Synthesis method of substituted tetrahydrofuran regulator of sodium channel

Abstract

Provided herein is a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof useful as sodium channel inhibitors. Also provided herein is a process for the preparation of compounds of Formula (II) and pharmaceutically acceptable salts thereof useful as sodium channel inhibitors. Methods for preparing various intermediate products and suitable salts thereof are also provided. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 430,568, filed December 6, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to injured tissue. However, in many cases, pain persists beyond its effectiveness, or patients would benefit from suppressing pain. Neuropathic pain is a form of chronic pain caused by sensory nerve damage (Dieleman, JP et al., "Incidence rates and treatment of neuropathic pain conditions in the general population". Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves and pain caused by individual nerve damage. Metabolic neuropathy includes post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. Individual nerve damage indications include post-amputation pain, postoperative nerve damage pain and nerve entrapment injury, such as neuropathic back pain.

[0004] Voltage-gated sodium channels (Na V ) is involved in pain signal transduction. V It is a biological mediator of electrical signaling because it mediates the rapid rise of the action potential of many excitable cell types (e.g., neurons, skeletal muscle cells, and cardiac myocytes). Evidence for the role of these channels in normal physiology, pathological conditions caused by mutations in sodium channel genes, preclinical studies in animal models, and clinical pharmacology of known sodium channel modulators all indicate that Na V Central role in pain perception (Rush, AM and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels) V1.8 Sodium Channels. Mol. Interv., 2007. 7(4): 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), 1849-64 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), 50-56 (2008). Na V Mediates the rapid rise of action potentials in a variety of excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and is therefore involved in initiating signal transduction in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, 3rd ed. (Sinauer Associates, Sunderland, MA, 2001)). V The role played in the initiation and propagation of neuronal signals, thus reducing Na V Antagonists of the current block or reduce nerve signal transmission and V Channels have been considered as possible targets for alleviating 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), pp. 144-58 (2008)). Several clinically useful analgesics have been identified as Na V Inhibitors of Na channels. Local anesthetics (such as lidocaine) inhibit VOther compounds that have been shown to effectively reduce pain, such as carbamazepine, lamotrigine, and tricyclic antidepressants, also have been shown to act through sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain, 6 Suppl. A, pp. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ current by the antidepressants sertraline and paroxetine. + currents by antidepressant sertraline and paroxetine). Journal of Membrane Biology (J. Membr. Biol.), 222(2), pp. 79-90 (2008).

[0005] Na V form a subfamily of the voltage-gated ion channel superfamily and include the family named Na V 1.1 to Na V 1.9 has 9 isoforms. The tissue localization of the nine isoforms is different. V 1.4 is the main sodium channel in skeletal muscle, and Na V 1.5 is the main sodium channel in myocardial cells. V 1.7, 1.8 and 1.9 are mainly located in the peripheral nervous system, while Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in the central and peripheral nervous systems. The nine isoforms have similar functional properties, but differ in the details of their voltage dependence and kinetics (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)).

[0006] After its discovery, Na V1.8 channels were identified as possible targets for analgesia (Akopian, AN, L. Sivilotti and JN Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). V 1.8 has been shown to be a sodium current carrier that sustains the discharge of action potentials in small dorsal root ganglion (DRG) neurons (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potential of nociceptive sensory neurons. + current,TTX-resistant Na + current, and Ca 2+ Current in the action potentials of nociceptive sensory neurons). Journal of Neuroscience (J. Neurosci.), 2002.22(23): p.10277-90). V 1.8 is involved in spontaneous firing in injured neurons, such as those that drive neuropathic pain (Roza, C. et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in injured sensory axons in mice. + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. Journal of Physiology, 2003. 550(Pt 3): 921-6; Jarvis, MF et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, reduces neuropathic and inflammatory pain in rats. V1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat). Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. USA), 2007. 104(20): p. 8520-5; Joshi, SK et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic pain states, but not in postoperative pain states. V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): 75-82; Lai, J. et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. V 1.8). Pain, 2002. 95(1-2): p. 143-52; Dong, XW et al., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): 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: 33; Black, JA et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. =Neuromas. Ann. Neurol., 2008. 64(6): 644-53; Coward, K. et al., Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): 41-50; Yiangou, Y. et al., SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Letters, 2006. Lett.), 2000.467(2-3): p. 249-52; Ruangsri, S. et al., Axonal voltage-gated sodium channel 1.8 (NaV1.8) Relationship of axonal voltage-gated sodium channel 1.8 (Na. V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.)《Journal of Biological Chemistry (J.Biol.Chem.)》286(46): p.39836-47). Expression of Na V The small DRG neurons of 1.8 include pain receptors involved in pain signaling. V 1.8 Mediating large-amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na+ currents, TTX-resistant Na+ currents, and Ca2+ currents in the action potential of nociceptive sensory neurons) + current,TTX-resistant Na + current, and Ca 2+ Current in the action potentials of nociceptive sensory neurons). Journal of Neuroscience (J. Neurosci.), 2002.22(23): p.10277-90). V 1.8 is required for the rapid repetitive action potentials in pain receptors and the spontaneous activity of injured neurons. (Choi, JS and SG Wixman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study) V 1.7 and Na V 1.8 sodium channels: a computer simulation study. J. Neurophysiol. 106(6): 3173-84; Renganathan, M., T.R. Cummins and S.G.W. Axman, “Contribution of Na(V)1.8 sodium channels to the electrogenic action potential of DRG neurons.” V)1.8sodium channels to action potentialelectrogenesis in DRG neurons. Journal of Neurophysiology, 2001.86(2):629-40; Roza, C. et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in injured sensory axons of mice. + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice). Journal of Physiology, 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V 1.8 appears to be a driver of hyperexcitability (Rush, AM et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences of the United States of America, 2006. 103(21): p. 8245-50). In some animal pain models, Na in DRG has been shown to be a driver of hyperexcitability. V 1.8 mRNA expression levels were increased (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(Pt2): 359-75; Strickland, IT et al., Changes in the expression of NaV1.7, NaV1.8, and NaV1.9 in different dorsal root ganglion populations innervating the rat knee joint in a chronic inflammatory joint pain model. V 1.7,Na V 1.8 and Na V1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain). European Journal of Pain, 2008. 12(5): 564-72; Qiu, F. et al., Increased expression of tetrodotoxin-resistant sodium channels NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. V 1.8 and Na V 1.9 within dorsal rootganglia in a rat model of bone cancer pain). Neurosci. Lett., 512(2): 61-6.

[0007] The present inventors have found that some voltage-gated sodium channel inhibitors have a poor therapeutic range (e.g., due to lack of Na V Therefore, there is still a need to develop selective voltage-gated sodium channel inhibitors, such as selective Na V 1.8 Inhibitors, and methods for their preparation. Summary of the Invention

[0008] In one aspect, the present invention relates to a process for preparing a compound of formula (I)

[0009]

[0010] or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the method comprises converting any one of the compounds of Formula (III), (IV), (VI)-(XV), and (XXII)-(XIX) to a compound of Formula (I) via chemistry described herein.

[0012] In a second aspect, the present invention relates to a method for preparing the following compound:

[0013]

[0014] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the method comprises converting any one of the compounds of Formula (IV), (VI)-(XV), (XX), and (XXII)-(XIX) to a compound of Formula (II) via chemistry described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Depicted is an XRPD pattern characteristic of Compound (VII), Form A.

[0017] Figure 2 Depicted is an XRPD pattern characteristic of Compound (VI), Form A.

[0018] Figure 3 Depicted is an XRPD pattern characteristic of Compound (I), Form A.

[0019] Figure 4 Depicted is the solid state of Compound (I), Form A 13 C NMR spectral characteristics.

[0020] Figure 5 Depicted is the solid state of Compound (I), Form A 19 F NMR spectral characteristics.

[0021] Figure 6 Depicted is the XRPD pattern of a spray-dried dispersion of Compound II of Example 11.

[0022] Figure 7A The XRPD pattern of the SDD tablet composition of Example 11 in the range of about 3° to about 40°2θ is depicted.

[0023] Figure 7B The XRPD pattern of the SDD tablet composition of Example 11 in the range of about 14° to about 16° 2Θ is depicted.

[0024] Figure 8A Depicts the solid state of the SDD tablet composition of Example 11 19 F NMR spectral characteristics.

[0025] Figure 8B Depicts the solid state of the powder of the SDD tablet composition of Example 11 13 C NMR spectral characteristics. DETAILED DESCRIPTION

[0026] 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 can prepare compounds of formula (I) from any one of compounds of formula (III), (IV), and (VI)-(XV), as described in Scheme A below. In other embodiments, one skilled in the art can prepare compounds of formula (I) from any one of compounds of formula (III), (IV), and (XXII)-(XIX), as summarized in Schemes A and C below. In some embodiments, one skilled in the art can prepare compounds of formula (II) from any one of compounds of formula (IV), (VI)-(XV), and (XX), as described in Scheme B below. In other embodiments, one skilled in the art can prepare compounds of formula (II) from any one of compounds of formula (IV), (XX), and (XXII)-(XIX), as summarized in Schemes B and C below.

[0027] Scheme A. Exemplary methods for preparing compounds of formula (I).

[0028]

[0029] in:

[0030] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; and

[0031] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0032] Scheme B. Exemplary methods for preparing compounds of formula (II).

[0033]

[0034] in:

[0035] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; and

[0036] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0037] Scheme C. Exemplary methods for preparing compounds of formula (IV).

[0038]

[0039] In one aspect, the method steps described herein may refer to the conversion of a starting compound of formula (III), (IV), (VI)-(XV), and (XXII)-(XIX) into a compound of formula (I). It will be appreciated by those skilled in the art that such methods may 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) into a compound of formula (I) proceeds through intermediate compounds (VII) and (III). Thus, it will be appreciated by those skilled in the art that the methods described for the conversion of a compound of formula (IV) into a compound of formula (I) may 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) into a compound of formula (I) proceeds through the preparation of intermediate compounds (III), (VII), (IV), and (IX)-(XII). Thus, it will be appreciated by those skilled in the art that the methods described for the conversion of a compound of formula (XIII) into a compound of formula (I) may be used to prepare any of intermediate compounds (III), (VII), (IV), and (IX)-(XII) using a compound of formula (XIII) as a starting material. In other embodiments, the compound of formula (IV) is converted to the compound of formula (I) via intermediate compounds (III), (VI), and (VII). In other embodiments, the compound of formula (IV) is converted to the compound of formula (I) via intermediate compounds (III), (VII), and (VIII). In other embodiments, the compound of formula (IV) is converted to the compound of formula (I) via intermediate compounds (III), (VI), (VII), and (VIII).

[0040] On the other hand, the method steps described herein may refer to the conversion of a starting compound of formula (IV), (VI)-(XV), (XX) and (XXII)-(XIX) into a compound of formula (II). It will be understood by those skilled in the art that such methods can also be used to prepare any intermediate between any starting compound and the compound of formula (II). For example, in some embodiments, the conversion of the compound of formula (IV) into the compound of formula (II) passes through intermediate compounds (VII) and (XX). Therefore, it will be understood by those skilled in the art that the method described for the conversion of the compound of formula (IV) into the compound of formula (II) can be used to prepare any of the intermediate compounds (VII) and (XX) from the compound of formula (IV). Similarly, in some embodiments, the conversion of the compound of formula (XIII) into the compound of formula (II) passes through the preparation of intermediate compounds (IV), (VII), (IX)-(XII) and (XX). Therefore, it will be understood by those skilled in the art that the method described for the conversion of the compound of formula (XIII) into the compound of formula (II) can be used to prepare any of the intermediate compounds (IV), (VII), (IX)-(XII) and (XX) using the compound of formula (XIII) as a starting material. In other embodiments, the compound of formula (IV) is converted to the compound of formula (II) via intermediate compounds (VI), (VII), and (XX). In other embodiments, the compound of formula (IV) is converted to the compound of formula (II) via intermediate compounds (VII), (VIII), and (XX). In other embodiments, the compound of formula (IV) is converted to the compound of formula (I) via intermediate compounds (VI), (VII), (VIII), and (XX).

[0041] Therefore, the present application contemplates the preparation of intermediate compounds (III), (IV), (VI)-(XV), (XX) and (XXII)-(XIX) using any intermediate or starting material prior to the prepared intermediate as a starting material. For example, intermediate compound (III) can be prepared using any of compounds (IV), (VI)-(XV) and (XXII)-(XXIX) as a starting material. Similarly, compound (XX) can be prepared using any of compounds (IV), (VI)-(XV) and (XXII)-(XXIX) as a starting material.

[0042] In another aspect, the present invention provides a method for preparing a compound of formula (I), comprising reacting a compound of formula (IV):

[0043]

[0044] or a salt thereof is converted into a compound of formula (I).

[0045] In some embodiments, the method of converting a compound of formula (IV) to a compound of formula (I) comprises preparing a compound of formula (VI):

[0046]

[0047] It may also be referred to as the quinine salt of the compound of formula (IV).

[0048] In some embodiments, the compound of formula (VI) can be prepared directly from the compound of formula (IV) by contacting the compound of formula (IV) with quinine in a suitable solvent. In some embodiments, the compound of formula (VI) can be prepared by dissolving the compound of formula (IV) and quinine in a suitable solvent. In some embodiments, the suitable solvent is a polar solvent. Those skilled in the art will appreciate that there are many solvents compatible with converting the compound of formula (IV) into the compound of formula (VI), including but not limited to: isopropanol, n-heptane, DCM, toluene, EtOAc, MTBE, acetonitrile, 2-MeTHF, MEK and combinations thereof. In some embodiments, the compound of formula (IV) is converted into the compound of formula (VI) in the presence of DCM, isopropanol, n-heptane and / or combinations thereof.

[0049] In some embodiments, the method of preparing a compound of formula (VI) comprises preparing a compound of formula (VIII):

[0050]

[0051] 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) may be converted to the compound of formula (VI) using any method known to those skilled in the art.

[0052] In some embodiments, the compound of formula (VI) can be prepared by contacting the compound of formula (VII) with quinine in a suitable solvent. In some embodiments, the compound of formula (VI) can be prepared by dissolving the compound of formula (VII) and quinine in a suitable solvent. In some embodiments, the suitable solvent is a polar solvent. It will be appreciated by those skilled in the art that there are many solvents compatible with converting the compound of formula (VII) into the compound of formula (VI), including but not limited to isopropyl alcohol, n-heptane, DCM, toluene, EtOAc, MTBE, acetonitrile, 2-MeTHF, MEK and combinations thereof. In some embodiments, the compound of formula (VII) is converted into the compound of formula (VI) in the presence of DCM, isopropyl alcohol, n-heptane and / or combinations thereof.

[0053] In some embodiments, compounds of formula (VI) can be prepared from compounds of formula (VII) by first converting the compound of formula (VII) to the free base, ie, a compound of formula (IV):

[0054]

[0055] The compound of formula (VII) can be converted to the free base compound of formula (IV) by any method known to those 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 solution. In some embodiments, the aqueous acid solution is aqueous hydrochloric acid.

[0056] In some embodiments, the method of converting a compound of formula (IV) to a compound of formula (I) comprises preparing a compound of formula (VII):

[0057]

[0058] It may also be referred to as the (R)-AMB or (R)-α-methylbenzylamine salt of the compound of formula (IV).

[0059] In some embodiments, the compound of formula (VII) can be prepared directly from the compound of formula (IV) by contacting the compound of formula (IV) with (R)-α-methylbenzylamine. In some embodiments, the compound of formula (VII) can be prepared directly from the compound of formula (IV) by contacting the compound of formula (IV) with (R)-α-methylbenzylamine in a suitable solvent. In some embodiments, the compound of formula (VII) can be prepared directly from the compound of formula (IV) by dissolving the compound of formula (IV) and (R)-α-methylbenzylamine in a suitable solvent. One of ordinary skill in the art will appreciate that there are many solvents that are compatible with converting the compound of formula (IV) to the compound of formula (VII). In some embodiments, the suitable solvent is toluene.

[0060] In some embodiments, the method of converting a compound of formula (IV) to a compound of formula (I) comprises contacting a compound of formula (IV), a compound of formula (VI), or a compound of formula (VII) with a compound of formula (V):

[0061]

[0062] To obtain a compound of formula (III):

[0063]

[0064] In some embodiments, the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) is contacted with the compound of formula (V) in the presence of a coupling reagent and a base. In some embodiments, the compound of formula (IV) is contacted with the compound of formula (V) in the presence of a coupling reagent and a base. In some embodiments, the compound of formula (VI) is contacted with the compound of formula (V) in the presence of a coupling reagent and a base. In some embodiments, the compound of formula (VII) is contacted with the 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 are compatible with the method of coupling the compound of formula (V) to the compound of formula (IV), the compound of formula (VI), or the 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 of ordinary skill in the art will appreciate that many bases are compatible with the method of coupling the compound of formula (V) to the compound of formula (IV), the compound of formula (VI), or the 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, and NaOH, among others. In other embodiments, the base can 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.

[0065] In some embodiments, the compound of formula (VI) or (VII) is first converted to a free base, i.e., a compound of formula (IV), before contacting the compound of formula (V). The compound of formula (VI) or (VII) can be converted to a free base compound of formula (IV) by any method known to those of ordinary skill in the art. In some embodiments, the 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 solution. In some embodiments, the aqueous acid solution is aqueous hydrochloric acid.

[0066] In some embodiments, the method 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):

[0067]

[0068] In some embodiments, the method 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 method 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 method 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).

[0069] In some embodiments, the compound of formula (VI) or (VII) is first converted to a free base, i.e., a compound of formula (IV), before being converted to a compound of formula (VIII). The compound of formula (VI) or (VII) can be converted to a free base compound of formula (IV) by any method known to those of ordinary skill in the art. In some embodiments, the 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 solution. In some embodiments, the aqueous acid solution is aqueous hydrochloric acid.

[0070] In certain embodiments, converting compound of formula (IV), compound of formula (VI) or compound of formula (VII) into compound of formula (VIII) includes treating compound of formula (IV), compound of formula (VI) or compound of formula (VII) with a chlorinating agent. Any chlorinating agent suitable for chlorinated compound IV or its salt (i.e. compound (VI) or (VII)) can be used. In certain embodiments, the chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl) or diphenylphosphinyl chloride (DPPCl). In certain embodiments, the chlorinating agent is oxalyl chloride. In certain embodiments, compound of formula (VIII) can be used for the next reaction in the method for preparing compound of formula (I) without further purification or separation.

[0071] In some embodiments, the treatment of the compound of formula (IV), the compound of formula (VI), 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, a non-nucleophilic base may be included to remove the byproduct HCl produced during the chlorination reaction. Therefore, any suitable non-nucleophilic base known to a person skilled in the art can be used. Suitable non-nucleophilic bases are typically tertiary amines or aromatic amines, wherein the nitrogen in the amine base does not carry an H atom. The non-nucleophilic base can be a large base that is non-nucleophilic due to steric hindrance. Examples of suitable bases include Huning's base, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]11-7-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 not exceeding about 90°C.

[0072] In some embodiments, converting the compound of formula (IV) to the compound of formula (I) comprises contacting the compound of formula (VIII) with the compound of formula (V) to obtain the compound of formula (III). In some embodiments, contacting the compound of formula (VIII) with the compound of formula (V) is carried out in the presence of a base. One of ordinary skill in the art will appreciate that many bases are compatible with the reaction between the compound of formula (VIII) and the compound of formula (V). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is triethylamine.

[0073] In some embodiments, the method of converting a compound of formula (IV) into a compound of formula (I) further comprises converting a compound of formula (III) into a compound of formula (I). In some embodiments, converting a compound of formula (III) into a compound of formula (I) comprises removing a protecting group from the compound of formula (III) to obtain a compound of formula (I). In some embodiments, converting a compound of formula (III) into a compound of formula (I) comprises treating the compound of formula (III) with an acid and water, such as an aqueous solution of an acid. One of ordinary skill in the art will appreciate that many acids are compatible with the method of removing a protecting group from the compound of formula (III) to obtain a compound of formula (I). In some embodiments, the acid is an aqueous solution of trifluoroacetic acid.

[0074] In some embodiments, the method 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.

[0075] Intermediate compound (V) can be prepared, for example, by the method depicted in Scheme D below.

[0076] Scheme D. Methods for preparing compounds of formula (V).

[0077]

[0078] where R 2 It is a C1-C6 alkyl group.

[0079] In some embodiments, the method of preparing a compound of formula (I) further comprises reacting a compound of formula (XVI):

[0080]

[0081] Converted to a compound of formula (V), wherein R 2 is a C1-C6 alkyl group. In some embodiments, R 2 In other embodiments, R 2 In some embodiments, the compound of formula (XVI) is a compound of formula (XVI-A):

[0082]

[0083] In other embodiments, the compound of formula (XVI) is a compound of formula (XVI-B):

[0084]

[0085] In some embodiments, converting the compound of formula (XVI) to the compound of formula (V) comprises treating the compound of formula (XVI) with water under reflux. In other embodiments, converting the compound of formula (XVI) to the compound of formula (V) comprises treating the compound of formula (XVI) with a base and water. One of ordinary skill in the art will appreciate that many bases will be compatible with the method of converting the compound of formula (XVI) to the compound of formula (V). In some embodiments, the base is NaOH.

[0086] 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, suitable solvents include MTBE and n-heptane.

[0087] In some embodiments, the method of preparing a compound of formula (V) further comprises reacting a compound of formula (XVII):

[0088]

[0089] Converted into the compound of formula (XVI).

[0090] In some embodiments, 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 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.

[0091] In some embodiments, the method of preparing the compound of formula (V) further comprises reacting a compound of formula (XVIII):

[0092]

[0093]

[0094] Converted into the compound of formula (XVII).

[0095] In some embodiments, the method for converting a compound of formula (XVIII) to a compound of formula (XVII) comprises treating the compound of formula (XVIII) with 2,2-dimethoxypropane in the presence of an acid. One of ordinary skill in the art will appreciate that many acids are compatible with the method for converting a compound of formula (XVIII) to a compound of formula (XVII). In some embodiments, the acid is methanesulfonic acid.

[0096] In some embodiments, the method of preparing a compound of formula (V) further comprises reacting a compound of formula (XIX):

[0097]

[0098] Converted into the compound of formula (XVIII).

[0099] In some embodiments, converting the compound of formula (XIX) to the compound of formula (XVIII) comprises contacting the compound of formula (XIX) with a reducing agent. In some embodiments, the reduction of the compound of formula (XIX) to the compound of formula (XVIII) is accomplished enzymatically. In some embodiments, the compound of formula (XIX) is contacted with the reducing agent in the presence of an enzyme. In some embodiments, the enzyme comprises a ketoreductase. In some embodiments, the enzyme comprises a glucose dehydrogenase. In some embodiments, the enzyme comprises a ketoreductase 117297 and a glucose dehydrogenase 117446.

[0100] In some embodiments, the method 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 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.

[0101] In a second aspect, the present invention relates to a process for preparing a compound of formula (II):

[0102]

[0103] It comprises the compound of formula (VII):

[0104]

[0105] Converted into the compound of formula (II).

[0106] In some embodiments, converting the compound of formula (VII) to the compound of formula (II) comprises contacting the compound of formula (VII) with a compound of formula (XXI):

[0107]

[0108] To obtain a compound of formula (XX):

[0109]

[0110] In some embodiments, the compound of formula (VII) is contacted with the compound of formula (XXI) in the presence of a coupling agent and a base. One of ordinary skill in the art will appreciate that many coupling agents are compatible with the method of coupling the compound of formula (V) to the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII). For example, in some embodiments, the coupling agent is 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl), diphenylphosphinyl chloride (DPPCL), isobutyl chloroformate (IBCF), or propylphosphonic anhydride (T3P). In some embodiments, the coupling agent is T3P. One of ordinary skill in the art will appreciate that many bases are compatible with the method of coupling the compound of formula (V) to the compound of formula (IV), the compound of formula (VI), or the 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, Hunin's base, DABCO, and NaOH. In other embodiments, the base can 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.

[0111] In some embodiments, the compound of formula (VII) is first converted into a free base, i.e., a compound of formula (IV), before contacting the compound of formula (XXI). The compound of formula (VII) can be converted into a free base compound of formula (IV) by any method known to those of ordinary skill in the art. In some embodiments, the compound of formula (VII) is converted into a free base compound of formula (IV) by treating the compound of formula (VII) with an acidic aqueous solution. In some embodiments, the acidic aqueous solution is an aqueous hydrochloric acid solution.

[0112] In some embodiments, 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):

[0113]

[0114] In some embodiments, the compound of formula (VII) is first converted into a free base, i.e., a compound of formula (IV), before being converted into a compound of formula (VIII). The compound of formula (VII) can be converted into a free base compound of formula (IV) by any method known to those of ordinary skill in the art. In some embodiments, the compound of formula (VII) is converted into a free base compound of formula (IV) by treating the compound of formula (VII) with an aqueous acid solution. In some embodiments, the aqueous acid solution is an aqueous hydrochloric acid solution.

[0115] In certain embodiments, the conversion of compound of formula (VII) into compound of formula (VIII) comprises the free alkali compound or compound of formula (VII) processed with chlorinating agent for formula (IV). Any chlorinating agent suitable for chlorinated compound IV or its salt (i.e. compound (VII)) can be used. In certain embodiments, chlorinating agent is thionyl chloride, methanesulfonyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, isobutyl chloroformate (IBCF), pivaloyl chloride (PivCl) or diphenylphosphinyl chloride (DPPCl). In certain embodiments, chlorinating agent is oxalyl chloride. In certain embodiments, compound of formula (VIII) can be used for the next reaction in the method for preparing compound of formula (I) without further purification or separation.

[0116] In some embodiments, the treatment of 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, a non-nucleophilic base may be included to remove the byproduct HCl produced during the chlorination reaction. Therefore, any suitable non-nucleophilic base known to a person of ordinary skill in the art can be used. Suitable non-nucleophilic bases are typically tertiary amines or aromatic amines, wherein the nitrogen in the amine base does not carry an H atom. The non-nucleophilic base can be a large base that is non-nucleophilic due to steric hindrance. Examples of suitable bases include Huning's base, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]11-7-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 of compound IV or the compound of formula (VII) and the chlorinating agent is carried out at a temperature not exceeding about 90°C.

[0117] In some embodiments, converting the compound of formula (VII) into the compound of formula (II) comprises contacting the compound of formula (VIII) with the compound of formula (XXI) to obtain the compound of formula (XX). In some embodiments, contacting the compound of formula (VIII) with the compound of formula (XXI) is carried out in the presence of a base. One of ordinary skill in the art will appreciate that many bases will be compatible with the reaction between the compound of formula (VIII) and the compound of formula (XXI). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is triethylamine. One of ordinary skill in the art will appreciate that many solvents will be compatible with the reaction between the compound of formula (VIII) and the compound of formula (XXI). In some embodiments, the solvent is toluene. In some embodiments, the compound of formula (XX) is obtained by distributing the reaction mixture between an organic layer comprising ethyl acetate and toluene and an aqueous layer.

[0118] In some embodiments, the compound of formula (XX) (prepared by a free base compound of formula (IV), a compound of formula (VII) or a compound of formula (VIII)) can be purified, for example, by recrystallizing it from a solvent comprising 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 a solvent at or near the boiling point, and a second solvent is subsequently added until the solution becomes turbid. The turbid suspension is cooled to room temperature (or cooled with an ice bath), and the solid is subsequently filtered.

[0119] In some embodiments, converting a compound of formula (VII) into a compound of formula (II) further includes converting a compound of formula (XX) into a compound of formula (II). In some embodiments, converting a compound of formula (XX) into a compound of formula (II) includes treating a compound of formula (XX) with ammonia to obtain a compound of formula (II). In some embodiments, a compound of formula (XX) can be treated with ammonia in the presence of a suitable solvent. In some embodiments, a suitable solvent is methanol, ethanol, IPA, MeCN, THF, 2-MeTHF, water, or a mixture thereof. In some embodiments, treating a compound of formula (XX) with ammonia can be carried out in the presence of a weak non-nucleophilic base. In some embodiments, the base is selected from Mg (OMe) 2, CaCl 2, DIPEA, and K 2 CO 3. In some embodiments, ammonia is in the form of a solution of ammonia in a solvent, ammonia is in the form of a gas in which ammonia is bubbled into the reaction mixture, or in the form of ammonium hydroxide or an ammonium salt in which ammonia is generated in situ. In some embodiments, ammonia is in the form of a solution of ammonia in methanol. In some embodiments, ammonia is in the form of a solution of ammonia in methanol and tetrahydrofuran. In some embodiments, the in situ generation of ammonia includes reacting ammonium hydroxide or an ammonium salt with an acid. In some embodiments, treatment of the compound of formula (XX) with ammonia is carried out in a solvent mixture comprising methanol and tetrahydrofuran.

[0120] In some embodiments, the method 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.

[0121] 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 methods of preparing compounds of formula (I).

[0122] Although a person skilled in the art can design a method for producing a compound of formula (IV) or a salt thereof (i.e., a compound of formula (VI) or a compound of formula (VII)) for preparing a compound of formula (I) or (II), the inventors of the present application consider using the following method to prepare a compound of formula III.

[0123] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (IX):

[0124]

[0125] Converted into the compound of formula (IV).

[0126] In some embodiments, converting a compound of formula (IX) into a compound of formula (IV) includes 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 can be used. In some embodiments, a strong base (e.g., NaOH, KOH, etc.) or a strong acid (HCl, sulfuric acid, etc.) can 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) can be carried out in a solvent or a solvent mixture. For example, ethanol, methanol, 1-propanol, 2-propanol, dioxane, water, THF, or a mixture thereof can be used. The hydrolysis reaction can be carried out at about 25°C to 75°C, about 30°C to 70°C, about 35°C to 65°C, about 40°C to 60°C, about 45°C to 60°C, about 50°C to 60°C, or about 55°C. As used in this paragraph, the term "about" before the temperature range applies to both ends of the range. It also means ±2.5°C. In some embodiments, converting the compound of formula (IX) to the compound of formula (IV) comprises treating the compound of formula (IX) with a base. One of ordinary skill in the art will appreciate that many bases will be compatible with the method for converting the compound of formula (IX) to the compound of formula (IV). In some embodiments, the base is potassium hydroxide.

[0127] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (X):

[0128]

[0129] Converted into a compound of formula (IX),

[0130] in:

[0131] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; and

[0132] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0133] In some embodiments, the compound of formula (X) is a compound of formula (X'):

[0134]

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

[0136]

[0137] In some embodiments, R 1 In some embodiments, Z is -C(O)-Z. In some embodiments, Z is methyl or 4-nitrophenyl. In some embodiments, Z is 4-nitrophenyl.

[0138] In some embodiments, the compound of formula (X) is selected from:

[0139]

[0140] In some embodiments, the compound of formula (X) is a compound of formula (XA):

[0141]

[0142] In some embodiments, the compound of formula (X) is a compound of formula (XB):

[0143]

[0144] In some embodiments, the compound of formula (X) is a compound of formula (X'-A):

[0145]

[0146] In some embodiments, the compound of formula (X) is a compound of formula (X'-B):

[0147]

[0148] In some embodiments, converting the compound of formula (X) to the compound of formula (IX) comprises treating the compound of formula (X) with a cyaniding agent. In some embodiments, the cyaniding agent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, and HCN. In some embodiments, the cyaniding agent is trimethylsilyl cyanide. In some embodiments, the compound of formula (X) is treated with 1.35-1.65 equivalents of trimethylsilyl cyanide. In some embodiments, treating the compound of formula (X) with a cyaniding agent is carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is selected from boron trifluoride etherate (BF3·OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, and SnCl4. In some embodiments, the Lewis acid is BF 3. OEt2. In some embodiments, there is 0.9-1.1 equivalents of BF3OEt3 based on the compound of formula (X). The cyanation reaction can be carried out in an organic solvent such as toluene, dichloromethane, 2-methylTHF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, CPME, MTBE, DMAc, t-BuOAc, etc. In some embodiments, the cyanation reaction is carried out at a temperature between -28°C and 0°C or between -28°C and -12°C. In some embodiments, the cyanation reaction is quenched with acetone (e.g., about 1.0 equivalents of acetone). In some embodiments, the quenching is carried out at a temperature between -28°C and 0°C or between -28°C and -12°C. In some embodiments, the compound of formula (IX) is obtained by partitioning the reaction mixture between an organic layer comprising ethanol and an aqueous layer comprising an aqueous potassium hydroxide solution.

[0149] Other non-limiting examples of compounds of formula (X) include:

[0150]

[0151] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (XI):

[0152]

[0153] Converted into the compound of formula (X).

[0154] In some embodiments, the compound of formula (XI) has formula (XI'):

[0155]

[0156]

[0157] In some embodiments, the compound of formula (XI) has the formula (XI"):

[0158]

[0159] In some embodiments, converting the compound of formula (XI) to the compound of formula (X) comprises contacting the compound of formula (XI) with an anhydride or an acyl halide to obtain the compound of formula (X). In some embodiments, contacting the compound of formula (XI) with an anhydride or an acyl halide is carried out in the presence of a base and a catalyst. One of ordinary skill in the art will appreciate that there are many bases that are compatible with the method of converting the compound of formula (XI) to the compound of formula (X). In some embodiments, the base is a non-nucleophilic base. In some embodiments, the base is selected from TEA, pyridine, Hunin'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 anhydride is acetic anhydride. In some embodiments, the acyl halide is 4-nitrobenzoyl chloride. In some embodiments, converting the compound of formula (XI) to the compound of formula (X) is carried out in a polar solvent. In some embodiments, the polar solvent is selected from toluene, cyclopentyl methyl ether (CPME), dichloromethane, dichloroethane, pyridine, chloroform, acetonitrile, THF, 2-MeTHF, EtOAc, IPAC, or a combination thereof.

[0160] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises recrystallizing the compound of formula (X) from a suitable solvent. In some embodiments, suitable solvents include acetone, water, and combinations thereof.

[0161] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (XII):

[0162]

[0163] Converted into the compound of formula (XI).

[0164] In some embodiments, the conversion of the compound of formula (XII) into the compound of formula (XI) includes treating the compound of formula (XII) with a reducing agent. In some embodiments, the reducing agent is selected from diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, titanocene and phenylsilane with polymethylhydrogensiloxane. In some embodiments, the reducing agent is diisobutylaluminum hydride. The reduction reaction can be carried out in an organic solvent or a solvent mixture. Suitable solvents include toluene, dichloromethane, 2-methylTHF, THF, TFT, MTBE, CPME, heptane or a mixture thereof. The reaction can 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 can be carried out in the presence of CuCl, CuI, CuTol, CuBr, CuF, Cu(II)Cl2, DMAP, 2,6-lutidine, LiI or pyridine.

[0165] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (XIII):

[0166]

[0167] Converted into the compound of formula (XII).

[0168] In certain embodiments, the conversion of a compound of formula (XIII) into a compound of formula (XII) comprises the hydrogenation of a compound of formula (XIII). In certain embodiments, hydrogenation is carried out in the presence of a hydrogenation catalyst. In certain 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 certain embodiments, hydrogenation is carried out in the presence of a suitable hydrogen source. In certain embodiments, the hydrogen source is selected from H2 gas, NiCl2 / NaBH4 in methanol and Et3SiH. In certain embodiments, hydrogenation is carried out in the presence of H2 gas using Pd / C (such as Johnson Matthey catalog number A503032-5 or A503014-5) as a catalyst. The hydrogenation reaction can be carried out in an organic solvent at about 20 to 40 bar. In certain embodiments, the hydrogenation reaction can also be carried out in an organic solvent at about 5 to 40 bar. In some embodiments, the hydrogenation reaction can be carried out at a temperature of 10-50°C. Lower pressures can be used with high temperatures, and vice versa. For example, about 5 bar at about 40°C may be suitable. In contrast, about 15 to 20 bar at about 30°C may be suitable. Those skilled in the art can match the pressure, temperature, and reaction time to obtain the desired results. The hydrogenation reaction can be carried out in an organic solvent or a 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 comprising 2-propanol, tetrahydrofuran, and catalytic trifluoroacetic acid. The asymmetric hydrogenation reaction can 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 NH4BF4.

[0169] In some embodiments, the method of preparing a compound of formula (I) or (II) further comprises reacting a compound of formula (XIV):

[0170]

[0171] Contacting with a compound of formula (XV):

[0172]

[0173] To obtain the compound of formula (XIII).

[0174] In certain embodiments, contacting 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. In certain embodiments, the coupling agent is selected from CDI and T3P. The coupling reaction between the compound of formula (XIV) and the compound of formula (XV) can be carried out in the presence of a mild or non-nucleophilic base. Examples of mild or non-nucleophilic bases suitable for the coupling reaction between the compound of formula (XIV) and the compound of formula (XV) include imidazole, DIPEA, TEA, NMM, TBD, Na2CO3, K3PO4, DBU, DABCO and MTBD. In certain embodiments, mild or non-nucleophilic bases are imidazole, DIPEA, TEA, NMM or TBD. In certain embodiments, the base is K2CO3. The coupling reaction between the compound of formula (XIV) and the compound of formula (XV) can be carried out in a polar aprotic solvent. The example of the polar aprotic solvent applicable to the claims of the present application includes a solvent comprising MTBE, toluene, EtOAc, MeCN, THF, DMC, MeOAc, NMP, DMF, DMSO, THF, 2-MeTHF and a combination thereof. The coupling reaction between the compound of formula (XIV) and the compound of formula (XV) can be carried out between about 20°C and about 60°C, between about 25°C and about 55°C, between about 30°C and about 50°C, between about 30°C and about 45°C, between about 30°C and about 40°C or at about 35°C. As used in this paragraph, the term "about" means ± 2.5°C. In certain embodiments, the compound of formula (XIV) is converted into an acyl chloride by a chlorinating agent, which is not separated before reacting with the compound of formula (XV). The example of the chlorinating agent applicable to coupling the compound of formula (XIV) and the compound of formula (XV) includes oxalyl chloride, thionyl chloride, phosgene etc. In some embodiments, the chlorinating agent is selected from oxalyl chloride and thionyl chloride.

[0175] Alternatively, the compound of formula (IV) may be prepared by reacting a compound of formula (XXII):

[0176]

[0177] Prepared by converting into a compound of formula (IV).

[0178] 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.

[0179] In some embodiments, the compound of formula (XXII) can be prepared by reacting a compound of formula (XXIII):

[0180]

[0181] It is converted into the compound of formula (XXII).

[0182] 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, the hydrogenation of the compound of formula (XXIII) is carried out in the presence of hydrogen gas and a palladium / carbon catalyst.

[0183] In some embodiments, the compound of formula (XXIII) can be prepared by reacting a compound of formula (XXIV):

[0184]

[0185] It is converted into a compound of formula (XXIII).

[0186] In some embodiments, converting the compound of formula (XXIV) to the compound of formula (XXIII) comprises treating the compound of formula (XXIV) with methanesulfonyl chloride in the presence of a base. In some embodiments, the base is triethylamine.

[0187] In some embodiments, the compound of formula (XXIV) is prepared by separating the compound of formula (XXV):

[0188]

[0189] It is converted into the compound of formula (XXIV).

[0190] 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.

[0191] In some embodiments, the compound of formula (XXV) is prepared by converting the compound of formula (XXVI):

[0192]

[0193] It is converted into the compound of formula (XXV).

[0194] In some embodiments, 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).

[0195] In some embodiments, the compound of formula (XXVI) is prepared by separating the compound of formula (XXVII):

[0196]

[0197] It is converted into the compound of formula (XXVI).

[0198] 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.

[0199] In some embodiments, the compound of formula (XXVII) is prepared by separating the compound of formula (XXVIII):

[0200]

[0201] It is converted into the compound of formula (XXVII).

[0202] In some embodiments, converting the compound of formula (XXVIII) to the compound of formula (XXVII) comprises treating the compound of formula (XXVIII) with benzyl-2,2,2-trifluoroethane-imidate in the presence of an acid. In some embodiments, the acid is trifluoromethanesulfonic acid.

[0203] In some embodiments, the compound of formula (XXVIII) is prepared by converting the compound of formula (XXIX):

[0204]

[0205] It is converted into the compound of formula (XVIII).

[0206] 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 NiCl2 / NaBH4 in methanol.

[0207] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XIII) to a compound of formula (I).

[0208] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XII) to a compound of formula (I).

[0209] In some embodiments, the present invention relates to a method 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).

[0210] In some embodiments, the present invention relates to a method 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).

[0211] In some embodiments, the present invention relates to a method 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).

[0212] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (VIII) to a compound of formula (I).

[0213] In some embodiments, the present invention relates to a method 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).

[0214] In some embodiments, the present invention relates to a method 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).

[0215] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (III) to a compound of formula (I).

[0216] In some embodiments, the present invention relates to a method 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).

[0217] In some embodiments, the present invention relates to a method 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).

[0218] In some embodiments, the present invention relates to a method 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).

[0219] In some embodiments, the present invention relates to a method 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).

[0220] In some embodiments, the present invention relates to a method 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).

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

[0222] In some embodiments, the present invention relates to a method 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).

[0223] In some embodiments, the present invention relates to a method 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).

[0224] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XIII) to a compound of formula (II).

[0225] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XII) to a compound of formula (II).

[0226] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XI) to a compound of formula (II).

[0227] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (X) to a compound of formula (II).

[0228] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (IX) to a compound of formula (II).

[0229] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (VIII) to a compound of formula (II).

[0230] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (VI) to a compound of formula (II).

[0231] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (IV) to a compound of formula (II).

[0232] In some embodiments, the present invention relates to a method 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).

[0233] In some embodiments, the present invention relates to a method 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).

[0234] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XXIII) to a compound of formula (II).

[0235] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XXIV) to a compound of formula (II).

[0236] In some embodiments, the present invention relates to a method 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).

[0237] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XXVI) to a compound of formula (II).

[0238] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XXVII) to a compound of formula (II).

[0239] In some embodiments, the present invention relates to a method 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).

[0240] In some embodiments, the present invention relates to a method 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 the method described herein for converting a compound of formula (XXIX) to a compound of formula (II).

[0241] In some embodiments, the present invention relates to a method of preparing intermediate compounds of formula (III), (IV), and (VI)-(XIII) using the methods described herein.

[0242] In some embodiments, the present invention relates to a method for preparing a compound of formula (III) or a salt thereof, comprising converting any one of compounds of formula (IV) and (VI)-(XIII) to a compound of formula (III) using a method disclosed herein.

[0243] In some embodiments, the present invention relates to a method for preparing a compound of formula (VIII) or a salt thereof, comprising converting any one of the compounds of formulae (IV) and (VI), (VII) and (IX)-(XIII) to a compound of formula (VIII) using the methods disclosed herein.

[0244] In some embodiments, the present invention relates to a method for preparing a compound of formula (VI) or a salt thereof, comprising converting any one of compounds of formula (IV) and (VII) and (IX)-(XIII) to a compound of formula (VI) using a method disclosed herein.

[0245] In some embodiments, the present invention relates to a method for preparing a compound of formula (VII) or a salt thereof, comprising converting any one of compounds of formula (IV) and (IX)-(XIII) to a compound of formula (VII) using the methods disclosed herein.

[0246] In some embodiments, the present invention relates to a method for preparing a compound of formula (IV) or a salt thereof, comprising converting any one of compounds of formula (IX)-(XIII) to a compound of formula (IV) using a method disclosed herein.

[0247] In some embodiments, the present invention relates to a method for preparing a compound of formula (IX) or a salt thereof, comprising converting any one of compounds of formula (X)-(XIII) to a compound of formula (IX) using a method disclosed herein.

[0248] In some embodiments, the present invention relates to a method for preparing a compound of formula (X) or a salt thereof, comprising converting any one of compounds of formula (XI)-(XIII) to a compound of formula (X) using a method disclosed herein.

[0249] In some embodiments, the present invention relates to a method for preparing a compound of formula (XI) or a salt thereof, comprising converting any one of the compounds of formulae (XII)-(XIII) to a compound of formula (XI) using a method disclosed herein.

[0250] In some embodiments, the present invention relates 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 disclosed herein.

[0251] In some embodiments, the present invention relates to a method of preparing an intermediate compound of formula (XX) using the methods described herein.

[0252] In some embodiments, the present invention relates to a method for preparing a compound of formula (XX) or a salt thereof, comprising converting any one of compounds of formula (IV) and (VI)-(XIII) into a compound of formula (XX) using a method disclosed herein.

[0253] In some embodiments, the present invention relates to a method of preparing intermediate compounds of formula (III), (IV), (VI)-(VIII), and (XXII)-(XXIX) using the methods described herein.

[0254] In some embodiments, the present invention relates to a method for preparing a compound of formula (III) or a salt thereof, comprising converting any one of the compounds of formula (IV), (VI)-(VIII), and (XXII)-(XXIX) to a compound of formula (III) using a method disclosed herein.

[0255] In some embodiments, the present invention relates to a method for preparing a compound of formula (VIII) or a salt thereof, comprising converting any one of the compounds of formula (IV), (VI)-(VII), and (XXII)-(XXIX) to a compound of formula (VIII) using the methods disclosed herein.

[0256] In some embodiments, the present invention relates to a method for preparing a compound of formula (VI) or a salt thereof, comprising converting any one of compounds of formula (IV), (VII), and (XXII)-(XXIX) to a compound of formula (VI) using a method disclosed herein.

[0257] In some embodiments, the present invention relates to a method for preparing a compound of formula (VII) or a salt thereof, comprising converting any one of compounds of formula (IV) and (XXII)-(XXIX) to a compound of formula (VII) using a method disclosed herein.

[0258] In some embodiments, the present invention relates to a method for preparing a compound of formula (IV) or a salt thereof, comprising converting any one of compounds of formula (XXII)-(XXIX) to a compound of formula (IV) using a method disclosed herein.

[0259] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXII) or a salt thereof, comprising converting any one of compounds of formula (XXIII)-(XXIX) to a compound of formula (XXII) using a method disclosed herein.

[0260] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXIII) or a salt thereof, comprising converting any one of compounds of formula (XXIV)-(XXIX) to a compound of formula (XXIII) using a method disclosed herein.

[0261] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXIV) or a salt thereof, comprising converting any one of compounds of formula (XXV)-(XXIX) to a compound of formula (XXIV) using a method disclosed herein.

[0262] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXV) or a salt thereof, comprising converting any one of compounds of formula (XXVI)-(XXIX) to a compound of formula (XXV) using a method disclosed herein.

[0263] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXVI) or a salt thereof, comprising converting any one of compounds of formula (XXVII)-(XXIX) to a compound of formula (XXVI) using a method disclosed herein.

[0264] In some embodiments, the present invention relates to a method for preparing a compound of formula (XXVII) or a salt thereof, comprising converting any one of compounds of formula (XXVIII)-(XXIX) to a compound of formula (XXVII) using a method disclosed herein.

[0265] In some embodiments, the present invention relates 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 herein.

[0266] In some embodiments, the present invention relates to a method of preparing intermediate compounds of formula (IV), (VI)-(VIII), (XX), and (XXII)-(XXIX) using the methods described herein.

[0267] In some embodiments, the present invention relates to a method for preparing a compound of formula (XX) or a salt thereof, comprising converting any one of the compounds of formula (IV), (VI)-(VIII), and (XXII)-(XXIX) into a compound of formula (XX) using a method disclosed herein.

[0268] In some embodiments, the present invention relates to a method of preparing intermediate compounds of formula (V) and (XVI)-(XIX) using the methods described herein.

[0269] In some embodiments, the present invention relates to a method for preparing a compound of formula (V) or a salt thereof, comprising converting any one of compounds of formula (XVI)-(XIX) to a compound of formula (V) using a method disclosed herein.

[0270] In some embodiments, the present invention relates to a method for preparing a compound of formula (XVI) or a salt thereof, comprising converting any one of compounds of formula (XVII)-(XIX) to a compound of formula (XVI) using a method disclosed herein.

[0271] In some embodiments, the present invention relates to a method for preparing a compound of formula (XVII) or a salt thereof, comprising converting any one of compounds of formula (XVIII)-(XIX) to a compound of formula (XVII) using a method disclosed herein.

[0272] In some embodiments, the present invention relates 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 disclosed herein.

[0273] In a third aspect, the present invention relates to an intermediate compound selected from Table A below.

[0274] Table A. Intermediate compounds of the present invention.

[0275]

[0276]

[0277]

[0278] in:

[0279] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z or -P(O)Z2;

[0280] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 Aryl; C1-C4 alkyl; and C1-C4 haloalkyl; and

[0281] R 2 It is a C1-C6 alkyl group.

[0282] In some embodiments, the present invention relates to a compound selected from Table B below.

[0283] Table B. Intermediate compounds of the present invention.

[0284]

[0285]

[0286] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. In addition, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March's Advanced Organic Chemistry, 5th Edition, Smith, MB and March, J., eds., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference in their entirety.

[0287] As used herein, in any chemical structure or formula, such as in the following structures, bold or hashed direct bonds (respectively) attached to a stereocenter of the compound are )

[0288]

[0289] The relative stereochemistry of this stereocenter relative to other stereocenters to which bold or hashed direct bonds are attached is indicated.

[0290] As used herein, in any chemical structure or formula, such as in the following structures, a bold or hashed wedge-shaped bond (respectively) attached to a stereogenic center of a compound is )

[0291]

[0292] The absolute stereochemistry of the stereocenter is indicated, as well as the relative stereochemistry of the stereocenter with respect to other stereocenters to which bold or hashed wedge bonds are attached.

[0293] As used herein, the prefix "rac-" when used in conjunction with a chiral compound refers to a racemic mixture of the compound. In compounds with the "rac-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound.

[0294] As used herein, the prefix "rel-" when used in conjunction with a chiral compound refers to a single enantiomer of unknown absolute configuration. In compounds having the "rel-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound.

[0295] As used herein, when referring to the compounds described in this application, the term "compound" refers to a collection of molecules having the same chemical structure except for the possible presence of isotopic variations in the constituent atoms of the molecules. The term "compound" includes a collection of such molecules, regardless of the purity of a given sample containing the collection of molecules. Thus, the term "compound" includes such a collection of molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid or pharmaceutical composition, or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0296] As used herein, the term "halo" means F, Cl, Br, or I.

[0297] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having the specified number of carbon atoms, attached to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" is an alkyl radical having from one to six carbon atoms.

[0298] As used herein, the term "alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl group having the specified number of carbon atoms. For example, "C1-C6 alkoxy" is of the formula -OR a A group in which R a is an alkyl group having one to six carbon atoms.

[0299] As used herein, the term "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halo group. For example, a "C1-C6 haloalkyl" is an alkyl group having one to six carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0300] As used herein, the term "haloalkoxy" refers to an alkoxy group having the specified number of carbon atoms wherein one or more hydrogen atoms of the alkyl group are replaced with a halo group.

[0301] Unless otherwise specified, the compounds of the present 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. In addition, 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 present invention.

[0302] Unless otherwise indicated, in the specification and claims, any atom in any compound of the present invention not specifically designated as a particular isotope is intended to represent any stable isotope of the designated element. In examples, when an atom in any compound of the present invention is not specifically designated as a particular isotope, no work has been performed to enrich the atom for that particular isotope, and thus, one of ordinary skill in the art would understand that such atom is likely present at approximately the natural abundance isotopic composition of the designated element.

[0303] As used herein, the term "stable" when referring to an isotope means that the isotope is known not to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes that do not exhibit the decay patterns identified in VS Shirley and CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0304] As used herein, in the specification and claims, "H" means hydrogen and includes any stable isotope of hydrogen, i.e. 1 H and D. In examples where atoms are represented as "H," no work has been performed to enrich the atoms for specific isotopes of hydrogen, and thus one of ordinary skill in the art will understand that such hydrogen atoms are likely present at approximately the natural abundance concentration of hydrogen.

[0305] 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, the protium is present at a concentration of at least the natural abundance of protium at the designated position.

[0306] As used herein, "D", "d" and " 2 H" refers to deuterium.

[0307] In some embodiments, the compounds described herein include each constituent atom at approximately the natural abundance isotopic composition of a designated element.

[0308] In some embodiments, the compounds described herein and pharmaceutically acceptable salts thereof include 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 a designated element ("isotopically labeled" compounds and salts). Examples of commercially available stable isotopes suitable for use in the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as 2 H. 13 C. 15 N. 18 O. 17 O and 31 P.

[0309] Isotopically labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceutical agents. In some embodiments, isotopically labeled compounds and salts are deuterated ( 2 H) labeled. Deuterium ( 2 H) The labeled compounds and salts are therapeutically useful and have advantages over unlabeled 2 Potential therapeutic advantages of H-labeled compounds. In general, deuterium (H)-labeled compounds and salts are more effective than non-isotopically labeled compounds and salts due to the kinetic isotope effect described below. 2 Isotope-labeled compounds and salts may have increased metabolic stability. Higher metabolic stability translates directly into increased half-life or reduced dosage in vivo, which in most cases represents a preferred embodiment of the present invention. Isotope-labeled compounds and salts can generally be prepared by following the procedures disclosed in the synthetic schemes, examples, and related descriptions, substituting readily available isotope-labeled reactants for non-isotope-labeled reactants.

[0310] deuterium( 2 H) labeled compounds and salts can manipulate the oxidative metabolic rate of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction caused by isotope nuclear exchange, which in turn is caused by a change in the ground state energy of the covalent bonds involved in the reaction. The exchange of heavier isotopes generally causes a decrease in the ground state energy of the chemical bond, thereby causing a reduction in rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along a multi-product reaction coordinate, the product distribution ratio can be substantially changed. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, then k H / k D= 2-7 ​​rate differences are typical. For further discussion, see SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference.

[0311] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the invention, or a pharmaceutically acceptable salt thereof, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of that isotope.

[0312] When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated as deuterium, the isotopic enrichment factor for such compound (or salt) with respect to this atom is at least 3000 (approximately 45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (approximately 52.5% deuterium incorporation), at least 4000 (approximately 60% deuterium incorporation), at least 4500 (approximately 67.5% deuterium incorporation), at least 5000 (approximately 75% deuterium incorporation), at least 5500 (approximately 82.5% deuterium incorporation), at least 6000 (approximately 90% deuterium incorporation), at least 6333.3 (approximately 95% deuterium incorporation), at least 6466.7 (approximately 97% deuterium incorporation), at least 6600 (approximately 99% deuterium incorporation), or at least 6633.3 (approximately 99.5% deuterium incorporation).

[0313] The term "compound of formula followed by a number (usually Roman numerals)" and the term "compound" followed by the same number (Roman numerals or other) are used interchangeably. For example, "compound of formula V" and "compound V" refer to the same compound.

[0314] When referring to a chemical reaction, the term "react" means the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of the two reactants initially added, i.e., there may be one or more intermediates produced in the mixing that ultimately result in the formation of the indicated and / or desired product.

[0315] When referring to a reaction, the term "performed in a solvent" or "performed in the presence of a solvent" means that the substrate and reagents are dissolved or suspended in the specified solvent or dissolved in a solvent mixture containing the specified solvent.

[0316] The term "chromatographic purification" refers to any purification method based on differential retention on a stationary phase. Methods of chromatographic purification include flash chromatography, medium pressure liquid chromatography, preparative thin layer chromatography, and high performance liquid chromatography.

[0317] 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 transforming a first compound or salt into a second compound or salt in one or more chemical steps.

[0318] The term "acid" refers to a chemical substance 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, isobutyric acid, n-valeric acid, isovaleric 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, etc.

[0319] The term "base" refers to a chemical species whose conjugate acid has a pKa (in water) greater than 7. The term includes "inorganic bases" such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monobasic, dibasic, or ternary), sodium hydride, and potassium hydride. The term also includes "anionic organic bases" such as methyllithium, butyllithium, lithium diisopropylamide, and sodium acetate. The term also includes "neutral organic bases" such as trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, dimethylcyclohexylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl-n-nonylamine, tri-n-butylamine, di-n-hexylmethylamine, dimethyl-n-dodecylamine, tri-n-pentylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), dimethylaminopyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DABCO), BN), 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-trimethylpyridine, 2,4,5-trimethylpyridine, 2,5,6-trimethylpyridine, 2,4,6-trimethylpyridine, 3,4,5-trimethylpyridine, and 3,5,6-trimethylpyridine.

[0320] The term "alcohol protecting group" refers to a chemical moiety suitable for protecting an alcohol group from unwanted side reactions during a synthetic procedure. Common alcohol protecting groups include methyl, ethyl, isopropyl, benzyl, 2-tetrahydropyranyl, acetyl, trifluoroacetyl, trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl or triarylsilyl. Other alcohol protecting groups are also well known in the art. See, for example, PGM Wuts et al., Greene's Protective Groups in Organic Synthesis (4th edition, 2006).

[0321] The term "deprotection" refers to the step of reacting a compound or salt containing a protecting group (e.g., an alcohol protecting group) under conditions suitable for removing the protecting group and exposing the protected moiety. For example, where the compound or salt contains an alcohol protecting group, the term "deprotection" refers to reacting the compound or salt under conditions suitable for removing the alcohol protecting group and exposing the alcohol. The conditions for removing various protecting groups are well known in the art. See, for example, PGM Wuts et al., Green's Protective Groups in Organic Synthesis (4th ed. 2006).

[0322] The term "hydrogenation catalyst" refers to any homogeneous or heterogeneous catalyst that catalyzes the hydrogenolysis of a benzyl carbon-oxygen single bond. Suitable hydrogenation catalysts are well known in the art and include palladium on activated carbon, platinum oxide, and Raney Nickel.

[0323] When referring to the reaction between a carboxylic acid or an acyl halide and an amine, the term "coupling" refers to the net transformation of the carboxylic acid or acyl halide and the amine to form an amide. The term includes the direct reaction between the carboxylic acid and the amine, as well as the reaction between an activated derivative of the carboxylic acid (e.g., a derivative formed by reaction between the carboxylic acid and a coupling reagent) and the amine.

[0324] 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]pyridine 3-oxide hexafluorophosphate (HATU), and 1-hydroxybenzotriazole (HOBt).

[0325] The term "monovalent cation" refers to any cation having a charge of +1, such as alkali metal cations, NH4 + and tetraalkylammonium.

[0326] The term "alkali metal cation" refers to a cation derived from a Group I metal atom, including but not limited to lithium (Li + ), sodium (Na + ), potassium (K + ), rubidium (Rb + ) and cesium (Cs + ).

[0327] The term "substituted benzyl" refers to a benzyl group substituted with 1 to 3 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen and cyano.

[0328] The term "about" means that the stated number can vary by ±10% relative to that value. When the term defines a temperature, the stated temperature can vary by ±10%. For example, approximately 80°C means between 72°C and 88°C. When the term "about" defines a pressure, the term means that the pressure can vary by ±10%. Thus, approximately 100 bar means between 90 bar and 110 bar. When the term defines a quantity (e.g., an equivalent or weight), the term means that the quantity can vary by ±10%. For example, approximately 1 equivalent means between 0.9 and 1.1 equivalents. When the term defines a time, the term means that the stated time can vary by ±10%. For example, approximately 1 hour means between 0.9 and 1.1 hours.

[0329] The term "leaving group" is a chemical group that is readily displaced by a desired introduced chemical moiety. Thus, the selection of a particularly suitable leaving group is informed by its ability to be readily displaced by an introduced chemical moiety, such as a CN group. Suitable leaving groups are well known in the art, for example, see Advanced Organic Chemistry, Jerry March, 5th Supplementary Edition, pp. 351-357, John Wiley and Sons, NY.

[0330] As used herein, the term "cyanating agent" (e.g., trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, HCN, etc.) yields a compound of Formula IX. In one embodiment, the reaction between the cyanating agent (e.g., trimethylsilyl cyanide) and the compound of Formula IX can be carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is boron trifluoride etherate (BF3OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf, SnCl4, etc. In other embodiments, the Lewis acid is BF3OEt2. The cyanation reaction can be carried out in an organic solvent such as toluene, dichloromethane, 2-methylTHF, acetonitrile, methanol, 1,2-dichloroethane, nitromethane, etc.

[0331] Solid forms of compounds of the present invention

[0332] 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 the form of a crystalline solid.

[0333] Solid form of compound (I)

[0334] In some embodiments, the present invention relates to compounds of formula (I)

[0335]

[0336] wherein the compound is in the form of a crystalline solid.

[0337] 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.

[0338] 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 compounds of formula (I) present in the composition are in a crystalline solid form. In some embodiments, 100% of the compounds of formula (I) present in the pharmaceutical composition are in a crystalline solid form.

[0339] In some embodiments, the crystalline solid form of the compound of Formula (I) is Form A.

[0340] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): α When measured radiometrically, the peak position comprises 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, or at least 20 approximate peak positions (°2θ±0.2) selected from the group consisting of 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.

[0341] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): α When measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 13.4, 17.2, and 18.9.

[0342] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): αWhen measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 9.0, 11.4, and 20.1.

[0343] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): α When measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 13.7, 13.8, and 24.8.

[0344] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): α comprising at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 13.4, 17.2, and 18.9 when measured radiometrically; and when using Cu K α When measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 9.0, 11.4, and 20.1.

[0345] In some embodiments, Form A is characterized by the following X-ray powder diffraction pattern (XRPD pattern): α When measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 13.4, 17.2, and 18.9; when Cu K α comprising at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 9.0, 11.4, and 20.1 when measured radiometrically; and when using Cu K α When measured radiometrically, it comprises at least one approximate peak position, at least two approximate peak positions, or at least three approximate peak positions (°2θ±0.2) selected from 13.7, 13.8, and 24.8.

[0346] In some embodiments, Form A is characterized by a solid state 19 F NMR spectrum: having at least one peak, at least two peaks, or at least three peaks at chemical shifts selected from the group consisting of -74.5, -139.5, and -161.5 ppm.

[0347] In some embodiments, Form A is characterized by a solid state 13C NMR spectrum: having 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 twelve peaks, at least thirteen peaks, at least fourteen peaks, at least fifteen peaks, at least sixteen peaks, at least seventeen peaks, at least eighteen peaks, at least nineteen peaks, at least twenty peaks, or at least twenty-one peaks at a chemical shift selected from the group consisting 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.

[0348] In some embodiments, Form A is characterized by an orthorhombic crystal 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 having the following dimensions as determined by single crystal X-ray analysis: α=90°; β=90°; and γ=90°.

[0349] Other embodiments of the present disclosure are set forth in the following numbered clauses:

[0350] 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,

[0351] in:

[0352] The compound of formula (I) is in the form of a crystalline solid;

[0353] The crystalline solid form is Form A; and / or

[0354] Form A is characterized as an orthorhombic crystal system as determined by single crystal X-ray analysis.

[0355] 2. The compound, composition or pharmaceutical composition of clause 1, wherein Form A is characterized by a P212121 space group as determined by single crystal X-ray analysis.

[0356] 3. The compound, composition or pharmaceutical composition of clause 1 or 2, wherein Form A is characterized by a unit cell having the following dimensions as determined by single crystal X-ray analysis: α=90°; β=90°; and γ=90°.

[0357] 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.

[0358] Solid form of compound (II)

[0359] In some embodiments, the present invention relates to compounds of formula (II)

[0360]

[0361] wherein the compound is in the form of a crystalline solid.

[0362] In some embodiments, the crystalline solid form is Form B.

[0363] In some embodiments, Form B is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2 degrees): 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2 degrees): 12.8, 14.1, 15.2, 18.5, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2 degrees): 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, 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 five, at least six, at least seven, at least eight, or at least nine diffractions at the following angles (2θ ± 0.2 degrees): 12.0, 12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2 degrees): 7.6, 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, 27.4, 28.6, and 28.9. In other embodiments, Form B is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-six, at least twenty-three, at least twenty-three, at least twenty-three, at least twenty-three, at least twenty-three, at least twenty-three, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-two ...five, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-five, at least twenty-two , at least twenty-five, at least twenty-six, or at least twenty-seven diffraction XRPD patterns: 7.6, 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, 27.4, 28.6, and 28.9.

[0364] In some embodiments, Form B is characterized by a solid-state peak at the chemical shift 13C NMR spectrum: 172.5, 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, 23.0 and 13.1 ppm.

[0365] In some embodiments, Form B is characterized by a solid-state peak at the chemical shift 19 FNMR spectrum: -137.1 and -152.8 ppm.

[0366] In some embodiments, Form B is characterized by a DSC thermogram having a melting onset at 182 °C and a peak at 183 °C.

[0367] In some embodiments, Form B is characterized by peaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm -1 IR spectrum with a peak at .

[0368] In some embodiments, Form B is characterized by an orthorhombic crystal 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 having the following dimensions as determined by single crystal X-ray analysis: α=90°; β=90°; and γ=90°.

[0369] Uses of the compounds, pharmaceutically acceptable salts and compositions of the present invention

[0370] Pharmaceutically acceptable salts and compositions

[0371] As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus the compounds of the present invention and pharmaceutically acceptable salts thereof are suitable 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, postoperative pain (e.g., bunionectomy pain, hernia repair pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia. Thus, in another aspect of the present invention, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more other therapeutic agents. In some embodiments, the other therapeutic agent is a sodium channel inhibitor.

[0372] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. "Pharmaceutically acceptable salts" of the compounds of the present invention include any non-toxic salts that, after administration to a recipient, can directly or indirectly provide the compounds of the present invention or their inhibitory active metabolites or residues. The salt may be in pure form, in the form of a mixture (e.g., a solution, a suspension, or a colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "its inhibitory active metabolite or residue" means that its metabolite or residue is also an inhibitor of voltage-gated sodium channels.

[0373] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group 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 salts formed by other methods such as ion exchange used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Other 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, as appropriate.

[0374] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention (eg, a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0375] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, as used herein, including any and all solvents, diluents or other liquid vehicles, dispersion or suspension adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., to suit the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers and known preparation techniques for preparing pharmaceutically acceptable compositions. Unless any conventional carrier medium is incompatible with the compounds of the present invention, for example, due to producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component of the pharmaceutically acceptable composition, its use is considered to be within the scope of the present invention. Some examples of substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates, glycine, sorbic acid, or potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; lanolin; sugars, such as lactose, glucose, Sugars and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

[0376] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0377] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0378] Dosage form and route of administration

[0379] The compounds of the present invention (e.g., compounds of formula (I) or (II)) or pharmaceutically acceptable salts thereof can be 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 unit of an agent appropriate for the individual to be treated.

[0380] Depending on the condition being treated, the compounds of this invention or their pharmaceutically acceptable salts can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments or drops), buccally (e.g., via oral or nasal spray), etc.

[0381] 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 compounds of the present invention or their pharmaceutically acceptable salts, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, cosolvents, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, 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 include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0382] Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known technology. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, in the form of a solution in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used to prepare injectables.

[0383] They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium before use.

[0384] In order to prolong the therapeutic effect of the compounds of the present invention, it may be necessary to slow down the absorption of the compound or its pharmaceutically acceptable salt from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. An injectable depot form is manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer (e.g., polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0385] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present 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 melts in the rectum or vaginal cavity and releases the active compound.

[0386] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, a compound of the invention or a pharmaceutically acceptable salt thereof is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as 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) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0387] Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings well-known in enteric coatings and pharmaceutical formulations. It can optionally contain an emulsifier and can also have a composition that optionally releases the active ingredient in a delayed manner only in or in a certain part of the intestinal tract. The example of spendable embedding composition includes polymeric substances and waxes.

[0388] The active compound or salt can also be in a microencapsulated form with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well-known in pharmaceutical formulation technology. In such solid dosage forms, the active compound or salt can be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As commonly practiced, such dosage forms can also include other substances in addition to the inert diluent, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer.

[0389] The dosage form for topical or transdermal administration of the compound of the present invention or its pharmaceutically acceptable salt includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer that may be needed under sterile conditions. It is also contemplated that ophthalmic preparations, ear drops and eye drops are within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0390] Solid dispersions and tablets

[0391] In another aspect, the present invention relates to a solid dispersion (e.g., a spray-dried dispersion) comprising a compound of the 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. Spray drying generally involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to promote drying of the droplets. For example, a liquid solution containing a compound of the invention (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, and at least one polymer can be sprayed into a warm, filtered air stream, which evaporates the solvent and conveys the dried product to a collector. The evaporated solvent and exhaust gases are removed from the collector and can be sent to a condenser to capture the solvent. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD series of spray dryers manufactured by Niro) (see US2004 / 0105820, US2003 / 0144257).

[0392] Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th edition, R.H. Perry, D.W. Green and 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.

[0393] An additional drying step may be required after spray drying to ensure removal of the solvent. 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, drum drying, or double cone vacuum drying (e.g., from about room temperature to about 200° C.).

[0394] In some embodiments, the solvent used in spray drying is a volatile solvent. For example, a volatile solvent may have a boiling point of less than 100° C. A mixture of volatile solvents or a mixture of volatile and non-volatile solvents may be used.

[0395] Exemplary solvents that can 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, ether, glacial acetic acid (HOAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropanol, isopropyl acetate, DCM, and toluene. Exemplary cosolvents include acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, and dioxane / water. In a two-solvent system, the solvent can be present in an amount of about 0.1% to about 99.9%. In some embodiments, water is a cosolvent with acetone, wherein water is present in an amount of about 0.1% to about 15%, for example, about 9% to about 11%, for example, about 10%. In some embodiments, water is a cosolvent with MEK, wherein water is present at about 0.1% to about 15%, for example, about 9% to about 11%, for example, about 10%. In some embodiments, the solvent system includes three solvents. Suitable solvents include the solvents described above, such as DCM, water, methanol, IPA, and mixtures thereof. In some embodiments, the solvent comprises DCM and methanol.

[0396] In some embodiments, the at least one polymer is selected from the group consisting of: hypromellose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and any combination thereof.

[0397] In some embodiments, at least one polymer is HPMCAS.

[0398] In another aspect, the present invention relates to a pharmaceutical composition comprising a solid dispersion disclosed herein. In some embodiments, the pharmaceutical composition may include one or more excipients. Examples of excipients include, but are not limited to, fillers, disintegrants, and lubricants.

[0399] Examples of fillers include, but are not limited to, microcrystalline cellulose, lactose monohydrate, mannitol, and mixtures thereof. In some embodiments, the filler comprises 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, wherein the microcrystalline cellulose is Avicel PH101. In some embodiments, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose is Avicel PH102. In some embodiments, the filler comprises microcrystalline cellulose, wherein the microcrystalline cellulose is a combination of Avicel PH101 and Avicel PH102.

[0400] 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.

[0401] 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.

[0402] In some embodiments, a pharmaceutical composition comprises a compound of the invention (eg, a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt thereof, at least one polymer, at least one filler, at least one lubricant, and at least one disintegrant.

[0403] In some embodiments, the present invention relates to a pharmaceutical composition comprising 45 to 55 wt% of a solid dispersion comprising a polymer and a compound of formula (II); 42-50 wt% of microcrystalline cellulose; 2-4 wt% of croscarmellose sodium; and 0.5-1.5 wt% of magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 50 wt% of the solid dispersion; about 46 wt% of microcrystalline cellulose; about 3 wt% of croscarmellose sodium; and about 1.0 wt% of magnesium stearate.

[0404] 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.

[0405] In some embodiments, the solid dispersion comprises 70-80 wt% polymer and 20-30 wt% compound of formula (II). In some embodiments, the solid dispersion comprises about 75 wt% polymer and about 25 wt% compound of formula (II). In some embodiments, the polymer is HPMCAS.

[0406] In some embodiments, the pharmaceutical composition comprises about 50 mg of the compound of formula (II).

[0407] In some embodiments, the pharmaceutical composition comprises an intragranular blend and an extragranular blend. In some embodiments, 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.

[0408] Uses of compounds, pharmaceutically acceptable salts, and compositions

[0409] In another aspect, the present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, 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 present invention provides a method of inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the voltage-gated sodium channel is Na V 1.8.

[0410] In another aspect, the present invention provides a method for treating pain in an individual or reducing its severity, comprising administering an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present invention provides a method for treating pain in an individual or reducing its severity, comprising administering an effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0411] In another aspect, the present invention provides 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 provides a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use as a medicament.

[0412] In another aspect, the present invention provides 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 provides a compound of formula (II) 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 1.8.

[0413] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method of treating pain in an individual or reducing its severity. In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in a method of treating pain in an individual or reducing its severity.

[0414] 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 use in 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 use in the manufacture of a medicament.

[0415] 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 inhibiting voltage-gated sodium channels. 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 inhibiting voltage-gated sodium channels. In some aspects, the voltage-gated sodium channel is Na V 1.8.

[0416] 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 use in the manufacture of a medicament for treating pain in an individual or reducing the severity thereof. 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 use in the manufacture of a medicament for treating pain in an individual or reducing the severity thereof.

[0417] In another aspect, the present invention provides a method for 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. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0418] In another aspect, the present invention provides 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, postoperative pain (e.g., bunionectomy pain, hernia repair pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Chuck-Mare-Doucet syndrome, incontinence, pathological cough, or arrhythmia 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.

[0419] In yet another aspect, the present invention provides 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, postoperative pain, hernia repair pain, bunionectomy pain, multiple sclerosis, Chuck-Mare-Doucet syndrome, incontinence, or cardiac arrhythmia 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.

[0420] In yet another aspect, the present invention provides a method for treating or alleviating the severity of intestinal pain in a subject, wherein the intestinal pain comprises pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0421] In another aspect, the present invention provides a method for treating individual neuropathic pain or alleviating its severity, which includes administering an effective amount of the compounds of this invention, its pharmaceutically acceptable salt or its pharmaceutical composition. 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 (for example, diabetic peripheral neuropathy). As used herein, phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy.

[0422] In another aspect, the present invention provides a method for treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-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 cephalus, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0423] In another aspect, the present invention provides a method for treating or reducing 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, musculoskeletal pain comprises osteoarthritis pain.

[0424] In another aspect, the present invention provides a method for treating or alleviating the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0425] In another aspect, the present invention provides a method for treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvar pain, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0426] In another aspect, the present invention provides a method for treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0427] In another aspect, the present invention provides a method for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises muscle fiber pain, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0428] In yet another aspect, the present invention provides a method for treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises reflex sympathetic dystrophy pain, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0429] In yet another aspect, the present invention provides a method for treating or reducing the severity of pathological cough in a subject, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0430] In another aspect, the present invention provides a method for treating acute pain in a subject or reducing its severity, 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 comprises acute postoperative pain.

[0431] In yet another aspect, the present invention provides a method for treating or lessening the severity of postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) in a subject, wherein the method comprises administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0432] In yet another aspect, the present invention provides 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.

[0433] In yet another aspect, the present invention provides 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.

[0434] In yet another aspect, the present invention provides a method for 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.

[0435] In yet another aspect, the present invention provides a method for 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.

[0436] In another aspect, the present invention provides a method for treating or reducing 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 comprises visceral pain caused by abdominoplasty.

[0437] In yet another aspect, the present invention provides a method for treating or reducing 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).

[0438] In another aspect, the present invention provides a method wherein a subject is treated with one or more other therapeutic agents administered concurrently with, prior to, or after treatment with an effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the other therapeutic agent is a sodium channel inhibitor.

[0439] In another aspect, the present invention provides a method for inhibiting a voltage-gated sodium channel 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. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0440] In another aspect, the present invention provides a method for treating or lessening the severity of acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, ataxia, Contraindications: Pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain (including chronic cancer pain and cancer breakthrough pain), stroke (e.g., central nervous system pathological pain after stroke), whiplash-related disorders associated disorders), fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed lumbar spine surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry's disease disease), mastocytosis, neurofibroma, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Chuck neuropathy osteoarthropathy, temporomandibular joint disorder, arthroplasty pain, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal dysmotility, the method comprising administering an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0441] In another aspect, the present invention provides a method of treating or lessening the severity of the following pain or disease in a subject: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headaches; migraines; tension headaches; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Chuck-Marie-Duchesne 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., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; Central pain; pain in spinal cord injury; pain after stroke; thalamic pain; phantom pain (e.g., after lower limb or upper limb amputation, breast removal); intractable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendinitis; injury pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pain; cesarean section pain; inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; toothache; multiple sclerosis (MS) pain; depression pain; leprosy pain; Behçet's disease pain; obesity dolorosa; phlebitis pain; Guillain-Barré pain pain); lower limb pain, toe dyskinesia; Haglund syndrome; erythromelalgia; Fabry disease pain; bladder and genitourinary diseases; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome type I (CRPS), complex regional pain syndrome type II (CRPS); widespread pain, paroxysmal severe pain, itching, 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.

[0442] In another aspect, the present invention provides a method for treating or lessening the severity of trigeminal neuralgia, botulinum toxin-treated migraine, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthesia, saphenous vein neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexus neuropathy, traumatic neuroma stump pain, or post-amputation pain 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.

[0443] Uses of compounds, pharmaceutically acceptable salts and compositions

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

[0445] In another aspect, the present invention provides a compound of the present 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. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0446] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating or alleviating the severity of the following pain or disease in a subject: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., hernia repair pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Chuck-Mare-Doucet syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0447] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in 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, postoperative pain, hernia repair pain, bunionectomy pain, multiple sclerosis, Chage-Mare-Doucet syndrome, incontinence, or cardiac arrhythmia in a subject.

[0448] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating intestinal pain in a subject or alleviating its severity, wherein the intestinal pain comprises pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis or interstitial cystitis.

[0449] On the other hand, the present invention provides a kind of compounds of this invention or its pharmaceutically acceptable salt or pharmaceutical composition, it is used to treat individual neuropathic pain or alleviate in the method for its severity.In some respects, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy or idiopathic small fiber neuropathy.In some respects, neuropathic pain includes diabetic neuropathy (for example, diabetic peripheral neuropathy).As used herein, phrase "idiopathic small fiber neuropathy" should be understood to include any small fiber neuropathy.

[0450] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in treating neuropathic pain in a subject or alleviating its severity, wherein the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-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.

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

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

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

[0454] In another aspect, the present invention provides 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 inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain.

[0455] In another aspect, the present invention provides 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 idiopathic pain in a subject, wherein the idiopathic pain comprises muscle fiber pain.

[0456] In another aspect, the present invention provides 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 idiopathic pain in a subject, wherein the idiopathic pain comprises reflex sympathetic dystrophy pain.

[0457] In another aspect, the present invention provides 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 pathological cough in a subject.

[0458] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating acute pain in a subject or reducing its severity. In some aspects, acute pain comprises acute postoperative pain.

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

[0460] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of bunionectomy pain in a subject.

[0461] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0462] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of herniorrhaphy pain in a subject.

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

[0464] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain comprises visceral pain caused by abdominoplasty.

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

[0466] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a subject with one or more other therapeutic agents, wherein the one or more other therapeutic agents are administered concurrently with, before, or after treatment with an effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition. In some embodiments, the other therapeutic agent is a sodium channel inhibitor.

[0467] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method for 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 present invention, a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na V 1.8.

[0468] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating or alleviating the severity of the following pain or disease in a subject: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement Central neuropathic pain in schizophrenia, neuroendocrine disorders, ataxia, multiple sclerosis, and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain (including chronic cancer pain and cancer flare-up pain), stroke (e.g., central neuropathic pain after stroke), whiplash-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, wax tear bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed lumbar spine surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis , transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Chuck neuropathic osteoarthropathy, temporomandibular joint disorder, arthroplasty pain, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0469] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating or alleviating the severity of the following pain or disease in a subject: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic neuralgia diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Chiak-Marie-Duce neuropathy; hereditary sensory neuropathies; 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., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., after amputation of a lower limb, upper limb, breast); intractable pain. Inflexible pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendinitis; injury pain; exercise-induced pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, cardiac pain; pelvic pain, renal colic, acute obstetric pain, labor pain; cesarean section pain; inflammatory pain, burn pain, traumatic pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; multiple Pain in MS; pain in depression; pain in leprosy; pain in Behçet's disease; adiposity dolorosa; pain in phlebitis; pain in Guillain-Barré; pain in the lower limbs with toe dyskinesia; Hägerund's syndrome; erythromelalgia; pain in Fabry's disease; bladder and genitourinary diseases; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, pruritus, tinnitus, or pain induced by angina.

[0470] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in a method of treating or lessening the severity of the following pain in a subject: trigeminal neuralgia, migraine treated with botulinum toxin, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthesia, saphenous vein neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexus neuropathy, traumatic neuroma stump pain, or post-amputation pain.

[0471] Pharmaceutical Manufacturing

[0472] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0473] In another aspect, the present invention provides a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of a medicament for inhibiting voltage-gated sodium channels. V 1.8.

[0474] 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 treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., hernia repair pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Chuck-Mare-Doucet syndrome, incontinence, pathological cough, or cardiac arrhythmia in a subject.

[0475] 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 treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, bunionectomy pain, multiple sclerosis, Chage-Male-Doucet syndrome, incontinence, or cardiac arrhythmia in a subject.

[0476] In another aspect, the present invention provides the use of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein for the manufacture of a medicament for treating or lessening the severity of intestinal pain in a subject, wherein the intestinal pain comprises pain from inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, endometriosis, polycystic ovary disease, salpingitis, cervicitis, or interstitial cystitis.

[0477] In yet another aspect, the present invention provides a compound of this invention, its pharmaceutically acceptable salt or its pharmaceutical composition, which is used to manufacture a medicament for treating individual neuropathic pain or alleviating its severity. 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).

[0478] 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 treating or reducing 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 pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy-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.

[0479] 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 treating or reducing the severity of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain comprises osteoarthritis pain.

[0480] 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 treating or alleviating the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0481] 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 treating or alleviating the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis, or vulvar pain.

[0482] 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 treating or lessening the severity of inflammatory pain in a subject, wherein the inflammatory pain comprises rheumatoid arthritis pain.

[0483] 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 treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises muscle fiber pain.

[0484] 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 treating or lessening the severity of idiopathic pain in a subject, wherein the idiopathic pain comprises reflex sympathetic dystrophy pain.

[0485] 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 treating or reducing the severity of pathological cough in a subject.

[0486] 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 treating acute pain in a subject or reducing its severity. In some aspects, acute pain comprises acute postoperative pain.

[0487] 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 treating or reducing the severity of postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hemorrhoidectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0488] 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 treating or lessening the severity of herniorrhaphy pain in a subject.

[0489] 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 treating or lessening the severity of inflammatory pain in a subject.

[0490] 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 treating or lessening the severity of shoulder arthroplasty pain or shoulder arthroscopy pain in a subject.

[0491] 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 treating or lessening the severity of abdominoplasty pain in a subject.

[0492] 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 treating or reducing the severity of visceral pain in a subject. In some aspects, the visceral pain comprises visceral pain caused by abdominoplasty.

[0493] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a neurodegenerative disease in an individual or alleviating its severity. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome (PTHS).

[0494] In another aspect, the present invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the manufacture of a medicament for use in combination with one or more other therapeutic agents, the one or more other therapeutic agents being administered simultaneously with, before, or after treatment with the compound or pharmaceutical composition. In some embodiments, the other therapeutic agent is a sodium channel inhibitor.

[0495] 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 treating or lessening the severity of the following pain or disease in a subject: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, tension headache and all other forms of headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia , movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, post-mastectomy pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain) , cancer pain (including chronic cancer pain and cancer flare-up pain), stroke (e.g., central neuropathic pain after stroke), whiplash-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, wax tear bone disease, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed lumbar spine surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral disc inflammatory disease, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Chuck neuropathic osteoarthropathy, temporomandibular joint disorder, arthroplasty pain, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0496] 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 treating or alleviating the severity of the following pain or disease in a subject: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache; migraine; tension headache; cluster headache; chronic and acute neuropathic pain, postherpetic pain Neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Chiak-Marie-Duce 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., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., after amputation of a lower limb, upper limb, or breast) ; Intractable pain; Acute pain, acute postoperative pain; Acute musculoskeletal pain; Joint pain; Mechanical low back pain; Neck pain; Tendonitis; Injury pain; Movement pain; Acute visceral pain; Pyelonephritis; Appendicitis; Cholecystitis; Intestinal obstruction; Hernia; Chest pain, Heart pain; Pelvic pain, Renal colic, Acute obstetric pain, Labor pain; Caesarean section pain; Inflammatory pain, Burn pain, Traumatic pain; Acute intermittent pain, Endometriosis; Acute herpes zoster pain; Sickle cell anemia; Acute pancreatitis; Breakout pain; Orofacial pain; Sinusitis pain; Toothache; Multiple Multiple sclerosis (MS) pain; depression pain; leprosy pain; Behçet's disease pain; obesity dolorosa; phlebitis pain; Guillain-Barré pain; lower limb pain and toe dyskinesia; Hägerund syndrome; erythromelalgia; Fabry disease pain; bladder and genitourinary diseases; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal severe pain, itching, tinnitus, or pain induced by angina.

[0497] 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 treating or lessening the severity of trigeminal neuralgia, migraine treated with botulinum toxin, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus neuropathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthesia, saphenous vein neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexus neuropathy, traumatic neuroma stump pain, or post-amputation pain in a subject.

[0498] Administration of compounds, pharmaceutically acceptable salts, and compositions

[0499] 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 an amount effective to treat or lessen the severity of one or more of the above-listed conditions.

[0500] According to the present method, the compounds, salts and compositions can be administered using any amount and any route of administration effective for treating one or more of the painful or non-painful diseases listed herein or reducing their severity. The exact amount required will vary from individual to individual, depending on the species, age and general condition of the individual, the severity of the condition, the specific agent, its mode of administration, etc. 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 expression "unit dosage form" refers to a physically discrete unit of a drug suitable for the individual to be treated. However, it should 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 individual or organism will depend on a variety of factors, including the condition to be treated and the severity of the condition; the activity of the specific compound or salt used; the specific composition used; the age, weight, general health, sex and diet of the individual; the time of administration, route of administration and excretion rate of the specific compound or salt used; the duration of treatment; drugs used in combination with or concurrently with the specific compound or salt used; and similar factors well known in the medical art. As used herein, the term "subject" or "patient" means an animal, preferably a mammal and most preferably a human.

[0501] Depending on the severity of the condition being treated, the pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally (e.g., oral or nasal spray), etc. In certain embodiments, the compounds, salts, and compositions of the present invention can be administered orally or parenterally at a dosage level of about 0.001 mg / kg to about 1000 mg / kg, once or more a day, to effectively achieve the desired therapeutic effect.

[0502] 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, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatics.

[0503] Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be prepared using suitable dispersants or wetting agents and suspending agents according to known technology. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, for example, in the form of a solution in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used to prepare injectables.

[0504] The injectable formulations can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0505] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer (e.g., polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations are also prepared by coating the compound in liposomes or microemulsions compatible with body tissues.

[0506] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0507] 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 (e.g., sodium citrate or dicalcium phosphate) and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as 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) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0508] The solid composition of similar type can also be used as the filler in soft-filled and hard-filled gelatin capsules, and the capsule uses excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol etc. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings well-known in enteric coatings and pharmaceutical formulation technology. It can optionally contain an emulsifier and can also have a composition that releases the active ingredient only in or preferentially in a certain part of the intestinal tract in a delayed manner. The example of spendable embedded composition includes polymeric substances and wax. The solid composition of similar type can also be used as the filler in soft-filled and hard-filled gelatin capsules, and the capsule uses excipients such as lactose and high molecular weight polyethylene glycol etc.

[0509] The active compound or salt can also be in the form of microencapsulation with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well-known in pharmaceutical formulation technology. In such solid dosage forms, the active compound or salt can be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As commonly practiced, such dosage forms can also include other substances in addition to the inert diluent, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. It can optionally contain an emulsifier and can also have a composition that releases the active ingredient only in or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0510] The dosage form for topical or transdermal administration of the compound or salt of the present invention includes an ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer that may be needed under sterile conditions. It is also contemplated that ophthalmic preparations, ear drops and eye drops are within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. This type of dosage form is prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0511] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compound is Na V 1.8 inhibitors, therefore, without wishing to be bound by any particular theory, the compounds, salts and compositions are particularly useful in treating patients in whom Na V1.8 activation or hyperactivation of a disease, condition or disorder associated with the disease, condition or disorder or reducing its severity. V 1.8 activation or hyperactivation, the disease, condition or disorder may also be referred to as "Na V 1.8 mediated diseases, conditions or disorders". Therefore, in another aspect, the present invention provides a method of treating or lessening the severity of a disease, condition or disorder, wherein Na is involved in the disease condition. V 1.8 activation or highly activated.

[0512] In the present invention, Na V The activity of compounds that are inhibitors of 1.8 can be determined according to the methods generally described in International Publication No. WO 2014 / 120808 A9 and U.S. Publication No. 2014 / 0213616 A1 (both incorporated by reference in their entireties), the methods described herein, and other methods known and available to those of ordinary skill in the art.

[0513] Other therapeutic agents

[0514] It will also be appreciated 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, before, or after one or more other desired therapies or medical procedures. The specific combination of therapies (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be obtained. It will also be appreciated that the therapy employed can achieve the desired effect for the same condition (e.g., a compound of the present invention can be administered simultaneously with another agent for treating the same condition), or it can achieve a different effect (e.g., controlling any side effects). As used herein, other therapeutic agents that are typically administered to treat or prevent a particular disease or condition are referred to as "suitable for the disease or condition being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones, such as Nabumetone; oxicams, such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids, such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates, such as Aspirin, Choline Magnesium Trisalicylate, Diflunisal; fenamates, such as Meclofenamic Acid;

[0014] In some embodiments, the present invention provides analgesic agents that are administered in combination with other analgesic agents, such as fentanyl, mefenamic acid, and pyrazoles, such as phenylbutazone, or opioid (narcotic) agonists, such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine. In addition, drug-free analgesic methods can be used in conjunction with the administration of one or more compounds of the present invention.For example, anesthetic methods (intraspinal infusion, nerve blocks), neurosurgical methods (neurolysis of CNS pathways), neurostimulation methods (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy methods (physical therapy, orthopedic devices, diathermy), or psychotherapy methods (cognitive methods - hypnosis, biofeedback, or behavioral methods) can also be used. Other suitable therapeutic agents or methods are generally described in "The Merck Manual", 19th edition, Robert S. Porter and Justin L. Kaplan, eds., Merck Sharp & Dohme, 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.

[0515] In another embodiment, the other suitable therapeutic agent is selected from the group consisting of:

[0516] (1) Opioid analgesics, such as morphine base, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, pethidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentozocin, or difelikefalin;

[0517] (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., )), indomethacin, ketoprofen, ketorolac (including but not limited to ketorolac tromethamine (e.g. ), meclofenamic acid, mefenamic acid, meloxicam, intravenous meloxicam (e.g. ), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

[0518] (3) barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0519] (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0520] (5) Histamine (H1) antagonists with sedative effects, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

[0521] (6) sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0522] (7) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0523] (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinane) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphinane), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinic acid, budipine, EN-3231 ( morphine base and dextromethorphan combination preparations), topiramate, neramexane, or perzinfotel including NR2B antagonists such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0524] (9) α-adrenergic, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

[0525] (10) tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;

[0526] (11) Anticonvulsants, such as carbamazepine ), lamotrigine, topiramate, lacosamide ) or valproate;

[0527] (12) Tachykinin (NK) antagonists, in particular, NK-3, NK-2 or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacycloocta[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)- 1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, netupitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0528] (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

[0529] (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;

[0530] (15) Coal tar analgesics, especially paracetamol;

[0531] (16) Antipsychotics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, and aripiprazole , sonapiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, or sarizotan;

[0532] (17) Vanilloid receptor agonists (e.g., resinferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300);

[0533] (18) β-adrenaline, such as propranolol;

[0534] (19) Local anesthetics, such as mexiletine;

[0535] (20) Corticosteroids, such as dexamethasone;

[0536] (21) 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1Dagonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0537] (22)5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinol (MDL-100907);

[0538] (23) Cholinergic (nicotinic) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

[0539] (twenty four) Tramadol ER IV Tramadol, Tapentadol ER

[0540] (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrimidin-7-one Imido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl)- -3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-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- Hydrogen-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0541] (26) α-2-δ ligands, such as gabapentin; ), Gabapentin GR Gabapentin, enacarbil; ), pregabalin; ), 3-methyl gabapentin, (1[α],3[α],5[α])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0542] (27) Cannabinoids, such as KHK-6188;

[0543] (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

[0544] (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, and trazodone;

[0545] (30) Norepinephrine (epinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine In particular, selective norepinephrine reuptake inhibitors such as reboxetine, especially (S,S)-reboxetine;

[0546] (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, ), milnacipran, and imipramine;

[0547] (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(1R,3 (S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboximidamide, NXN-462 or guanidinoethyl disulfide;

[0548] (33) Acetylcholinesterase inhibitors, such as donepezil;

[0549] (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0550] (35) Leukotriene B4 antagonists; for example, 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-pentanoic acid (ONO-4057) or DPC-11870;

[0551] (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);

[0552] (37) Sodium channel blockers, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201), or eslicarbazepine acetate;

[0553] (38)Na V1.7 Blockers, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and those disclosed in, for example, WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136); WO2012 / 125613 (US2012264749), WO2012 / 116440 ( US2014187533), WO2011026240 (US2012220605), US8883840, US8466188, WO2013 / 109521 (US2015005304), CN111217776, WO2020 / 117626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518, WO2014 / 201206, or WO2016 / 141035, the entire contents of each of which are incorporated herein by reference;

[0554] (38a)Na V1.7 Blockers, for example (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-diphenylmethylpiperazin-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'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridinyl)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'-piperidin]-1'-yl] 1,4'-piperidin]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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'-piperidin]-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'-piperidin]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropyloxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-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-propane-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-trifluoropropyloxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidinyl)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;

[0555] (39)Na V1.8 Blockers, such as PF-04531083, PF-06372865 and those disclosed in, for example, WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US20130303535, WO2013131018, US8466188, WO2013114250 (US2013274243), WO2 014 / 120808(US2014213616), WO2014 / 120815(US2014228371)WO2014 / 120820(US2014221435), WO2015 / 010065(US20 160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, WO2020 / 146682, WO 2020 / 146612, WO2020 / 014243, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667 (US2020140411), WO2020 / 144375, WO 2020 / 261114, WO2020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622 (CN112479996), WO2021 / 257490, WO20 21 / 257420, WO2021 / 257418, WO2022 / 263498, WO2022 / 235558, WO2022 / 235859, WO2023 / 138599, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each of which are incorporated herein by reference;

[0556] (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 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)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-( 4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide )benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(O-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, dihydrogen phosphate [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridinyl]methyl ester, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, dihydrogen phosphate (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1(2H) -yl) methyl ester, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)- phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoxaline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido) benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-2-(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-(trifluoromethyl)benzamido)benzoic acid -(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- benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-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)benzamide )-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-amino Benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]- phenyl)-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]benzoyl]amino]pyridine-2-carboxamide Formamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-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)- -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;

[0557] (40) Combined Na V 1.7 and Na V 1.8 Blockers, such as DSP-2230, Lohocla201 or BL-1021;

[0558] (41) 5-HT3 antagonists, such as ondansetron;

[0559] (42) TPRV1 receptor agonists, such as capsaicin, ); and pharmaceutically acceptable salts and solvates thereof;

[0560] (43) Nicotinic receptor antagonists, such as varenicline;

[0561] (44) N-type calcium channel antagonists, such as Z-160;

[0562] (45) Nerve growth factor antagonists, such as tanezumab;

[0563] (46) Endopeptidase stimulators, such as senrebotase;

[0564] (47) Angiotensin II antagonists, such as EMA-401;

[0565] (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g. ));

[0566] (49) Bupivacaine (including but not limited to bupivacaine liposomal injectable suspension (e.g. ), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine );and

[0567] (50) Bupivacaine and meloxicam combination (e.g., HTX-011).

[0568] In one embodiment, the other suitable therapeutic agent is selected from V-116517, pregabalin, controlled release pregabalin, ezogabine Ketamine / amitriptyline topical cream AVP-923, Perampanel (E-2007), Ralfinamide, Transdermal Bupivacaine CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0569] In another embodiment, the other 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.

[0570] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149); a TRPV modulator, such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652; an EGR1 inhibitor, such as Brivoglide (AYX1); an NGF inhibitor, such as Tanezumab, Fasinumab, ASP6294, MEDI7352; a μ-opioid agonist, such as Cebranopadol, NKTR181 (oxycodegol); a CB-1 agonist, such as NEO1940 (AZN1940); an imidazoline 12 agonist, such as CR4056; or a p75NTR-Fc modulator, such as LEVI-04.

[0571] In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590).

[0572] In another embodiment, the other therapeutic agent is Na V 1.7 Blockers, such as ST-2427, ST-2578 and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835 and / or WO2022 / 036297, the entire contents of each application being incorporated herein by reference.

[0573] In another embodiment, the other therapeutic agent is selected from ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra TM), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI 7352, and XT-150.

[0574] In another embodiment, the other 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, LY3 556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905, and ACD440.

[0575] In another embodiment, the other therapeutic agent is selected from HRS4800, ODM-111 / JMKX000623, LX9211, LY3556050, LY3857210, CFTX01554 / CFTX-1554, MEDI7352, MEDI0618, BAY3178275, BAY2395840, GSK3858279, STC-004, HALNEURON, OLP-1002, AT X01, ANP230, CC-8464, iN1011-N17, ST-2427, MSD199, FZ008, VYNAV-01, BL-017881, Profervia (Cilnidipine), LS-04, vixotrigine, FX301 / PCRX-301, PF-04531083, PF-01247324, and DSP-3905.

[0576] In another embodiment, the other therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na V 1.7 and Na V 1.8 Blocker.

[0577] The amount of the additional therapeutic agent present in the compositions of the present invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of the additional therapeutic agent in the compositions disclosed herein may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0578] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices (e.g., prostheses, artificial valves, vascular grafts, intravascular stents, and catheters). Thus, in another aspect, the present invention includes a composition for coating an implantable device comprising a compound or salt of the present invention as generally described above and in 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 as generally described above and in the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and general preparations of coated implantable devices are described in U.S. Patents 6,099,562; 5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release characteristics to the composition.

[0579] Another aspect of the present invention relates to inhibiting Na V 1.8 activity, the method comprising administering to a subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of the 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 culture or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0580] Suppresses Na in biological samples V 1.8 Activity is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying sodium channels in biological and pathological phenomena; and comparative evaluation of novel sodium channel inhibitors.

[0581] Synthesis of the compounds of the present invention

[0582] The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As will be appreciated by those skilled in the art, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups can 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 TGM Wuts et al., Protecting Groups in Green's Organic Synthesis (4th edition, 2006).

[0583] Radiolabeled analogs of the compounds of the present invention

[0584] In another aspect, the present invention relates to radiolabeled analogs of the compounds of the invention. As used herein, the term "radiolabeled analogs of the compounds of the invention" refers to compounds identical to the compounds of the invention as described herein (including all embodiments thereof) except that one or more atoms have been replaced with a radioisotope of an atom present in the compounds of the invention.

[0585] 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. 36 Cl, etc., and the isotopes whose decay patterns are identified in VS Shirley and CM Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0586] Radiolabeled analogs can be used in a variety of advantageous ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H) and / or carbon-14 ( 14 C) Labeled compounds are suitable for various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detectability.

[0587] In another aspect, the invention relates to a pharmaceutically acceptable salt of a radiolabeled analogue according to any one of the embodiments described herein for the compounds of the invention.

[0588] In another aspect, the present invention relates to a pharmaceutical composition comprising a radiolabeled analogue according to any one of the embodiments described herein for the compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0589] 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 conditions (including pain) in a subject, comprising administering an effective amount of a radiolabeled analogue according to any one of the embodiments described herein for the compounds of the present invention, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.

[0590] In another aspect, the present invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use according to any one of the embodiments described herein for the compounds of the present invention.

[0591] In another aspect, the present invention relates to the use of a radiolabeled analogue or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof for the manufacture of a medicament according to any one of the embodiments described herein for the compounds of the invention.

[0592] In another aspect, according to any of the embodiments described herein for the compounds of the invention, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can be used in combination therapy.

[0593] List examples

[0594] Other embodiments of the present disclosure are set forth in the following numbered clauses:

[0595] 1. A method for preparing a compound of formula (I):

[0596]

[0597] It comprises the compound of formula (IV):

[0598]

[0599] or a salt thereof is converted into the compound of formula (I).

[0600] 2. The method of embodiment 1, wherein converting the compound of formula (IV) to the compound of formula (I) comprises preparing a compound of formula (VI):

[0601]

[0602] 3. The method of embodiment 2, wherein preparing the compound of formula (VI) comprises reacting the compound of formula (IV) or the compound of formula (VII):

[0603]

[0604] Contact with quinine.

[0605] 4. The method of embodiment 1, wherein converting the compound of formula (IV) to the compound of formula (I) comprises preparing a compound of formula (VII):

[0606]

[0607] 5. The method of embodiment 3 or 4, wherein the compound of formula (VII) is obtained by contacting the compound of formula (IV) with (R)-α-methylbenzylamine.

[0608] 6. The method of any one of embodiments 1 to 5, wherein converting the compound of formula (IV) to the compound of formula (I) comprises contacting the compound of formula (IV), the compound of formula (VI), or the compound of formula (VII) with a compound of formula (V):

[0609]

[0610] To obtain a compound of formula (III):

[0611]

[0612] 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.

[0613] 8. The method of embodiment 7, wherein the coupling reagent is propanephosphonic anhydride (T3P) and the first base is triethylamine.

[0614] 9. The method of any one of embodiments 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 the compound of formula (VIII):

[0615]

[0616] 10. The method 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 agent.

[0617] 11. The method of embodiment 10, wherein the chlorinating agent 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 diphenylphosphinyl chloride (DPPCl).

[0618] 12. The method of embodiment 10 or 11, wherein the chlorinating agent is oxalyl chloride.

[0619] 13. The method of any one of embodiments 9 to 12, wherein converting the compound of formula (IV) to the compound of formula (I) comprises contacting the compound of formula (VIII) with a compound of formula (V):

[0620]

[0621] To obtain a compound of formula (III):

[0622]

[0623] 14. The method 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.

[0624] 15. The method of embodiment 14, wherein the second base is triethylamine.

[0625] 16. The method of any one of embodiments 6 to 8 or 13 to 15, 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).

[0626] 17. The method 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.

[0627] 18. The method of embodiment 17, wherein the first acid is an aqueous solution of trifluoroacetic acid.

[0628] 19. The method of any one of embodiments 1 to 18, further comprising recrystallizing the compound of formula (I) from a suitable solvent to obtain crystalline Form A of the compound of formula (I).

[0629] 20. The method of embodiment 19, wherein the suitable solvent comprises ethyl acetate and n-heptane.

[0630] 21. The method of any one of embodiments 6 to 8 or 13 to 20, further comprising reacting a compound of formula (XVI):

[0631]

[0632] Converted into a compound of formula (V),

[0633] where R 2 It is a C1-C6 alkyl group.

[0634] 22. The method 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 under reflux.

[0635] 23. The method 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.

[0636] 24. The method of embodiment 23, wherein the third base is NaOH.

[0637] 25. The method of any one of embodiments 21 to 24, wherein R 2 is tert-butyl or ethyl.

[0638] 26. The method of any one of embodiments 21 to 25, wherein the compound of formula (XVI) is a compound of formula (XVI-A):

[0639]

[0640] 27. The method of any one of embodiments 21 to 25, wherein the compound of formula (XVI) is a compound of formula (XVI-B):

[0641]

[0642] 28. The method of any one of embodiments 21 to 27, further comprising recrystallizing the compound of formula (V) from a suitable solvent.

[0643] 29. The method of embodiment 28, wherein the suitable solvent comprises MTBE and n-heptane.

[0644] 30. The method of any one of embodiments 21 to 29, further comprising reacting a compound of formula (XVII):

[0645]

[0646] Converted into the compound of formula (XVI).

[0647] 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.

[0648] 32. The method of embodiment 31, wherein the fourth base is Cs2CO3 or K3PO4.

[0649] 33. The method of embodiment 31 or 32, wherein the palladium catalyst is Pd(OAc)2.

[0650] 34. The method of any one of embodiments 31 to 33, wherein the ligand is XPhos or BrettPhos.

[0651] 35. The method of any one of embodiments 30 to 34, further comprising reacting a compound of formula (XVIII):

[0652]

[0653] Converted into the compound of formula (XVII).

[0654] 36. The method 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.

[0655] 37. The method of embodiment 36, wherein the second acid is methanesulfonic acid.

[0656] 38. The method of any one of embodiments 35 to 37, further comprising reacting a compound of formula (XIX):

[0657]

[0658] Converted into the compound of formula (XVIII).

[0659] 39. The method 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.

[0660] 40. The method of embodiment 39, wherein the compound of formula (XIX) is contacted with a reducing agent in the presence of an enzyme.

[0661] 41. The method of any one of embodiments 38 to 40, further comprising contacting 2-bromo-5-chloropyridine with 2-(tert-butoxy)-N-methoxy-N-methylacetamide to provide a compound of formula (XIX).

[0662] 42. The method of embodiment 41, wherein 2-bromo-5-chloropyridine is contacted with 2-(tert-butoxy)-N-methoxy-N-methylacetamide in the presence of a Grignard reagent.

[0663] 43. The method of embodiment 42, wherein the Grignard reagent is isopropylmagnesium chloride lithium chloride complex.

[0664] 44. A method for preparing a compound of formula (II):

[0665]

[0666] It comprises the compound of formula (VII):

[0667]

[0668] Converted into the compound of formula (II).

[0669] 45. The method of embodiment 44, wherein converting the compound of formula (VII) to the compound of formula (II) comprises contacting the compound of formula (VII) with a compound of formula (XXI):

[0670]

[0671] To obtain a compound of formula (XX):

[0672]

[0673] 46. ​​The method of embodiment 45, wherein contacting the compound of formula (VII) with the compound of formula (XXI) is in the presence of a coupling reagent and a first base.

[0674] 47. The method of embodiment 46, wherein the coupling reagent is propanephosphonic anhydride (T3P) and the first base is triethylamine.

[0675] 48. 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 the compound of formula (VIII):

[0676]

[0677] 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 agent.

[0678] 50. The method of embodiment 49, wherein the chlorinating agent 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 diphenylphosphinyl chloride (DPPCl).

[0679] 51. The method of embodiment 49 or 50, wherein the chlorinating agent is oxalyl chloride.

[0680] 52. The method of any one of embodiments 48 to 51, wherein converting the compound of formula (VII) to the compound of formula (II) comprises contacting the compound of formula (VIII) with a compound of formula (XXI):

[0681]

[0682] To obtain a compound of formula (XX):

[0683]

[0684] 53. The method of embodiment 52, wherein contacting the compound of formula (VIII) with the compound of formula (XXI) is performed in the presence of a second base.

[0685] 54. The method of embodiment 53, wherein the second base is triethylamine.

[0686] 55. The method of any one of embodiments 52 to 54, wherein contacting the compound of formula (VIII) with the compound of formula (XXI) is carried out in toluene.

[0687] 56. The method of any one of embodiments 45 to 47 or 52 to 55, 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).

[0688] 57. The method of embodiment 56, 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).

[0689] 58. The method of embodiment 57, wherein the ammonia is in the form of a solution of ammonia in a solvent, in the form of a gas in which ammonia gas is bubbled into the reaction mixture, or in the form of ammonium hydroxide or an ammonium salt in which ammonia is generated in situ.

[0690] 59. The method of embodiment 58, wherein the ammonia is in the form of a solution of ammonia in methanol.

[0691] 60. The method of embodiment 58, wherein the ammonia is in the form of a solution of ammonia in methanol and tetrahydrofuran.

[0692] 61. The method of embodiment 58, wherein generating ammonia in situ comprises reacting ammonium hydroxide or an ammonium salt with an acid.

[0693] 62. The process of any one of embodiments 57 to 61, wherein treating the compound of formula (XX) with ammonia is carried out in a solvent mixture comprising methanol and tetrahydrofuran.

[0694] 63. The method of any one of embodiments 44 to 62, further comprising recrystallizing the compound of formula (II) from a suitable solvent.

[0695] 64. The method of embodiment 63, wherein the suitable solvent comprises MeOH, THF, and water.

[0696] 65. The method of any one of embodiments 44 to 64, further comprising:

[0697]

[0698] Converted into the compound of formula (VII).

[0699] 66. The method 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.

[0700] 67. The method of any one of embodiments 1 to 43, 65 or 66, further comprising reacting a compound of formula (IX):

[0701]

[0702] Converted into the compound of formula (IV).

[0703] 68. The method 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.

[0704] 69. The method of embodiment 68, wherein the fifth base is potassium hydroxide.

[0705] 70. The method of any one of embodiments 67 to 69, further comprising reacting a compound of formula (X):

[0706]

[0707] Converted into the compound of formula (IX),

[0708] in:

[0709] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; and

[0710] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

[0711] 71. The method of embodiment 70, wherein the compound of formula (X) has formula (X'):

[0712]

[0713] 72. The method 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 cyanating agent.

[0714] 73. The method of embodiment 72, wherein the cyanation reagent is selected from the group consisting of trimethylsilyl cyanide, diethylaluminum cyanide, KCN, NaCN, TBACN, and HCN.

[0715] 74. The method of embodiment 73, wherein the cyanation reagent is trimethylsilyl cyanide.

[0716] 75. The method of embodiment 74, wherein the compound of formula (X) is treated with 1.35-1.65 equivalents of trimethylsilyl cyanide.

[0717] 76. The method of any one of embodiments 70 to 75, wherein treating the compound of formula (X) with a cyanating agent is carried out in the presence of a Lewis acid.

[0718] 77. The method of embodiment 76, wherein the Lewis acid is selected from boron trifluoride diethyl ether complex (BF3·OEt2), TiCl4, InCl3, AgSbF6, iodine, ZnBr2, Al(OiPr)3, MgCl2, Mn(acac)2, MnCl2, TMSOTf and SnCl4.

[0719] 78. The method of embodiment 77, wherein the Lewis acid is BF3OEt2.

[0720] 79. The method of embodiment 78, wherein 0.9-1.1 equivalents of BF3OEt3 are present based on the compound of formula (X).

[0721] 80. The method of any one of embodiments 70 to 79, wherein R 1 It is -C(O)-Z.

[0722] 81. The method of embodiment 80, wherein Z is methyl or 4-nitrophenyl.

[0723] 82. The method of embodiment 81, wherein Z is 4-nitrophenyl.

[0724] 83. The method of any one of embodiments 70 to 82, further comprising reacting a compound of formula (XI):

[0725]

[0726] Converted into the compound of formula (X).

[0727] 84. The method of embodiment 83, wherein the compound of formula (XI) has formula (XI'):

[0728]

[0729] 85. The method 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 provide the compound of formula (X).

[0730] 86. The method of embodiment 85, wherein contacting the compound of formula (XI) with an acid anhydride or an acid halide is carried out in the presence of a sixth base and a catalyst.

[0731] 87. The method of embodiment 86, wherein the sixth base is triethylamine and the catalyst is 4-dimethylaminopyridine (DMAP).

[0732] 88. The method of any one of embodiments 85 to 87, wherein the anhydride is acetic anhydride.

[0733] 89. The method of any one of embodiments 85 to 87, wherein the acyl halide is 4-nitrobenzoyl chloride.

[0734] 90. The method of any one of embodiments 83 to 89, further comprising recrystallizing the compound of formula (X) from a suitable solvent.

[0735] 91. The method of embodiment 90, wherein the suitable solvent comprises acetone and water.

[0736] 92. The method of any one of embodiments 83 to 91, further comprising reacting a compound of formula (XII):

[0737]

[0738] Converted into the compound of formula (XI).

[0739] 93. The method 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 agent.

[0740] 94. The method of embodiment 93, wherein the reducing agent is selected from diisobutylaluminum hydride, Red-Al, NaBH4 / BF3, titanocene with polymethylhydrogensiloxane, and phenylsilane.

[0741] 95. The method of embodiment 93 or 94, wherein the reducing agent is diisobutylaluminum hydride.

[0742] 96. The method of any one of embodiments 92 to 95, further comprising reacting a compound of formula (XIII):

[0743]

[0744] Converted into the compound of formula (XII).

[0745] 97. The method of embodiment 96, wherein converting the compound of formula (XIII) to the compound of formula (XII) comprises hydrogenating the compound of formula (XIII).

[0746] 98. The method of embodiment 97, wherein the hydrogenation is performed in the presence of a hydrogenation catalyst.

[0747] 99. The method of embodiment 98, wherein the hydrogenation catalyst is selected from the group consisting of Pd / C, Pd / Al2O3, Pt / C, Ni(Raney), Co(Raney), Rh / C, Ir / C, Ru / C, Pd(OH)2, homogeneous chiral Ru, and Rh.

[0748] 100. The method of any one of embodiments 97 to 99, wherein the hydrogenation is performed in the presence of a suitable hydrogen source.

[0749] 101. The method of embodiment 100, wherein the hydrogen source is selected from H2 gas, NiCl2 / NaBH4 in methanol, and Et3SiH.

[0750] 102. The method of any one of embodiments 97 to 101, wherein the hydrogenation is performed in the presence of H2 gas using Pd / C as a catalyst.

[0751] 103. The method of embodiment 102, wherein the H2 gas is present at a pressure of 5-40 bar.

[0752] 104. The method of any one of embodiments 97 to 103, wherein the hydrogenation is performed in a solvent mixture comprising 2-propanol, tetrahydrofuran, and catalytic trifluoroacetic acid.

[0753] 105. The method of any one of embodiments 97 to 104, wherein the hydrogenation is performed at a temperature of 10-50°C.

[0754] 106. The method of any one of embodiments 96 to 105, further comprising reacting a compound of formula (XIV):

[0755]

[0756] Contacting with a compound of formula (XV):

[0757]

[0758] To obtain the compound of formula (XIII).

[0759] 107. The method of embodiment 106, wherein contacting the compound of formula (XIV) with the compound of formula (XV) is performed in the presence of a coupling agent or a chlorinating agent.

[0760] 108. The method of embodiment 107, wherein the coupling agent is selected from CDI and T3P.

[0761] 109. The method of embodiment 107, wherein the chlorinating agent converts the compound of formula (XIV) into an acid chloride, which is not isolated prior to reacting with the compound of formula (XV).

[0762] 110. The method of embodiment 107 or 109, wherein the chlorinating agent is selected from oxalyl chloride and thionyl chloride.

[0763] 111. The method of any one of embodiments 1 to 43, 65 or 66, further comprising reacting a compound of formula (XXII):

[0764]

[0765] Converted into the compound of formula (IV).

[0766] 112. The method 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.

[0767] 113. The method of embodiment 112, wherein the oxidizing agent comprises TEMPO and NaOCl.

[0768] 114. The method of any one of embodiments 111 to 113, further comprising reacting a compound of formula (XXIII):

[0769]

[0770] Converted into the compound of formula (XXII).

[0771] 115. The method of embodiment 114, wherein converting the compound of formula (XXIII) to the compound of formula (XXII) comprises hydrogenating the compound of formula (XXIII).

[0772] 116. The method of embodiment 115, wherein the hydrogenation of the compound of formula (XXIII) is carried out in the presence of hydrogen gas and a palladium on carbon catalyst.

[0773] 117. The method of any one of embodiments 114 to 116, further comprising:

[0774]

[0775] Converted into the compound of formula (XXIII).

[0776] 118. The method of embodiment 117, wherein converting the compound of formula (XXIV) to the compound of formula (XXIII) comprises treating the compound of formula (XXIV) with methanesulfonyl chloride in the presence of a seventh base.

[0777] 119. The method of embodiment 118, wherein the seventh base is triethylamine.

[0778] 120. The method of any one of embodiments 117 to 119, further comprising reacting a compound of formula (XXV):

[0779]

[0780] Converted into the compound of formula (XXIV).

[0781] 121. The method 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.

[0782] 122. The method of embodiment 120 or 121, further comprising:

[0783]

[0784]

[0785] Converted into the compound of formula (XXV).

[0786] 123. The method 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).

[0787] 124. The method of embodiment 122 or 123, further comprising:

[0788]

[0789] Converted into the compound of formula (XXVI).

[0790] 125. The method 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.

[0791] 126. The method of embodiment 124 or 125, further comprising:

[0792]

[0793] Converted into the compound of formula (XXVII).

[0794] 127. The method 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-trifluoroethane-imidate in the presence of a third acid.

[0795] 128. The method of embodiment 127, wherein the third acid is trifluoromethanesulfonic acid.

[0796] 129. The method of any one of embodiments 126 to 128, further comprising reacting a compound of formula (XXIX):

[0797]

[0798] Converted into the compound of formula (XXVIII).

[0799] 130. The method of embodiment 129, wherein converting the compound of formula (XXIX) to the compound of formula (XXVIII) comprises hydrogenating the compound of formula (XXIX).

[0800] 131. The method of embodiment 130, wherein the hydrogenation of the compound of formula (XXIX) is carried out in the presence of NiCl2 / NaBH4 in methanol.

[0801] 132. A compound of the formula:

[0802]

[0803]

[0804]

[0805] in:

[0806] R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z or -P(O)Z2;

[0807] Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 Aryl; C1-C4 alkyl; and C1-C4 haloalkyl; and

[0808] R 2 It is a C1-C6 alkyl group.

[0809] 133. A compound of the formula:

[0810]

[0811]

[0812]

[0813] 134. A compound of formula (I):

[0814]

[0815] wherein the compound is in the form of a crystalline solid.

[0816] 135. A composition comprising a compound of formula (I):

[0817]

[0818] wherein the compound of formula (I) is in the form of a crystalline solid.

[0819] 136. The composition of embodiment 135, wherein at least 85% of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0820] 137. The composition of embodiment 135, wherein at least 90% of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0821] 138. The composition of embodiment 135, wherein at least 95% of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0822] 139. The composition of embodiment 135, wherein substantially all of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0823] 140. The composition of embodiment 135, wherein 100% of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0824] 141. A pharmaceutical composition comprising a compound of formula (I):

[0825]

[0826] and one or more pharmaceutically acceptable carriers or vehicles, wherein the compound of formula (I) is in the form of a crystalline solid.

[0827] 142. The pharmaceutical composition of embodiment 141, wherein at least 85% of the compound of formula (I) present in the pharmaceutical composition is in the form of a crystalline solid.

[0828] 143. The pharmaceutical composition of embodiment 141, wherein at least 90% of the compound of formula (I) present in the pharmaceutical composition is in the form of a crystalline solid.

[0829] 144. The pharmaceutical composition of embodiment 141, wherein at least 95% of the compound of formula (I) present in the pharmaceutical composition is in the form of a crystalline solid.

[0830] 145. The pharmaceutical composition of embodiment 141, wherein substantially all of the compound of formula (I) present in the composition is in the form of a crystalline solid.

[0831] 146. The pharmaceutical composition of embodiment 141, wherein 100% of the compound of formula (I) present in the pharmaceutical composition is in the form of a crystalline solid.

[0832] 147. The compound of embodiment 134, the composition of any one of embodiments 135 to 140, or the pharmaceutical composition of any one of embodiments 141 to 146, wherein the crystalline solid form is Form A.

[0833] 148. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, the peak position (°2θ) comprises at least one approximate peak selected from the group consisting of 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. ± 0.2).

[0834] 149. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least two approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0835] 150. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: αWhen measured radiometrically, at least three approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0836] 151. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least four approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0837] 152. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least five approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0838] 153. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least six approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0839] 154. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: αWhen measured radiometrically, at least seven approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0840] 155. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least eight approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0841] 156. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least nine approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0842] 157. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least ten approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0843] 158. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: αWhen measured radiometrically, at least eleven approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0844] 159. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least twelve approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0845] 160. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least thirteen approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0846] 161. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least fourteen approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0847] 162. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: αWhen measured radiometrically, at least fifteen approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0848] 163. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least sixteen approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0849] 164. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least seventeen approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0850] 165. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least eighteen approximate peak positions (°2θ) selected from the group consisting of 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 ± 0.2).

[0851] 166. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: αWhen measured radiometrically, at least nineteen approximate peak positions (°2θ) are selected from the group consisting of 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. ± 0.2).

[0852] 167. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α The approximate peak positions (°2θ) of the radiometric measurements include 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. ± 0.2)

[0853] 168. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least one approximate peak position (°2θ) selected from 13.4, 17.2, and 18.9 ± 0.2).

[0854] 169. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least two approximate peak positions (°2θ) selected from 13.4, 17.2, and 18.9 ± 0.2).

[0855] 170. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measuring radiometrically, the approximate peak positions (°2θ) at 13.4, 17.2, and 18.9 are included. ± 0.2)

[0856] 171. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, the peak position (°2θ) of the peak is selected from the group consisting of 9.0, 11.4, and 20.1. ± 0.2).

[0857] 172. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least two approximate peak positions (°2θ) selected from 9.0, 11.4, and 20.1 ± 0.2).

[0858] 173. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measuring radiometrically, the approximate peak positions (°2θ) at 9.0, 11.4, and 20.1 are included. ± 0.2)

[0859] 174. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least one approximate peak position (°2θ) selected from 13.7, 13.8, and 24.8 ± 0.2).

[0860] 175. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measured radiometrically, at least two approximate peak positions (°2θ) selected from 13.7, 13.8, and 24.8 ± 0.2).

[0861] 176. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern as follows: α When measuring radiometrically, the approximate peak positions (°2θ) at 13.7, 13.8, and 24.8 are included. ± 0.2)

[0862] 177. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0863] When using Cu K α When measured radiometrically, at least one approximate peak position (°2θ) selected from 13.4, 17.2, and 18.9 ± 0.2); and

[0864] When using Cu K αWhen measured radiometrically, at least one approximate peak position (°2θ) selected from 9.0, 11.4, and 20.1 ± 0.2).

[0865] 178. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0866] When using Cu K α When measuring radiometrically, at least two approximate peak positions (°2θ) selected from 13.4, 17.2 and 18.9 ± 0.2); and

[0867] When using Cu K α When measured radiometrically, at least two approximate peak positions (°2θ) selected from 9.0, 11.4, and 20.1 ± 0.2).

[0868] 179. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0869] When using Cu K α When measuring radiometrically, the approximate peak positions (°2θ) of 13.4, 17.2, and 18.9 ± 0.2); and

[0870] When using Cu K α When measuring radiometrically, the approximate peak positions (°2θ) at 9.0, 11.4, and 20.1 ± 0.2).

[0871] 180. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0872] When using Cu K α When measured radiometrically, at least one approximate peak position (°2θ) selected from 13.4, 17.2, and 18.9 ± 0.2);

[0873] When using Cu K α When measured radiometrically, at least one approximate peak position (°2θ) selected from 9.0, 11.4, and 20.1 ± 0.2); and

[0874] When using Cu K α When measuring radiometrically, at least one approximate peak position (°2θ) selected from 13.7, 13.8 and 24.8 ± 0.2).

[0875] 181. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0876] When using Cu K α When measuring radiometrically, at least two approximate peak positions (°2θ) selected from 13.4, 17.2 and 18.9 ± 0.2);

[0877] When using Cu K α When measured radiometrically, at least two approximate peak positions (°2θ) selected from 9.0, 11.4, and 20.1 ± 0.2); and

[0878] When using Cu K α When measuring radiometrically, at least two approximate peak positions (°2θ) selected from 13.7, 13.8 and 24.8 ± 0.2).

[0879] 182. The compound, composition, or pharmaceutical composition of embodiment 147, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising:

[0880] When using Cu K α When measuring radiometrically, the approximate peak positions (°2θ) of 13.4, 17.2, and 18.9 ± 0.2);

[0881] When using Cu K α When measuring radiometrically, the approximate peak positions (°2θ) at 9.0, 11.4, and 20.1 ± 0.2); and

[0882] When using Cu K α When measuring radiometrically, the approximate peak positions (°2θ) at 13.7, 13.8, and 24.8 ± 0.2).

[0883] 183. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 182, wherein Form A is characterized by a solid state 19 F NMR spectrum: having at least one peak at a chemical shift selected from the group consisting of -74.5, -139.5, and -161.5 ppm.

[0884] 184. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 182, wherein Form A is characterized by a solid state 19F NMR spectrum: having at least two peaks at chemical shifts selected from -74.5, -139.5, and -161.5 ppm.

[0885] 185. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 182, wherein Form A is characterized by a solid state 19 F NMR spectrum: peaks at chemical shifts of -74.5, -139.5, and -161.5 ppm.

[0886] 186. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

[0887] 187. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least two 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.

[0888] 188. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

[0889] 189. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13C NMR spectrum: 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.

[0890] 190. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

[0891] 191. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid 13 C NMR spectrum: 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.

[0892] 192. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

[0893] 193. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13C NMR spectrum: 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.

[0894] 194. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid 13 C NMR spectrum: 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.

[0895] 195. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid 13 C NMR spectrum: having at least ten 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.

[0896] 196. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least eleven 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.

[0897] 197. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13C NMR spectrum: having at least twelve 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.

[0898] 198. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least thirteen 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.

[0899] 199. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least fourteen 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.

[0900] 200. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least fifteen 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.

[0901] 201. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13C NMR spectrum: having at least sixteen 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.

[0902] 202. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 175, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least seventeen 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.

[0903] 203. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least eighteen 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.

[0904] 204. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: having at least nineteen 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.

[0905] 205. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid 13C NMR spectrum: having at least twenty 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.

[0906] 206. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 185, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

[0907] 207. The compound, composition, or pharmaceutical composition of any one of embodiments 147 to 206, wherein Form A is characterized by an orthorhombic crystal system, a P212121 space group, and a crystalline structure having a Cu Kα radiation pattern. The unit cell has the following dimensions as measured on an X-ray diffractometer at 100(2)K:

[0908] α=90°

[0909] β=90°

[0910] γ=90°.

[0911] 208. The compound, composition or pharmaceutical composition of embodiment 207, wherein the X-ray diffractometer is a Bruker X-ray diffractometer.

[0912] 209. A pharmaceutical composition comprising:

[0913] 45 to 55 wt% of a solid dispersion comprising a polymer and a compound of formula (II):

[0914]

[0915] 42-50 wt% microcrystalline cellulose;

[0916] 2-4 wt% croscarmellose sodium; and

[0917] 0.5-1.5wt% magnesium stearate.

[0918] 210. The pharmaceutical composition of embodiment 209, wherein the pharmaceutical composition is a tablet core composition.

[0919] 211. The pharmaceutical composition of embodiment 210, wherein the tablet core composition is coated with a tablet coating.

[0920] 212. The pharmaceutical composition of embodiment 211, wherein the tablet coating is Opadry Blue.

[0921] 213. The pharmaceutical composition of any one of embodiments 209 to 212, wherein the pharmaceutical composition comprises about 50 mg of the compound of formula (II).

[0922] 214. The pharmaceutical composition of any one of embodiments 209 to 213, wherein the polymer is HPMCAS.

[0923] 215. The pharmaceutical composition of any one of embodiments 209 to 214, wherein the solid dispersion comprises 70-80 wt% polymer and 20-30 wt% compound of formula (II).

[0924] 216. The pharmaceutical composition of embodiment 215, wherein the solid dispersion comprises about 75 wt% polymer and about 25 wt% compound of formula (II).

[0925] 217. The pharmaceutical composition of any one of embodiments 209 to 216, wherein the pharmaceutical composition comprises about 50 wt% solid dispersion; about 46 wt% microcrystalline cellulose; about 3 wt% croscarmellose sodium; and about 1.0 wt% magnesium stearate.

[0926] 218. The pharmaceutical composition of any one of embodiments 209 to 217, wherein the pharmaceutical composition comprises an intragranular blend and an extragranular blend.

[0927] 219. The pharmaceutical composition of embodiment 218, wherein 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.

[0928] Examples

[0929] General method. 1 H NMR (400 MHz) spectra were obtained as solutions in appropriately deuterated solvents, such as dimethyl sulfoxide-d6 (DMSO-d6).

[0930] Unless otherwise indicated, X-ray powder diffraction (XRPD) spectra were recorded at room temperature in reflection mode using a PANalytical Empyrean system (Malvern PANalytical, Inc., Westborough, Massachusetts) equipped with a sealed tube source and a PIXcel 1D Medipix 3 detector. The X-ray generator was operated at 45 kV and 40 mA using a copper radiator. The powder sample was placed in a backfill sample holder and loaded into the instrument. The sample was scanned over a range of about 3° to about 40° 2θ with a step size of 0.0131° and a time of 49.73 s per step.

[0931] Unless otherwise indicated, solid-state NMR analyses were performed on a Bruker-Biospin 400 MHz wide-aperture spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. The samples were packed in a 4 mm ZrO2 rotor and spun under magic angle spinning (MAS) conditions, with the rotation speed typically set to 12.5 kHz. 1 H MAS T1 saturation recovery relaxation experiments were used to measure proton relaxation time in order to establish 13 C Cross-polarization (CP) MAS experiments using appropriate recirculation delay. 19 FMAS T1 saturation recovery relaxation test to measure the fluorine relaxation time in order to establish 19 The F MAS experiment was performed with an appropriate recycle delay. The CP contact time for the carbon CPMAS experiment was set to 2 ms. A CP proton pulse with a linear ramp-up (from 50% to 100%) was used. The carbon Hartmann-Hahn match was optimized on an external reference sample (glycine). Carbon and fluorine spectra were recorded under proton decoupling using a TPPM15 decoupling sequence with a field strength of approximately 100 kHz.

[0932] abbreviation

[0933] Unless otherwise noted or the context indicates otherwise, the following abbreviations shall be understood to have the following meanings:

[0934] abbreviation meaning

[0935] NMR Nuclear Magnetic Resonance

[0936] ESI-MS electrospray mass spectrometry

[0937] LC / MS liquid chromatography-mass spectrometry

[0938] UPLC ultra-performance liquid chromatography

[0939] HPLC / MS / MS High-performance liquid chromatography / tandem mass spectrometry

[0940] IS internal standard

[0941] HPLC high-performance liquid chromatography

[0942] SFC Supercritical Fluid Chromatography

[0943] ESI electrospray ionization

[0944] kg kilogram

[0945] g grams

[0946] mg milligrams

[0947] abbreviation meaning

[0948] L liter

[0949] mL milliliters

[0950] μL microliter

[0951] nL nanoliter

[0952] mol mole

[0953] mmol millimole

[0954] hr, h hours

[0955] min

[0956] ms milliseconds

[0957] mm millimeter

[0958] μm micrometer

[0959] nm nanometer

[0960] MHz Megahertz

[0961] Hz Hertz

[0962] N equivalent (concentration)

[0963] M molar (concentration)

[0964] mM millimolar (concentration)

[0965] μM micromolar (concentration)

[0966] ppm parts per million

[0967] %w / v weight-volume concentration

[0968] %w / w weight-weight concentration

[0969] Ac2O acetic anhydride

[0970] BnBr benzyl bromide

[0971] t-BuOH tert-Butanol

[0972] CDI 1,1'-Carbonyldiimidazole

[0973] DAST (diethylamino)sulfur trifluoride

[0974] DCM dichloromethane

[0975] DCE dichloroethane

[0976] DIAD Diisopropyl azodicarboxylate

[0977] DIBAL Diisobutylaluminum hydride

[0978] DIEA, DIPEA N,N-diisopropylethylamine

[0979] DMA N,N-dimethylacetamide

[0980] DMAP dimethylaminopyridine

[0981] DMF N,N-dimethylformamide

[0982] DMSO dimethyl sulfoxide

[0983] DRG dorsal root ganglion

[0984] EtOH

[0985] abbreviation meaning

[0986] EtOAc

[0987] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0988] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0989] T3P Propylphosphonic anhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane 2,4,6-trioxide

[0990] mCPBA meta-chloroperbenzoic acid

[0991] MeOH methanol

[0992] MsCl methanesulfonyl chloride

[0993] MTBE methyl tert-butyl ether

[0994] NCS N-chlorosuccinimide

[0995] NIS N-iodosuccinimide

[0996] NMP N-Methylpyrrolidone

[0997] PdCl2(dtbpf) 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride

[0998] PTSA p-Toluenesulfonic acid

[0999] STAB Sodium triacetoxyborohydride

[1000] TBAF Tetrabutylammonium fluoride

[1001] TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate

[1002] TCFH Chloro-N,N,N',N'-tetramethylformamidine hexafluorophosphate

[1003] THF Tetrahydrofuran

[1004] TEA triethylamine

[1005] Tf2O trifluoromethanesulfonic anhydride

[1006] TFA trifluoroacetic acid

[1007] TMSCl trimethylsilyl chloride

[1008] TMSCN Trimethylsilyl cyanide

[1009] RB Round Bottom Flask

[1010] RT Room temperature

[1011] ca. approximately (roughly)

[1012] E-VIPR Electrically Stimulated Voltage Ion Probe Reader

[1013] HEK human embryonic kidney

[1014] KIR2.1 inward rectifier potassium channel 2.1

[1015] DMEM Dulbecco's Modified Eagle's Medium

[1016] FBS fetal bovine serum

[1017] NEAA non-essential amino acids

[1018] HEPES 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid

[1019] DiSBAC6(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethyloxanol

[1020] CC2-DMPE Chlorocoumarin-2-dimyristoylphosphatidylethanolamine

[1021] abbreviation meaning

[1022] VABSC-1 Voltage Analytical Background Suppression Compound

[1023] HS human serum

[1024] BSA bovine serum albumin

[1025] SDD Spray Dried Dispersion

[1026] HPMCAS Hydroxypropyl methylcellulose acetate succinate

[1027] PTFE polytetrafluoroethylene

[1028] Example 1 - Preparation of compounds (IV) and (VII)

[1029] Compound VII can be prepared by the following method:

[1030]

[1031] In some embodiments, R 1 is -C(O)CH3, as described below in step 4A. In some embodiments, R 1 is -C(O)(4-nitrophenyl), as described below in Step 4B.

[1032] Step 1: Synthesis of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (XIII)

[1033]

[1034] Compound XIV (Alichem, 3.832 kg, 18.955 moles) was added to a 140 L reactor that had been previously vacuum dried and flushed with N2 gas. 18.85 L of anhydrous acetonitrile was added, and the solution was cooled to -2 ° C. Carbonyldiimidazole (Chem Impex, 99.5%, 3.280 kg, 19.92 moles, 1.05 equivalents) was added portionwise (from 4 × 820 g bottles, pre-weighed in an N2 drying oven). Each bottle of CDI was added 1-2 minutes apart to avoid sudden gas evolution of CO2. During the addition, the temperature was changed to +2 ° C. The solution was stirred at 0 ° C to -2 ° C for 1.5 hours. A solution of compound XV in THF (containing 4.028 kg of XII; 20.42 moles, 1.077 equivalents) was quickly added using a metering pump. The pump and container were rinsed with 2 L of anhydrous acetonitrile, 325 mesh anhydrous potassium carbonate (3.276 kg, 23.70 moles, 1.25 equivalents) was quickly added, and the reaction mixture was stirred at 35° C. for 5 hours, then cooled to 15° C. and maintained overnight. MTBE (24.5 L) was added, followed by 62.4 kg of 0.62 N H SO and then rinsed with 5 L of deionized water. The aqueous layer (pH 8) was re-extracted with 20 L of MTBE. The total MTBE was concentrated in vacuo to a dry solid and further concentrated to a dry solid with 10 L of IPA.

[1035] For recrystallization, the solid was dissolved in 25.5 L of IPA and transferred to a 140 L reactor with a 5 L IPA rinse; the solution was heated to 35 ° C. A pump was set to deliver 47.1 kg of deionized water; this was slowly adde...

Claims

1. A method for preparing a compound of formula (I): It comprises the compound of formula (IV): or a salt thereof is converted into the compound of formula (I).

2. The method according to claim 1, wherein converting the compound of formula (IV) into the compound of formula (I) comprises preparing a compound of formula (VI):

3. The method according to claim 2, wherein preparing the compound of formula (VI) comprises making the compound of formula (IV) or the compound of formula (VII): Contact with quinine.

4. 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):

5. The process 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. The method according to any one of claims 1 to 5, wherein converting the compound of formula (IV) to the compound of formula (I) comprises contacting the compound of formula (IV), the compound of formula (VI) or the compound of formula (VII) with a compound of formula (V): To obtain a compound of formula (III):

7. The method according to 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):

8. The method of claim 7, wherein converting the compound of formula (IV) to the compound of formula (I) comprises contacting the compound of formula (VIII) with a compound of formula (V): To obtain a compound of formula (III):

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

10. The method according to 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 method for preparing a compound of formula (II): It comprises the compound of formula (VII): Converted into the compound of formula (II).

12. The method of claim 11, wherein converting the compound of formula (VII) to the compound of formula (II) comprises contacting the compound of formula (VII) with a compound of formula (XXI): To obtain a compound of formula (XX):

13. 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):

14. 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. 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, further comprising reacting a compound of formula (IV): Converted into the compound of formula (VII).

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. The method according to any one of claims 1 to 10, 16 or 17, further comprising reacting a compound of formula (IX): Converted into the compound of formula (IV).

19. The method according to claim 18, further comprising reacting a compound of formula (X): Converted into the compound of formula (IX), in: R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z, or -P(O)Z2; and Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 aryl; C1-C4 alkyl; and C1-C4 haloalkyl.

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

21. The method according to claim 19 or 20, further comprising reacting a compound of formula (XI): Converted into the compound of formula (X).

22. The method of claim 21, wherein the compound of formula (XI) has formula (XI'):

23. The method according to claim 21 or 22, further comprising reacting a compound of formula (XII): Converted into the compound of formula (XI).

24. The method according to claim 23, further comprising reacting a compound of formula (XIII): Converted into the compound of formula (XII).

25. The method of claim 24, further comprising reacting a compound of formula (XIV): Contacting with a compound of formula (XV): To obtain the compound of formula (XIII).

26. A compound of the formula: in: R 1 is -C(O)-Z, -C(O)OZ, -C(O)CH=CH-Z or -P(O)Z2; Z is selected from C6-C4 optionally substituted by CN, halo, NO2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and / or C1-C4 haloalkoxy. 10 Aryl; C1-C4 alkyl; and C1-C4 haloalkyl; and R 2 It is a C1-C6 alkyl group.

27. A compound of the formula:

28. A compound of formula (I): wherein the compound is in the form of a crystalline solid.

29. A composition comprising a compound of formula (I): wherein the compound of formula (I) is in the form of a crystalline solid.

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

31. 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 the form of a crystalline solid.

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

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. The compound, composition, or pharmaceutical composition of claim 33, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD pattern): α When measured radiometrically, the peak comprises at least one approximate peak position (°2θ±0.2) selected from the group consisting of 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.

35. The compound, composition, or pharmaceutical composition of claim 33, wherein Form A is characterized by an X-ray powder diffraction pattern (XRPD) pattern: α When measured radiometrically, it comprises at least one approximate peak position (°2θ±0.2) selected from the group consisting of 13.4, 17.2, and 18.

9.

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

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

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

39. The compound, composition or pharmaceutical composition of any one of claims 33 to 38, wherein Form A is characterized by a solid state 13 C NMR spectrum: 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.

40. The compound, composition or pharmaceutical composition according to any one of claims 33 to 38, wherein Form A is characterized by an orthorhombic crystal system, a P212121 space group and a crystal structure having a Cu Kα radiation pattern. The unit cell has the following dimensions as measured on an X-ray diffractometer at 100(2)K:

41. A pharmaceutical composition comprising: 45 to 55 wt% of a solid dispersion comprising a polymer and a compound of formula (II): 42-50 wt% microcrystalline cellulose; 2-4 wt% croscarmellose sodium; and 0.5-1.5wt% magnesium stearate.

42. The pharmaceutical composition of claim 40, wherein the pharmaceutical composition is a tablet core composition.

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

44. The pharmaceutical composition of any one of claims 40 to 42, wherein the pharmaceutical composition comprises about 50 mg of the compound of formula (II).

45. The pharmaceutical composition of any one of claims 40 to 43, wherein the pharmaceutical composition comprises an intragranular blend and an extragranular blend.

Images