Processes for the synthesis of substituted tetrahydrofuran modulators of sodium channels

Abstract

The present application provides manufacturing methods for producing compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful as inhibitors of sodium channels. The present application also provides manufacturing methods for making compounds of formula (II) and pharmaceutically acceptable salts thereof that are useful as inhibitors of sodium channels. Manufacturing methods for producing various intermediate products and suitable salts thereof are also provided. In some embodiments, the manufacturing methods include converting any of the compounds of formulas (III), (IV), (VI)-(XV), and (XXII)-(XIX) to the compound of formula (I) via the chemical processes described in this disclosure. JPEG2026501116000211.jpg47120

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 430,568, filed December 6, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from pain suppression. 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):pp. 681-688). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include nerve entrapment injuries such as post-amputation pain, postoperative nerve injury pain, and neuropathic back pain.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. V Sodium channel receptors (SCRs) are biological mediators of electrical signaling and mediate the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells). Evidence for a role for these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all support the role of Na in pain sensation. V(Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V 1.8 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,DSand Bannon,AW,Sodium and Nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56 (2008)). Na V Na mediates the rapid upstroke of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac myocytes) and is therefore involved in the initiation of signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Na plays a key role in the initiation and propagation of neuronal signals. V Because of the role played by Na V Antagonists that reduce current can prevent or reduce nerve signaling, VIt has been thought that these channels are likely to reduce pain in conditions where hyperexcitability is observed (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)). Several clinically useful analgesics are known to be sodium-gated. V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which block pain by inhibiting channels and have been shown to be effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); 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)).

[0004] Na V form a subfamily of the voltage-gated ion channel superfamily and V 1.1~Na V There are nine isoforms, designated 1.1 and 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the primary sodium channel in skeletal muscle, and Na V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, and Na V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but they differ in the details of their voltage dependence and kinetic 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)).

[0005] At the time of their discovery, Na V The 1.8 channel was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562):pp. 257-62). Subsequently, Na V 1.8 has been shown to be a carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (Blair, NT and BP Bean, 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 V1.8 is involved in spontaneous firing in injured 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 V 1.8 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,XW,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, HL, 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, JA, et al. 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 V The small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling.V 1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, 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 required for rapid repetitive action potentials in nociceptors and for spontaneous activity of injured 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): pp. 921-926. In depolarized or damaged DRG neurons, Na V1.8 appears to be a driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21):p.8245-50). In some animal pain models, Na V The 1.8 mRNA expression level shows 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): pp. 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). The present inventors have found that some voltage-gated sodium channel inhibitors, for example, have a poor therapeutic window (e.g., Na VWe have found that selective NaCl-containing steroids have limitations as therapeutic agents due to their lack of isoform selectivity, low efficacy, and / or other reasons. V There remains a need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors, and manufacturing methods for making same. [Prior art documents] [Non-patent literature]

[0006] [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] 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 3] 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 4] 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 5] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [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, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62 [Non-Patent Document 11] 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 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

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[0007] In one aspect, the present invention provides a compound of formula (I)

[0008] [ka]

[0009] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the method of manufacture comprises converting any of the compounds of formula (III), (IV), (VI)-(XV), and (XXII)-(XIX) to a compound of formula (I) via a chemical process described herein.

[0011] In one aspect, the present invention provides a compound of formula (II):

[0012] [ka]

[0013] or a method for preparing a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the method of manufacture comprises converting any of the compounds of formula (IV), (VI)-(XV), (XX), and (XXII)-(XIX) to a compound of formula (II) via a chemical process described herein. [Brief explanation of the drawings]

[0015] [Figure 1] 1 shows an XRPD pattern characteristic of Compound (VII), Form A.

[0016] [Figure 2] 1 shows an XRPD pattern characteristic of Compound (VI), Form A.

[0017] [Figure 3] 1 shows an XRPD pattern characteristic of Compound (I), Form A.

[0018] [Figure 4] 1 shows the solid state 13C NMR spectral characteristics of Compound (I), Form A.

[0019] [Figure 5] 1 shows the solid state 19F NMR spectral characteristics of Compound (I), Form A.

[0020] [Figure 6] 1 shows the XRPD pattern of the spray-dried dispersion of Compound II of Example 11.

[0021] [Figure 7A] FIG. 7A shows the XRPD pattern of the SDD tablet composition of Example 11 over the range of about 3° to about 40° 2θ.

[0022] [Figure 7B]FIG. 7B shows the XRPD pattern of the SDD tablet composition of Example 11 over the range of about 14° to about 16° 2θ.

[0023] [Figure 8A] FIG. 8A shows the solid-state 19F NMR spectral profile of the SDD tablet composition of Example 11.

[0024] [Figure 8B] FIG. 8B shows the solid-state 13C NMR spectral profile of the powder of the SDD tablet composition of Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0025] In the present disclosure, Disclosed herein are synthetic processes and methods for preparing compounds of formula (I) and compounds of formula (II). In some embodiments, one skilled in the art could prepare a compound of formula (I) from any one of compounds of formulas (III), (IV), and (VI)-(XV), as described in Scheme A below. In other embodiments, one skilled in the art could prepare a compound of formula (I) from any one of compounds of formulas (III), (IV), and (XXII)-(XIX), as summarized in Schemes A and C below. In some embodiments, one skilled in the art could prepare a compound of formula (II) from any one of compounds of formulas (IV), (VI)-(XV), and (XX), as described in Scheme B below. In other embodiments, one skilled in the art could prepare a compound of formula (II) from any one of compounds of formulas (IV), (XX), and (XXII)-(XIX), as summarized in Schemes B and C below.

[0026] Scheme AA Exemplary Process I for Preparing Compounds of Formula (I)

[0027] [ka]

[0028] During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 It is selected from aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0029] Scheme BB Exemplary Process II for Preparing Compounds of Formula (II).

[0030] [ka]

[0031] During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 It is selected from aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0032] Scheme CC Exemplary Process IV for preparing compounds of formula (IV).

[0033] [ka]

[0034] The process steps described in this disclosure may refer to converting a starting compound of formula II-V and VII-XXI to a compound of formula I. One of ordinary skill in the art will understand that these processes can also be used to prepare any intermediate between any starting compound and a compound of formula (I). For example, in some embodiments, the conversion of a compound of formula (IV) to a compound of formula (I) is via intermediate compounds (VII) and (III). As such, one of ordinary skill in the art will understand that the processes described for converting a compound of formula (IV) to a compound of formula (I) can be used to prepare any of intermediate compounds (VII) and (III) from a compound of formula (IV). Similarly, in some embodiments, the conversion of a compound of formula (XIII) to a compound of formula (I) is via the preparation of intermediate compounds (III), (VII), (IV), and (IX)-(XII). As such, one skilled in the art will understand that the methods described for converting a compound of formula (XIII) to a compound of formula (I) can be used to prepare any of intermediate compounds (III), (VII), (IV), and (IX)-(XII) from a compound of formula (XIII). For example, the conversion of a compound of formula (IV) to a compound of formula (I) is via intermediate compounds (III), (VI), and (VII). In yet other embodiments, the conversion of a compound of formula (IV) to a compound of formula (I) is via intermediate compounds (III), (VII), and (VIII). In other embodiments, the conversion of a compound of formula (IV) to a compound of formula (I) is via intermediate compounds (III), (VI), (VII), and (VIII).

[0035] In other aspects, the process steps described in this disclosure may refer to converting a starting compound of formula (IV), (VI)-(XV), (XX), and (XXII)-(XIX) to a compound of formula (II). One skilled in the art will understand that these processes can also be used to prepare any intermediate between any starting compound and a compound of formula (II). For example, in some embodiments, the conversion of a compound of formula (IV) to a compound of formula (II) is via intermediate compounds (VII) and (XX). As such, one skilled in the art will understand that the process described for converting a compound of formula (IV) to a compound of formula (II) can be used to prepare any of intermediate compounds (VII) and (XX) from a compound of formula (IV). Similarly, in some embodiments, the conversion of a compound of formula (XIII) to a compound of formula (II) is via the preparation of intermediate compounds (IV), (VII), (IX)-(XII), and (XX). As such, one skilled in the art will appreciate that the methods described for converting a compound of formula (XIII) to a compound of formula (II) can be used to prepare any of intermediate compounds (IV), (VII), (IX)-(XII), and (XX) from a compound of formula (XIII). In other embodiments, the conversion of a compound of formula (IV) to a compound of formula (II) is via intermediate compounds (VI), (VII), and (XX). In yet other embodiments, the conversion of a compound of formula (IV) to a compound of formula (II) is via intermediate compounds (VII), (VIII), and (XX). In other embodiments, the conversion of a compound of formula (IV) to a compound of formula (I) is via intermediate compounds (VI), (VII), (VIII), and (XX).

[0036] Thus, the present application provides for the preparation of intermediate compounds (III), (IV), starting from any intermediate or starting material preceding the intermediate to be prepared. It is contemplated that compounds (VI) to (XV), (XX), and (XXII) to (XIX) can be prepared. For example, intermediate compound (III) can be prepared starting from any of compounds (IV), (VI) to (XV), and (XXII) to (XXIX). Similarly, compound (XX) can be prepared starting from any of compounds (IV), (VI) to (XV), and (XXII) to (XXIX).

[0037] In another aspect, the present invention provides a process for preparing formula (I), comprising: Compounds of formula (IV):

[0038] [ka]

[0039] or a salt thereof to a compound of formula (I):

[0040] In some embodiments, the process of converting a compound of formula (IV) to a compound of formula (I) comprises converting a compound of formula (VI):

[0041] [ka]

[0042] (which may also be referred to as the quinine salt of the compound of formula (IV)). In some embodiments, a compound of formula (VI) may be prepared directly from a compound of formula (IV) by contacting the compound of formula (IV) with quinine in a suitable solvent. In some embodiments, a compound of formula (VI) may be prepared by dissolving a compound of formula (IV) and quinine in a suitable solvent. In some embodiments, the suitable solvent is a polar solvent. One skilled in the art will recognize that there are many solvents suitable for converting a compound of formula (IV) to a compound of formula (VI). These include, but are not limited to, isopropanol, n-heptane, DCM, toluene, EtOAc, MTBE, acetonitrile, 2-MeTHF, MEK, and combinations thereof. In some embodiments, a compound of formula (IV) is converted to a compound of formula (VI) in the presence of DCM, isopropanol, n-heptane, and / or combinations thereof.

[0043] In some embodiments, the process for preparing a compound of formula (VI) comprises preparing a compound of formula (VIII):

[0044] [ka]

[0045] and contacting the compound of formula (VII) with quinine. The compound of formula (VII) may also be referred to as the (R)-AMB or (R)-α-methylbenzylamine salt of the compound of formula (IV). The compound of formula (VII) can be converted to the compound of formula (VI) using any method known to those skilled in the art.

[0046] In some embodiments, a compound of formula (VI) may be prepared from a compound of formula (VII) by contacting a compound of formula (VII) with quinine in a suitable solvent. In some embodiments, a compound of formula (VI) may be prepared by dissolving a compound of formula (VII) and quinine in a suitable solvent. In some embodiments, the suitable solvent is a polar solvent. One skilled in the art will recognize that there are many solvents suitable for converting a compound of formula (VII) to a compound of formula (VII). These include, but are not limited to, isopropanol, n-heptane, DCM, toluene, EtOAc, MTBE, acetonitrile, 2-MeTHF, MEK, and combinations thereof. In some embodiments, a compound of formula (VII) is converted to a compound of formula (VI) in the presence of DCM, isopropanol, n-heptane, and / or combinations thereof.

[0047] In some embodiments, a compound of formula (VI) may be prepared from a compound of formula (VII) by first converting the compound of formula (VII) to the free base, i.e., a compound of formula (IV).

[0048] [ka]

[0049] The compound of formula (VII) may be converted to the free base compound of formula (IV) by any method known to one of ordinary skill in the art. In some embodiments, the compound of formula (VII) is converted to the free base compound of formula (IV) by treating the compound of formula (VII) with an aqueous acid. In some embodiments, the aqueous acid is aqueous hydrochloric acid (HCl).

[0050] In some embodiments, the process of converting a compound of formula (IV) to a compound of formula (I) comprises converting a compound of formula (VII):

[0051] [ka]

[0052] (which may also be referred to as the (R)-AMB or (R)-α-methylbenzylamine salt of the compound of formula (IV)).

[0053] In some embodiments, a compound of formula (VII) may be prepared directly from a compound of formula (IV) by contacting a compound of formula (IV) with (R)-α-methylbenzylamine. In some embodiments, a compound of formula (VII) may be prepared directly from a compound of formula (IV) by contacting a compound of formula (IV) with (R)-α-methylbenzylamine in a suitable solvent. In some embodiments, a compound of formula (VII) may be prepared directly from a compound of formula (IV), by contacting a compound of formula (IV), and It may be prepared directly from the compound of formula (IV) by dissolving (R)-α-methylbenzylamine in a suitable solvent. Those skilled in the art will recognize that there are many solvents suitable for converting the compound of formula (IV) to the compound of formula (VII). In some embodiments, the suitable solvent is toluene.

[0054] In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) comprises converting a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) to a compound of Formula (V):

[0055] [ka]

[0056] to obtain a compound of formula (III):

[0057] [ka]

[0058] In some embodiments, a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) is contacted with a compound of Formula (V) in the presence of a coupling reagent and a base. In some embodiments, a compound of Formula (IV) is contacted with a compound of Formula (V) in the presence of a coupling reagent and a base. In some embodiments, a compound of Formula (VI) is contacted with a compound of Formula (V) in the presence of a coupling reagent and a base. In some embodiments, a compound of Formula (VII) is contacted with a compound of Formula (V) in the presence of a coupling reagent and a base. One of ordinary skill in the art will appreciate that many coupling reagents may be suitable for the process of coupling a compound of Formula (V) to a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII). For example, in some embodiments, the coupling reagent is 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), or propylphosphonic anhydride (T3P). In some embodiments, the coupling reagent is T3P. One skilled in the art will appreciate that many bases may be suitable for the process of coupling a compound of Formula (V) to a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is selected from trimethylamine, N-methylimidazole, pyridine, 4-methylmorpholine, Hunig's base, DABCO, NaOH, and the like. In other embodiments, the base may be any C1-C4 alkyl tertiary amine, such as triethylamine, ethyldimethylamine, ethyldipropylamine, and various other alkyl combinations thereof. In some embodiments, the base is triethylamine.

[0059] In some embodiments, a compound of Formula (VI) or (VII) is first converted to a free base, i.e., a compound of Formula (IV), and then contacted with a compound of Formula (V). A compound of Formula (VI) or (VII) may be converted to a free base compound of Formula (IV) by any method known to one of ordinary skill in the art. In some embodiments, a compound of Formula (VI) or (VII) is converted to a free base compound of Formula (IV) by treating the compound of Formula (VI) or (VII) with an aqueous acid. In some embodiments, the aqueous acid is aqueous hydrochloric acid (HCl).

[0060] In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) comprises converting a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) to a compound of Formula (VIII).

[0061] [ka]

[0062] In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) comprises converting a compound of Formula (IV) to a compound of Formula (VIII). In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) comprises converting a compound of Formula (VI) to a compound of Formula (VIII). In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) comprises converting a compound of Formula (VII) to a compound of Formula (VIII).

[0063] In some embodiments, a compound of Formula (VI) or (VII) is first converted to a free base, i.e., a compound of Formula (IV), and then converted to a compound of Formula (VIII). A compound of Formula (VI) or (VII) may be converted to a free base compound of Formula (IV) by any method known to one of ordinary skill in the art. In some embodiments, a compound of Formula (VI) or (VII) is converted to a free base compound of Formula (IV) by treating the compound of Formula (VI) or (VII) with an aqueous acid. In some embodiments, the aqueous acid is aqueous hydrochloric acid (HCl).

[0064] In some embodiments, converting a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) to a compound of Formula (VIII) comprises treating a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) with a chlorinating reagent. Any chlorinating agent suitable for chlorinating compound IV or a salt thereof (i.e., compound (VI) or (VII)) may be used. In some embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), or diphenylphosphinic chloride (DPPCl). In some embodiments, the chlorinating agent is oxalyl chloride. In some embodiments, the compound of Formula (VIII) is subjected to the next reaction in the process for preparing a compound of Formula (I) without further purification or isolation. In some embodiments, treating a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII) with a chlorinating agent is carried out in the presence of a non-nucleophilic base. Without being bound by theory, the non-nucleophilic base may be included to capture the by-product HCl generated during the chlorination reaction. Therefore, any suitable non-nucleophilic base known to those skilled in the art may be used. Suitable non-nucleophilic bases are typically tertiary amines or aromatic amines in which the nitrogen of the amine base does not bear an H atom. The non-nucleophilic base may also be a bulky base that is non-nucleophilic due to steric hindrance. Examples of suitable bases include Hunig's base, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or 1,5-diazabicyclo(4.3.0)non-5-ene, or a mixture thereof. In some embodiments, the reaction between compound IV and the chlorinating agent is carried out at a temperature of about 90° C. or less.

[0065] In some embodiments, the compound of formula (IV) is The conversion to Formula (I) comprises contacting a compound of Formula (VIII) with a compound of Formula (V) to obtain a compound of Formula (III). In some embodiments, contacting a compound of Formula (VIII) with a compound of Formula (V) is carried out in the presence of a base. One skilled in the art will appreciate that many bases are compatible with the reaction between a compound of Formula (VIII) and a compound of Formula (V). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is triethylamine.

[0066] In some embodiments, the process of converting a compound of Formula (IV) to a compound of Formula (I) further comprises converting a compound of Formula (III) to a compound of Formula (I). In some embodiments, converting a compound of Formula (III) to a compound of Formula (I) comprises deprotecting the compound of Formula (III) to obtain a compound of Formula (I). In some embodiments, converting a compound of Formula (III) to a compound of Formula (I) comprises treating the compound of Formula (III) with an acid and water, for example, an aqueous acid. One skilled in the art will appreciate that many acids may be compatible with the process of deprotecting a compound of Formula (III) to obtain a compound of Formula (I). In some embodiments, the acid is aqueous trifluoroacetic acid.

[0067] In some embodiments, the process for preparing a compound of Formula (I) further comprises recrystallizing the compound of Formula (I) from a suitable solvent to obtain a crystalline form of the compound of Formula (I). In some embodiments, the crystalline form is Form A of the compound of Formula (I), as described more fully below. In some embodiments, suitable solvents include ethyl acetate and n-heptane. In some embodiments, Form A of Compound (I) can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an anti-solvent. In other embodiments, Form A can be obtained by the procedure described in Example 7.

[0068] Intermediate compound (V) may be prepared, for example, by the process shown in Scheme D below.

[0069] Scheme D. Process for preparing compounds of formula (V).

[0070] [ka]

[0071] In the formula, R 2 is C1-C6 alkyl.

[0072] In some embodiments, the process for preparing a compound of formula (I) comprises preparing a compound of formula (XVI):

[0073] [ka]

[0074] to a compound of formula (V), wherein R 2 is C1-C6 alkyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is tert-butyl. In some embodiments, the compound of formula (XVI) is a compound of formula (XVI-A):

[0075] [ka]

[0076] In other embodiments, the compound of formula (XVI) is a compound of formula (XVI-B):

[0077] [ka]

[0078] In some embodiments, converting a compound of Formula (XVI) to a compound of Formula (V) comprises treating a compound of Formula (XVI) with water at reflux. In other embodiments, converting a compound of Formula (XVI) to a compound of Formula (V) comprises treating a compound of Formula (XVI) with a base and water. One skilled in the art will appreciate that many bases are compatible with the process of converting a compound of Formula (XVI) to a compound of Formula (V). In some embodiments, the base is NaOH.

[0079] In some embodiments, the compound of Formula (V) prepared from the compound of Formula (XVI) is recrystallized from a suitable solvent prior to use in the process for preparing the compound of Formula (I). In some embodiments, the suitable solvent comprises MTBE and n-heptane.

[0080] In some embodiments, the process for preparing a compound of formula (V) comprises preparing a compound of formula (XVII):

[0081] [ka]

[0082] to a compound of formula (XVI).

[0083] In some embodiments, converting a compound of Formula (XVII) to a compound of Formula (XVI) comprises treating a compound of Formula (XVII) with NH2-C(O)-(C1-C6 alkyl), a base, a palladium catalyst, and a ligand. In some embodiments, the base is Cs2CO3 or K3PO4. In some embodiments, the base is Cs2CO3. In other embodiments, the base is K3PO4. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, the ligand is XPhos or BrettPhos. In some embodiments, the ligand is XPhos. In other embodiments, the ligand is BrettPhos.

[0084] In some embodiments, the process for preparing a compound of formula (V) comprises preparing a compound of formula (XVIII):

[0085] [ka]

[0086] to a compound of formula (XVII).

[0087] In some embodiments, the process for converting a compound of Formula (XVIII) to a compound of Formula (XVII) comprises treating a compound of Formula (XVIII) with 2,2-dimethoxypropane in the presence of an acid. One skilled in the art will appreciate that many acids are suitable for the process for converting a compound of Formula (XVIII) to a compound of Formula (XVII). In some embodiments, the acid is methanesulfonic acid.

[0088] In some embodiments, the process for preparing a compound of formula (V) comprises reacting a compound of formula (XIX):

[0089] [ka]

[0090] to a compound of formula (XBIII).

[0091] In some embodiments, converting a compound of Formula (XIX) to a compound of Formula (XVIII) comprises contacting a compound of Formula (XIX) with a reducing agent. In some embodiments, the reduction of a compound of Formula (XIX) to a compound of Formula (XVIII) is carried out using an enzyme. In some embodiments, the compound of Formula (XIX) is contacted with a reducing agent in the presence of the enzyme. In some embodiments, the enzyme comprises a ketone reductase. In some embodiments, the enzyme comprises a glucose dehydrogenase. In some embodiments, the enzyme comprises a ketone reductase 117297 and a glucose dehydrogenase 117446.

[0092] In some embodiments, the process for preparing a compound of Formula (V) further comprises contacting 2-bromo-5-chloropyridine with 2-(tert-butoxy)-N-methoxy-N-methylacetamide to obtain a compound of Formula (XIX). In some embodiments, 2-bromo-5-chloropyridine is treated with The compound is contacted with 2-(tert-butoxy)-N-methoxy-N-methylacetamide in the presence of a Grignard reagent, in some embodiments, the Grignard reagent is isopropylmagnesium chloride or isopropylmagnesium chloride lithium chloride complex.

[0093] In a second aspect, the present invention provides a compound of formula (II):

[0094] [ka]

[0095] 1. A process for preparing a compound of formula (VII):

[0096] [ka]

[0097] to a compound of formula (II).

[0098] In some embodiments, converting a compound of Formula (VII) to a compound of Formula (II) comprises converting a compound of Formula (VII) to a compound of Formula (XXI):

[0099] [ka]

[0100] to obtain a compound of formula (XX):

[0101] [ka]

[0102] In some embodiments, contacting a compound of Formula (VII) with a compound of Formula (XXI) is carried out in the presence of a coupling reagent and a base. Those skilled in the art will appreciate that many coupling reagents may be suitable for coupling a compound of Formula (V) to a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII). For example, in some embodiments, the coupling reagent is 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), diphenylphosphinic chloride (DPPCL), isobutyl chloroformate (IBCF), or propylphosphonic anhydride (T3P). In some embodiments, the coupling agent is T3P. Those skilled in the art will appreciate that many bases may be suitable for coupling a compound of Formula (V) to a compound of Formula (IV), a compound of Formula (VI), or a compound of Formula (VII). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is selected from trimethylamine, N-methylimidazole, pyridine, 4-methylmorpholine, Hunig's base, DABCO, NaOH, and the like. In other embodiments, the base may be any C1-C4 alkyl tertiary amine, such as triethylamine, ethyldimethylamine, ethyldipropylamine, and various other alkyl combinations thereof. In some embodiments, the base is triethylamine, 4-methylmorpholine (NMM), or 1-methylimidazole (NMI). In some embodiments, the base is triethylamine.

[0103] In some embodiments, the compound of formula (VII) is first converted to a free base, i.e., a compound of formula (IV), and then contacted with a compound of formula (XXI). The compound of formula (VII) can be converted to the free base compound of formula (IV) by any method known to those skilled in the art. In some embodiments, the compound of formula (VII) is converted to the free base compound of formula (IV) by treating the compound of formula (VII) with an aqueous acid. In some embodiments, the aqueous acid is aqueous hydrochloric acid (HCl).

[0104] In some embodiments, converting the compound of Formula (VII) to a compound of Formula (II) comprises converting the compound of Formula (VII) to a compound of Formula (VIII):

[0105] [ka]

[0106] In some embodiments, the compound of formula (VII) is first converted to a free base, i.e., a compound of formula (IV), and then converted to a compound of formula (VIII). The compound of formula (VII) can be converted to the free base compound of formula (IV) by any method known to those skilled in the art. In some embodiments, the compound of formula (VII) is converted to the free base compound of formula (IV) by treating the compound of formula (VII) with an aqueous acid. In some embodiments, the aqueous acid is aqueous hydrochloric acid (HCl).

[0107] In some embodiments, converting a compound of Formula (VII) to a compound of Formula (VIII) comprises treating a free base compound of Formula (IV) or a compound of Formula (VII) with a chlorinating reagent. Any chlorinating agent suitable for chlorinating compound IV or a salt thereof (i.e., compound (VII)) may be used. In some embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), or diphenylphosphinic chloride (DPPCl). In some embodiments, the chlorinating agent is oxalyl chloride. In some embodiments, the compound of Formula (VIII) is subjected to the next reaction in the process for preparing a compound of Formula (I) without further purification or isolation.

[0108] In some embodiments, treating the free base compound of Formula (IV) or the compound of Formula (VII) with a chlorinating agent is carried out in the presence of a non-nucleophilic base. Without being bound by theory, the non-nucleophilic base may be included to capture the by-product HCl generated during the chlorination reaction. Therefore, any suitable non-nucleophilic base known to those skilled in the art may be used. Suitable non-nucleophilic bases are typically tertiary amines or aromatic amines in which the nitrogen of the amine base does not carry an H atom. The non-nucleophilic base may also be a bulky base that is non-nucleophilic due to steric hindrance. Examples of suitable bases include Hunig's base, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, butylamine, or 1,5-diazabicyclo(4.3.0)non-5-ene, or a mixture thereof. In some embodiments, the reaction between the free base compound of Formula (IV) or the compound of Formula (VII) and the chlorinating agent is carried out at a temperature of about 90° C. or less.

[0109] In some embodiments, converting a compound of Formula (VII) to a compound of Formula (II) comprises contacting a compound of Formula (VIII) with a compound of Formula (XXI) to obtain a compound of Formula (XX). In some embodiments, contacting a compound of Formula (VIII) with a compound of Formula (XXI) is carried out in the presence of a base. One skilled in the art will appreciate that many bases are compatible with the reaction between a compound of Formula (VIII) and a compound of Formula (XXI). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is triethylamine. One skilled in the art will appreciate that many solvents are suitable for the reaction between a compound of Formula (VIII) and a compound of Formula (XXI). In some embodiments, the solvent is toluene. In some embodiments, the compound of Formula (XX) is obtained by separating the reaction mixture between an organic layer comprising ethyl acetate and toluene and an aqueous layer.

[0110] In some embodiments, the compound of Formula (XX) (prepared from either the free base compound of Formula (IV), the compound of Formula (VII), or the compound of Formula (VIII)) may be purified by recrystallizing it from a solvent containing, for example, methanol or water, or a mixture thereof. Other suitable combinations of two solvents include ethanol / water, toluene / heptane, IPA / water, etc. In any of these combinations, the compound of Formula (XX) is dissolved in one solvent at or near the boiling temperature, and then the second solvent is added until the solution becomes cloudy. The cloudy suspension is cooled to room temperature (or cooled in an ice bath), and then the solid is filtered.

[0111] In some embodiments, converting a compound of Formula (VII) to a compound of Formula (II) comprises converting a compound of Formula (XX) The method further comprises converting a compound of Formula (XX) to a compound of Formula (II). In some embodiments, converting a compound of Formula (XX) to a compound of Formula (II) comprises treating the compound of Formula (XX) with ammonia to obtain a compound of Formula (II). In some embodiments, the compound of Formula (XX) may be treated with ammonia in the presence of a suitable solvent. In some embodiments, the suitable solvent is methanol, ethanol, IPA, MeCN, THF, 2-MeTHF, water, or a mixture thereof. In some embodiments, treating the compound of Formula (XX) with ammonia may be carried out in the presence of a weak non-nucleophilic base. In some embodiments, the base is selected from Mg(OMe)2, CaCl2, DIPEA, and K2CO3. In some embodiments, the ammonia is in the form of a solution of ammonia in a solvent, ammonia in gas form by bubbling ammonia gas into the reaction mixture, or in the form of ammonium hydroxide or an ammonium salt where ammonia is generated in situ. In some embodiments, the ammonia is in the form of a solution of ammonia in methanol. In some embodiments, the ammonia is in the form of a solution of ammonia in methanol and tetrahydrofuran. In some embodiments, the in situ generation of ammonia comprises reacting ammonium hydroxide or an ammonium salt with an acid. In some embodiments, treating the compound of Formula (XX) with ammonia is carried out in a solvent mixture comprising methanol and tetrahydrofuran.

[0112] In some embodiments, the process for preparing a compound of Formula (II) further comprises recrystallizing the compound of Formula (II) from a suitable solvent. In some embodiments, the suitable solvent comprises MeOH, THF, water, or a combination thereof. In other embodiments, the suitable solvent comprises acetone and water.

[0113] In some embodiments, compounds of formula (VII) useful for preparing compounds of formula (II) are obtained from compounds of formula (IV), as described above for the process for preparing compounds of formula (I).

[0114] While one skilled in the art would be able to devise methods to produce the compound of formula (IV) or a salt thereof (i.e., a compound of formula (VI) or (VII)) used to prepare a compound of formula (I) or formula (II), the inventors of the present application contemplate using the following process to prepare a compound of formula III.

[0115] In some embodiments, the process for preparing a compound of formula (I) or (II) comprises preparing a compound of formula (IX):

[0116] [ka]

[0117] to a compound of formula (IV).

[0118] In some embodiments, converting a compound of Formula (IX) to a compound of Formula (IV) involves hydrolyzing the CN group of the compound of Formula (IX). Any base or acid suitable for hydrolyzing the CN group without affecting other functional groups in the compound of Formula (VII) may be used. In some embodiments, a strong base (e.g., NaOH, KOH, etc.) or a strong acid (e.g., HCl, sulfuric acid, etc.) may be used. In other embodiments, the CN group in the compound of Formula (IX) is enzymatically hydrolyzed using a nitrilase. The CN hydrolysis of the compound of Formula (IX) may be carried out in a solvent or solvent mixture. For example, ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof may be used. The hydrolysis reaction may be carried out at about 25-75°C, about 30-70°C, about 35-65°C, about 40-60°C, about 45-60°C, about 50-60°C, or about 55°C. As used in this paragraph, the term "approximately" before a temperature range applies to both ends of the range. This term also refers to ±2.5°C. In some embodiments, converting a compound of Formula (IX) to a compound of Formula (IV) comprises treating a compound of Formula (IX) with a base. One of ordinary skill in the art will appreciate that many bases are suitable for the process of converting a compound of Formula (IX) to a compound of Formula (IV). In some embodiments, the hydroxide base is potassium hydroxide.

[0119] In some embodiments, the process for preparing a compound of formula (I) or (II) comprises preparing a compound of formula (X):

[0120] [ka]

[0121] into a compound of formula (IX), During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 It is selected from aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0122] In some embodiments, the compound of formula (X) is a compound of formula (X'):

[0123] [ka]

[0124] In some embodiments, the compound of formula (X) is a compound of formula (X″):

[0125] [ka]

[0126] In some embodiments, R 1 is -C(O)-Z. In some embodiments, Z is methyl or 4-nitrophenyl. In some embodiments, Z is 4-nitrophenyl.

[0127] In some embodiments, the compound of formula (X) is

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] is selected from.

[0135] In some embodiments, the compound of formula (X) is a compound of formula (XA):

[0136] [ka]

[0137] In some embodiments, the compound of formula (X) is a compound of formula (XB):

[0138] [ka]

[0139] In some embodiments, the compound of formula (X) is a compound of formula (X'-A):

[0140] [ka]

[0141] In some embodiments, the compound of formula (X) is a compound of formula (X'-B):

[0142] [ka]

[0143] In some embodiments, converting a compound of Formula (X) to a compound of Formula (IX) comprises treating the compound of Formula (X) with a cyanate reagent. In some embodiments, the cyanating agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, and HCN. In some embodiments, the cyanate reagent is trimethylsilyl cyanide. In some embodiments, the compound of Formula (X) is treated with 1.35 to 1.65 equivalents of trimethylsilyl cyanide. In some embodiments, treating the compound of Formula (X) with a cyanate reagent is carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is boron trifluoride ethyl etherate (BFOEt), TiCl, InCl, AgSbF, iodine, ZnBr, Al(OiPr), MgCl, Mn(acac), MnCl, TMSOTf, SnCl, or the like. In some embodiments, the Lewis acid is BFOEt. In some embodiments, 0.9 to 1.1 equivalents of BFOEt are present based on the compound of Formula (X). The cyanation reaction may be carried out in an organic solvent, such as toluene, dichloromethane, 2-methyl-THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, CPME, MTBE, DMAc, t-BuOAc, or the like. In some embodiments, the cyanation reaction is carried out at a temperature of −28 to 0° C. or −28 to −12° C. In some embodiments, the cyanation reaction is quenched with acetone (e.g., about 1.0 equivalent of acetone). In some embodiments, the quenching is carried out at a temperature of −28 to 0° C. or −28 to −12° C. In some embodiments, the compound of Formula (IX) is obtained by partitioning the reaction mixture between an organic layer containing ethanol and an aqueous layer containing aqueous potassium hydroxide.

[0144] Other non-limiting examples of compounds of formula (X) include:

[0145] [ka]

[0146] In some embodiments, the process for preparing a compound of formula (I) or (II) comprises preparing a compound of formula (XI):

[0147] [ka]

[0148] to a compound of formula (X).

[0149] In some embodiments, the compound of formula (XI) has the formula (XI').

[0150] [ka]

[0151] In some embodiments, the compound of formula (XI) has the formula (XI″):

[0152] [ka]

[0153] In some embodiments, converting a compound of Formula (XI) to a compound of Formula (X) comprises contacting a compound of Formula (XI) with an acid anhydride or an acid halide to obtain a compound of Formula (X). In some embodiments, contacting a compound of Formula (XI) with an acid anhydride or an acid halide is carried out in the presence of a base and a catalyst. One of ordinary skill in the art will recognize that there are many bases that would be compatible with the process of converting a compound of Formula (XI) to a compound of Formula (X). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is selected from TEA, pyridine, Hunig's base, K2CO3, Na2CO3, NaHCO3, 2,6-lutidine, NMM, and DABCO. In some embodiments, the base is triethylamine and the catalyst is 4-dimethylaminopyridine (DMAP). In some embodiments, the acid anhydride is acetic anhydride. In some embodiments, the acid halide is 4-nitrobenzoyl chloride. In some embodiments, the conversion of a compound of Formula (XI) to a compound of Formula (X) is carried out in a polar solvent, hi some embodiments, the polar solvent is selected from toluene, cyclopentyl methyl ether (CPME), dichloromethane, dichloroethane, pyridine, chloroform, acetonitrile, THF, 2-MeTHF, EtOAc, IRC, or a combination thereof.

[0154] In some embodiments, the process for preparing a compound of Formula (I) or (II) further comprises recrystallizing the compound of Formula (X) from a suitable solvent. In some embodiments, the suitable solvent comprises acetone, water, and combinations thereof.

[0155] In some embodiments, the process for preparing a compound of formula (I) or (II) comprises preparing a compound of formula (XII):

[0156] [ka]

[0157] to a compound of formula (XI).

[0158] In some embodiments, converting a compound of Formula (XII) to a compound of Formula (XI) comprises treating the compound of Formula (XII) with a reducing reagent. In some embodiments, the reducing reagent is selected from the group consisting of diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, titanocene containing polymethylhydrosiloxane, and phenylsilane. In some embodiments, the reducing reagent is diisobutylaluminum hydride. The reduction reaction may be carried out in an organic solvent or solvent mixture. Suitable solvents include toluene, dichloromethane, 2-methyl-THF, THF, TFT, MTBE, CPME, heptane, or a mixture thereof. The reaction may be carried out below room temperature, for example, at about −78° C. to 0° C., about −60° C. to 0° C., about −50° C. to −10° C., about −40° C. to −10° C., about −30° C. to −10° C., about −30° C. to −15° C., about −25° C. to −15° C., or about −20° C. The reduction reaction may be carried out in the presence of CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl2, DMAP, 2,6-lutidine, LiI, or pyridine.

[0159] In some embodiments, the process for preparing a compound of Formula (I) or (II) comprises preparing a compound of Formula (XIII):

[0160] [ka]

[0161] to a compound of formula (XII).

[0162] In some embodiments, converting a compound of Formula (XIII) to a compound of Formula (XII) comprises hydrogenating the compound of Formula (XIII). In some embodiments, the hydrogenation is carried out in the presence of a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is selected from Pd / C, Pd / Al2O3, Pt / C, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH)2, homogeneous chiral Ru, and Rh. In some embodiments, the hydrogenation is carried out in the presence of a suitable hydrogen source. In some embodiments, the hydrogen source is selected from H2 gas, NiCl2 / NaBH4 in methanol, and Et3SiH. In some embodiments, the hydrogenation is carried out in the presence of H2 gas using Pd / C (e.g., Johnson Matthey catalog number A503032-5 or A503014-5) as a catalyst. The hydrogenation reaction may be carried out in an organic solvent at about 20-40 bar. In some embodiments, the hydrogenation reaction may be carried out in an organic solvent at about 5-40 bar. In some embodiments, the hydrogenation reaction may be carried out at a temperature of 10-50°C. At higher temperatures, lower pressures may be used, and vice versa. For example, about 5 bar may be suitable at about 40°C. Conversely, about 15-20 bar may be suitable at about 30°C. One skilled in the art can tailor the pressure, temperature, and reaction time to achieve the desired results. The hydrogenation reaction may be carried out in an organic solvent or solvent mixture. In one embodiment, the organic solvent is IPA, EtOAc, MeOH, nBuOH, THF, MTBE, CPME, IPAc, nBuAc, toluene, ethanol, or a mixture thereof. In some embodiments, the hydrogenation is carried out in a solvent mixture containing 2-propanol, tetrahydrofuran, and catalytic trifluoroacetic acid. The asymmetric hydrogenation reaction may be carried out in the presence of citric acid, benzoic acid, TFA, AcOH, H2SO4, H3PO4, MSA, Cs2CO3, CuCl, MgF2, LiBr, CsF, ZnI, LiOTf, imidazole, KF, Bu4NOAc, and / or NHBF4.

[0163] In some embodiments, the process for preparing a compound of formula (I) or (II) comprises preparing a compound of formula (XIV):

[0164] [ka]

[0165] is coupled with a compound of formula X(XV):

[0166] [ka]

[0167] Further comprising obtaining a compound of formula (XIII).

[0168] In some embodiments, contacting the compound of Formula (XIV) with the compound of Formula (XV) is carried out in the presence of a coupling agent or chlorinating agent. In some embodiments, the coupling agent is selected from CDI and T3P. The coupling reaction between the compounds of Formula (XIV) and (XV) may be carried out in the presence of a weak base or a non-nucleophilic base. Examples of weak bases or non-nucleophilic bases suitable for the coupling reaction between the compounds of Formula (XIV) and (XV) include imidazole, DIPEA, TEA, NMM, TBD, Na2CO3, K3PO4, DBU, DABCO, and MTBD. In some embodiments, the weak base or non-nucleophilic base is imidazole, DIPEA, TEA, NMM, or TBD. In some embodiments, the base is K2CO3. The coupling reaction between the compounds of Formula (XIV) and (XV) may be carried out in a polar aprotic solvent. Examples of polar aprotic solvents that may be suitable for the claims of the present application include solvents including MTBE, toluene, EtOAc, MeCN, THF, DMC, MeOAc, NMP, DMF, DMSO, THF, 2-MeTHF, and combinations thereof. The coupling reaction between the compound of formula (XIV) and the compound of formula (XV) may be carried out at about 20°C to about 60°C, about 25°C to about 55°C, about 30°C to about 50°C, about 30°C to about 45°C, about 30°C to about 40°C, or about 35°C. As used in this paragraph, the term "approximately" means ±2.5°C. In some embodiments, the chlorinating agent converts the compound of formula (XIV) to an acid chloride that is not isolated prior to reaction with the compound of formula (XV). Examples of chlorinating agents suitable for coupling the compound of formula (XIV) with the compound of formula (XV) include oxalyl chloride, thionyl chloride, phosgene, and the like. In some embodiments, the chlorinating agent is selected from oxalyl chloride and thionyl chloride.

[0169] Alternatively, a compound of formula (IV) can be reacted with a compound of formula (XXII):

[0170] [ka]

[0171] to a compound of formula (IV).

[0172] In some embodiments, converting the compound of Formula (XXII) to the compound of Formula (IV) comprises treating the compound of Formula (XXII) with an oxidizing agent. In some embodiments, the oxidizing agent comprises TEMPO and NaOCl.

[0173] In some embodiments, the compound of formula (XXII) is a compound of formula (XXIII):

[0174] [ka]

[0175] can be obtained by converting the compound of formula (XXII)

[0176] In some embodiments, converting the compound of Formula (XXIII) to the compound of Formula (XXII) comprises hydrogenating the compound of Formula (XXIII). In some embodiments, hydrogenating the compound of Formula (XXIII) is performed in the presence of hydrogen and a palladium on carbon catalyst.

[0177] In some embodiments, the compound of formula (XXIII) is a compound of formula (XXIV):

[0178] [ka]

[0179] can be obtained by converting the compound of formula (XXIII)

[0180] In some embodiments, converting the compound of Formula (XXIV) to the compound of Formula (XXIII) comprises treating the compound of Formula (XXIV) with mesyl chloride in the presence of a base. In some embodiments, the base is triethylamine.

[0181] In some embodiments, the compound of formula (XXIV) is a compound of formula (XXV):

[0182] [ka]

[0183] to a compound of formula (XXIV).

[0184] In some embodiments, converting the compound of Formula (XXV) to the compound of Formula (XXIV) comprises treating the compound of Formula (XXV) with methylmagnesium chloride.

[0185] In some embodiments, the compound of formula (XXV) is a compound of formula (XXVI):

[0186] [ka]

[0187] to a compound of formula (XXV).

[0188] In some embodiments, converting a compound of Formula (XXVI) to a compound of Formula (XXV) comprises reacting a compound of Formula (XXVI) with This involves treatment with tetra-N-butylammonium fluoride (TBAF).

[0189] In some embodiments, the compound of formula (XXVI) is a compound of formula (XXVII):

[0190] [ka]

[0191] to a compound of formula (XXVI).

[0192] In some embodiments, converting the compound of Formula (XXVII) to the compound of Formula (XXVI) comprises treating the compound of Formula (XXVII) with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride.

[0193] In some embodiments, the compound of formula (XXVII) is a compound of formula (XXVIII):

[0194] [ka]

[0195] to a compound of formula I.

[0196] In some embodiments, converting a compound of Formula (XXVIII) to a compound of Formula (XXVII) comprises treating a compound of Formula (XXVIII) with benzyl-2,2,2-trichloroethane-imidate in the presence of an acid. In some embodiments, the acid is triflic acid.

[0197] In some embodiments, the compound of formula (XXVIII) is a compound of formula (XXIX):

[0198] [ka]

[0199] to a compound of formula (XVIII).

[0200] In some embodiments, converting the compound of Formula (XXIX) to the compound of Formula (XXVIII) comprises hydrogenating the compound of Formula (XXIX). In some embodiments, the hydrogenation of the compound of Formula (XXIX) is carried out in the presence of NiCl / NaBH in methanol.

[0201] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XIII) to a compound of formula (I) using a process described herein for converting a compound of formula (XIII) to a compound of formula (I).

[0202] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XII) to a compound of formula (I) using a method described herein for converting a compound of formula (XII) to a compound of formula (I).

[0203] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XI) to a compound of formula (I) using a method described herein for converting a compound of formula (XI) to a compound of formula (I).

[0204] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (X) to a compound of formula (I) using a method described herein for converting a compound of formula (X) to a compound of formula (I).

[0205] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (IX) to a compound of formula (I) using a method described herein for converting a compound of formula (IX) to a compound of formula (I).

[0206] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (VIII) to a compound of formula (I) using a method described herein for converting a compound of formula (VIII) to a compound of formula (I).

[0207] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (VII) to a compound of formula (I) using a method described herein for converting a compound of formula (VII) to a compound of formula (I).

[0208] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (VI) to a compound of formula (I) using a method described herein for converting a compound of formula (VI) to a compound of formula (I).

[0209] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (III) to a compound of formula (I) using a method described herein for converting a compound of formula (III) to a compound of formula (I).

[0210] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXII) to a compound of formula (I) using a method described herein for converting a compound of formula (XXII) to a compound of formula (I).

[0211] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXIII) to a compound of formula (I) using a method described herein for converting a compound of formula (XXIII) to a compound of formula (I).

[0212] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXIV) to a compound of formula (I) using a method described herein for converting a compound of formula (XXIV) to a compound of formula (I).

[0213] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXV) to a compound of formula (I) using a method described herein for converting a compound of formula (XXV) to a compound of formula (I).

[0214] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXVI) to a compound of formula (I) using a method described herein for converting a compound of formula (XXVI) to a compound of formula (I).

[0215] In some embodiments, the present invention relates to a process for preparing a compound of formula (XXVII), or a salt thereof, comprising converting a compound of formula (I) to a compound of formula (XXVII) using a method described herein for converting a compound of formula () to a compound of formula (I).

[0216] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXVIII) to a compound of formula (I) using a method described herein for converting a compound of formula (XXVIII) to a compound of formula (I).

[0217] In some embodiments, the present invention relates to a process for preparing a compound of formula (I), or a salt thereof, comprising converting a compound of formula (XXIX) to a compound of formula (I) using a method described herein for converting a compound of formula (XXIX) to a compound of formula (I).

[0218] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XIII) to a compound of formula (II) using a method described herein for converting a compound of formula (XIII) to a compound of formula (II).

[0219] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XII) to a compound of formula (II) using a method described herein for converting a compound of formula (XII) to a compound of formula (II).

[0220] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XI) to a compound of formula (II) using a method described herein for converting a compound of formula (XI) to a compound of formula (II).

[0221] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (X) to a compound of formula (II) using a method described herein for converting a compound of formula (X) to a compound of formula (II).

[0222] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (IX) to a compound of formula (II) using a method described herein for converting a compound of formula (IX) to a compound of formula (II).

[0223] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (VIII) to a compound of formula (II) using a method described herein for converting a compound of formula (VIII) to a compound of formula (II).

[0224] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (VI) to a compound of formula (II) using a method described herein for converting a compound of formula (VI) to a compound of formula (II).

[0225] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (IV) to a compound of formula (II) using a method described herein for converting a compound of formula (IV) to a compound of formula (II).

[0226] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XX) to a compound of formula (II) using a method described herein for converting a compound of formula (XX) to a compound of formula (II).

[0227] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXII) to a compound of formula (II) using a method described herein for converting a compound of formula (XXII) to a compound of formula (II).

[0228] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXIII) to a compound of formula (II) using a method described herein for converting a compound of formula (XXIII) to a compound of formula (II).

[0229] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXIV) to a compound of formula (II) using a method described herein for converting a compound of formula (XXIV) to a compound of formula (II).

[0230] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXV) to a compound of formula (II) using a method described herein for converting a compound of formula (XXV) to a compound of formula (II).

[0231] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXVI) to a compound of formula (II) using a method described herein for converting a compound of formula (XXVI) to a compound of formula (II).

[0232] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXVII) to a compound of formula (II) using a method described herein for converting a compound of formula (XXVII) to a compound of formula (II).

[0233] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXVIII) to a compound of formula (II) using a method described herein for converting a compound of formula (XXVIII) to a compound of formula (II).

[0234] In some embodiments, the present invention relates to a process for preparing a compound of formula (II), or a salt thereof, comprising converting a compound of formula (XXIX) to a compound of formula (II) using a method described herein for converting a compound of formula (XXIX) to a compound of formula (II).

[0235] In some embodiments, the present invention is directed to methods for preparing intermediate compounds of formulas (III), (IV), and (VI)-(XIII) using the methods described herein.

[0236] In some embodiments, the present invention is directed to a method for preparing a compound of formula (III) or a salt thereof, comprising converting any of compounds of formulas (IV) and (VI)-(XIII) to a compound of formula (III) using a method described herein.

[0237] In some embodiments, the present invention is directed to a method for preparing a compound of formula (VIII) or a salt thereof, comprising converting any of the compounds of formulas (IV) and (VI), (VII), and (IX)-(XIII) to a compound of formula (VIII) using a method disclosed in the present disclosure.

[0238] In some embodiments, the present invention is directed to a method for preparing a compound of formula (VI) or a salt thereof, comprising converting any of the compounds of formulas (IV) and (VII), and (IX)-(XIII) to a compound of formula (VI) using a method disclosed in the present disclosure.

[0239] In some embodiments, the present invention is directed to a method for preparing a compound of formula (VII) or a salt thereof, comprising converting any of compounds of formulas (IV) and (IX)-(XIII) to a compound of formula (VII) using a method described herein.

[0240] In some embodiments, the present invention is directed to a method for preparing a compound of formula (IV) or a salt thereof, comprising converting any of compounds of formulas (IX)-(XIII) to a compound of formula (IV) using a method disclosed in the present disclosure.

[0241] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (IX) or a salt thereof, comprising converting any of compounds (X) to (XIII) into a compound of formula (IX).

[0242] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention is directed to a process for preparing a compound of formula (X) or a salt thereof, comprising converting any of compounds of formula (XI)-(XIII) to a compound of formula (X).

[0243] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XI) or a salt thereof, comprising converting any of compounds (XII) to (XIII) into a compound of formula (XI).

[0244] In some embodiments, the present invention is directed to a method for preparing a compound of formula (XII) or a salt thereof, comprising converting a compound of formula (XIII) to a compound of formula (XII) using a method described herein.

[0245] In some embodiments, the present invention is directed to methods for preparing intermediate compounds of formula (XX) using the methods described herein.

[0246] In some embodiments, the present invention is directed to a method for preparing a compound of formula (XX) or a salt thereof, comprising converting any of compounds of formulas (IV) and (VI)-(XIII) to a compound of formula (XX) using a method described herein.

[0247] In some embodiments, the present invention is directed to methods for preparing intermediate compounds of formulas (III), (IV), (VI)-(VIII), and (XXII)-(XXIX) using the methods described herein.

[0248] In some embodiments, the present invention provides a method for preparing a compound of formula (III), or a salt thereof, comprising: The present disclosure is directed to a method for preparing any of the compounds of formula (IV), (VI)-(VIII), and (XXII)-(XXIX), comprising converting the compound of formula (IV), (VI)-(VIII), and (XXII)-(XXIX) to a compound of formula (III) using the methods disclosed in the present disclosure.

[0249] In some embodiments, the present invention provides a method for preparing a compound of formula (VIII), or a salt thereof, comprising: The present disclosure is directed to a method for preparing a compound of formula (IV), (VI)-(VII), and (XXII)-(XXIX), comprising converting the compound of formula (IV), (VI)-(VII), and (XXII)-(XXIX) to a compound of formula (VIII) using the methods disclosed herein. In some embodiments, the present invention provides a method for preparing a compound of formula (VI), or a salt thereof, comprising: The present disclosure is directed to a method for preparing any of the compounds of formula (VII), (IV), and (XXII)-(XXIX), comprising converting the compound of formula (VI) using the methods disclosed in the present disclosure.

[0250] In some embodiments, the present invention provides a method for preparing a compound of formula (VII), or a salt thereof, comprising: The present invention is directed to a method for preparing a compound of formula (VII) comprising converting any of compounds (IV) and (XXII)-(XXIX) to a compound of formula (VII) using the methods disclosed herein.

[0251] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (IV) or a salt thereof, comprising converting any of compounds (XXII) to (XXIX) into a compound of formula (IV).

[0252] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XXII) or a salt thereof, comprising converting any of compounds (XXIII) to (XXIX) into a compound of formula (XXII).

[0253] In some embodiments, the present invention provides a method for preparing a compound of formula (XXIII), or a salt thereof, comprising: The present disclosure is directed to a method for preparing a compound of formula (XXIII), comprising converting any of compounds (XXIV)-(XXIX) to a compound of formula (XXIII) using the methods disclosed in the present disclosure.

[0254] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XXIV) or a salt thereof, comprising converting any of compounds (XXV) to (XXIX) into a compound of formula (XXIV).

[0255] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XXV) or a salt thereof, comprising converting any of compounds (XXVI) to (XXIX) into a compound of formula (XXV).

[0256] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XXVI) or a salt thereof, comprising converting any of compounds (XXVII) to (XXIX) into a compound of formula (XXVI).

[0257] In some embodiments, the present invention provides a compound of formula (I) using the methods disclosed in this disclosure. The present invention relates to a process for preparing a compound of formula (XXVII) or a salt thereof, comprising converting any of compounds (XXVIII) to (XXIX) into a compound of formula (XXVII).

[0258] In some embodiments, the present invention is directed to a method for preparing a compound of formula (XXVIII) or a salt thereof, comprising converting a compound of formula (XXIX) to a compound of formula (XXVIII) using a method disclosed in the present disclosure.

[0259] In some embodiments, the present invention is directed to methods for preparing intermediate compounds of formulas (IV), (VI)-(VIII), (XX), and (XXII)-(XXIX) using the methods described herein.

[0260] In some embodiments, the present invention provides a method for preparing a compound of formula (XX), or a salt thereof, comprising: The present disclosure is directed to preparing any of the compounds of formula (IV), (VI)-(VIII), and (XXII)-(XXIX), including converting them to compounds of formula (XX) using the methods disclosed in this disclosure.

[0261] In some embodiments, the present invention is directed to methods for preparing intermediate compounds of formulae (V) and (XVI)-(XIX) using the methods described herein.

[0262] In some embodiments, the present application provides a compound of formula (I) using the methods described herein. The present invention is directed to a process for preparing a compound of formula (V) or a salt thereof, comprising converting any of compounds of formula (XVI) to (XIX) into a compound of formula (V).

[0263] In some embodiments, the present application provides a compound of formula (I) using the methods described herein. The present invention is directed to a process for preparing a compound of formula (XVI) or a salt thereof, comprising converting any of the compounds of formula (XVII)-(XIX) to a compound of formula (XVI).

[0264] In another embodiment, the present application provides a method for producing a compound of formula The present invention is directed to a process for preparing a compound of formula (XVII) or a salt thereof, comprising converting any of compounds of formula (XVIII)-(XIX) to a compound of formula (XVII).

[0265] In some embodiments, the present invention is directed to a method for preparing a compound of formula (XVIII) or a salt thereof, comprising converting a compound of formula (XIX) to a compound of formula (XVIII) using a method described herein.

[0266] In a third aspect, the present invention relates to an intermediate compound selected from Table A below.

[0267] Table A. Intermediate compounds of the present invention.

[0268] [ka] [ka] [ka]

[0269] During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl; R2 is C1-C6 alkyl.

[0270] In some embodiments, the present invention relates to a compound selected from Table B below.

[0271] Table B. Intermediate compounds of the present invention.

[0272] [ka] [ka]

[0273] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th Edition, CAS Edition. Further, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0274] As used herein, in any chemical structure or formula, a bold or dashed straight bond attached to a chiral center of the compound, such as in the following formulas (respectively [ka] )teeth,

[0275] [ka]

[0276] A bold or dashed linear bond indicates the relative stereochemistry of a chiral center relative to the other chiral center to which it is attached.

[0277] As used herein, in any chemical structure or formula, a bold or dashed wedge-shaped bond attached to a chiral center of the compound, such as in the following formulas (respectively [ka] )teeth,

[0278] [ka]

[0279] A bold or dashed wedge-shaped bond indicates the absolute stereochemistry of a chiral center relative to the other chiral center to which it is attached, as well as the relative stereochemistry of the chiral center.

[0280] As used herein, the prefix "rac-" when used in reference to a chiral compound refers to a racemic mixture of the compound. In compounds bearing the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0281] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds bearing the "rel-" prefix, the (R) and (S)-designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound.

[0282] As used herein, the term "compound," when referring to a compound described in this application, refers to a collection of molecules having the same chemical structure except that isotopic variations may exist among the constituent atoms of the molecule. The term "compound" includes a collection of molecules regardless of the purity of a given sample containing such a collection of molecules. Thus, the term "compound" is a collective term for molecules in pure form, molecules in the form of a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or molecules in the form of a hydrate, solvate, or co-crystal, etc.

[0283] As used herein, the term "halo" means F, Cl, Br, or I.

[0284] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having from 1 to 6 carbon atoms.

[0285] As used herein, the term "alkoxy" refers to a group of the formula -OR a where R a is an alkyl group having the specified number of carbon atoms. For example, a "C1-C6 alkoxy" group is a group of the formula -OR a where R a is an alkyl group having 1 to 6 carbon atoms.

[0286] As used herein, the term "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group.

[0287] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the alkyl group's hydrogen atoms is replaced by a halo group.

[0288] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Furthermore, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are within the scope of the invention.

[0289] In this specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the invention is intended to represent any stable isotope of the specified element. In the examples, when an atom is not specifically designated as a particular isotope of any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore, one of ordinary skill in the art would understand that such atom was likely present in about the natural abundance isotopic composition of the specified element.

[0290] As used herein, the term "stable," when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes whose decay mode is not identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0291] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 Includes H and D. In the examples, when an atom is designated as "H," no attempt was made to enrich that atom in a particular isotope of hydrogen, and thus, one of skill in the art would understand that such hydrogen atom was likely present in a concentration about the natural abundance of hydrogen.

[0292] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated position at least at the natural abundance concentration of protium.

[0293] As used herein, "D," "d," and " 2 "H" refers to deuterium.

[0294] In some embodiments, the compounds described in this application contain each constituent atom in an isotopic composition at about the natural abundance of the specified element.

[0295] In some embodiments, the compounds described herein, and pharmaceutically acceptable salts thereof, 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 ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 Examples include, but are not limited to, P.

[0296] Isotopically labeled compounds and salts can be used in several beneficial ways, including as pharmaceuticals. In some embodiments, isotopically labeled compounds and salts are deuterium ( 2 H) labeled. For example, deuterium (2 H) The labeled compounds and salts are therapeutically useful and non- 2 3H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled counterparts due to kinetic isotope effects, as described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosages, which under most circumstances represent preferred embodiments of the present invention. Isotopically labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes, examples, and related description, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0297] deuterium( 2 H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy of the covalent bond involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond and therefore a decrease in rate-limiting bond scission. If bond scission occurs within or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is attached to a carbon atom at a non-exchangeable position, k H / k D A rate difference of 2 to 7 is typical. For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0298] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharmaceutically acceptable salt thereof can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of the isotope.

[0299] When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (about 45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (about 52.5% deuterium incorporation), at least 4000 (about 60% deuterium incorporation), at least 4500 (about 67.5% deuterium incorporation), at least 5000 (about 75% deuterium incorporation), at least 5500 (about 82.5% deuterium incorporation), at least 6000 (about 90% deuterium incorporation), at least 6333.3 (about 95% deuterium incorporation), at least 6466.7 (about 97% deuterium incorporation), at least 6600 (about 99% deuterium incorporation), or at least 6633.3 (about 99.5% deuterium incorporation).

[0300] The term "compound of formula" followed by a number (typically a Roman numeral) and the term "compound" followed by the same number (Roman numeral or otherwise) may be used interchangeably. For example, "a compound of formula V" and "compound V" refer to the same compound.

[0301] When referring to a chemical reaction, the term "reacting" means the addition or mixing of two or more reagents under appropriate conditions to produce a designated and / or desired product. It will be appreciated that the reaction that produces the designated and / or desired product may not necessarily result directly from the combination of the two reagents initially added; i.e., there may be one or more intermediates produced in the mixture that ultimately lead to the formation of the designated and / or desired product.

[0302] With respect to a reaction, the terms "carried out in a solvent" or "carried out in the presence of a solvent" mean that one or more substrates and reagents are dissolved or suspended in a particular solvent or in a mixture of solvents that includes a particular solvent.

[0303] The term "chromatographic purification" refers to any method of purification that relies 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.

[0304] The term "converting," as used herein to refer to the step of converting a first compound or salt into a second compound or salt, refers to the process of changing the first compound or salt into the second compound or salt in one or more chemical steps.

[0305] The term "acid" refers to a chemical species having a pKa (in water) of less than 7. The term includes inorganic (mineral) acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, etc. The 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, malonic acid, and the like.

[0306] 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), dimethyl "Neutral organic bases" include methylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[0307] The term "alcohol protecting group" refers to a chemical moiety suitable for protecting an alcohol group from undesired side reactions during synthetic procedures. 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, PGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0308] The term "deprotection" refers to a step of reacting a compound or salt containing a protecting group, such as an alcohol protecting group, under conditions suitable to remove the protecting group and reveal the protected moiety. For example, if the compound or salt contains an alcohol protecting group, the term "deprotection" refers to reacting the compound or salt under conditions suitable to remove the alcohol protecting group and reveal the alcohol. Conditions for removing various protecting groups are well known in the art. See, for example, PGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0309] The term "hydrogenation catalyst" refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of benzylic carbon-oxygen single bonds. Suitable hydrogenation catalysts are well known in the art and include palladium on activated carbon, platinum oxide, and Raney nickel.

[0310] The term "coupling," when referring to a reaction between a carboxylic acid or acid halide and an amine, refers to the final transformation that combines the carboxylic acid or acid halide with 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 the derivative formed by the reaction between a carboxylic acid and a coupling reagent) and an amine.

[0311] 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).

[0312] The term "monovalent cation" refers to alkali metal cations, NH4 + It refers to any cation with a +1 charge, such as ammonium, ammonium nitrate, and tetraalkylammonium.

[0313] The term "alkali metal cation" refers to lithium (Li + ), sodium (Na+), potassium (K + ), rubidium (Rb + ), and cesium (Cs + "I" refers to a cation derived from a Group I metal atom, including but not limited to:

[0314] The term "substituted benzyl" refers to a benzyl group substituted with one to three substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, and cyano.

[0315] The term "about" means that a stated number can vary by ±10% from that value. When a term defines a temperature, the stated temperature can vary by ±10%. For example, about 80°C means 72°C to 88°C. When a term defines a pressure, the term "about" means that the pressure can vary by ±10%. Thus, about 100 bar means 90 to 110 bar. When a term defines a quantity (such as equivalents or weight), the term means that the quantity can vary by ±10%. For example, about 1 equivalent means 0.9 to 1.1 equivalents. When a term defines a time, the term means that the stated time can vary by ±10%. For example, about 1 hour means 0.9 to 1.1 hours.

[0316] The term "leaving group" refers to a chemical group that is easily displaced by a desired incoming chemical moiety. Thus, the selection of a particular suitable leaving group is determined based on its ability to be easily displaced 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 Ed., pp. 351-357, John Wiley and Sons, NY.

[0317] As used herein, the term "cyanating agent" (e.g., trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, etc.) refers to a compound of Formula IX. In one embodiment, the reaction between a cyanating agent (e.g., trimethylsilyl cyanide) and a compound of Formula IX may be carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is boron trifluoride ethyl etherate (BFOEt), TiCl, InCl, AgSbF, iodine, ZnBr, Al(OiPr), MgCl, Mn(acac), MnCl, TMSOTf, SnCl, etc. In further embodiments, the Lewis acid is BFOEt. The cyanation reaction may be carried out in an organic solvent, such as toluene, dichloromethane, 2-methyl-THF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, etc.

[0318] Solid Forms of the Compounds of the Invention In another aspect, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof in solid form. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is in a crystalline solid form.

[0319] Solid forms of compound (I) In some embodiments, the present invention relates to compounds of formula (I):

[0320] [ka]

[0321] wherein the compound is in a crystalline solid form.

[0322] In some embodiments, the present invention relates to a composition comprising a compound of Formula (I), wherein the compound of Formula (I) is in a crystalline solid form. In some embodiments, at least 85% of the compound of Formula (I) present in the composition is in a crystalline solid form. In some embodiments, at least 90% of the compound of Formula (I) present in the composition is in a crystalline solid form. In some embodiments, at least 95% of the compound of Formula (I) present in the composition is in a crystalline solid form. In some embodiments, substantially all of the compound of Formula (I) present in the composition is in a crystalline solid form. In some embodiments, 100% of the compound of Formula (I) present in the composition is in a crystalline solid form.

[0323] In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) and one or more pharmaceutically acceptable carriers or vehicles, wherein the compound of Formula (I) is in a crystalline solid form. In some embodiments, at least 85% of the compound of Formula (I) present in the pharmaceutical composition is in a crystalline solid form. In some embodiments, at least 90% of the compound of Formula (I) present in the pharmaceutical composition is in a crystalline solid form. In some embodiments, at least 95% of the compound of Formula (I) present in the pharmaceutical composition is in a crystalline solid form. In some embodiments, substantially all of the compound of Formula (I) present in the composition is in a crystalline solid form. In some embodiments, 100% of the compound of Formula (I) present in the pharmaceutical composition is in a crystalline solid form.

[0324] In some embodiments, the crystalline solid form of Compound (I) is Form A.

[0325] In some embodiments, Form A is Cu K selected from 9.0, 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 30.7, and 32.1. αWhen measured using radiation, the X-ray powder diffraction pattern (XRPD) is characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one approximate peak position, at least two approximate peak positions, at least three approximate peak positions, at least four approximate peak positions, at least five approximate peak positions, at least six approximate peak positions, at least seven approximate peak positions, at least eight approximate peak positions, at least nine approximate peak positions, at least ten approximate peak positions, at least eleven approximate peak positions, at least twelve approximate peak positions, at least thirteen approximate peak positions, at least fourteen approximate peak positions, at least fifteen approximate peak positions, at least sixteen approximate peak positions, at least seventeen approximate peak positions, at least eighteen approximate peak positions, at least nineteen approximate peak positions, at least twenty approximate peak positions (°2θ±0.2).

[0326] In some embodiments, Form A has the following amino acids: 13.4, 17.2, and 18.9 Cu K α It is characterized by an X-ray powder diffraction pattern (XRPD) containing at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using radiation.

[0327] In some embodiments, Form A has a β-glucan content of 9.0, 11.4, and 20.1 Cu K α It is characterized by an X-ray powder diffraction pattern (XRPD) containing at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using radiation.

[0328] In some embodiments, Form A has a molecular weight of 13.7, 13.8, and 24.8 Cu K α It is characterized by an X-ray powder diffraction pattern (XRPD) containing at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using radiation.

[0329] In some embodiments, Form A is Cu K selected from 9.0, 11.4, and 20.1. α When measured using Cu Kα radiation, the X-ray powder diffraction pattern (XRPD) pattern is characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using Cu Kα radiation, selected from 13.4, 17.2, and 18.9; and at least one approximate peak position and at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2).

[0330] In some embodiments, Form A is Cu K selected from 13.4, 17.2, 18.9 αor an X-ray powder diffraction pattern (XRPD) pattern characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using Cu Kα radiation selected from 9.0, 11.4, and 20.1; or an X-ray powder diffraction pattern (XRPD) pattern characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using Cu Kα radiation selected from 13.7, 13.8, and 24.8. It is characterized by an X-ray powder diffraction pattern (XRPD) pattern containing at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) when measured using Kα radiation.

[0331] In some embodiments, Form A is characterized by a solid-state 19F NMR spectrum having at least one peak, at least two peaks, or at least three peaks at chemical shifts selected from −74.5, −139.5, and −161.5 ppm.

[0332] In some embodiments, Form A is characterized by a solid state C NMR spectrum comprising at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, at least nine peaks, at least ten peaks, at least eleven peaks, at least 12 peaks, at least 13 peaks, at least 14 peaks, at least 15 peaks, at least 16 peaks, at least 17 peaks, at least 18 peaks, at least 19 peaks, at least 20 peaks, or at least 21 peaks at chemical shifts selected from 169.8, 25.1, and 11.6 ppm, including 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, .

[0333] In some embodiments, Form A is characterized by an orthorhombic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a P212121 space group as determined by single crystal X-ray analysis. In other embodiments, Form A is characterized by a unit cell determined by single crystal X-ray analysis with the following dimensions: a=7.0(1) Å, b=8.3(1) Å, c=38.8(1) Å, α=90°, β=90°, and γ=90°.

[0334] Further embodiments of the present disclosure are described in the following numbered clauses: 1. A compound of formula (I), a composition comprising a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers or vehicles,

[0335] The compound of formula (I) is in a crystalline solid form, the crystalline solid form is Form A, and / or Form A is characterized by an orthorhombic crystalline structure as determined by single crystal X-ray analysis.

[0336] 2. The compound, composition, or pharmaceutical composition of clause 1, wherein Form A is characterized by the P212121 space group as determined by single crystal X-ray analysis.

[0337] 3. Form A is a compound, composition, or pharmaceutical composition described in clause 1 or clause 2 characterized by a unit cell as determined by single crystal X-ray analysis having the following dimensions: a=7.0(1) Å, b=8.3(1) Å, c=38.8(1) Å, α=90°, β=90°, and γ=90°.

[0338] In some embodiments, Form A of Compound (I) can be obtained by dissolving the compound in ethyl acetate and then crystallizing the compound by adding n-heptane as an anti-solvent. In other embodiments, Form A can be obtained by the procedure described in Example 7.

[0339] Solid Forms of Compound II In some embodiments, the present invention provides a compound of formula (II) in a crystalline solid form:

[0340] [ka] Regarding.

[0341] In some embodiments, the crystalline solid form is Form B.

[0342] In some embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (°2θ±0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, or at least four diffractions at angles (°2θ±0.2) of 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (°2θ±0.2) of 12.0, 112.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 9.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having at least one, at least two, at least three, at least four, at least 5, at least 6, at least 7, at least 8, or at least 9 diffractions at angles 12.0, 19.3, and 20.3 (°2θ±0.2). In other embodiments, Form B is characterized by an XRPD pattern having diffractions at angles (°2θ±0.2) of 7.6, 9.2, 212.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0, 27.4, 8.6, and 28.9.In other embodiments, Form B is characterized by an XRPD pattern having at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, or at least 27 diffractions at angles 7.6, 27.4, 28.6, and 28.9 (°2θ±0.2). 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9, 17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0, 24.2, 25.2, 26.9, 27.0,.

[0343] In some embodiments, Form B is a solid having peaks at chemical shifts of 172.5, 23.172.1, 168.5, 168.3, 168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5, 80.2, 63.2, 44.3, 0, and 13.1 ppm. 13 It is characterized by its C NMR spectrum.

[0344] In some embodiments, Form B is a solid having peaks at chemical shifts of −137.1 and −152.8 ppm. 19 It may be characterized by F NMR spectroscopy.

[0345] In some embodiments, Form B is characterized by a DSC thermogram with a melting onset at 182°C with a peak at 183°C.

[0346] In some embodiments, Form B has peaks of 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 It is characterized by an IR spectrum with a peak of

[0347] In some embodiments, Form B is characterized by an orthorhombic crystalline system as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a P212121 space group as determined by single crystal X-ray analysis. In other embodiments, Form B is characterized by a unit cell as determined by single crystal X-ray analysis with the following dimensions: a=7.3929(2) Å, b=14.5827(4) Å, c=18.9312(6) Å, α=90°, β=90°, and γ=90°.

[0348] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions of the Invention Pharmaceutically Acceptable Salts and Compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels. Accordingly, the present compounds and pharmaceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally, a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0349] As used herein, the term "pharmaceutically acceptable" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound of the invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0350] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, methylpropional ... Salts derived from appropriate bases include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0351] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0352] As used in this disclosure, a pharmaceutically acceptable composition of the present invention additionally includes pharmaceutically acceptable carriers, adjuvants, or vehicles, including any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as used herein, appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is contemplated within the scope of this disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (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, ethyl cellulose, etc.), and the like. and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents; preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0353] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0354] In another aspect, the present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0355] Dosage form and route of administration The compounds of the present invention (e.g., compounds of Formula (I) or Formula (II)), or pharmaceutically acceptable salts thereof, may be formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "dosage unit form" refers to a physically discrete unit of agent appropriate for the subject to be treated.

[0356] The compounds of the present invention or pharmaceutically acceptable salts thereof can be administered to humans and other animals orally, rectally, parenterally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the condition being treated.

[0357] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the compound of the present invention or its pharmaceutically acceptable salt, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0358] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0359] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0360] In order to prolong the therapeutic effect of a compound of the present invention, it may be desirable to slow the absorption of the compound or its pharmaceutically acceptable salt from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0361] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the invention or a pharmaceutically acceptable salt thereof with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0362] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) hygroscopic agent, such as glycerol; d) disintegrating agent, such as agar. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0363] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain emulsifying agents and can be of a composition that they release the active ingredient only, or in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0364] The active compound or salt may also be in microencapsulated form with one or more of the above-mentioned excipients.Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art.In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch.Such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is common practice.In the case of capsules, tablets, and pills, the dosage form may also contain a buffering agent.

[0365] Dosage forms for topical or transdermal administration of the compounds of the present invention or their pharmaceutically acceptable salts include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0366] Solid dispersions and tablets In another aspect, the present invention relates to a solid dispersion (e.g., a spray-dried dispersion) comprising a compound of the present invention (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, and at least one polymer. Spray drying converts a liquid feed into a dry particulate form. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to promote drying of the liquid droplets. For example, a liquid solution comprising a compound of the present invention (e.g., a compound of Formula (I) or Formula (II)), or a pharmaceutically acceptable salt thereof, and at least one polymer may be sprayed into a stream of hot, filtered gas, which evaporates the solvent and carries the dried product to a collector. The evaporated solvent and spent gas are removed from the collector and can be sent to a condenser to recover the solvent. For example, commercially available spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro) (see U.S. Patent Application Publication No. 2004 / 0105820, U.S. Patent Application Publication No. 2003 / 0144257).

[0367] Spray drying techniques and methods can be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H.Perry, D.W. Green & J.O. Maloney, eds.), McGraw-Hill book co. (1984) and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). All three references are incorporated herein by reference in their entirety.

[0368] An additional drying step may be required after spray drying to ensure solvent removal. Other drying techniques include, but are not limited to, tray drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., from about room temperature to about 200°C).

[0369] In some embodiments, the solvent used in spray drying is a volatile solvent. The volatile solvent can have, for example, a boiling point below 100° C. Mixtures of volatile solvents or mixtures of volatile and non-volatile solvents can also be used.

[0370] Exemplary solvents that may be tested include acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HOAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, DCM, and toluene. Exemplary cosolvents include acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, and dioxane / water. In two-solvent systems, the solvent may be present at about 0.1% to about 99.9%. In some embodiments, water is a co-solvent with acetone, where water is present at about 0.1% to about 15%, e.g., about 9% to about 11%, e.g., about 10%. In some embodiments, water is a co-solvent with MEK, where water is present at about 0.1% to about 15%, e.g., about 9% to about 11%, e.g., about 10%. In some embodiments, the solvent system comprises three solvents. Suitable solvents include those described above, e.g., DCM, water, methanol, IPA, and mixtures thereof. In some embodiments, the solvent comprises DCM and methanol.

[0371] In some embodiments, the at least one polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.

[0372] In some embodiments, at least one polymer is HPMCAS.

[0373] In another aspect, the present invention relates to a pharmaceutical composition comprising the solid dispersion disclosed herein. In some embodiments, the pharmaceutical composition may comprise one or more excipients. Examples of excipients include, but are not limited to, fillers, disintegrants, and lubricants.

[0374] Examples of fillers include, but are not limited to, microcrystalline cellulose, lactose monohydrate, mannitol, and mixtures thereof. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler comprises lactose monohydrate. In some embodiments, the filler comprises mannitol. In some embodiments, the filler comprises a mixture of microcrystalline cellulose and lactose monohydrate. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is Avicel PhH101. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is Avicel PH102. In some embodiments, the filler comprises microcrystalline cellulose, and the microcrystalline cellulose is a combination of Avicel PH101 and Avicel PH102.

[0375] Examples of suitable disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, and mixtures thereof. In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the disintegrant comprises crospovidone.

[0376] Examples of suitable lubricants include, but are not limited to, sodium stearyl fumarate, magnesium stearate, and mixtures thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate. In some embodiments, the lubricant comprises magnesium stearate.

[0377] In some embodiments, the pharmaceutical composition comprises a compound of the present invention (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant.

[0378] In some embodiments, the present invention relates to a pharmaceutical composition comprising 45-55% by weight of a solid dispersion comprising a polymer and a compound of Formula (II), 42-50% by weight of microcrystalline cellulose, 2-4% by weight of croscarmellose sodium, and 0.5-1.5% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50% by weight of the solid dispersion, about 46% by weight of microcrystalline cellulose, about 3% by weight of croscarmellose sodium, and about 1.0% by weight of magnesium stearate.

[0379] In some embodiments, the pharmaceutical composition is a tablet core composition. In some embodiments, the tablet core composition is coated with a tablet coating. In some embodiments, the tablet coating is Opadry Blue.

[0380] In some embodiments, the solid dispersion comprises 70-80% by weight of the polymer and 20-30% by weight of the compound of Formula (II). In some embodiments, the solid dispersion comprises about 75% by weight of the polymer and about 25% by weight of the compound of Formula (II). In some embodiments, the polymer is HPMCAS.

[0381] In some embodiments, the pharmaceutical composition comprises about 50 mg of the compound of Formula (II).

[0382] In some embodiments, the pharmaceutical composition comprises an intragranular blend and an extragranular blend, in which the intragranular blend comprises about 200 mg of the solid dispersion, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate, and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesium stearate.

[0383] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions In another aspect, the invention features a method of inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the invention features a method of inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the voltage-gated sodium channels are Na V It is 1.8.

[0384] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In yet another aspect, the present invention is directed to a method of treating or lessening the severity of pain in a subject, comprising administering an effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0385] In another aspect, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament. In another aspect, the present invention is directed to a compound of formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0386] In another aspect, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. In another aspect, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. In some aspects, the voltage-gated sodium channel is Na V It is 1.8.

[0387] In another aspect, the invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity of pain in a subject. In another aspect, the invention features a compound of formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity of pain in a subject.

[0388] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament. In another aspect, the present invention provides the use of a compound of formula (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0389] In another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. In another aspect, the present invention provides the use of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. In some aspects, the voltage-gated sodium channel is Na V It is 1.8.

[0390] In yet another aspect, the present invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pain in a subject. In yet another aspect, the present invention provides the use of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pain in a subject.

[0391] In another aspect, the present invention is directed to a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0392] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0393] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0394] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0395] In yet another aspect, the present invention is directed to a method for treating or reducing the severity of neuropathic pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0396] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, spinal stenosis pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0397] In yet another aspect, the present invention is directed to a method for treating or lessening the severity of musculoskeletal pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis.

[0398] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritis, back pain, cold pain, burn pain, or dental pain, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0399] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0400] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0401] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises fibromyalgia pain, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0402] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises pain of reflex sympathetic dystrophy, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0403] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0404] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of acute pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the acute pain includes acute post-operative pain.

[0405] In yet another aspect, the present invention is directed to a method for treating or lessening the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0406] In yet another aspect, the present invention is directed to a method for treating or lessening the severity of bunionectomy pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0407] In yet another aspect, the present invention is directed to a method for treating or lessening the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0408] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of herniorrhaphy pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0409] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of abdominoplasty pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0410] In yet another aspect, the present invention is directed to a method of treating or lessening the severity of visceral pain in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0411] In yet another aspect, the present invention is directed to a method for treating or lessening the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0412] In yet another aspect, the invention is directed to methods in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0413] In another aspect, the present invention is directed to a method for inhibiting voltage-gated sodium channels in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0414] In another aspect, the present invention provides a method for the treatment of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic pain in a subject. neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., post-stroke central neuropathic pain), traumatic cervical syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, tetanus Smallpox, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis , chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0415] In another aspect, the present invention provides a method for the treatment of 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; persistent / Chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; multiple sclerosis The present invention relates to a method for treating or lessening the severity of pain in MS; pain in depression; pain in leprosy; pain in Behcet's disease; adiposity dolorosa; pain in phlebitis; pain in Guillain-Barré syndrome; painful legs and moving toes; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain 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, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0416] In another aspect, the present invention is directed to a method for treating or lessening the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain after amputation surgery in a subject, comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0417] Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use - Patent application In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0418] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. V It is 1.8.

[0419] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0420] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-surgical pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0421] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain.

[0422] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0423] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain from spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0424] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0425] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in 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 dental pain.

[0426] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0427] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0428] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

[0429] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes pain of reflex sympathetic dystrophy.

[0430] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of pathological cough in a subject.

[0431] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of acute pain in a subject. In some aspects, the acute pain comprises acute post-operative pain.

[0432] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of post-operative pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0433] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of bunionectomy pain in a subject.

[0434] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0435] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of herniorrhaphy pain in a subject.

[0436] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of abdominoplasty pain in a subject.

[0437] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain includes abdominoplasty visceral pain.

[0438] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0439] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method in which a subject is treated with an effective amount of one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0440] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It is 1.8.

[0441] In another aspect, the present invention provides a method for the treatment of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, Post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., post-stroke central neuropathic pain), traumatic neck syndrome, fragility fractures, vertebral fractures, ankylosed spine Spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis In another aspect of the present invention, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity of rheumatoid arthritis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0442] In another aspect, the present invention provides a method for the treatment of 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; persistent / Chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; poststroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; multiple sclerosis The present invention features a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of pain in MS; pain in depression; pain in leprosy; pain in Behcet's disease; adiposity dolorosa; pain in phlebitis; pain in Guillain-Barré syndrome; painful legs and moving toes; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain 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.

[0443] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method for treating or lessening the severity of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the femoral nerve, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery in a subject.

[0444] Drug manufacturing In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0445] In another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. V It is 1.8.

[0446] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0447] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia in a subject.

[0448] In yet another aspect, the present invention provides the use of a compound, pharmaceutically acceptable salt, or pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain, irritable bowel syndrome, endometriosis, polycystic ovarian disease, salpingitis, cervicitis, or interstitial cystitis pain.

[0449] In yet another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0450] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, medication-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, HIV-induced neuropathy; pain after spinal cord injury, pain of spinal stenosis, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0451] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, the musculoskeletal pain includes osteoarthritis.

[0452] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0453] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis, or vulvodynia.

[0454] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

[0455] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

[0456] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes the pain of reflex sympathetic dystrophy.

[0457] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pathological cough in a subject.

[0458] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of acute pain in a subject. In some aspects, acute pain includes acute post-surgical pain.

[0459] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or lessening the severity of post-operative pain in a subject (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain).

[0460] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of herniorrhaphy pain in a subject.

[0461] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0462] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0463] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of abdominoplasty pain in a subject.

[0464] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain includes abdominoplasty visceral pain.

[0465] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0466] In yet another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0467] In another aspect, the present invention provides a method for the treatment of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, tension headache, all other headache forms, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, herpes in a subject. Post-injury neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., post-stroke central neuropathic pain), traumatic cervical syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, tetanus Smallpox, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis and the like. The present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating or lessening the severity of rheumatoid arthritis, chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorder, painful knee replacement surgery, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0468] In another aspect, the present invention provides a method for treating 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; splenic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; persistent / chronic Postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom limb pain (e.g., after lower limb, upper limb, or mastectomy); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tenosynovitis; injury pain; movement pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute shingles pain; sickle cell disease; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; multiple sclerosis The present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment or reduction of the severity of: pain in MS (multiple sclerosis); pain in depression; pain in leprosy; pain in Behcet's disease; adiposity dolorosa; pain in phlebitis; pain in Guillain-Barré syndrome; painful legs and moving toes; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; bladder and genitourinary disorders; urinary incontinence, pathological cough; overactive bladder; bladder pain 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.

[0469] In another aspect, the present invention provides use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or lessening of the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery.

[0470] Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions In certain embodiments of the present invention, an "effective amount" of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or lessen the severity of one or more of the conditions listed above.

[0471] The compounds, salts, and compositions of the present invention can be administered in any amount and via any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders listed herein. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the subject being treated. However, it will be understood that the total daily dosage of the compounds, salts, and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound or salt used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular compound or salt used; the duration of treatment; drugs used in combination with or concomitantly with the particular compound or salt used, and similar factors well known in the medical arts. As used herein, the term "subject" or "patient" means an animal, preferably a mammal, and most preferably a human.

[0472] The pharmaceutically acceptable compositions of the invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), buccally as an oral or nasal spray, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the invention can be administered orally or parenterally, one or more times daily, at dosage levels of about 0.001 mg / kg to about 1000 mg / kg effective to obtain the desired therapeutic effect.

[0473] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound or salt, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0474] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution (USP), and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0475] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0476] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0477] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound or salt of the invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0478] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, carbonate, cellulose, cellulose acetate, cellulose acetate, cellulose stearate, cellulose acetate, cellulose acetate stearate ... Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0479] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can optionally be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0480] The active compound or salt may also be in microencapsulated form containing one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may optionally be of a composition that releases the active ingredient(s) only, or preferentially, in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0481] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. The present invention also contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0482] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds V1.8 inhibitors, and therefore, without wishing to be bound by any particular theory, the compounds, salts, and compositions V These compounds are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation or overactivity of Na 1.8 is implicated. V When activation or overactivity of 1.8 is involved in a particular disease, condition, or disorder, the disease, condition, or disorder may also be associated with Na V 1.8-mediated disease, condition, or disorder. V The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 is implicated in the disease state.

[0483] Na V The activity of the compounds utilized in this invention as inhibitors of 1.8 may be assayed according to the methods generally described in WO 2014 / 120808 A9 and U.S. 2014 / 021361 (both of which are incorporated by reference in their entireties), the methods described herein, as well as other methods known and available to those of skill in the art.

[0484] Additional medications It will also be understood that the compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, prior to, or after one or more other desired therapies or medical treatments. The particular combination of therapies (treatments or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or treatments and the desired therapeutic effect to be achieved. It will also be understood that the therapies used may achieve the desired effect for the same disorder (e.g., a compound of the present invention may be administered simultaneously with another agent used to treat the same disorder) or may achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated." For example, exemplary additional therapeutic agents include non-opioid analgesics (indoles, e.g., etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones, e.g., nabumetone; oxicams, e.g., piroxicam; para-aminophenol derivatives, e.g., acetaminophen; propionic acids, e.g., fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; salicylates, e.g., aspirin, Examples of analgesic agents include, but are not limited to, choline magnesium trisalicylate, diflunisal; fenamates, such as meclofenamic acid and mefenamic acid; and pyrazoles, such as phenylbutazone, or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches can be utilized in conjunction with the administration of one or more compounds of the present invention.For example, anesthetic (spinal injection, nerve blockade), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physics (physical therapy, orthotic devices, diathermy), or psychology (cognitive-pulmonary, biofeedback, or behavioral) approaches may also be utilized. Additional suitable 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 the Food and Drug Administration (website www.fda.gov), the entire contents of which are incorporated herein by reference.

[0485] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butaphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen (including, but not limited to, intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including, but not limited to, ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac, (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methoherbital, methohexital, pentobarbital, phenobarbital, (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepatate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine; (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichlorphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination preparation of morphine and dextromethorphan, topiramate, NR2B antagonists including neramexane or perzinfotel, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone, (9) alpha-adrenergic agents such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline, (11) anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproic acid; (12) Tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,lg][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[(2R,3S )-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), a precipitating agent, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S), (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal tar analgesics, especially paracetamol, (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resinferatoxin or siboamide) or antagonists (e.g., capsazepine, GRC-15300), (18) beta-adrenergics, e.g., propranolol; (19) Local anesthetics, such as mexiletine, (20) Corticosteroids, e.g., dexamethasone, (21) 5-HT receptor agonists or antagonists, in particular 5-HT receptor antagonists such as eletriptan, sumatriptan, naratriptan, zolitriptan, or rizatriptan. 1B / 1D agonist, (22)5-HT 2A Receptor antagonists, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), (23) Cholinergic (nicotinic) analgesics, such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine. (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentazole ER (Nucynta®), (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-4-one (wardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-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)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide, (26) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, (27) Cannabinoids, such as KHK-6188, (28) Metabolic glutamate subtype 1 receptor (mGluRl) antagonists, (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone. (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3 -amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide, (33) Acetylcholinesterase inhibitors, for example, donepezil, (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870, (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504), (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201) or eslicarbazepine acetate, (38)Na V1.7 Blockers, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Bixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and International Publication No. 2011 / 140425 (US2011 / 306607); International Publication No. 2012 / 106499 (US2012 / 196869 ); International Publication No. 2012 / 112743 (US2012 / 245136); International Publication No. 2012 / 125613 (US2012 / 264749), International Publication No. 2012 / 116440 (US2014 / 187533), International Publication No. 2011026240 (US2012220605), US8883840, US8466188, International Publication No. 2013 / 109521 (US2015 / 005304), CN111217776, WO 2020 / 117626, WO 2021 / 252822, WO 2021 / 252818, WO 2021 / 252820, WO 2014 / 201173, WO 2012 / 125973, WO 2013 / 086229, WO 2013 / 134518, WO 2014 / 201206, or WO 2016 / 141035 (the entire contents of each application are incorporated herein by reference); (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]- 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[ 3,4-Dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-Piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl) spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-1'-yl]methanone, (39)Na such as PF-04531083 and PF-06372865 V1.8 blockers, and International Publication No. 2008 / 135826 (US2009048306), International Publication No. 2006 / 011050 (US Patent Application Publication No. 2008312235), International Publication No. 2013 / 061205 (US Patent Application Publication No. 2014296313), US20130303535, International Publication No. 2013131018,US8466188, International Publication No. 2013114250 (US Patent Application Publication No. 2013274243), International Publication No. 2014 / 120808 (US Patent Application Publication No. 2014213616), International Publication No. 2014 / 120815 (US Patent Application Publication No. 2014228371), International Publication No. 2014 / 120820 (US Patent Application Publication No. 2014221435), International Publication No. 2015 / 010065 (US Patent Application Publication No. 20160152561), International Publication No. 2015 / 089361 (US Patent Application Publication No. 20150166589), International Publication No. 2019 / 014352 (U.S. Patent Application Publication No. 20190016671), WO 2018 / 213426, WO 2020 / 146682, WO 2020 / 146612, WO 2020 / 014243, WO 2020 / 014246, WO 2020 / 092187, WO 2020 / 092667 (U.S. Patent Application Publication No. 2020140411), WO 2020 / 144375, WO 2020 / 261114, WO 2020 / 140959, WO 2020 / 151728, WO 2021 / 032074, WO 2021 / 047622 (China Patent No. 112479996), International Publication No. 2021 / 257490, International Publication No. 2021 / 257420, International Publication No. 2021 / 257418, International Publication No. 2022 / 263498, International Publication No. 2022 / 235558, International Publication No. 2022 / 235859, International Publication No. 2023 / 138599, China Patent No. 1123907 45, Chinese Patent No. 111808019, Chinese Patent No. 112225695, Chinese Patent No. 112457294, Chinese Patent No. 112300051, Chinese Patent No. 112300069, Chinese Patent No. 112441969, and Chinese Patent No. 114591293 (the entire contents of each application are incorporated herein by reference); (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]dihydrogen methyl phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-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]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N -(3-Sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dicolinic acid 4-(2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3 -sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro -2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide amide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)- 3-(Difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-Trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy) phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide, 4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2 -Methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, (40)Na V 1.7 and Na V 1.8 Blocker combinations, such as DSP-2230, Lohocla201 or BL-1021, (41) 5-HT3 antagonists, such as ondansetron, (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, for example, varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) Nerve growth factor antagonists, such as tanezumab; (46) Endopeptidase stimulators, such as senrebotase; (47) Angiotensin II antagonists, for example, EMA-401, (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®)); (49) Bupivacaine (including, but not limited to, bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

[0486] In one embodiment, the additional suitable therapeutic agent is selected from V-116517, pregabalin, extended-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.

[0487] In another embodiment, the additional suitable therapeutic agent is selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide, N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide, or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0488] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, e.g., Operanserin (VVZ149), a TRPV modulator, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, an EGR1 inhibitor, e.g., Brivoglide (AYX1), an NGF inhibitor, e.g., Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist, e.g., Cebranopadol, NKTR181 (Oxycodegol), a CB-1 agonist, e.g., NEO1940 (AZN1940), an imidazoline 12 agonist, e.g., CR4056, or a p75NTR-Fc modulator, e.g., LEVI-04.

[0489] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0490] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427, or ST-2578, and those disclosed in WO 2010 / 129864, WO 2015 / 157559, WO 2017 / 059385, WO 2018 / 183781, WO 2018 / 183782, WO 2020 / 072835, and / or WO 2022 / 036297, the entire contents of each of which are incorporated herein by reference.

[0491] In another embodiment, the additional therapeutic agent is selected from the group consisting of ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, opilanserin (Unafra™), bribolizide, 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.

[0492] In another embodiment, the additional therapeutic agent is selected from Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, and ACD440.

[0493] In another embodiment, the additional therapeutic agent is HRS4800, ODM-111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, OLP-1002, ATX01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, Selected from BL-017881, Profevia (clinidipine), LS-04, bixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0494] In another embodiment, the additional therapeutic agent is one of the Na V 1.7 and Na V and sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0495] The amount of additional therapeutic agent present in the compositions of the invention can be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions of the present disclosure can range from about 10% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0496] 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, artificial valves, vascular grafts, stents, and catheters. Accordingly, in another aspect, the present invention includes compositions for coating implantable devices, comprising a compound or salt of the present invention, generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound or salt of the present invention, generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable top coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart sustained release characteristics in the composition.

[0497] Another aspect of the present invention is to detect Na in a biological sample or a subject. V With respect to inhibiting 1.8 activity, the method includes administering to a subject or contacting the biological sample with a 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, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0498] Na in biological samples VInhibition of 1.8 activity is useful for a variety of purposes known to those of skill in the art, including, but not limited to, the study of sodium channels in biological and pathological phenomena and the comparative evaluation of new sodium channel inhibitors.

[0499] Synthesis of Compounds of the Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other analogous methods, and other methods known to those skilled in the art. As will be understood by those skilled in the art, functional groups of intermediate compounds in the methods described below 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 T.G.M.Wuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0500] Radiolabeled Analogs of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioactive isotopes of the atoms present in the compounds of the present invention.

[0501] As used herein, the term "radioisotope" refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C. 32 P, 35 S, 18 F, 36Cl, as well as isotopes whose decay modes are identified in VS Shirley & CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0502] 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 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0503] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analogue according to any of the embodiments described herein in relation to the compounds of the invention.

[0504] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analogue, or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein in connection with the compounds of the invention, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0505] In another aspect, the present invention relates to methods of inhibiting voltage-gated sodium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of a radiolabeled analogue, pharmaceutically acceptable salt thereof, and pharmaceutical composition thereof, according to any of the embodiments described herein with respect to the compounds of the invention.

[0506] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0507] In another aspect, the invention relates to the use of a radiolabeled analogue or a pharmaceutically acceptable salt thereof, according to any of the embodiments described herein in relation to the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0508] In another aspect, the radiolabeled analogs, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof may be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention.

[0509] Enumerated Embodiments Further embodiments of the present disclosure are described in the following numbered clauses: 1. A process for preparing a compound of formula (I):

[0510] [ka]

[0511] Compounds of formula (IV):

[0512] [ka]

[0513] or a salt thereof to a compound of formula (I).

[0514] 2. The process of embodiment 1, wherein said converting said compound of formula (IV) to said compound of formula (I) comprises preparing a compound of formula (VI):

[0515] [ka]

[0516] 3. Converting the compound of formula (VI) to a compound of formula (IV) or a compound of formula (VII):

[0517] [ka]

[0518] 3. The method of claim 2, comprising contacting a quinine with

[0519] 4. The process of embodiment 1, wherein converting the compound of formula (IV) to the compound of formula (I) comprises preparing a compound of formula (VII):

[0520] [ka]

[0521] 5. The process according to embodiment 3 or 4, wherein the compound of formula (VII) is obtained by contacting the compound of formula (IV) with (R)-α-methylbenzylamine.

[0522] 6. The method of any one of embodiments 1 to 5, wherein converting a compound of formula (IV) to a compound of formula (I) comprises converting a compound of formula (IV), a compound of formula (VI), or a compound of formula (VII) to a compound of formula (V):

[0523] [ka]

[0524] to obtain a compound of formula (III):

[0525] [ka]

[0526] 7. The method of embodiment 6, wherein contacting the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) with the compound of formula (V) is carried out in the presence of a coupling reagent and a first base.

[0527] 8. The process of embodiment 7, wherein the coupling reagent is propanephosphonic anhydride (T3P) and the first base is triethylamine.

[0528] 9. The method of any one of embodiments 1 to 5, wherein converting a compound of formula (IV) to a compound of formula (I) comprises converting a compound of formula (IV), a compound of formula (VI), or a compound of formula (VII) to a compound of formula (VIII):

[0529] [ka]

[0530] 10. The process of embodiment 9, wherein converting the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) to the compound of formula (VIII) comprises treating the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) with a chlorinating reagent.

[0531] 11. The process of embodiment 10, wherein the chlorinating reagent is selected from phosgene, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), and diphenylphosphinic chloride (DPPCl).

[0532] 12. The process of embodiment 10 or 11, wherein the chlorinating reagent is oxalyl chloride.

[0533] 13. The method of any one of embodiments 9-12, wherein converting a compound of formula (IV) to a compound of formula (I) comprises converting a compound of formula (VIII) to a compound of formula (V):

[0534] [ka]

[0535] to obtain a compound of formula II.

[0536] [ka]

[0537] 14. The process of embodiment 13, wherein contacting the compound of formula (VIII) with the compound of formula (V) is carried out in the presence of a second base.

[0538] 15. The process of embodiment 14, wherein the second base is triethylamine.

[0539] 16. The process of any one of embodiments 6-8 or 13-15, wherein converting a compound of formula (IV) to a compound of formula (I) further comprises converting a compound of formula (III) to a compound of formula (I).

[0540] 17. The process of embodiment 16, wherein converting the compound of formula (III) to the compound of formula (I) comprises treating the compound of formula (III) with a first acid and water.

[0541] 18. The method of manufacturing of embodiment 17, wherein the first acid is aqueous trifluoroacetic acid.

[0542] 19. The process of any one of embodiments 1-18, further comprising recrystallizing the compound of formula (I) from a suitable solvent to obtain crystalline Form A of the compound of formula (I).

[0543] 20. The process of embodiment 19, wherein the suitable solvent comprises ethyl acetate and n-heptane.

[0544] 21. The method of any one of embodiments 6-8, or 13-20, comprising the step of:

[0545] [ka]

[0546] to a compound of formula I, In the formula, R 2 is C1-C6 alkyl.

[0547] 22. The process of embodiment 21, wherein converting the compound of formula (XVI) to the compound of formula (V) comprises treating the compound of formula (XVI) with water at reflux.

[0548] 23. The process of embodiment 21, wherein converting the compound of formula (XVI) to the compound of formula (V) comprises treating the compound of formula (XVI) with a third base and water.

[0549] 24. The method of embodiment 23, wherein the third base is NaOH.

[0550] 25. R 2 The process of any one of embodiments 21 to 24, wherein is tert-butyl or ethyl.

[0551] 26. The method of any one of embodiments 21-25, wherein the compound of formula (XVI) is a compound of formula (XVI-A):

[0552] [ka]

[0553] 27. The method of any one of embodiments 21-25, wherein the compound of formula (XVI) is a compound of formula (XVI-B):

[0554] [ka]

[0555] 28. The process of any one of embodiments 21-27, further comprising recrystallizing the compound of formula (V) from a suitable solvent.

[0556] 29. The process of embodiment 28, wherein the suitable solvent comprises MTBE and n-heptane.

[0557] 30. The method of any one of embodiments 21 to 29, wherein the compound of formula (XVII):

[0558] [ka]

[0559] to a compound of formula (XVI).

[0560] 31. The method of embodiment 30, wherein converting the compound of formula (XVII) to the compound of formula (XVI) comprises treating the compound of formula (XVII) with NH2-C(O)-(C1-C6 alkyl), a fourth base, a palladium catalyst, and a ligand.

[0561] 32. The method of embodiment 31, wherein the fourth base is Cs2CO3 or K3PO4.

[0562] 33. The method of embodiment 31 or 32, wherein the palladium catalyst is Pd(OAc)2.

[0563] 34. The method of any one of embodiments 31 to 33, wherein the ligand is XPhos or BrettPhos.

[0564] 35. The method of any one of embodiments 30-34, wherein the compound of formula (XVIII):

[0565] [ka]

[0566] to a compound of formula (XVII).

[0567] 36. The process of embodiment 35, wherein converting the compound of formula (XVIII) to the compound of formula (XVII) comprises treating the compound of formula (XVIII) with 2,2-dimethoxypropane in the presence of a second acid.

[0568] 37. The process of embodiment 36, wherein the second acid is methanesulfonic acid.

[0569] 38. The method of any one of embodiments 35 to 37, wherein a compound of formula (XIX):

[0570] [ka]

[0571] to a compound of formula (XVIII).

[0572] 39. The process of embodiment 38, wherein converting the compound of formula (XIX) to the compound of formula (XVIII) comprises contacting the compound of formula (XIX) with a reducing agent.

[0573] 40. The process of embodiment 39, wherein the compound of formula (XIX) is contacted with a reducing agent in the presence of an enzyme.

[0574] 41. The process of any one of embodiments 38-40, further comprising contacting 2-bromo-5-chloropyridine with 2-(tert-butoxy)-N-methoxy-N-methylacetamide to obtain a compound of formula (XIX).

[0575] 42. 2-Bromo-5-chloropyridine The process of embodiment 41, wherein the compound is contacted with 2-(tert-butoxy)-N-methoxy-N-methylacetamide in the presence of a Grignard reagent.

[0576] 43. The method of preparation according to embodiment 42, wherein the Grignard reagent is isopropylmagnesium chloride lithium chloride complex.

[0577] 44. A process for preparing a compound of formula (II):

[0578] [ka]

[0579] Compounds of formula (VII):

[0580] [ka]

[0581] to a compound of formula (II).

[0582] 45. The method of embodiment 44, wherein converting the compound of formula (VII) to the compound of formula (II) comprises converting the compound of formula (VII) to a compound of formula (XXI):

[0583] [ka]

[0584] to obtain a compound of formula (XX):

[0585] [ka]

[0586] 46. ​​The process of embodiment 45, wherein contacting the compound of formula (VII) with the compound of formula (XXI) is carried out in the presence of a coupling reagent and a first base.

[0587] 47. The process of embodiment 46, wherein the coupling reagent is propanephosphonic anhydride (T3P) and the first base is triethylamine.

[0588] 48. The process according to embodiment 44, wherein converting the compound of formula (VII) to the compound of formula (II) comprises converting the compound of formula (VII) to the compound of formula (VIII):

[0589] [ka]

[0590] 49. The method of embodiment 48, wherein converting the compound of formula (VII) to the compound of formula (VIII) comprises treating the compound of formula (VII) with a chlorinating reagent.

[0591] 50. The process of embodiment 49, wherein the chlorinating reagent is selected from the group consisting of phosgene, thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl), and diphenylphosphinic chloride (DPPCl).

[0592] 51. The process of embodiment 49 or 50, wherein the chlorinating reagent is oxalyl chloride.

[0593] 52. The method of any one of embodiments 48 to 51, further comprising: Converting a compound of formula (VII) to a compound of formula (II) converts a compound of formula (VIII) to a compound of formula (XXI):

[0594] [ka]

[0595] to obtain a compound of formula (XX).

[0596] [ka]

[0597] 53. The method of embodiment 52, wherein contacting the compound of formula (VIII) with the compound of formula (XXI) is carried out in the presence of a second base.

[0598] 54. The method of embodiment 53, wherein the second base is triethylamine.

[0599] 55. The process of any one of embodiments 52-54, wherein contacting the compound of Formula (VIII) with the compound of Formula (XXI) is carried out in toluene.

[0600] 56. The process of any one of embodiments 45-47 or 52-55, wherein converting a compound of formula (VII) to a compound of formula (II) further comprises converting a compound of formula (XX) to a compound of formula (II).

[0601] 57. The process of embodiment 56, wherein converting the compound of formula (XX) to the compound of formula (II) comprises reacting the compound of formula (XX) with ammonia to obtain the compound of formula (II).

[0602] 58. The process of embodiment 57, wherein the ammonia is in the form of a solution of ammonia in a solvent, ammonia in gaseous form by bubbling ammonia gas into the reaction mixture, or ammonia in the form of ammonium hydroxide or an ammonium salt generated in situ.

[0603] 59. The method of embodiment 58, wherein the ammonia is in the form of a solution of ammonia in methanol.

[0604] 60. The process of embodiment 58, wherein the ammonia is in the form of a solution of ammonia in methanol and tetrahydrofuran.

[0605] 61. The method of embodiment 58, wherein the in situ generation of ammonia comprises reacting ammonium hydroxide or the ammonium salt with an acid.

[0606] 62. The process of any one of embodiments 57-61, wherein treating the compound of Formula (XX) with ammonia is carried out in a solvent mixture comprising methanol and tetrahydrofuran.

[0607] 63. The process of any one of embodiments 44-62, further comprising recrystallizing the compound of formula (II) from a suitable solvent.

[0608] 64. The process of embodiment 63, wherein suitable solvents include MeOH, THF, and water.

[0609] 65. The method of any one of embodiments 44-64, wherein the compound of formula (IV):

[0610] [ka]

[0611] to a compound of formula (VII).

[0612] 66. The process of embodiment 65, wherein converting the compound of formula (IV) to the compound of formula (VII) comprises contacting the compound of formula (IV) with (R)-α-methylbenzylamine.

[0613] 67. The method of any one of embodiments 1-43, 65, or 66, comprising producing a compound of formula (IX):

[0614] [ka]

[0615] to a compound of formula (IV).

[0616] 68. The process of embodiment 67, wherein converting the compound of formula (IX) to the compound of formula (IV) comprises treating the compound of formula (IX) with a fifth base.

[0617] 69. The method of embodiment 68, wherein the fifth base is potassium hydroxide.

[0618] 70. The method of any one of embodiments 67-69, wherein the compound of formula (X):

[0619] [ka]

[0620] to a compound of formula (IX), During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0621] 71. The method of embodiment 70, wherein the compound of formula (X) has formula (X'):

[0622] [ka]

[0623] 72. The process of embodiment 71, wherein converting the compound of formula (X) to the compound of formula (IX) comprises treating the compound of formula (X) with a cyanate reagent.

[0624] 73. The method of embodiment 72, wherein the cyanating agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, and HCN.

[0625] 74. The method of preparation of embodiment 73, wherein the cyanate reagent is trimethylsilyl cyanide.

[0626] 75. The process of embodiment 74, wherein the compound of formula (X) is treated with 1.35 to 1.65 equivalents of trimethylsilyl cyanide.

[0627] 76. The process of any one of embodiments 70-75, wherein treating the compound of Formula (X) with a cyanate reagent is carried out in the presence of a Lewis acid.

[0628] 77. The method of embodiment 76, wherein the Lewis acid is selected from boron trifluoride diethyl etherate (BF3·Et2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, and SnCl4.

[0629] 78. The method of preparation according to embodiment 77, wherein the Lewis acid is BF3OEt2.

[0630] 79. The process of embodiment 78, wherein 0.9 to 1.1 equivalents of BF3OEt3 are present, based on the compound of formula (X).

[0631] 80. R 1 The method of any one of embodiments 70 to 79, wherein is —C(O)—Z.

[0632] 81. The process of embodiment 80, wherein Z is methyl or 4-nitrophenyl.

[0633] 82. The method of preparation of embodiment 81, wherein Z is 4-nitrophenyl.

[0634] 83. The method of any one of embodiments 70-82, wherein the compound of formula (XI):

[0635] [ka]

[0636] to a compound of formula (X).

[0637] 84. The method of embodiment 83, wherein the compound of formula (XI) has formula (XI'):

[0638] [ka]

[0639] 85. The process of embodiment 84, wherein converting the compound of formula (XI) to the compound of formula (X) comprises contacting the compound of formula (XI) with an acid anhydride or an acid halide to obtain the compound of formula (X).

[0640] 86. The process of embodiment 85, wherein contacting the compound of formula (XI) with the acid anhydride or acid halide is carried out in the presence of a sixth base and a catalyst.

[0641] 87. The sixth base is triethylamine and the catalyst is The method of manufacturing of embodiment 86, wherein the pyridine is 4-dimethylaminopyridine (DMAP).

[0642] 88. The method of any one of embodiments 85-87, wherein the acid anhydride is acetic anhydride.

[0643] 89. The method of any one of embodiments 85-87, wherein the acid halide is 4-nitrobenzoyl chloride.

[0644] 90. The process of any one of embodiments 83-89, further comprising recrystallizing the compound of formula (X) from a suitable solvent.

[0645] 91. The method of manufacturing of embodiment 90, wherein the suitable solvent comprises acetone and water.

[0646] 92. The method of any one of embodiments 83-91, wherein the compound of formula (XII):

[0647] [ka]

[0648] to a compound of formula (XI).

[0649] 93. The process of embodiment 92, wherein converting the compound of formula (XII) to the compound of formula (XI) comprises treating the compound of formula (XII) with a reducing reagent.

[0650] 94. The method of embodiment 93, wherein the reducing reagent is selected from diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, titanocenes containing polymethylhydrosiloxanes, and phenylsilanes.

[0651] 95. The method of preparation of embodiment 93 or embodiment 94, wherein the reducing reagent is diisobutylaluminum hydride.

[0652] 96. The method of any one of embodiments 92-95, wherein the compound of formula (XIII):

[0653] [ka]

[0654] to a compound of formula (XII).

[0655] 97. The process of embodiment 96, wherein converting the compound of formula (XIII) to the compound of formula (XII) comprises hydrogenating the compound of formula (XIII).

[0656] 98. The process of embodiment 97, wherein the hydrogenation is carried out in the presence of a hydrogenation catalyst.

[0657] 99. The process of embodiment 98, wherein the hydrogenation catalyst is selected from Pd / C, Pd / Al2O3, Pt / C, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH)2, homogeneous chiral Ru, and Rh.

[0658] 100. The process of any one of embodiments 97-99, wherein the hydrogenation is carried out in the presence of a suitable hydrogen source.

[0659] 101. The method of claim 100, wherein the hydrogen source is selected from H2 gas, NiCl2 / NaBH4 in methanol, and Et3SiH.

[0660] 102. The process of any one of embodiments 97-101, wherein the hydrogenation is carried out in the presence of H2 gas using Pd / C as a catalyst.

[0661] 103. The method of embodiment 102, wherein the H2 gas is present at a pressure of 5 to 40 barg.

[0662] 104. The process of any one of embodiments 97-103, wherein the hydrogenation is carried out in a solvent mixture comprising 2-propanol, tetrahydrofuran, and catalytic trifluoroacetic acid.

[0663] 105. The process of any one of embodiments 97-104, wherein the hydrogenation is carried out at a temperature of 10 to 50°C.

[0664] 106. The method of any one of embodiments 96-105, wherein the compound of formula (XIV):

[0665] [ka]

[0666] with a compound of formula (XV):

[0667] [ka]

[0668] to obtain a compound of formula (XIII).

[0669] 107. The process of embodiment 106, wherein the contacting of the compound of formula (XIV) with the compound of formula (XV) is carried out in the presence of a coupling agent or a chlorinating agent.

[0670] 108. The method of embodiment 107, wherein the coupling agent is selected from CDI and T3P.

[0671] 109. The process of embodiment 107, wherein the chlorinating agent converts the compound of formula (VIV) into an acid chloride, and the acid chloride is not isolated before reacting with the compound of formula (XV).

[0672] 110. The process of embodiment 107 or embodiment 109, wherein the chlorinating agent is selected from oxalyl chloride and thionyl chloride.

[0673] 111. The method of any one of embodiments 1 to 43, 65, or 66, comprising producing a compound of formula (XXII):

[0674] [ka]

[0675] to a compound of formula (IV).

[0676] 112. The process of embodiment 111, wherein converting the compound of formula (XXII) to the compound of formula (IV) comprises treating the compound of formula (XXII) with an oxidizing agent.

[0677] 113. The method of embodiment 112, wherein the oxidizing agent comprises TEMPO and NaOCl.

[0678] 114. The method of any one of embodiments 111 to 113, wherein the compound of formula (XXIII):

[0679] [ka]

[0680] to a compound of formula (XXII).

[0681] 115. The process of embodiment 114, wherein converting the compound of formula (XXIII) to the compound of formula (XXII) comprises hydrogenating the compound of formula (XXIII).

[0682] 116. The process of embodiment 115, wherein hydrogenating the compound of formula (XXIII) is carried out in the presence of hydrogen and a palladium on carbon catalyst.

[0683] 117. The method of any one of embodiments 114-116, wherein the compound of formula (XXIV):

[0684] [ka]

[0685] to a compound of formula (XXIII).

[0686] 118. The process of embodiment 117, wherein converting the compound of formula (XXIV) to the compound of formula (XXIII) comprises treating the compound of formula (XXIV) with mesyl chloride in the presence of a seventh base.

[0687] 119. The method of preparation of embodiment 118, wherein the seventh base is triethylamine.

[0688] 120. The method of any one of embodiments 117-119, wherein the compound of formula (XXV) is:

[0689] [ka]

[0690] to a compound of formula (XXIV).

[0691] 121. The process of embodiment 120, wherein converting the compound of formula (XXV) to the compound of formula (XXIV) comprises treating the compound of formula (XXV) with methylmagnesium chloride.

[0692] 122. The method of preparation according to embodiment 120 or embodiment 121, wherein the compound of formula (XXVI):

[0693] [ka]

[0694] to a compound of formula (XXV) 123. The process of embodiment 122, wherein converting the compound of formula (XXVI) to the compound of formula (XXV) comprises treating the compound of formula (XXVI) with tetra-N-butylammonium fluoride (TBAF).

[0695] 124. The method of preparation according to embodiment 122 or embodiment 123, wherein the compound of formula (XXVII):

[0696] [ka]

[0697] to a compound of formula (XXVI).

[0698] 125. The process of embodiment 124, wherein converting the compound of formula (XXVII) to the compound of formula (XXVI) comprises treating the compound of formula (XXVII) with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride.

[0699] 126. The method of preparing a compound of formula (XXVIII):

[0700] [ka]

[0701] to a compound of formula (XXVII).

[0702] 127. The process of embodiment 126, wherein converting the compound of formula (XXVIII) to the compound of formula (XXVII) comprises treating the compound of formula (XXVIII) with benzyl-2,2,2-trichloroethane-imidate in the presence of a third acid.

[0703] 128. The method of embodiment 127, wherein the third acid is triflic acid.

[0704] 129. The method of any one of embodiments 126-128, wherein the compound of formula (XXIX):

[0705] [ka]

[0706] to a compound of formula (XXVIII).

[0707] 130. The process of embodiment 129, wherein converting the compound of formula (XXIX) to the compound of formula (XXVIII) comprises hydrogenating the compound of formula (XXIX).

[0708] 131. The process according to embodiment 130, wherein the hydrogenation of the compound of formula (XXIX) is carried out in the presence of NiCl2 / NaBH4 in methanol.

[0709] 132. A compound of the formula:

[0710] [ka] [ka] [ka]

[0711] During the ceremony, R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; Z is CN, halo, NO2, C1-C4 alkyl, C6-C optionally substituted with C1-C4 alkoxy, C1-C4 haloalkyl, and / or C1-C4 haloalkoxy 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl; R 2 is C1-C6 alkyl.

[0712] 133. A compound of the formula:

[0713] [ka] [ka]

[0714] 134. A compound of formula (I),

[0715] [ka]

[0716] wherein the compound is in a crystalline solid form.

[0717] 135. A compound of formula (I),

[0718] [ka]

[0719] A composition wherein the compound of formula (I) is in a crystalline solid form.

[0720] 136. The composition of embodiment 1, wherein at least 85% of the compound of formula (I) present in the composition is in crystalline solid form.

[0721] 137. The composition of embodiment 1, wherein at least 90% of the compound of formula (I) present in the composition is in crystalline solid form.

[0722] 138. The composition of embodiment 1, wherein at least 95% of the compound of formula (I) present in the composition is in crystalline solid form.

[0723] 139. The composition of embodiment 1, wherein substantially all of the compound of formula (I) present in the composition is in crystalline solid form.

[0724] 140. The composition of embodiment 135, wherein 100% of the compound of formula (I) present in the composition is in crystalline solid form.

[0725] 141. Compound of formula (I):

[0726] [ka]

[0727] and one or more pharmaceutically acceptable carriers or vehicles, wherein the compound of formula (I) is in crystalline solid form.

[0728] 142. The pharmaceutical composition of embodiment 1, wherein at least 85% of the compound of formula (I) present in the pharmaceutical composition is in crystalline solid form.

[0729] 143. The pharmaceutical composition of embodiment 1, wherein at least 90% of the compound of formula (I) present in the pharmaceutical composition is in crystalline solid form.

[0730] 144. The pharmaceutical composition of embodiment 1, wherein at least 95% of the compound of formula (I) present in the pharmaceutical composition is in crystalline solid form.

[0731] 145. The pharmaceutical composition of embodiment 141, wherein substantially all of the compound of formula (I) present in the composition is in crystalline solid form.

[0732] 146. The pharmaceutical composition of embodiment 141, wherein 100% of the compound of formula (I) present in the pharmaceutical composition is in crystalline solid form.

[0733] 147. The compound of embodiment 134, the composition of any one of embodiments 135-140, or the pharmaceutical composition of any one of embodiments 141-146, wherein the crystalline solid form is Form A.

[0734] 148. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one approximate peak position (°2θ±0.2) when measured using radioactivity.

[0735] 149. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0736] 150. Form A is 9.0, 30.7, and 32.1 Cu K α The compound, composition, or pharmaceutical composition of embodiment 1411.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 7, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least three approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0737] 151. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least four approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0738] 152. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least five approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0739] 153. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 6 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0740] 154. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least 7 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0741] 155. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least 8 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0742] 156. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 9 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0743] 157. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least 10 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0744] 158. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 11 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0745] 159. Form A: 9.0, 30.7, 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 12 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0746] 160. Form A is 9.0, 30.7, and 32.1 Cu K αThe compound, composition, or pharmaceutical composition of embodiment 1411.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 7, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 13 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0747] 161. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 14 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0748] 162. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 15 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0749] 163. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 16 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0750] 164. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 17 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0751] 165. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 18 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0752] 166. Form A: 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 Cu K α148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least 19 approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0753] 167. Cu K with Form A of 9.0, 30.7, and 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 32.1 α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising approximate peak positions (°2θ±0.2), when measured using radioactive rays.

[0754] 168. Form A is 13.4, 17.2, and 18.9 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) when measured using radioactivity.

[0755] 169. Form A is 13.4, 17.2, and 18.9 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0756] 170. Cu K of Form A is 13.4, 17.2, and 18.9. α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising approximate peak positions (°2θ±0.2), when measured using radioactive rays.

[0757] 171. Form A is 9.0, 11.4, and 20.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one approximate peak position (°2θ±0.2) when measured using radioactivity.

[0758] 172. Form A is 9.0, 11.4, and 20.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0759] 173. Cu K of Form A is 9.0, 11.4, and 20.1. α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising approximate peak positions (°2θ±0.2), when measured using radioactive rays.

[0760] 174. Form A is 13.7, 13.8, and 24.8 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) when measured using radioactivity.

[0761] 175. Form A is 13.7, 13.8, and 24.8 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0762] 176. Cu K of Form A is 13.7, 13.8, and 24.8. α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising approximate peak positions (°2θ±0.2), when measured using radioactive rays.

[0763] 177. Form A is 13.4, 17.2, and 18.9 Cu K α the approximate position (°2θ±0.2) of at least one peak as measured using radioactive rays; 9.0, 11.4, and 20.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) as measured using radioactive isotopes.

[0764] 178. Form A is 13.4, 17.2, and 18.9 Cu K α At least two approximate peak positions (°2θ±0.2) when measured using radioactive materials; 9.0, 11.4, and 20.1 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0765] 179. Form A is Cu K of 13.4, 17.2, and 18.9 α The approximate peak position (°2θ±0.2) when measured using radiation, and Cu K of 9.0, 11.4, and 20.1 α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising, when measured using radioactive rays, approximately:

[0766] 180. Form A is 13.4, 17.2, and 18.9 Cu K α the approximate position (°2θ±0.2) of at least one peak as measured using radioactive rays; 9.0, 11.4, and 20.1 Cu K α the approximate position (°2θ±0.2) of at least one peak as measured using radioactive rays; 13.7, 13.8, and 24.8 Cu K α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) as measured using radioactive isotopes.

[0767] 181. Form A is 13.4, 17.2, and 18.9 Cu K α At least two approximate peak positions (°2θ±0.2) when measured using radioactive materials; 9.0, 11.4, and 20.1 Cu K α At least two approximate peak positions (°2θ±0.2) when measured using radioactive materials; 13.7, 13.8, and 24.8 Cu K α148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least two approximate peak positions (°2θ±0.2) when measured using radioactive rays.

[0768] 182. Form A is Cu K of 13.4, 17.2, and 18.9 α The approximate peak position (°2θ±0.2) when measured using radiation, Cu K of 9.0, 11.4, and 20.1 α the approximate peak position (°2θ±0.2) as measured using radioactivity, and Cu K of 13.7, 13.8, and 24.8 α 148. The compound, composition, or pharmaceutical composition of embodiment 147, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising, when measured using radioactive rays, approximately:

[0769] 183. Form A is -74.5, -13 9 A solid having at least one peak at a chemical shift selected from -161.5 ppm and -161.5 ppm. 19 The compound, composition, or pharmaceutical composition of any one of embodiments 147-182, characterized by a F NMR spectrum.

[0770] 184. Form A is -74.5, -13 9 A solid having at least two peaks at chemical shifts selected from -161.5 ppm, -161.5 ppm, and -161.5 ppm. 19 The compound, composition, or pharmaceutical composition of any one of embodiments 147-182, characterized by a F NMR spectrum.

[0771] 185. Form A is -74.5, -13 9 Solids with peaks at chemical shifts of -161.5 ppm and -161.5 ppm 19The compound, composition, or pharmaceutical composition of any one of embodiments 147-182, characterized by a F NMR spectrum.

[0772] 186. Form A is a solid having at least one peak at a chemical shift selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0773] 187. Form A is a solid having at least two peaks at chemical shifts selected from 169.8, 25.1, and 11.6 ppm. 13 The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum of: 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 188. Form A is a solid having at least three peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0774] 189. Form A is a solid having at least four peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0775] 190. Form A is a solid having at least five peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0776] 191. Form A is a solid having at least six peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0777] 192. Form A is a solid having at least seven peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0778] 193. Form A is a solid having at least eight peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0779] 194. Form A is a solid having at least nine peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0780] 195. Form A is a solid having at least 10 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0781] 196. Form A is a solid having at least 11 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0782] 197. Form A is a solid having at least two peaks at chemical shifts selected from 169.8, 25.1, and 11.6 ppm at 1157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0783] 198. Form A is a solid having at least 13 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0784] 199. Form A is a solid having at least 14 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0785] 200. Form A is a solid having at least 15 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0786] 201. Form A is a solid having at least 16 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0787] 202. Form A is a solid having at least 17 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 176. The compound, composition, or pharmaceutical composition of any one of embodiments 147-175, characterized by a C NMR spectrum.

[0788] 203. Form A is a solid having at least 18 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0789] 204. Form A is a solid having at least 19 peaks at chemical shifts selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0790] 205. Form A is a solid having at least 20 peaks at chemical shifts selected from 169.8, 25.1, and 11.6 ppm. 13 The compound, composition, or pharmaceutical composition of any one of embodiments 147-18, characterized by a C NMR spectrum of 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 5.

[0791] 206. Form A is a solid having chemical shifts of 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. 13 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147-185, characterized by a C NMR spectrum.

[0792] 207. Form A has an orthorhombic crystal structure, a P212121 space group, and Cu K αThe compound, composition, or pharmaceutical composition according to any one of embodiments 147-206, characterized by a unit cell having dimensions measured at 100(2) K on an X-ray diffractometer equipped with radiation (λ=1.54178 Å).

[0793] a=7.0(1)Å α=90° b=8.3(1)Å, β=90° c = 38.8(1)Å γ = 90°.

[0794] 208. The compound, composition, or pharmaceutical composition of embodiment 207, wherein the X-ray diffractometer is a Bruker X-ray diffractometer.

[0795] 209. A pharmaceutical composition comprising: 45 to 55% by weight of a solid dispersion comprising a polymer and a compound of formula (II);

[0796] [ka]

[0797] 42 to 50% by weight of microcrystalline cellulose; 2 to 4% by weight of croscarmellose sodium; 0.5 to 1.5% by weight of magnesium stearate.

[0798] 210. The pharmaceutical composition described in embodiment 209, wherein the pharmaceutical composition is a tablet core composition.

[0799] 211. The pharmaceutical composition of embodiment 210, wherein the tablet core composition is coated with a tablet coating.

[0800] 212. The pharmaceutical composition of embodiment 211, wherein the tablet coating is Opadry Blue.

[0801] 213. The pharmaceutical composition of any one of embodiments 209-212, wherein the pharmaceutical composition comprises about 50 mg of the compound of formula (II).

[0802] 214. A pharmaceutical composition described in any one of embodiments 209-213, wherein the polymer is HPMCAS.

[0803] 215. The pharmaceutical composition of any one of embodiments 209-214, wherein the solid dispersion comprises 70-80% by weight of polymer and 20-30% by weight of compound of formula (II).

[0804] 216. The pharmaceutical composition of embodiment 215, wherein the solid dispersion comprises about 75% by weight of the polymer and about 25% by weight of the compound of formula (II).

[0805] 217. The pharmaceutical composition of any one of embodiments 209-216, wherein the pharmaceutical composition comprises about 50% by weight of the solid dispersion, about 46% by weight of microcrystalline cellulose, about 3% by weight of croscarmellose sodium, and about 1.0% by weight of magnesium stearate.

[0806] 218. A pharmaceutical composition described in any one of embodiments 209-217, wherein the pharmaceutical composition comprises an intragranular blend and an extragranular blend.

[0807] 219. The pharmaceutical composition of embodiment 218, wherein the intragranular blend comprises about 200 mg of solid dispersion, about 93.6 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 0.4 mg of magnesium stearate, and the extragranular blend comprises about 90.4 mg of microcrystalline cellulose, about 6.0 mg of croscarmellose sodium, and about 3.6 mg of magnesium stearate. [Example]

[0808] Common Method 1 H NMR (400 MHz) spectra were obtained as solutions in suitable deuterated solvents such as dimethylsulfoxide-d6 (DMSO-d6).

[0809] Unless otherwise specified, X-ray powder diffraction (XRPD) spectra were recorded in reflectance mode at room temperature using a PANalytical Empyrean system equipped with a sealed-tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA using copper wire (1.54060 Å). Powder samples were placed in a back-filled sample holder and loaded into the instrument. Samples were scanned over the range of approximately 3° to approximately 40° 2θ with a step size of 0.0131° and 49.73 seconds per step.

[0810] Unless otherwise stated, solid-state NMR analyses were performed using a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. Samples were packed into a 4 mm ZrO rotor and spun under magnetic angular spinning (MAS) conditions, typically with the spin speed set at 12.5 kHz. 13 To set the recycle delay characteristic of a C cross-polarization (CP) MAS experiment, the proton relaxation time is 1 Measured using H MAS T1 saturation recovery relaxation experiments. 19 To set the recycle delay for the F MAS experiment, ...

Claims

1. A process for preparing a compound of formula (I) comprising: 【Chemistry 143】 Compound of formula (IV): 【Chemistry 144】 or a salt thereof to the compound of formula (I).

2. 10. The method of claim 1, wherein converting the compound of formula (IV) to the compound of formula (I) comprises preparing a compound of formula (VI): 【Chemistry 145】

3. Preparing the compound of formula (VI) may involve preparing the compound of formula (IV) or the compound of formula (VII): 【Chemistry 146】 3. The method of claim 2, comprising contacting the

4. 10. The method of claim 1, wherein converting the compound of formula (IV) to the compound of formula (I) comprises preparing a compound of formula (VII): 【Chemistry 147】

5. The method according to claim 3 or 4, wherein the compound of formula (VII) is obtained by contacting the compound of formula (IV) with (R)-α-methylbenzylamine.

6. 6. The method of any one of claims 1 to 5, wherein converting a compound of formula (IV) to the compound of formula (I) comprises converting the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) to a compound of formula (V): 【Chemistry 148】 to obtain a compound of formula (III): 【Chemistry 149】

7. 6. The method of any one of claims 1 to 5, wherein converting the compound of formula (IV) to the compound of formula (I) comprises converting the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) to a compound of formula (VIII): [Chemical 150]

8. 8. The method of claim 7, wherein converting the compound of formula (IV) to the compound of formula (I) comprises converting the compound of formula (VIII) to a compound of formula (V): 【Chemistry 151】 to obtain a compound of formula (III): 【Chemistry 152】

9. 9. The method of claim 6 or 8, wherein converting the compound of formula (IV) to the compound of formula (I) further comprises converting the compound of formula (III) to the compound of formula (I).

10. 10. The process of any one of claims 1 to 9, further comprising recrystallizing the compound of formula (I) from a suitable solvent to obtain crystalline Form A of the compound of formula (I).

11. A process for preparing a compound of formula (II): 【Chemistry 153】 Compound of formula (VII): 【Chemistry 154】 to the compound of formula (II).

12. 12. The method of claim 11, wherein converting the compound of formula (VII) to the compound of formula (II) comprises converting the compound of formula (VII) to a compound of formula (XXI): 【Chemistry 155】 to obtain a compound of formula (XX). 【Chemistry 156】

13. 12. The method of claim 11 , wherein converting the compound of formula (VII) to the compound of formula (II) comprises converting the compound of formula (VII) to a compound of formula (VIII): 【Chemistry 157】

14. 13. The method of claim 12, wherein converting the compound of formula (VII) to the compound of formula (II) further comprises converting the compound of formula (XX) to the compound of formula (II).

15. 15. The method of claim 14, wherein converting the compound of formula (XX) to the compound of formula (II) comprises treating the compound of formula (XX) with ammonia to obtain the compound of formula (II).

16. The method according to any one of claims 11 to 15, comprising reacting a compound of formula (IV): 【Chemistry 158】 to said compound of formula (VII).

17. 17. The method of claim 16, wherein converting the compound of formula (IV) to the compound of formula (VII) comprises contacting the compound of formula (IV) with (R)-α-methylbenzylamine.

18. 18. The method of any one of claims 1 to 10, 16, or 17, comprising reacting a compound of formula (IX): 【Chemistry 159】 to said compound of formula (IV).

19. 19. The method of claim 18, wherein the compound of formula (X): [Chemical 160] to the compound of formula (IX), During the ceremony, R １ is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z ２ and Z is CN, halo, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, and / or C １ -C ４ C optionally substituted with haloalkoxy ６ -C １０ Aryl; C １ -C ４ alkyl; and C １ -C ４ haloalkyl.

20. 20. The method of claim 19, wherein the compound of formula (X) has the formula (X'): 【Chemistry 161】

21. 21. The method of claim 19 or 20, comprising reacting a compound of formula (XI): 【Chemistry 162】 to said compound of formula (X).

22. 22. The method of claim 21 , wherein the compound of formula (XI) has the formula (XI′): 【Chemical 163】

23. 23. The method of claim 21 or 22, comprising reacting a compound of formula (XII): 【Chemistry 164】 to said compound of formula (XI).

24. 24. The method of claim 23, comprising reacting a compound of formula (XIII): 【Chemistry 165】 to said compound of formula (XII).

25. 25. The method of claim 24, comprising reacting a compound of formula (XIV): 【Chemistry 166】 with a compound of formula (XV): 【Chemistry 167】 to obtain the compound of formula (XIII).

26. A compound of the formula: 【Chemistry 168-1】 【Chemistry 168-2】 【Chemistry 168-3】 (In the formula, R １ is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z ２ and Z is CN, halo, NO ２ , C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ haloalkyl, and / or C １ -C ４ C optionally substituted with haloalkoxy ６ -C １０ Aryl; C １ -C ４ alkyl; and C １ -C ４ haloalkyl; R ２ is C １ -C ６ alkyl).

27. A compound of the formula: 【Chemistry 169-1】 【Chemistry 169-2】

28. A compound of formula (I) 【Chemistry 170】 A compound that is in a crystalline solid form.

29. Compounds of formula (I) include: 【Chemistry 171】 A composition wherein said compound of formula (I) is in a crystalline solid form.

30. 30. The composition of claim 29, wherein at least 85% of the compound of formula (I) present in the composition is in crystalline solid form.

31. A compound of formula (I) with: 【Chemistry 172】 A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or vehicles, wherein the compound of formula (I) is in a crystalline solid form.

32. 32. The pharmaceutical composition of claim 31, wherein at least 85% of the compound of formula (I) present in the pharmaceutical composition is in crystalline solid form.

33. 33. The compound of claim 28, the composition of claim 29 or 30, or the pharmaceutical composition of claim 31 or 32, wherein the crystalline solid form is Form A.

34. Form A is CuK α 34. The compound, composition, or pharmaceutical composition of claim 33, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) selected from 9.0, 11.4, 13.4, 13.7, 13.8, 14.6, 15.3, 17.0, 17.2, 18.9, 20.1, 23.9, 24.5, 24.8, 26.3, 28.0, 28.1, 28.3, 30.7, and 32.1, as measured using radioactive rays.

35. Form A is CuK α 34. The compound, composition, or pharmaceutical composition of claim 33, characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising at least one approximate peak position (°2θ±0.2) selected from 13.4, 17.2, and 18.9, when measured using radioactive rays.

36. 34. The compound, composition, or pharmaceutical composition of claim 33, wherein Form A is Cu K selected from 13.4, 17.2, and 18.9 α at least one approximate peak position (°2θ±0.2) as measured using radioactive rays; Cu K selected from 9.0, 11.4, and 20.1 α at least one approximate peak position (°2θ±0.2) as measured using radioactive rays; 1. A compound, composition, or pharmaceutical composition characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising:

37. 34. The compound, composition, or pharmaceutical composition of claim 33, wherein Form A is Cu K selected from 13.4, 17.2, and 18.9 α at least one approximate peak position (°2θ±0.2) as measured using radioactive rays; Cu K selected from 9.0, 11.4, and 20.1 α at least one approximate peak position (°2θ±0.2) as measured using radioactive rays; Cu K selected from 13.7, 13.8, and 24.8 α at least one approximate peak position (°2θ±0.2) as measured using radioactive rays; 1. A compound, composition, or pharmaceutical composition characterized by an X-ray powder diffraction pattern (XRPD) pattern comprising:

38. Form A is a solid having at least one peak at a chemical shift selected from −74.5, −139.5, and −161.5 ppm. １９ 38. The compound, composition, or pharmaceutical composition of any one of claims 33 to 37, characterized by a F NMR spectrum.

39. Form A is a solid having at least one peak at a chemical shift selected from 169.8, 157.7, 151.3, 146.1, 142.8, 141.0, 135.3, 134.8, 126.4, 123.9, 122.6, 108.9, 85.1, 79.8, 70.2, 67.3, 59.3, 48.4, 44.0, 25.1, and 11.6 ppm. １３ 39. The compound, composition, or pharmaceutical composition of any one of claims 33 to 38, characterized by a C NMR spectrum.

39. The compound, composition, or pharmaceutical composition according to any one of claims 33 to 38, wherein Form A is a compound having an orthorhombic crystal system and a P2 １ 2 １ 2 １ Space group and Cu K α and a unit cell having the following dimensions measured at 100(2) K in an X-ray diffractometer equipped with radiation (λ=1.54178 Å): a=7.0(1)Å α=90° b=8.3(1)Å, β=90° c=38.8(1)Å γ=90°.

40. 1. A pharmaceutical composition comprising: 45-55% by weight of a solid dispersion comprising a polymer and a compound of formula (II); 【Chemistry 173】 42-50% by weight of microcrystalline cellulose; 2-4% by weight of croscarmellose sodium; 0.5 to 1.5% by weight of magnesium stearate.

41. 41. The pharmaceutical composition of claim 40, which is a tablet core composition.

42. 42. The pharmaceutical composition of claim 41, wherein the tablet core composition is coated with a tablet coating.

43. 43. The pharmaceutical composition according to any one of claims 40 to 42, comprising about 50 mg of the compound of formula (II).

44. 44. The pharmaceutical composition of any one of claims 40 to 43, comprising an intragranular blend and an extragranular blend.

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