approaches may be used in conjunction with the administration of one or more compounds of the present invention.For example, anesthetics (spinal injection, nerve block), neurosurgical procedures (neurolysis of CNS pathways), nerve stimulation (percutaneous electroneurotherapy, dorsal column stimulation), physical therapy (physiotherapy, orthotic devices, diathermy), or psychiatric approaches (cognitive methods - pulmonary function, biofeedback, or behavioral methods) may also be used. Additional appropriate therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), 2011, and on the website of the Food and Drug Administration (www.fda.gov), the entire contents of which are incorporated herein by reference.

[0366] In another embodiment, additional suitable therapeutic agents are selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyfen, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butafanol, nalbufine, pentazocine, or diferikephalin. (2) Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen (intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketrolac (ketrolactromethamine (e.g., Toradol®), but not limited to these), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimeslide, nitroflubiprofen, orsalazine, oxaprozine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetine, or zomepirac, (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mefobarbital, metharbital, methexital, pentobarbital, phenobarbital, (4) Benzodiazepines having a sedative effect, for example, chlordiazepoxide, chlorazepatinate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam. (5) Histamine (H1) antagonists having a sedative effect, for example, diphenhydramine, pyriramine, promethazine, chlorpheniramine, or chlorcyclidine. (6) Sedatives, for example, glutethimid, meprobamate, methaqualone, or dichlorphenazone, (7) Skeletal muscle relaxants, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine, (8) NMDA receptor antagonists, e.g., dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline kinin, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), combination preparations of morphine and dextromethorphan), topiramate, neramexane or persinfotel containing an NR2B antagonist, e.g., ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone, (9) Alpha-adrenaline, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexemmetomidine, modafinyl, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamide-l,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline (10) Tricyclic antidepressants, for example, desipramine, imipramine, amitriptyline, or nortriptyline, (11) Anticonvulsants, for example, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproic acid, (12) Tachykikinin (NK) antagonists, especially NK-3, NK-2, or NK-1 antagonists, for example, (alpha-R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazosino[2,1g][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[(2R,3S )-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazole-3-one (MK-869), precipitant, ranepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), (13) Muscarinic antagonists, for example oxybutynin, tolterodine, propiverine, tropsium chloride, dalifenacin, solifenacin, temiverine, and ipratropium, (14) COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, delacoxib, etoricoxib, or lumiracoxib, (15) Coal tar analgesics, especially paracetamol, (16) Neuroleptics, for example, droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesolidazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, certindol, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, lacloprid, zotepine, bifepurnox, asenapine, lurasidone, amisulpride, paraperidone, palindore, eprivanserin, osanetant, limonabant, meclinertan, Miraxion®, or sarizotan. (17) Vanilloid receptor agonists (e.g., resinferatoxin or ciboamide) or antagonists (e.g., capsazepine, GRC-15300), (18) Beta-adrenaline, for example, propranolol, (19) Local anesthetics, for example, mexiletine, (20) Corticosteroids, for example, dexamethasone, (21) 5-HT receptor agonists or antagonists, in particular 5-HT receptor agonists such as eletriptan, sumatriptan, naratriptan, zolitriptan, or rizatriptan. 1B / 1D Agonist, (22)5-HT 2A Receptor antagonists, for example, R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), (23) Cholinergic (nicotinic) analgesics, for example, isopronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinyl methoxy)-2-chloropyridine (ABT-594), or nicotine, (24) Tramadol (registered trademark), Tramadol ER (Ultram ER (registered trademark)), IV Tramadol, Tapentazole ER (Nucynta (registered trademark)), (25) PDE5 inhibitors, e.g., 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]Indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazine-4-one (waldenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidine-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one, 5-[2-ethoxy-5-(4-ethylpiperazine-1-ylsulfonyl)pyridine-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-ONE, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]-N-(pyrimidine-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidine-5-yl)-N-[2-(l-methylpyrrolidine-2-yl)ethyl]-4-propoxybenzenesulfonamide, (26) Alpha-2-delta ligands, e.g., gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hepta-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- Proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hepta-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-one, C-[1-(1H-tetrazole-5-ylmethyl)-cycloheptile]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid, (27) Cannabinoids, e.g., KHK-6188, (28) Metabolic glutamate subtype 1 receptor (mGluRl) antagonists, (29) Serotonin reuptake inhibitors, for example, sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, esitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiopine, ritoxetine, dapoxetine, nefazodone, sericlamine, and trazodone. (30) Norepinephrine reuptake inhibitors, e.g., maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensin, and biloxazine (Vivalan®), in particular selective norepinephrine reuptake inhibitors, e.g., reboxetine, in particular (S,S)-reboxetine, (31) Dual serotonin-norepinephrine reuptake inhibitors, e.g., venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine. (32) Inducible nitric oxide synthase (iNOS) inhibitors, e.g., S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitride; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- Thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitride, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide, (33) Acetylcholinesterase inhibitors, for example, donepezil, (34) Prostaglandin E2 subtype 4 (EP4) antagonists, for example, N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridine-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridine-3-yl]carbonyl}amino)ethyl]benzoic acid, (35) Leukotriene B4 antagonists, e.g., l-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057) or DPC-11870, (36) 5-lipoxygenase inhibitors, e.g., dileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504), (37) Sodium channel blockers, e.g., lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate. (38) Na V1.7 Blockers, e.g., XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Bixotrigin), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 / 196869); WO2012 / 112743 (US2012 / 245136); WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), W Disclosed in O2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), CN111217776, WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035 (the entire contents of each application are incorporated herein by reference), (38a)Na V1.7 Blockers, e.g., (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methylphenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro Ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxyphenyl)methanone, 1-(4-benzhydrylpiperazine-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[ 3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonilicate, (4-isopropoxy-3-methylphenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl (L)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- [Iyl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-Piperidine]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-Bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, (39) Na V1.8 Blockers, e.g., PF-04531083, PF-06372865, and e.g., WO2008 / 135826 (US2009 / 048306), WO2006 / 011050 (US2008 / 312235), WO2013 / 061205 (US2014 / 296313), US2013 / 0303535, WO2013 / 131018, US8466188, WO2013 / 114250 (US2013 / 274243), WO2014 / 120808(US2014 / 213616), WO2014 / 120815(US2014 / 228371), WO2014 / 120820(US2014 / 221435), WO2015 / 010065(US2016 / 0152561), WO2015 / 089361(US2015 / 0166589), WO2019 / 014352(US2019 / 0016671), WO2018 / 213426, WO2020 / 146682, WO202 0 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020 / 140411), WO2020 / 144375, WO2020 / 2 61114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622(CN112479996), WO2021 / 257490, WO2021 / 257420 , as disclosed in WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293 (the entire contents of each application are incorporated herein by reference), (39a)Na V1.8 Blockers, e.g., 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2- Xo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -Fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro Phenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridine-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridine-4- (Iyl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-2-oxopyridine-1(2H)-yl)methyldihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 3-(4-Chloro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 4-(3-(4-(Trifluoromethoxy)phenoxy)Quinoxaline-2-Carboxamide)Picolinic Acid, 2-(2,4-Difluorophenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 2-(4-Fluoro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 3-(2,4-Difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-Carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridine-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N -(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-Bis(trifluoromethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide) benzoic acid, 5-(4,5-Dichloromethyl 4-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamide)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 5-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) picolinic acid, 4-(4,5-Dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide) picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamide) benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamide)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4- Luorofenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3 -Sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro -2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4, 6-Bis(trifluoromethyl)benzamide, 5-Chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide Mido, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenoxy, Nyl)-2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)- 3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluorophenyl)-2,3,4-Trifluoro-6-[2-Methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-Carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy) Phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluorophenyl)-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-(triduteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-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, (40)Na V 1.7 and Na V 1.8 Combinations of blockers, e.g., DSP-2230, Lohocla201 or BL-1021, (41) 5-HT3 antagonists, e.g., ondansetron, (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof. (43) Nicotinic receptor antagonists, e.g., varenicline, (44) N-type calcium channel antagonists, e.g., Z-160, (45) Nerve growth factor antagonists, e.g., tanezumab, (46) Endopeptidase stimulants, e.g., senlevotase, (47) Angiotensin II antagonists, e.g., EMA-401, (48) Acetaminophen (including, but not limited to, intravenous acetaminophen (e.g., Ofrmev®)), (49) Bupivacaine (including, but not limited to, bupivacaine liposome injection suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)), and (50) A combination of bupivacaine and meloxicam (e.g., HTX-011). In one embodiment, additional suitable therapeutic agents are selected from V-116517, pregabalin, sustained-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), rufinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0367] In another embodiment, additional suitable therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-yl)acetamide, N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridine-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazole-2-yl)methyl)oxetane-3-amine.

[0368] In another embodiment, additional therapeutic agents are selected from GlyT2 / 5HT2 inhibitors, e.g., Operanserin (VVZ149), TRPV modulators, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, EGR1 inhibitors, e.g., Brivoglide (AYX1), NGF inhibitors, e.g., tanezumab, facinumab, ASP6294, MEDI7352, Mu opioid agonists, e.g., cebranopadol, NKTR181 (oxycodegol), CB-1 agonists, e.g., NEO1940 (AZN1940), imidazoline 12 agonists, e.g., CR4056, or p75NTR-Fc modulators, e.g., LEVI-04.

[0369] In another embodiment, the additional therapeutic agent is oryceridine or ropivacaine (TLC590).

[0370] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, e.g., ST-2427 or ST-2578, as disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and / or WO2022 / 036297 (the entire contents of each application are incorporated herein by reference).

[0371] In another embodiment, additional therapeutic agents include ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra®), Brivolizide, 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 are selected.

[0372] In another embodiment, additional 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, LY3556050, AP-325, Tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, and ACD440.

[0373] In another embodiment, additional therapeutic agents include HRS4800, ODM-111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, and OLP-1. Select from 002, ATX01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, BL-017881, Profervia (silnidipine), LS-04, bixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0374] In another embodiment, the additional therapeutic agent is the Na identified above. V 1.7 and Na V 1.8 These are sodium channel inhibitors (also known as sodium channel blockers), such as 1.8-blockers.

[0375] The amount of additional therapeutic agents present in the composition of the present invention may be less than or equal to the amount typically administered in a composition containing the therapeutic agent as the sole active agent. The amount of additional therapeutic agents in the composition of this disclosure may range from about 10% to 100% of the amount typically present in a composition containing the agent as the sole therapeutic active agent.

[0376] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents, and catheters. Therefore, in another embodiment, the present invention includes compositions for coating implantable devices, generally comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. In yet another embodiment, the present invention includes implantable devices coated with compositions comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. General preparations of suitable coatings and coated implantable devices are described in U.S. Patents 6,099,562, 5,886,026, and 5,304,121. The coatings are typically biocompatible polymer materials such as hydrogel polymers, polymethyldisiloxanes, polycaprolactones, polyethylene glycols, polylactic acid, ethylene vinyl acetates, and mixtures thereof. The coating may be further covered with a suitable top coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or a combination thereof, as needed, to impart sustained-release properties to the composition.

[0377] Another aspect of the present invention is Na in a biological sample or subject. V 1.8 With regard to inhibiting activity, the method includes administering to a subject or contacting the biological sample with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0378] Na in biological samples V1.8 Inhibition of activity is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena, and the comparative evaluation of novel sodium channel inhibitors.

[0379] K. Pharmaceutical Compositions Another aspect of the present invention provides a pharmaceutical composition comprising compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical composition comprises compound I in a solid form selected from neat form A of compound I, neat form B of compound I, neat form E of compound I, acetone solvate hydrate form A of compound I, ethanol solvate form A of compound I, hydrate form A of compound I, and dehydrated hydrate form A of compound I. In some embodiments, the pharmaceutical composition comprises compound I in a solid amorphous form which is the amorphous form of compound I.

[0380] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, and (b) at least one pharmaceutically acceptable carrier.

[0381] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compound I in a solid form selected from neat form A of compound I, neat form B of compound I, neat form E of compound I, acetone solvate hydrate form A of compound I, ethanol solvate form A of compound I, hydrate form A of compound I, and dehydrated hydrate form A of compound I, and (b) at least one pharmaceutically acceptable carrier.

[0382] When used in this disclosure, the pharmaceutically acceptable compositions of the present invention also include, in addition, pharmaceutically acceptable carriers, adjuvants, or vehicles, including all solvents, diluents, or other liquid vehicles, dispersing or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the specific dosage form desired as used herein. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. The use of any conventional carrier medium is intended to be within the scope of this disclosure, except where such conventional carrier media would be incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutically acceptable composition.Some examples of materials that may serve as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose). Examples of ingredients include, but are not limited to, colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances. Preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0383] L. Compound Synthesis The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As those skilled in the art will understand, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art. The use of protecting groups is described in detail in TGMWuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0384] M. Radiolabeled analog of compound In another aspect, the present invention relates to radiolabeled analogs of the compounds of the present invention. As used herein, the term “radiolabeled analog of the compounds of the present invention” means a compound that is identical to the compounds of the present invention, as described herein, including all embodiments herein, except that one or more atoms are substituted with radioisotopes of atoms present in the compounds of the present invention.

[0385] As used herein, the term “radioisotope” refers to an isotope of an element known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C, 32 P, 35 S, 18 F, 36 Examples include Cl, as well as isotopes whose decay modes have been identified in V.S. Shirley & CMLederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0386] Radiolabeled analogs can be used in many beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection capabilities.

[0387] In another aspect, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs according to any of the embodiments described herein relating to the compounds of the present invention.

[0388] In another aspect, the present invention relates to a pharmaceutical composition comprising a radiolabeled analog or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, according to any embodiment described herein in relation to the compound of the present invention.

[0389] In another aspect, 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 disorders, including pain, in a subject, comprising administering an effective amount of a radiolabeled analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, as described herein in relation to the compounds of the present invention.

[0390] In another aspect, the present invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use in accordance with any of the embodiments described herein relating to the compounds of the present invention.

[0391] In another aspect, the present invention relates to the use of radiolabeled analogs or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of pharmaceuticals, according to any of the embodiments described herein relating to the compounds of the present invention.

[0392] In another embodiment, radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be used in combination therapy according to any of the embodiments described herein relating to the compounds of the present invention.

[0393] N. Non-limiting exemplary embodiments Further embodiments of this disclosure are described in the following numbered embodiments. 1.Compound I [ka] Compound I, in which the amorphous form of a substantially amorphous compound I is (i.e., less than 15% of compound I is in a crystalline form, less than 10% of compound I is in a crystalline form, or less than 5% of compound I is in a crystalline form). 2. An amorphous form of the substantially amorphous compound I according to Embodiment 1, wherein compound I is 100% amorphous. 3. An amorphous form of the substantially amorphous compound I described in Embodiment 1 or Embodiment 2, characterized by an X-ray powder diffractogram substantially similar to that of Figure 1. 4. Having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 177.6±0.2ppm, 172.0±0.2ppm, 162.6±0.2ppm, 155.2±0.2ppm, 149.9±0.2ppm, 147.0±0.2ppm, 121.0±0.2ppm, 120.1±0.2ppm, 119.1±0.2ppm, 116.0±0.2ppm, 114.6±0.2ppm, 113.8±0.2ppm, 15.5±0.2ppm, and 7.7±0.2ppm. 13 Amorphous form of compound I described in any one of embodiments 1 to 3, characterized by a 13C SSNMR spectrum. It has peaks at 5.177.6±0.2ppm, 172.0±0.2ppm, 162.6±0.2ppm, 155.2±0.2ppm, 149.9±0.2ppm, 147.0±0.2ppm, 121.0±0.2ppm, 120.1±0.2ppm, 119.1±0.2ppm, 116.0±0.2ppm, 114.6±0.2ppm, 113.8±0.2ppm, 15.5±0.2ppm, and 7.7±0.2ppm. 13 Amorphous form of compound I described in any one of embodiments 1 to 4, characterized by a 13C SSNMR spectrum. 6. Substantially the same as Figure 2 13An amorphous form of the substantially amorphous compound I described in any one of Embodiments 1 to 5, characterized by a 13C SSNMR spectrum. 7. It has one or two peaks selected from -61.9±0.2 ppm and -142.1±0.2 ppm. 19 Amorphous form of the substantially amorphous compound I described in any one of Embodiments 1 to 6, characterized by an F SSNMR spectrum. 8. Substantially similar to Figure 3 19 Amorphous form of the substantially amorphous compound I described in any one of Embodiments 1 to 7, characterized by an F SSNMR spectrum. 9. Neat form A of substantially crystalline compound I (i.e., less than 15% of compound I is amorphous, less than 10% of compound I is amorphous, or less than 5% of compound I is amorphous). 10. Neat form A of compound I as described in Embodiment 9, wherein the neat form A of compound I is 100% crystalline. Neat form A of substantially crystalline compound I according to Embodiment 9 or Embodiment 10, characterized by an X-ray powder diffractogram having one or two signals selected from 11.9.5 ± 0.2 degrees 2-theta, 12.3 ± 0.2 degrees 2-theta, and 13.5 ± 0.2 degrees 2-theta. 12. Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 11, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 9.5 ± 0.2 degrees 2-theta, 12.3 ± 0.2 degrees 2-theta, and 13.5 ± 0.2 degrees 2-theta, and (b) one or two signals selected from 11.3 ± 0.2 degrees 2-theta, 15.9 ± 0.2 degrees 2-theta, and 20.5 ± 0.2 degrees 2-theta. Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 12, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 13.9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 11.3±0.2° 2-theta, 15.9±0.2° 2-theta, 20.5±0.2° 2-theta, 14.6±0.2° 2-theta, 16.6±0.2° 2-theta, and 23.5±0.2° 2-theta. 14. Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 13, characterized by an X-ray powder diffractogram substantially similar to that of Figure 4. 15.170.4±0.2ppm, 163.8±0.2ppm, 162.4±0.2ppm, 160.9±0.2ppm, 158.6±0.2ppm, 158.3±0.2ppm, 154.6±0.2ppm, 154.0±0.2ppm, 14 8.3±0.2ppm, 147.6±0.2ppm, 146.9±0.2ppm, 145.9±0.2ppm, 143.5±0.2ppm, 143.1±0.2ppm, 141.9±0.2ppm, 127.4±0.2ppm, 125.3±0 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 0.2 ppm, 123.6 ± 0.2 ppm, 122.2 ± 0.2 ppm, 121.3 ± 0.2 ppm, 120.7 ± 0.2 ppm, 117.9 ± 0.2 ppm, 117.3 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.8 ± 0.2 ppm, 114.2 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.8 ± 0.2 ppm, 15.4 ± 0.2 ppm, and 8.2 ± 0.2 ppm. 13 Neat form A of substantially crystalline compound I as described in any one of embodiments 9 to 14, characterized by a 1C SSNMR spectrum. 16.170.4±0.2ppm, 163.8±0.2ppm, 162.4±0.2ppm, 160.9±0.2ppm, 158.6±0.2ppm, 158.3±0.2ppm, 154.6±0.2ppm, 154.0 ±0.2ppm, 148.3±0.2ppm, 147.6±0.2ppm, 146.9±0.2ppm, 145.9±0.2ppm, 143.5±0.2ppm, 143.1±0.2ppm, 141.9±0.2ppm, 1 It has peaks at 27.4±0.2 ppm, 125.3±0.2 ppm, 123.6±0.2 ppm, 122.2±0.2 ppm, 121.3±0.2 ppm, 120.7±0.2 ppm, 117.9±0.2 ppm, 117.3±0.2 ppm, 116.3±0.2 ppm, 115.8±0.2 ppm, 114.2±0.2 ppm, 113.6±0.2 ppm, 112.8±0.2 ppm, 15.4±0.2 ppm, and 8.2±0.2 ppm. 13 Neat form A of substantially crystalline compound I as described in any one of embodiments 9 to 15, characterized by a 1C SSNMR spectrum. 17. Substantially the same as Figure 5 13 Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 16, characterized by a 1C SSNMR spectrum. 18. It has one or two peaks selected from -61.2±0.2 ppm, -61.6±0.2 ppm, -138.6±0.2 ppm, -140.3±0.2 ppm, -142.0±0.2 ppm, and -146.0±0.2 ppm. 19 Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 17, characterized by having an F SSNMR spectrum. It has peaks at -61.2±0.2 ppm, -61.6±0.2 ppm, -138.6±0.2 ppm, -140.3±0.2 ppm, -142.0±0.2 ppm, and -146.0±0.2 ppm. 19 Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 18, characterized by having an F SSNMR spectrum. 20. Substantially the same as Figure 619 Neat form A of substantially crystalline compound I according to any one of embodiments 9 to 19, characterized by an F SSNMR spectrum. 21. The following unit cell dimensions were measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ=1.54178 Å): a 9.6 ± 0.1 Å α 94.3 ± 0.1° b 12.6 ± 0.1 Å β 97.3 ± 0.1° c 18.7 ± 0.1 Å γ 107.3 ± 0.1°. Neat form A of substantially crystalline compound I as described in any one of embodiments 9 to 20, characterized by... 22. Neat form B of substantially crystalline compound I (i.e., less than 15% of compound I is amorphous, less than 10% of compound I is amorphous, or less than 5% of compound I is amorphous). 23. The neat form B of compound I as described in Embodiment 22, wherein the neat form B of compound I is 100% crystalline. Neat form B of substantially crystalline compound I as described in Embodiment 22 or Embodiment 23, characterized by an X-ray powder diffractogram having one or two signals selected from 24.4.8 ± 0.2 degrees 2-theta, 13.3 ± 0.2 degrees 2-theta, and 18.5 ± 0.2 degrees 2-theta. 25. Neat form B of substantially crystalline compound I as described in any one of Embodiments 22 to 24, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 4.8 ± 0.2 degrees 2-theta, 13.3 ± 0.2 degrees 2-theta, and 18.5 ± 0.2 degrees 2-theta, and (b) one or two signals selected from 6.0 ± 0.2 degrees 2-theta, 16.5 ± 0.2 degrees 2-theta, and 16.9 ± 0.2 degrees 2-theta. Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 25, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 26.4.8±0.2° 2-theta, 13.3±0.2° 2-theta, 18.5±0.2° 2-theta, 6.0±0.2° 2-theta, 16.5±0.2° 2-theta, 16.9±0.2° 2-theta, 14.1±0.2° 2-theta, 14.7±0.2° 2-theta, and 15.2±0.2° 2-theta. 27. Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 26, characterized by an X-ray powder diffractogram substantially similar to that of Figure 7. 28.176.9±0.2ppm, 171.7±0.2ppm, 164.0±0.2ppm, 161.4±0.2ppm, 160.7±0.2ppm, 155.3±0.2ppm, 154.8±0.2ppm, 1 48.6±0.2ppm, 147.6±0.2ppm, 146.4±0.2ppm, 145.7±0.2ppm, 144.8±0.2ppm, 127.7±0.2ppm, 125.4±0.2ppm, 122.0 Having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from ±0.2 ppm, 121.5 ±0.2 ppm, 118.4 ±0.2 ppm, 116.3 ±0.2 ppm, 114.8 ±0.2 ppm, 113.8 ±0.2 ppm, 112.6 ±0.2 ppm, 17.8 ±0.2 ppm, 15.0 ±0.2 ppm, 10.7 ±0.2 ppm, 9.6 ±0.2 ppm, and 8.8 ±0.2 ppm. 13 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 27, characterized by a 13C SSNMR spectrum. 29.176.9±0.2ppm, 171.7±0.2ppm, 164±0.2ppm, 161.4±0.2ppm, 160.7±0.2ppm, 155.3±0.2ppm, 154.8± 0.2ppm, 148.6±0.2ppm, 147.6±0.2ppm, 146.4±0.2ppm, 145.7±0.2ppm, 144.8±0.2ppm, 127.7±0.2ppm, It has peaks at 125.4±0.2 ppm, 122.0±0.2 ppm, 121.5±0.2 ppm, 118.4±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 112.6±0.2 ppm, 17.8±0.2 ppm, 15.0±0.2 ppm, 10.7±0.2 ppm, 9.6±0.2 ppm, and 8.8±0.2 ppm. 13 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 28, characterized by a 13C SSNMR spectrum. 30. Substantially the same as Figure 8 13 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 29, characterized by a 13C SSNMR spectrum. 31. It has one or two peaks selected from -61.6±0.2 ppm, -138±0.2 ppm, -139.7±0.2 ppm, -143.4±0.2 ppm, and -144.9±0.2 ppm. 19 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 30, characterized by an F SSNMR spectrum. It has peaks at -61.6±0.2 ppm, -138±0.2 ppm, -139.7±0.2 ppm, -143.4±0.2 ppm, and -144.9±0.2 ppm. 19 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 31, characterized by an F SSNMR spectrum. 33. Substantially similar to Figure 9 19 Neat form B of substantially crystalline compound I according to any one of embodiments 22 to 32, characterized by an F SSNMR spectrum. 34. Neat form E of substantially crystalline compound I (i.e., less than 15% of compound I is amorphous, less than 10% of compound I is amorphous, or less than 5% of compound I is amorphous). 35. A substantially crystalline neat form E of compound I according to Embodiment 34, wherein the neat form E of compound I is 100% crystalline. Neat form E of substantially crystalline compound I according to Embodiment 34 or Embodiment 35, characterized by an X-ray powder diffractogram having one or two signals selected from 36.8.6±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 12.6±0.2 degrees 2-theta. 37. Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 36, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 8.6±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 12.6±0.2 degrees 2-theta, and (b) one or two signals selected from 14.1±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta. Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 37, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 38.8.6±0.2° 2-theta, 10.1±0.2° 2-theta, 12.6±0.2° 2-theta, 14.1±0.2° 2-theta, 20.3±0.2° 2-theta, 23.2±0.2° 2-theta, 11.5±0.2° 2-theta, 14.2±0.2° 2-theta, and 15.1±0.2° 2-theta. 39. Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 38, characterized by an X-ray powder diffractogram substantially similar to that of Figure 10. 40.170.0±0.2ppm, 163.0±0.2ppm, 162.3±0.2ppm, 161.3±0.2ppm, 159.3±0.2ppm, 154.7±0.2ppm, 150.6±0.2ppm, 149.8 ±0.2ppm, 148.6±0.2ppm, 148.3±0.2ppm, 147.1±0.2ppm, 144.9±0.2ppm, 143.9±0.2ppm, 143.5±0.2ppm, 126.9±0.2ppm, It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 126.0±0.2ppm, 124.1±0.2ppm, 122.6±0.2ppm, 120.8±0.2ppm, 117.8±0.2ppm, 116.7±0.2ppm, 115.2±0.2ppm, 114.1±0.2ppm, 113.1±0.2ppm, 15.9±0.2ppm, 15.3±0.2ppm, and 8.4±0.2ppm. 13 Neat form E of substantially crystalline compound I as described in any one of embodiments 34 to 39, characterized by a 1C SSNMR spectrum. 41.170.0±0.2ppm, 163.0±0.2ppm, 162.3±0.2ppm, 161.3±0.2ppm, 159.3±0.2ppm, 154.7±0.2ppm, 150.6±0. 2ppm, 149.8±0.2ppm, 148.6±0.2ppm, 148.3±0.2ppm, 147.1±0.2ppm, 144.9±0.2ppm, 143.9±0.2ppm, 143.5±0 It has peaks at 0.2 ppm, 126.9 ± 0.2 ppm, 126.0 ± 0.2 ppm, 124.1 ± 0.2 ppm, 122.6 ± 0.2 ppm, 120.8 ± 0.2 ppm, 117.8 ± 0.2 ppm, 116.7 ± 0.2 ppm, 115.2 ± 0.2 ppm, 114.1 ± 0.2 ppm, 113.1 ± 0.2 ppm, 15.9 ± 0.2 ppm, 15.3 ± 0.2 ppm, and 8.4 ± 0.2 ppm. 13 Neat form E of substantially crystalline compound I as described in any one of embodiments 34-40, characterized by a 13C SSNMR spectrum. 42. Substantially the same as Figure 11 13Neat form E of substantially crystalline compound I as described in any one of embodiments 34 to 41, characterized by a 13C SSNMR spectrum. It has one or two peaks selected from 43. -60.9±0.2ppm, -62.5±0.2ppm, -63.1±0.2ppm, -135.1±0.2ppm, -137.1±0.2ppm, -140.7±0.2ppm, and -141.9±0.2ppm. 19 Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 42, characterized by having an F SSNMR spectrum. It has peaks at 44.-60.9±0.2 ppm, -62.5±0.2 ppm, -63.1±0.2 ppm, -135.1±0.2 ppm, -137.1±0.2 ppm, -140.7±0.2 ppm, and -141.9±0.2 ppm. 19 Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 43, characterized by having an F SSNMR spectrum. 45. Substantially the same as Figure 12 19 Neat form E of substantially crystalline compound I according to any one of embodiments 34 to 44, characterized by an F SSNMR spectrum. 46. ​​The following unit cell dimensions were measured at 100 K using a Rigaku diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ=1.54178 Å): a 8.7 ± 0.1 Å α 92.7 ± 0.1° b 12.2 ± 0.1 Å β 96.3 ± 0.1° c 20.9 ± 0.1 Å γ 98.6 ± 0.1°. A neat form E of a substantially crystalline compound I as described in any one of embodiments 34 to 45, characterized by the above. 47. The following unit cell dimensions were measured at 298 K using a Rigaku diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ=1.54178 Å): a 8.9 ± 0.1 Å α 92.6 ± 0.1° b 12.3 ± 0.1 Å β 97.1 ± 0.1° c 21.1 ± 0.1 Å γ 98.5 ± 0.1°. A neat form E of a substantially crystalline compound I as described in any one of embodiments 34 to 46, characterized by the above. 48. Acetone solvate hydrate form A of a substantially crystalline compound I (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, or less than 5% of compound I is in amorphous form). 49. Form A of a substantially crystalline acetone solvate hydrate of compound I according to Embodiment 48, wherein the acetone solvate hydrate of compound I is 100% crystalline. Form A of a substantially crystalline acetone solvate hydrate of compound I as described in Embodiment 48 or Embodiment 49, characterized by an X-ray powder diffractogram having one or two signals selected from 50.17.2±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 25.9±0.2 degrees 2-theta. 51. A substantially crystalline acetone solvate hydrate form A of compound I as described in any one of embodiments 48 to 50, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 17.2 ± 0.2 degrees 2-theta, 18.1 ± 0.2 degrees 2-theta, and 25.9 ± 0.2 degrees 2-theta, and (b) one or two signals selected from 12.9 ± 0.2 degrees 2-theta, 15.6 ± 0.2 degrees 2-theta, and 24.8 ± 0.2 degrees 2-theta. Form A of a substantially crystalline acetone solvate hydrate of compound I as described in any one of embodiments 48 to 51, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 52.9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 12.9±0.2° 2-theta, 15.6±0.2° 2-theta, 24.8±0.2° 2-theta, 8.1±0.2° 2-theta, 12.3±0.2° 2-theta, and 17.6±0.2° 2-theta. 53. Form A of a substantially crystalline compound I acetone solvate hydrate, characterized by an X-ray powder diffractogram substantially similar to that of Figure 13, as described in any one of Embodiments 48 to 52. 54.212.9±0.2ppm, 211.6±0.2ppm, 179.2±0.2ppm, 178.9±0.2ppm, 178.4±0.2pp m, 174.7±0.2ppm, 174.1±0.2ppm, 172.7±0.2ppm, 172.2±0.2ppm, 163.1±0.2ppm, 156.7±0.2ppm, 155.6±0.2ppm, 152.3±0.2ppm, 150.1±0.2ppm, 148.7±0.2ppm, 1 47.9±0.2ppm, 147.0±0.2ppm, 145.1±0.2ppm, 125.5±0.2ppm, 124.5±0.2ppm, 122 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 0.5±0.2ppm, 121.6±0.2ppm, 121.1±0.2ppm, 118.5±0.2ppm, 118.1±0.2ppm, 117.4±0.2ppm, 116.8±0.2ppm, 115.7±0.2ppm, 115.3±0.2ppm, 113.9±0.2ppm, 113.2±0.2ppm, 112.4±0.2ppm, 30±0.2ppm, 29.5±0.2ppm, 18.4±0.2ppm, 17.6±0.2ppm, 8.8±0.2ppm, and 8.1±0.2ppm. 13 A substantially crystalline compound I acetone solvate hydrate form A, characterized by a 13C SSNMR spectrum, as described in any one of embodiments 48 to 53. 163. 1±0.2ppm, 156.7±0.2ppm, 155.6±0.2ppm, 152.3±0.2ppm, 150.1±0.2ppm, 148.7±0.2ppm, 147.9±0.2ppm, 147.0±0.2ppm, 145.1±0.2ppm, 125.5±0.2ppm It has peaks at m, 124.5±0.2ppm, 122.5±0.2ppm, 121.6±0.2ppm, 121.1±0.2ppm, 118.5±0.2ppm, 118.1±0.2ppm, 117.4±0.2ppm, 116.8±0.2ppm, 115.7±0.2ppm, 115.3±0.2ppm, 113.9±0.2ppm, 113.2±0.2ppm, 112.4±0.2ppm, 30±0.2ppm, 29.5±0.2ppm, 18.4±0.2ppm, 17.6±0.2ppm, 8.8±0.2ppm, and 8.1±0.2ppm. 13 A substantially crystalline compound I acetone solvate hydrate form A, characterized by a 13C SSNMR spectrum, as described in any one of embodiments 48 to 54. 56. Substantially the same as Figure 14 13 A substantially crystalline compound I, as described in any one of embodiments 48 to 55, in an acetone solvate hydrate form, characterized by a 13C SSNMR spectrum. It has one or two peaks selected from 57.-60.4±0.2ppm, -61.2±0.2ppm, -61.6±0.2ppm, -62.7±0.2ppm, -135.9±0.2ppm, -136.1±0.2ppm, -139.6±0.2ppm, -140.6±0.2ppm, -141.7±0.2ppm, -145.2±0.2ppm, and -145.7±0.2ppm. 19 A substantially crystalline compound I acetone solvate hydrate form A of any one of embodiments 48 to 56, characterized by having an F SSNMR spectrum. It has peaks at 58.-60.4±0.2ppm, -61.2±0.2ppm, -61.6±0.2ppm, -62.7±0.2ppm, -135.9±0.2ppm, -136.1±0.2ppm, -139.6±0.2ppm, -140.6±0.2ppm, -141.7±0.2ppm, -145.2±0.2ppm, and -145.7±0.2ppm. 19 A substantially crystalline compound I acetone solvate hydrate form A of any one of embodiments 48 to 57, characterized by having an F SSNMR spectrum. 59. Substantially the same as Figure 15 19 A substantially crystalline compound I acetone solvate hydrate form as described in any one of embodiments 48 to 58, characterized by its F SSNMR spectrum. 60. The following unit cell dimensions were measured at 100 K using a Rigaku diffractometer with a monoclinic crystal system, P21 space group, and Cu Kα radiation (λ=1.54178 Å): a 9.2 ± 0.1 Å α 90° b 39.8 ± 0.1 Å β 96.3 ± 0.1° c 12.9 ± 0.1 Å γ 90°. A substantially crystalline compound I acetone solvate hydrate form as described in any one of embodiments 48 to 59, characterized by the above. 61. Ethanol solvate form A of a substantially crystalline compound I (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, or less than 5% of compound I is in amorphous form). 62. Form A of a substantially crystalline ethanol solvate of compound I according to Embodiment 61, wherein the ethanol solvate hydrate of compound I is 100% crystalline. A substantially crystalline ethanol solvate form A of compound I as described in Embodiment 61 or Embodiment 62, characterized by an X-ray powder diffractogram having one or two signals selected from 63.9.4 ± 0.2 degrees 2-theta, 16.1 ± 0.2 degrees 2-theta, and 26.0 ± 0.2 degrees 2-theta. 64.Ethanol solvate form A of a substantially crystalline compound I according to any one of embodiments 61 to 63, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 9.4±0.2 degrees 2-theta, 16.1±0.2 degrees 2-theta, and 26.0±0.2 degrees 2-theta, and (b) one or two signals selected from 15.1±0.2 degrees 2-theta, 17.0±0.2 degrees 2-theta, and 22.4±0.2 degrees 2-theta. Form A of a substantially crystalline ethanol solvate of compound I according to any one of embodiments 61 to 64, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 65.9.4±0.2° 2-theta, 16.1±0.2° 2-theta, 26.0±0.2° 2-theta, 15.1±0.2° 2-theta, 17.0±0.2° 2-theta, 22.4±0.2° 2-theta, 13.2±0.2° 2-theta, 13.6±0.2° 2-theta, and 13.8±0.2° 2-theta. 66. Ethanol solvate form A of substantially crystalline compound I according to any one of embodiments 61 to 65, characterized by substantially similar X-ray powder diffractograms in Figure 16. 67.178.2±0.2ppm, 175.7±0.2ppm, 163.9±0.2ppm, 163.4±0.2ppm, 162.8±0.2ppm, 154.9±0.2ppm, 148. 1±0.2ppm, 146.0±0.2ppm, 145.2±0.2ppm, 125.9±0.2ppm, 123.1±0.2ppm, 121.8±0.2ppm, 120.4±0.2pp It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from m, 119.5±0.2ppm, 116.9±0.2ppm, 116.3±0.2ppm, 114.8±0.2ppm, 113.8±0.2ppm, 56.5±0.2ppm, 18.4±0.2ppm, 17.2±0.2ppm, 9.2±0.2ppm, and 7.9±0.2ppm. 13 Form A of the ethanol solvate of substantially crystalline compound I described in any one of embodiments 61 to 66, characterized by a 13C SSNMR spectrum. 68.178.2±0.2ppm, 175.7±0.2ppm, 163.9±0.2ppm, 163.4±0.2ppm, 162.8±0.2ppm, 154.9±0. 2ppm, 148.1±0.2ppm, 146.0±0.2ppm, 145.2±0.2ppm, 125.9±0.2ppm, 123.1±0.2ppm, 121.8± It has peaks at 0.2 ppm, 120.4±0.2 ppm, 119.5±0.2 ppm, 116.9±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 56.5±0.2 ppm, 18.4±0.2 ppm, 17.2±0.2 ppm, 9.2±0.2 ppm, and 7.9±0.2 ppm. 13 Form A of the ethanol solvate of substantially crystalline compound I described in any one of embodiments 61 to 67, characterized by a 1C SSNMR spectrum. 69. Substantially the same as Figure 17 13 A substantially crystalline compound I ethanol solvate form A, as characterized by a 1C SSNMR spectrum, as described in any one of embodiments 61 to 68. It has one or two peaks selected from 70-61.1±0.2 ppm, -138.1±0.2 ppm, and -141.2±0.2 ppm. 19 A substantially crystalline compound I ethanol solvate form A of any one of embodiments 61 to 69, characterized by having an F SSNMR spectrum. It has peaks at 71, -61.1±0.2 ppm, -138.1±0.2 ppm, and -141.2±0.2 ppm. 19 A substantially crystalline compound I ethanol solvate form A of any one of embodiments 61 to 70, characterized by having an F SSNMR spectrum. 72. Substantially the same as Figure 18 19 Form A of the ethanol solvate of substantially crystalline compound I described in any one of embodiments 61 to 71, characterized by its F SSNMR spectrum. 73. The following unit cell dimensions were measured at 100 K using a Bruker diffractometer with a monoclinic crystal system, P21 / c space group, and Cu Kα radiation (λ=1.54178 Å): a 17.0 ± 0.1 Å α 90° b 11.1 ± 0.1 Å β 105.9 ± 0.1° c 13.2 ± 0.1 Å γ 90°. A substantially crystalline compound I ethanol solvate form A as described in any one of embodiments 61 to 72, characterized by the above. 74. Substantially crystalline compound I hydrate form A (i.e., less than 15% of compound I is amorphous, less than 10% of compound I is amorphous, or less than 5% of compound I is amorphous). 75. A substantially crystalline hydrate form A of compound I according to Embodiment 74, wherein the dehydrated hydrate form A of compound I is 100% crystalline. A substantially crystalline compound I hydrate form A as described in Embodiment 74 or Embodiment 75, characterized by an X-ray powder diffractogram having one or two signals selected from 76.8.7 ± 0.2 degrees 2-theta, 12.4 ± 0.2 degrees 2-theta, and 18.8 ± 0.2 degrees 2-theta. 77. A substantially crystalline compound I hydrate form A according to any one of embodiments 74 to 76, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 8.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, and 18.8±0.2 degrees 2-theta, and (b) one or two signals selected from 12.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, and 19.8±0.2 degrees 2-theta. A substantially crystalline compound I hydrate form A according to any one of embodiments 74 to 77, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 78.8.7±0.2° 2-theta, 12.4±0.2° 2-theta, 18.8±0.2° 2-theta, 12.7±0.2° 2-theta, 17.5±0.2° 2-theta, 19.8±0.2° 2-theta, 13.1±0.2° 2-theta, 16.3±0.2° 2-theta, and 21.1±0.2° 2-theta. 79. A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 78, characterized by an X-ray powder diffractogram substantially similar to that of Figure 19. 80. Dehydrated hydrate form A of substantially crystalline compound I (i.e., less than 15% of compound I is amorphous, less than 10% of compound I is amorphous, or less than 5% of compound I is amorphous). 81. A substantially crystalline dehydrated hydrate A of compound I according to Embodiment 81, wherein the dehydrated hydrate A of compound I is 100% crystalline. Dehydrated hydrate form A of substantially crystalline compound I according to Embodiment 81 or Embodiment 82, characterized by an X-ray powder diffractogram having one or two signals selected from 82.8.7±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, and 18.7±0.2 degrees 2-theta. 83. Dehydrated hydrate form A of substantially crystalline compound I according to any one of embodiments 81 to 83, characterized by an X-ray powder diffractogram having (a) one or two signals selected from 8.7±0.2° 2-theta, 15.9±0.2° 2-theta, and 18.7±0.2° 2-theta, and (b) one or two signals selected from 12.4±0.2° 2-theta, 12.6±0.2° 2-theta, 17.3±0.2° 2-theta, and 19.8±0.2° 2-theta. Dehydrated hydrate form A of substantially crystalline compound I according to any one of embodiments 81 to 84, characterized by an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 84.8.7±0.2° 2-theta, 15.9±0.2° 2-theta, 18.7±0.2° 2-theta, 12.4±0.2° 2-theta, 12.6±0.2° 2-theta, 17.3±0.2° 2-theta, 19.8±0.2° 2-theta, 13.1±0.2° 2-theta, 16.3±0.2° 2-theta, and 21.1±0.2° 2-theta. 85. Dehydrated hydrate form A of substantially crystalline compound I according to any one of embodiments 81 to 85, characterized by substantially similar X-ray powder diffractograms in Figure 20. 86.177.3±0.2ppm, 172.8±0.2ppm, 170.5±0.2ppm, 162.0±0.2ppm, 154.3±0.2ppm, 154.0±0.2ppm, 150.2±0.2ppm, 148.7 ±0.2ppm, 147.6±0.2ppm, 146.6±0.2ppm, 145.5±0.2ppm, 126.3±0.2ppm, 125.0±0.2ppm, 123.8±0.2ppm, 122.4±0.2ppm, It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 121.6±0.2ppm, 120.6±0.2ppm, 118.4±0.2ppm, 117.9±0.2ppm, 117.0±0.2ppm, 116.0±0.2ppm, 114.7±0.2ppm, 114.4±0.2ppm, 112.8±0.2ppm, 17.7±0.2ppm, 17.1±0.2ppm, and 8.7±0.2ppm. 13 A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 86, characterized by a 1C SSNMR spectrum. 87.177.3±0.2ppm, 172.8±0.2ppm, 170.5±0.2ppm, 162.0±0.2ppm, 154.3±0.2ppm, 154.0±0.2ppm, 150.2±0. 2ppm, 148.7±0.2ppm, 147.6±0.2ppm, 146.6±0.2ppm, 145.5±0.2ppm, 126.3±0.2ppm, 125.0±0.2ppm, 123.8±0 It has peaks at 0.2 ppm, 122.4 ± 0.2 ppm, 121.6 ± 0.2 ppm, 120.6 ± 0.2 ppm, 118.4 ± 0.2 ppm, 117.9 ± 0.2 ppm, 117.0 ± 0.2 ppm, 116.0 ± 0.2 ppm, 114.7 ± 0.2 ppm, 114.4 ± 0.2 ppm, 112.8 ± 0.2 ppm, 17.7 ± 0.2 ppm, 17.1 ± 0.2 ppm, and 8.7 ± 0.2 ppm. 13 A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 87, characterized by a 13C SSNMR spectrum. 88. Substantially the same as Figure 22 13 A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 88, characterized by a 1C SSNMR spectrum. It has one or two peaks selected from 89.-59.4±0.2 ppm, -60.2±0.2 ppm, -135.0±0.2 ppm, -138.4±0.2 ppm, -141.7±0.2 ppm, and -144.0±0.2 ppm. 19 A substantially crystalline compound I hydrate form A according to any one of embodiments 74 to 89, characterized by having an F SSNMR spectrum. It has peaks at 90.-59.4±0.2 ppm, -60.2±0.2 ppm, -135.0±0.2 ppm, -138.4±0.2 ppm, -141.7±0.2 ppm, and -144.0±0.2 ppm. 19 A substantially crystalline compound I hydrate form A according to any one of embodiments 74 to 90, characterized by having an F SSNMR spectrum. 91. Substantially similar to Figure 23 19A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 91, characterized by its F SSNMR spectrum. 92. The following unit cell dimensions were measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ=1.54178 Å): a 10.5 ± 0.1 Å α 91.3 ± 0.1° b 11.2 ± 0.1 Å β 103.9 ± 0.1° c 19.2 ± 0.1 Å γ 98.4 ± 0.1°. A substantially crystalline compound I hydrate form A as described in any one of embodiments 74 to 92, characterized by the above. 93. The following unit cell dimensions were measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ=1.54178 Å): a 10.4 ± 0.1 Å α 90.7 ± 0.1° b 11.2 ± 0.1 Å β 104.7 ± 0.1° c 19.3 ± 0.1 Å γ 98.0 ± 0.1°. A dehydrated hydrate form A of a substantially crystalline compound I as described in any one of embodiments 81 to 92, characterized by the above. 94. A pharmaceutical composition comprising compound I as described in any one of Embodiments 1 to 93, and further comprising, optionally, one or more additional therapeutic agents. 95. The pharmaceutical composition according to Embodiment 94, wherein the pharmaceutical composition comprises one or more additional pain-modulating compounds. 96. Compound I according to any one of Embodiments 1 to 93, or the pharmaceutical composition according to Embodiment 94 or 95, for use in the treatment of pain. 97. Use of compound I according to any one of embodiments 1 to 93, or the pharmaceutical composition according to embodiment 94 or 95, in the manufacture of a drug for the treatment of pain. 98. A method for treating pain, comprising administering compound I described in any one of embodiments 1 to 93, or a pharmaceutical composition described in embodiment 94 or 95, to a subject in need thereof. 99. Compound I described in any one of Embodiments 1 to 93, or the composition described in Embodiment 94 or 95, administered in combination with one or more additional therapeutic agents, the compound or composition for use described in Embodiment 96, the use described in Embodiment 97, or the method described in Embodiment 98. 100. A compound or composition for use, use or method, according to Embodiment 99, comprising one or more additional therapeutic agents, one or more additional pain-modulating compounds. 101. A method for preparing neat form A of crystalline compound I, comprising: (i) combining compound I and ethyl acetate; (ii) distilling under vacuum at 50°C; (iii) adding ethyl acetate; (iv) distilling under vacuum at 50°C; (v) heating to 75°C; (vi) adding heptane; (vii) cooling to 40°C; (viii) adding a seed of crystalline compound I in form A; (ix) holding at 40°C for 1.5 hours; (x) adding heptane over 5 hours; (xi) cooling the slurry to 20°C over 5 hours; (xii) holding at 20°C for 11 hours; (xiii) collecting the solid; and (xiv) drying the solid in a vacuum oven at 45°C for 46 hours with a small nitrogen bleed to obtain neat form A of crystalline compound I. 102. A method for producing neat form B of crystalline compound I, comprising: (i) adding hydrate form A of compound I to an oven set to 180°C; and (ii) cooling under ambient conditions to obtain neat form B of crystalline compound I. 103. A method for producing neat form E of crystalline compound I, comprising: (i) combining hydrate form A of compound I and trifluorotoluene; (ii) heating the slurry to 80°C; and (iii) cooling to room temperature to obtain neat form E of crystalline compound I. 104. A method for preparing a hydrated form A of crystalline compound I, comprising: (i) saturating acetone with compound I; (ii) adding water dropwise until the final volume reaches 20%; and (iii) holding at room temperature overnight to obtain a hydrated form A of crystalline compound I. 105. A method for preparing ethanol solvate form A of crystalline compound I, comprising: (i) combining compound I and ethyl acetate; (ii) heating the slurry to 50°C; (iii) adding ethanol and distilling under vacuum at 50°C; (iv) adding ethanol and distilling under vacuum at 50°C; (v) adding ethanol and distilling under vacuum at 50°C to a minimum volume; (vi) adding ethanol and distilling under vacuum at 50°C; and (vii) drying the solid in a vacuum oven at 45°C for 42 hours using a small nitrogen bleed to obtain ethanol solvate form A of crystalline compound I. 106. A method for preparing a dehydrated hydrate form A of crystalline compound I, comprising: (i) combining the ethanol solvate form A of compound I and acetone; (ii) stirring the slurry while heating to 50°C; (iii) adding water over 1 hour; (iv) adding a seed of crystalline compound I hydrate form A; (v) stirring for 30 minutes; (vi) adding water over 8 hours; (vii) stirring at 50°C for 5 hours; (viii) cooling the slurry to 20°C over 3 hours; (ix) stirring for 2 hours; (x) collecting the solid and washing it with acetone:water in a 1:2 ratio; and (xi) drying the solid in a vacuum oven at 50°C with minimal nitrogen bleed to obtain crystalline compound I hydrate form A. 107. A method for preparing an amorphous form of compound I, comprising: (i) dissolving compound I in acetone; (ii) filtering and evaporating the solvent by centrifugal evaporation at 50°C and 12 mbar for 1 hour; and (iii) drying overnight in a vacuum oven at 50°C to obtain an amorphous form of compound I.

[0394] Additional embodiments of this disclosure are described in the following numbered sections. 1. A process for preparing the compound of formula (I), [ka] Compound of formula (A1): [ka] This includes converting to the compound of formula (I), where X 1 and X 2 Each of these processes is independently selected from halogens. 2. Converting the compound of formula (A1) to the compound of formula (I) is equivalent to converting the compound of formula (A1) to the compound of formula (E-A1): [ka] The process described in Section 1, which includes converting to [a specific format]. 3. Converting the compound of formula (A1) to the compound of formula (E-A1) is equivalent to converting the compound of formula (A1) to the compound of formula (D-1): [ka] The process described in Section 2, which includes bringing into contact with the object. 4. The process described in Section 3, wherein the compound of formula (A1) is brought into contact with the compound of formula (D-1) in the presence of a first palladium catalyst and a first base. 5. The process described in Section 4, wherein the first palladium catalyst is a palladium-phosphine complex. 6. The process according to Section 4 or 5, wherein the first palladium catalyst is PdCl2(dtbdpf). 7. The process described in any one of sections 4-6, wherein the first base is selected from potassium carbonate, potassium phosphate, and potassium fluoride. 8. A process described in any one of sections 1 to 7, wherein the conversion of a compound of formula (A1) to a compound of formula (I) further includes the conversion of a compound of formula (E-A1) to a compound of formula (I). 9. The process described in Section 8, wherein the conversion of the compound of formula (E-A1) to the compound of formula (I) includes treating the compound of formula (E-A1) with a first acid. 10. The process described in Section 9, wherein the first acid is selected from sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. 11. Formula (A 1-1 ) compounds: [ka] The process described in any one of sections 1 to 10, further comprising converting to the compound of formula (A1). 12. Formula (A 1-1 Converting the compound of formula (A1) to the compound of formula (A1) is possible. Formula (A 1-1 The process involves treating the compound with trifluoromethanesulfonic acid anhydride to form a trifuryl intermediate, A step of treating the trifuryl intermediate with a cyanation reagent, A step of treating the cyanation intermediate with a second base to form a cyanated trifuryl intermediate, The process according to Section 11, comprising the step of treating a cyanated trifuryl intermediate with an aqueous base to form a compound of formula (A1). 13. The process described in Section 12, wherein the cyanating reagent is trimethylsilyl cyanide, sodium cyanide, and potassium cyanide. 14. The process according to Section 12 or 13, wherein the second base is selected from 4-methylmorpholine, trimethylamine, and Hünig bases. 15. The process described in any one of sections 12 to 14, wherein the aqueous base is an aqueous solution of sodium bicarbonate. 16. Formula (A 1-2 ) compounds: [ka] Formula (A 1-1 The process described in any one of sections 11 to 15, further comprising converting to a compound of ). 17. Formula (A 1-2 The compound of formula (A1-1 It can be converted to a compound of formula (A 1-2 The process described in Section 16, comprising treating the compound of ) with a halogenating reagent. 18. The process described in Section 17, wherein the halogenating agent is a chlorinating agent selected from phosphorus oxychloride. 19.Formula (A 1-3 ) compounds: [ka] Formula (A 1-2 The process described in any one of sections 16-18, further comprising converting to a compound of ). 20. Formula (A 1-3 The compound of formula (A 1-3 It can be converted to a compound of formula (A 1-3 The process described in Section 19, comprising treating the compound of ) with a second acid. 21. The process described in Section 20, wherein the second acid is an aqueous solution of hydrochloric acid. 22. Formula (A 1-4 ) compounds: [ka] Formula (A 1-3 The process described in any one of sections 19-21, further comprising converting to a compound of ). 23.Formula (A 1-4 The compound of formula (A 1-3 It can be converted to a compound of formula (A) in the presence of a third base. 1-4 The process described in Section 22, comprising treating the compound of ) with diethyl malonate. 24. The process described in Section 23, wherein the third base is an alkali alkoxide. 25. The process described in Section 23 or 24, wherein the third base is a sodium ethoxide. 26. Formula (A 1-5 ) compounds: [ka] Formula (A 1-4The process described in any one of sections 23-25, further comprising converting to a compound of ). 27. Formula (A 1-5 The compound of formula (A 1-4 The compound of formula (A) can be converted in the presence of a fourth base, a second palladium catalyst, and a first preferred ligand. 1-5 The process described in Section 26, comprising treating the compound of ) with carbon monoxide. 28. The process described in Section 27, wherein the fourth base is triethylamine. 29. The process according to Section 27 or 28, wherein the second palladium catalyst is Pd(OAc)2. 30. The process according to any one of sections 27 to 29, wherein the first preferred ligand is 1,1'-bis(diphenylphosphino)ferrocene (DPPF). 31.X 1 and X 2 Each of the following processes is chloro, as described in any one of sections 1-30. 32. A process for preparing the compound of formula (I), [ka] Compound of formula (A3): [ka] A process that includes converting to the compound of formula (I). 33. Converting the compound of formula (A3) to the compound of formula (I) is equivalent to converting the compound of formula (A3) to the compound of formula (E-A3): [ka] The process described in Section 32, which includes converting to [a specific format]. 34. Converting the compound of formula (A3) to the compound of formula (E-A3) is equivalent to converting the compound of formula (A3) to the compound of formula (D-1): [ka] The process described in Section 33, which includes bringing into contact with the object. 35. The process described in Section 34, wherein the compound of formula (A3) is brought into contact with the compound of formula (D-1) in the presence of a first palladium catalyst and a first base. 36. The process described in Section 35, wherein the first palladium catalyst is PdCl2(dtbdpf). 37. The process described in Section 35 or 36, wherein the first base is potassium phosphate. 38. The process described in...

Claims

1. A substantially crystalline compound I, 【Chemistry 1】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a neat form A of a substantially pure compound I.

2. The neat form A of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, or 6 signals selected from 9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 11.3±0.2° 2-theta, 15.9±0.2° 2-theta, 20.5±0.2° 2-theta, 14.6±0.2° 2-theta, 16.6±0.2° 2-theta, and 23.5±0.2° 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 4, and / or (iii) 170.4±0.2ppm, 163.8±0.2ppm, 162.4±0.2ppm, 160.9±0.2ppm, 158.6±0.2ppm, 158.3±0.2ppm, 154.6±0.2ppm, 154.0±0.2ppm, 1 48.3±0.2ppm, 147.6±0.2ppm, 146.9±0.2ppm, 145.9±0.2ppm, 143.5±0.2ppm, 143.1±0.2ppm, 141.9±0.2ppm, 127.4±0.2ppm, 125.3±0 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 2 ppm, 123.6 ± 0.2 ppm, 122.2 ± 0.2 ppm, 121.3 ± 0.2 ppm, 120.7 ± 0.2 ppm, 117.9 ± 0.2 ppm, 117.3 ± 0.2 ppm, 116.3 ± 0.2 ppm, 115.8 ± 0.2 ppm, 114.2 ± 0.2 ppm, 113.6 ± 0.2 ppm, 112.8 ± 0.2 ppm, 15.4 ± 0.2 ppm, and 8.2 ± 0.2 ppm. １３ C SSN NMR spectrum, and / or (iv) Substantially the same as Figure 5 １３ C SSN NMR spectrum, and / or (v) Having 1, 2, 3, 4, 5, or 6 peaks selected from -61.2±0.2 ppm, -61.6±0.2 ppm, -138.6±0.2 ppm, -140.3±0.2 ppm, -142.0±0.2 ppm, and -146.0±0.2 ppm. １９ F SSN NMR spectrum, and / or (vi) Substantially similar to Figure 6 １９ F SSN NMR spectrum, and / or (vii) The following unit cell dimensions measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ = 1.54178 Å): a 9.6±0.1Å α 94.3±0.1° b 12.6±0.1Å β 97.3±0.1° A substantially crystalline compound I according to claim 1, characterized by c 18.7±0.1 Å and γ 107.3±0.1°.

3. A substantially crystalline compound I, 【Chemistry 2】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a neat form B of a substantially pure compound I.

4. The neat form B of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, or 9 signals selected from 4.8±0.2° 2-theta, 13.3±0.2° 2-theta, 18.5±0.2° 2-theta, 6.0±0.2° 2-theta, 16.5±0.2° 2-theta, 16.9±0.2° 2-theta, 14.1±0.2° 2-theta, 14.7±0.2° 2-theta, and 15.2±0.2° 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 7, and / or (iii) 176.9±0.2ppm, 171.7±0.2ppm, 164.0±0.2ppm, 161.4±0.2ppm, 160.7±0.2ppm, 155.3±0.2ppm, 154.8±0.2ppm, 148.6±0.2ppm, 147.6±0.2ppm, 146.4±0.2ppm, 145.7±0.2ppm, 144.8±0.2ppm, 127.7±0.2ppm, 125.4±0.2ppm, 122.0 Having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from ±0.2 ppm, 121.5 ±0.2 ppm, 118.4 ±0.2 ppm, 116.3 ±0.2 ppm, 114.8 ±0.2 ppm, 113.8 ±0.2 ppm, 112.6 ±0.2 ppm, 17.8 ±0.2 ppm, 15.0 ±0.2 ppm, 10.7 ±0.2 ppm, 9.6 ±0.2 ppm, and 8.8 ±0.2 ppm. １３ C SSN NMR spectrum, and / or (iv) Substantially the same as Figure 8 １３ C SSN NMR spectrum, and / or (v) Having one, two, three, four, or five peaks selected from -61.6±0.2 ppm, -138±0.2 ppm, -139.7±0.2 ppm, -143.4±0.2 ppm, and -144.9±0.2 ppm. １９ F SSN NMR spectrum, and / or (vi) Substantially the same as Figure 9 １９ A substantially crystalline compound I according to claim 1, characterized by an F SSN NMR spectrum.

5. A substantially crystalline compound I, 【Transformation 3】 A substantially crystalline compound I, wherein the crystalline compound I is a neat form E of substantially pure compound I.

6. The neat form E of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, or 9 signals selected from 8.6±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 15.1±0.2 degrees 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 10, and / or (iii) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks selected from 170.0±0.2 ppm, 163.0±0.2 ppm, 162.3±0.2 ppm, 161.3±0.2 ppm, 159.3±0.2 ppm, 154.7±0.2 ppm, 150.6±0.2 ppm, 149.8±0.2 ppm, 148.6±0.2 ppm, 148.3±0.2 ppm, 147.1±0.2 ppm, 144.9±0.2 ppm, 143.9±0.2 ppm, 143.5±0.2 ppm, 126.9±0.2 ppm, 126.0±0.2 ppm, 124.1±0.2 ppm, 122.6±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 116.7±0.2 ppm, 115.2±0.2 ppm, 114.1±0.2 ppm, 113.1±0.2 ppm, 15.9±0.2 ppm, 15.3±0.2 ppm, and 8.4±0.2 ppm １３ C SSNMR spectrum, and / or (iv) Substantially the same as Figure 11 １３ C SSN NMR spectrum, and / or (v) Having 1, 2, 3, 4, 5, 6, or 7 peaks selected from -60.9±0.2 ppm, -62.5±0.2 ppm, -63.1±0.2 ppm, -135.1±0.2 ppm, -137.1±0.2 ppm, -140.7±0.2 ppm, and -141.9±0.2 ppm. １９ F SSN NMR spectrum, and / or (vi) Substantially similar to Figure 12 １９ F SSN NMR spectrum, and / or (vii) The following unit cell dimensions measured at 100 K using a Rigaku diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ = 1.54178 Å): a 8.7±0.1Å α 92.7±0.1° b 12.2±0.1Å β 96.3±0.1° c 20.9±0.1 Å γ 98.6±0.1°, and / or (viiii) The following unit cell dimensions were measured at 298 K using a Rigaku diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ = 1.54178 Å): a 8.9±0.1Å α 92.6±0.1° b 12.3±0.1Å β 97.1±0.1° A substantially crystalline compound I according to claim 1, characterized by c 21.1±0.1 Å and γ 98.5±0.1°.

7. A substantially crystalline compound I, 【Chemistry 4】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a pure acetone solvate hydrate form A of compound I.

8. The acetone solvate hydrate form A of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, or 9 signals selected from 9.5±0.2° 2-theta, 12.3±0.2° 2-theta, 13.5±0.2° 2-theta, 12.9±0.2° 2-theta, 15.6±0.2° 2-theta, 24.8±0.2° 2-theta, 8.1±0.2° 2-theta, 12.3±0.2° 2-theta, and 17.6±0.2° 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 13, and / or (iii) 212.9±0.2ppm, 211.6±0.2ppm, 179.2±0.2ppm, 178.9±0.2ppm, 178.4±0.2p pm, 174.7±0.2ppm, 174.1±0.2ppm, 172.7±0.2ppm, 172.2±0.2ppm, 163.1±0.2ppm , 156.7±0.2ppm, 155.6±0.2ppm, 152.3±0.2ppm, 150.1±0.2ppm, 148.7±0.2ppm, 1 47.9±0.2ppm, 147.0±0.2ppm, 145.1±0.2ppm, 125.5±0.2ppm, 124.5±0.2ppm, 122 .. 5±0.2ppm, 121.6±0.2ppm, 121.1±0.2ppm, 118.5±0.2ppm, 118.1±0.2ppm, 117.4 ±0.2ppm, 116.8±0.2ppm, 115.7±0.2ppm, 115.3±0.2ppm, 113.9±0.2ppm, 113.2±0 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 2 ppm, 112.4 ± 0.2 ppm, 30 ± 0.2 ppm, 29.5 ± 0.2 ppm, 18.4 ± 0.2 ppm, 17.6 ± 0.2 ppm, 8.8 ± 0.2 ppm, and 8.1 ± 0.2 ppm. １３ C SSN NMR spectrum, and / or (iv) Substantially the same as Figure 14 １３ C SSN NMR spectrum, and / or (v) Having one or two peaks selected from -60.4±0.2 ppm, -61.2±0.2 ppm, -61.6±0.2 ppm, -62.7±0.2 ppm, -135.9±0.2 ppm, -136.1±0.2 ppm, -139.6±0.2 ppm, -140.6±0.2 ppm, -141.7±0.2 ppm, -145.2±0.2 ppm, and -145.7±0.2 ppm. １９ F SSN NMR spectrum, and / or (vi) Substantially the same as Figure 15 １９ F SSN NMR spectrum, and / or (vii) Monoclinic system, P2 １ The following unit cell dimensions were measured at 100 K using a Rigaku diffractometer with space group and Cu Kα radiation (λ = 1.54178 Å): a 9.2±0.1Å α 90° b 39.8±0.1Å β 96.3±0.1° A substantially crystalline compound I according to claim 1, characterized by c 12.9 ± 0.1 Å and γ 90°.

9. A substantially crystalline compound I, 【Transformation 5】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a pure ethanol solvate form A of compound I.

10. The ethanol solvate form A of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, or 9 signals selected from 9.4±0.2° 2-theta, 16.1±0.2° 2-theta, 26.0±0.2° 2-theta, 15.1±0.2° 2-theta, 17.0±0.2° 2-theta, 22.4±0.2° 2-theta, 13.2±0.2° 2-theta, 13.6±0.2° 2-theta, and 13.8±0.2° 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 16, and / or (iii) 178.2±0.2ppm, 175.7±0.2ppm, 163.9±0.2ppm, 163.4±0.2ppm, 162.8±0.2ppm, 154.9±0.2ppm, 148 .1±0.2ppm, 146.0±0.2ppm, 145.2±0.2ppm, 125.9±0.2ppm, 123.1±0.2ppm, 121.8±0.2ppm, 120.4±0.2ppm It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from m, 119.5±0.2 ppm, 116.9±0.2 ppm, 116.3±0.2 ppm, 114.8±0.2 ppm, 113.8±0.2 ppm, 56.5±0.2 ppm, 18.4±0.2 ppm, 17.2±0.2 ppm, 9.2±0.2 ppm, and 7.9±0.2 ppm. １３ C SSN NMR spectrum, and / or (iv) Substantially the same as Figure 17 １３ C SSN NMR spectrum, and / or (v) Having one, two, or three peaks selected from -61.1 ± 0.2 ppm, -138.1 ± 0.2 ppm, and -141.2 ± 0.2 ppm. １９ F SSN NMR spectrum, (vi) Substantially the same as Figure 18 １９ F SSN NMR spectrum, and / or (vii) Monoclinic system, P2 １ The following unit cell dimensions were measured at 100 K using a Bruker diffractometer with the / c space group and Cu Kα radiation (λ = 1.54178 Å): a 17.0±0.1Å α 90° b 11.1±0.1Å β 105.9±0.1° A substantially crystalline compound I according to claim 1, characterized by c 13.2 ± 0.1 Å and γ 90°.

11. A substantially crystalline compound I, 【Transformation 6】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a hydrate form A of the crystalline compound I.

12. The hydrate form A of the aforementioned compound I is (i) an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, or 9 signals selected from 8.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 12.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, and 21.1±0.2 degrees 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 19, and / or (iii) 177.3±0.2ppm, 172.8±0.2ppm, 170.5±0.2ppm, 162.0±0.2ppm, 154.3±0.2ppm, 154.0±0.2ppm, 150.2±0.2ppm, 148. 7±0.2ppm, 147.6±0.2ppm, 146.6±0.2ppm, 145.5±0.2ppm, 126.3±0.2ppm, 125.0±0.2ppm, 123.8±0.2ppm, 122.4±0.2ppm, It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks selected from 121.6±0.2 ppm, 120.6±0.2 ppm, 118.4±0.2 ppm, 117.9±0.2 ppm, 117.0±0.2 ppm, 116.0±0.2 ppm, 114.7±0.2 ppm, 114.4±0.2 ppm, 112.8±0.2 ppm, 17.7±0.2 ppm, 17.1±0.2 ppm, and 8.7±0.2 ppm. １３ C SSN NMR spectrum, and / or (iv) Substantially the same as Figure 22 １３ C SSN NMR spectrum, and / or (v) Having 1, 2, 3, 4, 5, or 6 peaks selected from -59.4±0.2 ppm, -60.2±0.2 ppm, -135.0±0.2 ppm, -138.4±0.2 ppm, -141.7±0.2 ppm, and -144.0±0.2 ppm. １９ F SSN NMR spectrum, and / or (vi) Substantially the same as Figure 23 １９ F SSN NMR spectrum, and / or (vii) The following unit cell dimensions measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ = 1.54178 Å): a 10.5±0.1Å α 91.3±0.1° b 11.2±0.1Å β 103.9±0.1° A substantially crystalline compound I according to claim 1, characterized by c 19.2±0.1 Å and γ 98.4±0.1°.

13. A substantially crystalline compound I, 【Transformation 7】 A substantially crystalline compound I, wherein the crystalline compound I is substantially a dehydrated hydrate form A of a substantially pure compound I.

14. The dehydrated hydrate form A of the aforementioned compound I is (i) Characterized by an X-ray powder diffractogram having 2, 3, 4, 5, 6, 7, 8, 9, or 10 signals selected from 8.7±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 12.6±0.2 degrees 2-theta, 17.3±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.3±0.2 degrees 2-theta, and 21.1±0.2 degrees 2-theta, and / or (ii) An X-ray powder diffractogram substantially similar to that of Figure 20, and / or (iii) The following unit cell dimensions measured at 100 K using a Bruker diffractometer with a triclinic crystal system, P-1 space group, and Cu Kα radiation (λ = 1.54178 Å): a 10.4±0.1Å α 90.7±0.1° b 11.2±0.1Å β 104.7±0.1° A substantially crystalline compound I according to claim 1, characterized by c 19.3±0.1 Å and γ 98.0±0.1°.

15. Compound I is substantially amorphous, 【Transformation 8】 A substantially amorphous compound I, wherein the compound I is in an amorphous form.

16. The amorphous form of compound I is (i) An X-ray powder diffractogram substantially similar to that of Figure 1, and / or (ii) A 13C SSN NMR spectrum having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks selected from 177.6±0.2 ppm, 172.0±0.2 ppm, 162.6±0.2 ppm, 155.2±0.2 ppm, 149.9±0.2 ppm, 147.0±0.2 ppm, 121.0±0.2 ppm, 120.1±0.2 ppm, 119.1±0.2 ppm, 116.0±0.2 ppm, 114.6±0.2 ppm, 113.8±0.2 ppm, 15.5±0.2 ppm, and 7.7±0.2 ppm, and / or (iii) Substantially the same as Figure 2 １３ C SSN NMR spectrum, and / or (iv) Having one or two peaks selected from -61.9 ± 0.2 ppm and -142.1 ± 0.2 ppm １９ F SSN NMR spectrum, and / or (v) Substantially the same as Figure 3 １９ A substantially amorphous compound I according to claim 15, characterized by an F SSN NMR spectrum.

17. A pharmaceutical composition comprising compound I as described in any one of claims 1 to 16.

18. The pharmaceutical composition according to claim 17, further comprising one or more additional therapeutic agents, wherein the one or more additional therapeutic agents optionally comprise one or more additional pain-modulating compounds.

19. Compound I according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17 or 18, for use in the treatment of pain, wherein the pain, as necessary, 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 cardiac arrhythmia.

20. The use of compound I according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17 or 18, in the manufacture of a drug for the treatment of pain, wherein the pain, as necessary, 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 cardiac arrhythmia.

21. A method for treating pain, comprising administering compound I according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17 or 18, to a subject in need thereof, wherein the pain may include, if necessary, 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 cardiac arrhythmia.

22. Compound I according to any one of claims 1 to 16, or the composition according to claim 17 or 18, is administered in combination with one or more additional therapeutic agents, wherein, if necessary, the one or more additional therapeutic agents comprise one or more additional pain-modulating compounds, the compound or composition for use according to claim 19, the use according to claim 20, or the method according to claim 21.

23. Use of compound I according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 17 or 18, as a pharmaceutical agent.

24. A process for preparing the compound of formula (I), 【Chemistry 9】 Formula (A １ Compounds of: 【Chemistry 10】 This includes converting to the compound of formula (I), where X １ and X ２ Each of these processes is independently selected from halogens.

25. The above formula (A １ Converting the compound of formula (A) to the compound of formula (I) is the same as converting the compound of formula (A １ The compound of formula (E-A １ Compounds of: 【Chemistry 11】 The process according to claim 24, which includes converting to

26. The above formula (A １ The compound of the above formula (E-A １ Converting to a compound of the above formula (A １ The compound of formula (D-1): 【Chemistry 12】 The process according to claim 25, comprising bringing into contact with

27. The above formula (A １ Converting the compound of formula (E-A) to the compound of formula (I) is equivalent to converting the compound of formula (E-A) １ The process according to claim 25 or 26, further comprising converting a compound of formula (I) to a compound of formula (I).

28. Formula (A １－１ Compounds of: 【Chemistry 13】 The above formula (A １ The process according to any one of claims 24 to 27, further comprising converting to a compound of ).

29. Formula (A １－２ Compounds of: 【Chemistry 14】 The above formula (A １－１ The process according to claim 28, further comprising converting to a compound of ).

30. Formula (A １－３ Compounds of: 【Chemistry 15】 The above formula (A １－２ The process according to claim 29, further comprising converting to a compound of ).

31. Formula (A １－４ Compounds of: 【Chemistry 16】 The above formula (A １－３ The process according to claim 30, further comprising converting to a compound of ).

32. Formula (A １－５ Compounds of: 【Chemistry 17】 The above formula (A １－４ The process according to claim 31, further comprising converting to a compound of ).

33. X １ and X ２ The process according to any one of claims 24 to 32, wherein each of them is chloro.

34. A process for preparing the compound of formula (I), [Chemistry 18] Formula (A ３ Compounds of: 【Chemistry 19】 A process comprising converting to the compound of formula (I).

35. The above formula (A ３ Converting the compound of formula (A) to the compound of formula (I) is the same as converting the compound of formula (A ３ The compound of formula (E-A ３ Compounds of: 【Chemistry 20】 The process according to claim 34, which includes converting to

36. The above formula (A ３ The compound of the above formula (E-A ３ Converting to a compound of the above formula (A ３ The compound of formula (D-1): 【Chemistry 21】 The process according to claim 35, comprising bringing into contact with

37. The above formula (A ３ Converting the compound of formula (E-A) to the compound of formula (I) is equivalent to converting the compound of formula (E-A) ３ The process according to claim 35 or 36, further comprising converting a compound of formula (I) to a compound of formula (I).

38. Formula (A ３－１ Compounds of: 【Chemistry 22】 The above formula (A ３ The process according to any one of claims 34 to 38, further comprising converting to a compound of ).

39. Formula (A ３－２ Compounds of: 【Chemistry 23】 The above formula (A ３－１ The process according to claim 38, further comprising converting to a compound of ).

40. Compound of formula (D-2): 【Chemistry 24】 The process according to any one of claims 26 to 33 or 36 to 39, further comprising converting to the compound of formula (D-1).

41. Compound of formula (B-1): 【Chemistry 25】 The process according to claim 40, further comprising converting to the compound of formula (D-2).

42. Converting the compound of formula (B-1) to the compound of formula (D-2) is equivalent to converting the compound of formula (B-1) to the compound of formula (C-1): 【Chemistry 26】 The process according to claim 41, comprising contacting with a base in the presence of a base, wherein the base is optionally potassium carbonate.

43. Compound of formula (B-2): 【Chemistry 27】 The process according to claim 42, further comprising converting to the compound of formula (B-1).

44. Compound of formula (B-3): 【Chemistry 28】 The process according to claim 43, further comprising converting to the compound of formula (B-2).

45. Compound of formula (B-4): 【Chemistry 29】 The process according to claim 44, further comprising converting to the compound of formula (B-3).

46. Compound of formula (B-5): 【Transformation 30】 The process according to claim 45, further comprising converting to the compound of formula (B-4).

47. Compound of formula (C-2): 【Chemistry 31】 The process according to any one of claims 42 to 46, further comprising converting to a compound of formula (C-1), wherein PG is a suitable protecting group.

48. Compound of formula (C-3): 【Chemistry 32】 The process according to claim 47, further comprising converting to the compound of formula (C-2), wherein PG is a suitable protecting group.

49. Compound of formula (C-4): 【Transformation 33】 The process according to claim 48, further comprising converting to the compound of formula (C-3).

50. The process further includes converting the compound of formula (I) to a solvate of the compound of formula (I), wherein the solvate of the compound of formula (I) is, if necessary, a compound of formula (F): 【Transformation 34】 The process according to any one of claims 24 to 49.

51. The process according to claim 50, further comprising converting the solvate of the compound of formula (I) to form A of the compound of formula (I). 【Request Item 52】 【Chemistry 35】 A compound selected from among them.

53. A compound of formula (I) prepared by the process described in any one of claims 24 to 51: 【Transformation 36】 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

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