Hydroxy and (halo)alkoxy-substituted tetrahydrofurans as regulators of sodium channels

Abstract

Compounds of formula I and pharma- ceutically acceptable salts thereof are provided that are useful as inhibitors of sodium channels.Also provided are pharmaceutical compositions comprising the compounds or pharma- ceutically acceptable salts, and methods of using the compounds, pharma- ceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.In yet another aspect, the present invention relates to a method of treating or reducing the severity in a subject of various diseases, disorders, or conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, by administering the compounds, pharma- ceutically acceptable salts, or pharmaceutical compositions to the subject. JPEG2024520643000060.jpg5465

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 197,141, filed on 4 June 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness, or in which the patient would benefit from pain suppression. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain, 2008. 137(3): p.681-8). Neuropathic pain can be divided into two categories: pain caused by systemic metabolic damage to nerves, and pain caused by discrete nerve damage. Metabolic neuropathy includes postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include pain after amputation, postoperative nerve injury pain, and nerve entrapment injuries such as neuropathic back pain. Neuropathic pain is a leading cause of disorders worldwide that negatively impact patients' sleep, mood, and function. Clin.Ther.,2018 40(6):p.828-49.

[0003] Voltage-gated sodium channels (Na V ) is involved in pain signaling. VNav 1.8 mediates the rapid increase in action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and is therefore involved in the initiation of electrical signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Support for the claim that Nav plays a crucial and central role in pain signaling stems from (1) an evaluation of the role Nav plays in normal physiological function, (2) pathological conditions resulting from mutations in the Nav1.8 gene (SCN10A), (3) preclinical studies in animal models, and (4) the pharmacological effects of known Nav1.8 modulators. Furthermore, because Nav1.8 expression is limited to peripheral neurons, particularly those sensing pain (e.g., dorsal root ganglia), Nav1.8 inhibitors are less likely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse tendencies associated with opioid therapy. Therefore, targeting the underlying biology of pain through selective Nav1.8 inhibition represents a novel approach to analgesic development that could address the urgent and unmet need for safe and effective acute and chronic pain therapy (Rush, A.M. and TRCummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Nav1.8). V1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64 (2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p.50-56 (2008). Na in the initiation and propagation of neuronal signals. V Due to the role that Na plays, V Antagonists that reduce current can prevent or reduce nerve signaling, Na V Channels have been thought to be likely to reduce pain in conditions where high excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p.144-58 (2008)). Several clinically useful analgesics use Na V It has been identified as a channel inhibitor. Local anesthetics such as lidocaine are Na V Other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been shown to be effective in reducing pain by blocking channels, are also suggested to act by inhibiting sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p.3-9 (2002), Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008)).

[0004] Na V forms a subfamily of the voltage-gated ion channel superfamily, and Na V 1.1 to Na V 1.9, including nine isoforms designated as such. The tissue localization of the nine isoforms is different. Na V 1.4 is the primary sodium channel of skeletal muscle, and Na V 1.5 is the primary sodium channel of cardiomyocytes. Na V 1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, and Na V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central nervous system and the peripheral nervous system. The functional behaviors of the nine isoforms are similar, but they are distinct in the details of their voltage-dependence and kinetic behaviors (Catterall, W.A., Goldin, A.L., and Waxman, S.G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397(2005)).

[0005] At the time of their discovery, the Na V 1.8 channel was identified as likely to be a target for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Subsequently, Na V1.8 has been shown to be the carrier of sodium current that maintains action potential firing in small dorsal root ganglion (DRG) neurons in nociceptive sensory neurons (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+). + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is involved in spontaneous firing in damaged neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na V1.8 in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82、Lai,J.,et al.,Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel,Na V 1.8.Pain,2002.95(1-2):p.143-52、Dong,X.W.,et al.,Small interfering RNA-mediated selective knockdown of Na V1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats.Neuroscience,2007.146(2):p.812-21, Huang, HL, et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.Mol.Pain,2008.4:p.33, Black, JA, et al. al.,Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas.Ann.Neurol.,2008.64(6):p.644-53, Coward,K.,et al.,Immunolocalization of SNS / PN3 and NaN / SNS2 sodium channels in human pain states.Pain,2000.85(1-2):p.41-50, Yiangou,Y.,et al.,SNS / PN3 and SNS2 / NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves.FEBS Lett.,2000.467(2-3):p.249-52, Ruangsri,S.,et al.,Relationship of axonal voltage-gated sodium channel 1.8(Na V 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats.J.Biol.Chem.286(46):p.39836-47). Na V Small DRG neurons expressing 1.8 contain nociceptors involved in pain signaling.V 1.8 mediates large-amplitude action potentials in small neurons of the dorsal root ganglia (Blair, NT and BPBean, Roles of tetrodotoxin (TTX)-sensitive Na + current, TTX-resistant Na + current, and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is necessary for rapid repetitive action potentials in nociceptors and spontaneous activity of injured neurons (Choi, JS and SG Waxman, Physiological interactions between Na V 1.7 and Na V 1.8 sodium channels: a computer simulation study.J.Neurophysiol.106(6):p.3173-84, Renganathan, M., TRCummins, and SGWaxman, Contribution of Na( V )1.8 sodium channels to action potential electrogenesis in DRG neurons J.Neurophysiol.,2001.86(2):p.629-40, Roza,C.,et al.,The tetrodotoxin-resistant Na + channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRG neurons, Na V1.8 appears to be a driving factor for hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na V 1.8 mRNA expression levels have been shown to increase in DRGs (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135 (Pt 2): p.359-75; Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6). The inventors of this invention believe that some voltage-gated sodium channel inhibitors may have an insufficient therapeutic window (e.g., Na VIt was discovered that it has limitations as a therapeutic agent due to a lack of isoform selectivity, low potency, and / or other reasons. Therefore, selective Na V The need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors, remains. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Dieleman,JP,et al.,Incidence rates and treatment of neuropathic pain conditions in the general population.Pain,2008.137(3):p.681-8 [Non-Patent Document 2] Clin.Ther.,2018 40(6):p.828-49 [Non-Patent Document 3] Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001) [Non-Patent Document 4] Rush, AMand TRCummins, Painful Research:Identification of a Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium Channels.Mol.Interv.,2007.7(4):p.192-5) [Non-Patent Document 5] England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics.Expert Opin.Investig.Drugs 17(12), p.1849-64(2008) [Non-Patent Document 6] Krafte, DSand Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56 (2008) [Non-Patent Document 7] Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders.CNS Neurol.Disord.Drug Targets 7 (2), p.144-58(2008) [Non-Patent Document 8] Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action.Eur.J.Pain 6 Suppl.A, p.3-9(2002) [Non-Patent Document 9] Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008) [Non-Patent Document 10] Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology.XLVII.Nomenclature and structure-function relationships of voltage-gated sodium channels.Pharmacol.Rev.57(4), p.397(2005) [Non-Patent Document 11] Akopian, A.N., L. Sivilotti, and J.N. Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62 Non-Patent Document 12 Blair, N.T. and B.P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90 Non-Patent Document 13 Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6 Non-Patent Document 14 Jarvis, M.F., et al., A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U S A, 2007. 104(20): p. 8520-5 Non-Patent Document 15 Joshi, S.K., et al., Involvement of the TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82

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[0007] In one embodiment, the present invention relates to compounds described herein, or pharmaceutically acceptable salts thereof.

[0008] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

[0009] In yet another aspect, the present invention relates to a method for inhibiting voltage-gated sodium channels in a subject by administering a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition to the subject.

[0010] In yet another aspect, the present invention relates to a method for treating or alleviating the severity of various diseases, disorders, or 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., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition to a subject. [Brief explanation of the drawing]

[0011] [Figure 1] The XRPD pattern characteristics of amorphous compound 4 are shown. [Figure 2] The XRPD pattern characteristics of amorphous compound 21 are shown. [Figure 3] The XRPD pattern characteristics of amorphous compound 23 are shown. [Modes for carrying out the invention]

[0012] In one embodiment, the present invention relates to a compound of formula (I), [ka] Or with respect to the pharmaceutically acceptable salt thereof, X 2a is N, N + -O - , or CR 2a And, X 3a is N, N + -O - CR 3a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n And, X 4a is N, N + -O - CR 4a , C-CONR2, or C-CH 1-n (RA )(OH)(CH2OH) n and X 5a is N, N + -O - or C-R 5a and X 6a is N, N + -O - or C-R 6a and each R is independently H or C1-C6 alkyl, n is 0 or 1, R A is H or CH3, R 2a R 3a R 4a R 5a and R 6a are each independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 4b1 and R 4b2 one of which is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy and the other is H, R 5b1 and R 5b2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl, X 3c is N or C-R 3c and X 4c is N or C-R 4c and X 5c is N or C-R 5c and X 6c is N or C-R 6c and R 2c is H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2-(C3-C6 cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, L 1 is a bond or O, L 2 is a bond or C1-C6 alkylene, R 3c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 4c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 5c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 6c is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, provided that two or less of X 2a , X 3a , X 4a , X<z 5a , and X 6a are N or N + -O - and, X 3a and X 4a at least one of which is N, N + -O - , C-R 3a , or C-R 4a and, X 3c , X 4c , X5c, and X 6c where one or less of these is N, provided.

[0013] For the purposes of the present invention, chemical elements are those in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thThe general principles of organic chemistry are identified according to Ed. Furthermore, the general principles of organic chemistry are found in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5 th This is described in Ed.,Smith, MB and March, J., John Wiley & Sons, New York: 2001, and its entire contents are incorporated herein by reference.

[0014] As used herein, the term “compounds of the present invention” refers to the compounds of formula (I) described herein, all of its embodiments (e.g., formula (IA), etc.), and the compounds specified in Table A.

[0015] As described herein, the compounds of the present invention have a plurality of variable groups (e.g., X 3a , R A , R 5b1 This includes, for example. As those skilled in the art will recognize, the combinations of groups envisioned by the present invention are combinations that result in the formation of stable or chemically viable compounds. In this context, “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their formation, detection, and, if necessary, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable or chemically viable compound is a compound that remains substantially unchanged when held at a temperature of 40°C or less for at least one week in the absence of moisture or other chemically reactive conditions.

[0016] The chemical structures illustrated herein will be understood by those skilled in the art, and are therefore intended to be understood. For example, with respect to formulas (I), (IA), (IA-1), (IB), and (IB-1), X 2a and X 3a They are joined by a single bond, X 5a and X 6aThey are joined by a double bond, X 4c and X 5c Although they are linked by single bonds, the bonds between these groups can be hidden by atomic labeling in the chemical structure. Using a different style, formula I can be depicted as follows to show the bonds. [ka]

[0017] Furthermore, substituents represented as "CF3" or "F3C" in the chemical structure refer to trifluoromethyl substituents, regardless of whether their representation appears in the chemical structure.

[0018] As used herein, the term "halo" means F, Cl, Br, or I.

[0019] As used herein, the term "alkyl" refers to a linear or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, which is unsaturated and has a specified number of carbon atoms, and is bonded to the rest of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having 1 to 6 carbon atoms.

[0020] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds and a specified number of carbon atoms, which are bonded to the rest of the molecule by single bonds. For example, a “C2-C6 alkenyl” group is an alkenyl group having 2 to 6 carbon atoms.

[0021] As used herein, the term “cycloalkyl” refers to a stable, non-aromatic monocyclic or bicyclic (condensed, cross-linked, or spiro) saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, having a specified number of carbon ring atoms, which are bonded to the rest of the molecule by single bonds. For example, a “C3-C8 cycloalkyl” group is a cycloalkyl group having 3 to 8 carbon atoms.

[0022] As used herein, the term "haloalkyl" refers to an alkoxy group having a specified number of carbon atoms, in which one or more hydrogen atoms of the alkyl group are replaced by a halo group. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0023] As used herein, the term "alkoxy" refers to the formula -OR a It refers to the radical of, in the formula, R a This is an alkyl group having a specified number of carbon atoms. For example, a "C1-C6 alkoxy" group is defined by the formula -OR a It is a radical of, and in the formula, R a It is an alkyl group having 1 to 6 carbon atoms.

[0024] As used herein, the term "haloalkoxy" refers to an alkoxy group having a specified number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are replaced by a halo group.

[0025] As used herein, the term "alkylene" refers to a divalent linear or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, which is unsaturated and has a specified number of carbon atoms, and is bonded to the rest of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having 1 to 6 carbon atoms.

[0026] As used herein, the term “optionally substituted” refers to a group that is either unsubstituted or substituted with a substituent that is subsequently identified. For example, “optionally substituted with one or two halos” means either unsubstituted, substituted with one halo group, or substituted with two halo groups.

[0027] Unless otherwise specified, the compounds of the present invention include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), structural isomers, and tautomers of the compounds specified herein by their chemical name and chemical structure, whether or not they are specified by their chemical name or chemical structure. Furthermore, monoisomers, double bond isomers, structural isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, structural isomers, and tautomers, are within the scope of the present invention.

[0028] As used herein, in any chemical structure or formula, a straight bond that is not a thick line attached to the stereocenter of a compound, as in the following formula, is: [ka] This indicates that the stereochemistry of the stereocenter is unspecified. The compound may have any stereochemistry, or a mixture of stereochemistrys, at its stereocenter.

[0029] When used herein, in any chemical structure or formula, a straight bond between a stereocenter of a compound, represented by a thick or dashed line, as in the following formula, is: [ka] The relative stereochemistry of the chiral center with respect to other stereocenters to which it is attached by a thick or dashed linear bond is shown.

[0030] When used herein, in any chemical structure or formula, a wedge-shaped bond, indicated by a thick or dashed line, attached to the stereocenter of a compound, as in the following formula, [Chemistry] The absolute and relative stereochemistry of a stereocenter is shown relative to other stereocenters where solid lines or dashed wedge-shaped bonds are connected.

[0031] As used herein, the prefix "rac-" when used in connection with a chiral compound refers to a racemic mixture of the compound. In a compound having the "rac-" prefix, the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compound.

[0032] As used herein, the prefix "rel-" when used in connection with a chiral compound refers to a single enantiomer of unknown absolute configuration. In a compound having the "rel-" prefix, the (R)- and (S)-designators in the chemical name reflect the relative stereochemistry of the compound but do not necessarily reflect the absolute stereochemistry of the compound. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configuration of some stereocenters is known while only the relative configuration of other stereocenters is known. In these instances, the stereochemical designators associated with stereocenters of known absolute configuration are marked with an asterisk (*), e.g., (R*)- and (S*)-, while the stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters relative to other stereocenters of unknown absolute configuration but do not necessarily reflect the relative stereochemistry to stereocenters of known absolute configuration.

[0033] As used herein, the term “compound” refers to a collection of molecules having the same chemical structure, except that isotopic variations may exist between the constituent atoms of the molecules, when referring to the compounds of the present invention. The term “compound” includes such collections of molecules regardless of the purity of a given sample containing such collections of molecules. Accordingly, the term “compound” includes such collections of molecules in their 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 hydrates, solvates, or cocrystals.

[0034] As used herein, the term “amorphous” refers to a solid material that does not possess long-range order in its molecular positioning. Amorphous solids are generally glassy or supercooled liquids in which molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., no molecular packing and no long-range order. Amorphous solids are generally rather isotropic, meaning they exhibit similar properties in all directions and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature, indicating a transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material that does not have a sharp, characteristic crystalline peak in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, the solid material may contain amorphous compounds, for example, the solid material may be characterized by the absence of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline but amorphous as determined by the XRPD). Instead, one or more broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. For a typical comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. Solid materials containing amorphous compounds may be characterized by a broader temperature range of melting of the solid material compared to, for example, the melting range of a pure crystalline solid. Other techniques, such as solid-state NMR, may be used to characterize the crystalline or amorphous form.

[0035] In this specification and in the claims, unless otherwise specified, any atom not specifically designated as a particular isotope of any compound of the present invention is intended to represent any stable isotope of the specified element. In the examples, if an atom is not specifically designated as a particular isotope of any compound of the present invention, no effort is made to enrich that atom in a particular isotope, and therefore, a person skilled in the art will understand that such an atom likely existed in the isotopic composition of the specified element at approximately its natural abundance.

[0036] As used herein, the term “stable” means, when referring to an isotope, that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, those whose decay modes are not identified in the Table of Nuclides (January 1980) by V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory.

[0037] As used herein and in the claims, "H" refers to hydrogen, any stable isotope of hydrogen, i.e. 1 This includes H and D. In the examples, when an atom is designated as "H", no attempt is made to concentrate that atom in a specific isotope of hydrogen, and therefore, those skilled in the art will understand that such hydrogen atoms likely existed in the approximately naturally occurring isotopic composition of hydrogen.

[0038] When used herein, 1 "H" refers to protium. When an atom in the compound of the present invention or a pharmaceutically acceptable salt thereof is designated as protium, protium is present at the designated position at least at the naturally occurring concentration of protium.

[0039] As used herein, "D", "d", and " 2 "H" refers to deuterium.

[0040] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts contain each constituent atom in an approximately naturally occurring isotopic composition of the specified elements.

[0041] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable salts contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope of the specified element ("isotope-labeled" compound and salt). Examples of commercially available stable isotopes suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example, respectively. 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P is one example, but it is not limited to these.

[0042] Isotope-labeled compounds and salts can be used in several beneficial ways, including as pharmaceuticals. In some embodiments, the isotope-labeled compounds and salts contain deuterium ( 2 H) Labeled. Deuterium ( 2 H) Labeled compounds and salts are therapeutically useful and non 2 It has potential therapeutic advantages over H-labeled compounds. Generally speaking, deuterium ( 2 H) Labeled compounds and salts may have higher metabolic stability compared to unlabeled compounds due to the kinetic isotope effect described below. This higher metabolic stability translates directly to an increased in vivo half-life or lower doses, which in most circumstances represents a preferred embodiment of the present invention. Isotopically labeled compounds and salts can typically be prepared by performing the procedures disclosed in the synthesis scheme, examples, and related descriptions, and by replacing unisotopically labeled reactants with readily available isotopely labeled reactants.

[0043] deuterium( 2H) Labeled compounds and salts can manipulate the oxidative metabolic rate of compounds through first-order kinetic isotope effects. First-order kinetic isotope effects are changes in the rate of chemical reactions resulting from the exchange of isotopic nuclei, which are then caused by changes in the ground state energy of the covalent bonds involved in the reaction. The exchange of heavier isotopes usually results in a decrease in the ground state energy of the chemical bond, and therefore a decrease in the rate-determining bond cleavage. If the bond cleavage occurs within or near the saddle point region along the coordination of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is bonded to a carbon atom in a non-exchangeable position, k H / k D A typical velocity difference is 2 to 7. For further consideration, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference in its entirety.

[0044] The concentration of an isotope (e.g., deuterium) incorporated at a given position in the isotope-labeled compound or a pharmaceutically acceptable salt thereof of the present invention may be defined by an isotope enrichment factor. As used herein, the term “isotope enrichment factor” means the ratio between the abundance of the isotope at a given position in the isotope-labeled compound (or salt) and the natural abundance of the isotope.

[0045] When the atom in the compound of the present invention or a pharmaceutically acceptable salt thereof is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (approximately 45% deuterium incorporated). In some embodiments, the isotopic enrichment factors are at least 3500 (approximately 52.5% deuterium incorporated), at least 4000 (approximately 60% deuterium incorporated), at least 4500 (approximately 67.5% deuterium incorporated), at least 5000 (approximately 75% deuterium incorporated), at least 5500 (approximately 82.5% deuterium incorporated), at least 6000 (approximately 90% deuterium incorporated), at least 6333.3 (approximately 95% deuterium incorporated), at least 6466.7 (approximately 97% deuterium incorporated), at least 6600 (approximately 99% deuterium incorporated), or at least 6633.3 (approximately 99.5% deuterium incorporated).

[0046] In some embodiments, the present invention relates to compounds of formula (IA). [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, X 2a , X 3a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c It is defined as shown above in relation to equation (I).

[0047] In some embodiments, the present invention relates to the compound of formula (IA-1) [ka] Or, with respect to its pharmaceutically acceptable salt, in the formula, X 3a , X 4a , R 4b1 , R4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c are defined as shown above in relation to formula (I).

[0048] In some embodiments, the present invention relates to a compound of formula (I-B) [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein X 2a , X 3a , X 4a , X 5a , X 6a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , X 3c , X 4c , X 5c , X 6c , and R 2c are defined as shown above in relation to formula (I). [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2a H is H.

[0051] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 3a This refers to N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n In some embodiments, X 3a In other embodiments, X 3a C-CH 1-n (R A )(OH)(CH2OH) n In other embodiments, X 3a C-CH 1-n (R A )(OH)(CH2OH) n Therefore, n is 1.

[0052] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 4a This refers to N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n In some embodiments, X 4a In other embodiments, X 4a C-CH 1-n (R A )(OH)(CH2OH) n In other embodiments, X 4a C-CH 1-n (R A )(OH)(CH2OH) n Therefore, n is 1.

[0053] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 3a and X 4a One of them is N, and the other is C-CONR2 or C-CH 1-n (R A )(OH)(CH2OH) n That is the case.

[0054] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein X 3a C-CH 1-n (R A )(OH)(CH2OH) n In one such embodiment, the compound is as follows: [ka]

[0055] In this compound, R A H is , and n is 1.

[0056] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 5b2 is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 5b2 is CH3, CH(CH3)2, or CF3. In some embodiments, R 5b2 is CH(CH3)2. In some embodiments, R 5b2 This is CF3.

[0057] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R5b1 is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 5b1 is H, CH3, or CF3. In some embodiments, R 5b1 H is H. In some embodiments, R 5b1 This is CH3.

[0058] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C1-C6 alkoxy. In some embodiments, R 4b1 is H or OCH3. In some embodiments, R 4b1 H is H. In some embodiments, R 4b1 This is OCH3.

[0059] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4b2 is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In some embodiments, R 4b2 is OH. In some embodiments, R 4b2 is a C1-C6 alkoxy. In some embodiments, R 4b2 is OCH3, OCH2CH3, or OCH(CH3)2. In some embodiments, R 4b2 In some embodiments, R 4b2 is OCH2CH3. In some embodiments, R 4b2 This is OCH(CH3)2.

[0060] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 2cR is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. In some embodiments, R 2c R is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2. In some embodiments, R 2c is CH3 or OCH3. In some embodiments, R 2c is CH3. In some embodiments, R 2c This is OCH3.

[0061] In some embodiments, the present invention relates to one compound of formula (I), (IA), and (IB), or a pharmaceutically acceptable salt thereof, wherein X 3c CR 3c And R 3c is a halo or a C1-C6 alkyl group. In some embodiments, R 3c In other embodiments, R 3c This is CH3.

[0062] In some embodiments, the present invention relates to one compound of formula (IA-1) and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 3c is a halo or a C1-C6 alkyl group. In some embodiments, R 3c In other embodiments, F is F, and in other embodiments, R 3c This is CH3.

[0063] In some embodiments, the present invention relates to one compound of formula (I), (IA), and (IB), or a pharmaceutically acceptable salt thereof, wherein X 4c CR 4c And R 4c is a halo. In some embodiments, R 4c It is F.

[0064] In some embodiments, the present invention relates to one compound of formula (IA-1) and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4c is a halo. In some embodiments, R 4c It is F.

[0065] In some embodiments, the present invention relates to one compound from formulas (I), (IA), and (IB), or a pharmaceutically acceptable salt thereof, wherein R 5c H is H.

[0066] In some embodiments, the present invention relates to one compound from formulas (I), (IA), and (IB), or a pharmaceutically acceptable salt thereof, wherein R 6c H is H.

[0067] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4b2 These are C1-C6. In some embodiments, R 4b2 is OCH2CH3 or OCH3. In some embodiments, R 4b2 This is OCH3.

[0068] In some embodiments, the present invention relates to one compound from formula (I), (IA), (IA-1), (IB), and (IB-1), or a pharmaceutically acceptable salt thereof, wherein R 4b1 These are C1-C6. In some embodiments, R 4b2 is OCH2CH3 or OCH3. In some embodiments, R 4b1 This is OCH3.

[0069] In some embodiments, the present invention relates to any one compound of formula (I), (IA), (IA-1), (IB), and (IB-1), or any embodiment thereof, i.e., a non-salt form of the compound.

[0070] In some embodiments, the present invention relates to compounds selected from Table A, or pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to compounds selected from Table A, i.e., compounds in non-salt forms. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0071] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0072] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention” and the term is used herein.

[0073] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0074] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0075] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0076] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0077] In some embodiments, the present invention relates to compounds of the following formulas: [ka] or relating to pharmaceutically acceptable salts thereof. In other embodiments, the present invention relates to unsalted forms of the aforementioned compounds. Such compounds are considered “compounds of the present invention,” and for this reason, the term is used herein.

[0078] Salts, compositions, uses, formulations, administration, and additional agents pharmaceutically acceptable salts and compositions As discussed herein, the present invention provides compounds and pharmaceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus the compounds and pharmaceutically acceptable salts thereof are useful in treating diseases, disorders and conditions including, but are not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmias. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise the compounds described herein or pharmaceutically acceptable salts thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agents are sodium channel inhibitors.

[0079] As used herein, the term “pharmaceutically acceptable” means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of the compound of the present invention includes any non-toxic salt that can be used to provide the compound of the present disclosure or an inhibitory metabolite or residue thereof, either directly or indirectly, at the time of administration to the recipient. The salt may be in pure form, a mixture with one or more other substances (e.g., a solution, suspension, or colloid), or in the form of a hydrate, solvate, or cocrystal. As used herein, the term “inhibitory metabolite or residue thereof” means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0080] Pharmacopoeia-acceptable salts are well known in the art. For example, SMBerge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmacopoeia-acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4This includes alkyl) tetrasalts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0081] As used herein, the pharmaceutically acceptable compositions of the present invention also include, as used herein, all solvents, diluents, or other liquid vehicles suitable for the desired specific dosage form, including pharmaceutically acceptable carriers, adjuvants, or vehicles, such as dispersing or suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium becomes incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutically acceptable composition, its use is intended to be within the scope of this disclosure.Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose). Examples of ingredients include sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances. Preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0082] In another embodiment, the present invention is characterized by a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0083] In another embodiment, the present invention is characterized by 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.

[0084] Use of compounds and pharmaceutically acceptable salts and compositions In another embodiment, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a subject, the method comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0085] In yet another aspect, the present invention features a method for treating or alleviating the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from aponeurosis resection, hernia repair, or abdominal wall reconstruction), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, the method comprising administering an effective amount of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0086] In yet another aspect, the present invention is characterized by a method for treating or alleviating the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia, the method comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0087] In yet another embodiment, the present invention is characterized by a method for treating or alleviating the severity of intestinal pain in subjects, including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0088] In yet another embodiment, the present invention features a method for treating or reducing the severity of neuropathic pain in a subject comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the term "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0089] In yet another aspect, the present invention is characterized by a method for treating or alleviating the severity of neuropathic pain in subjects including postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy, pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0090] In yet another embodiment, the present invention features a method for treating or reducing the severity of musculoskeletal pain in a subject comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0091] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of musculoskeletal pain, which includes osteoarthritis, back pain, cold pain, burn pain, or toothache, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0092] In yet another embodiment, the present invention is characterized by a method for treating or reducing the severity of inflammatory pain in subjects, the inflammatory pain including rheumatoid arthritis pain or vulvodynia, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0093] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of inflammatory pain in subjects, the inflammatory pain including rheumatoid arthritis pain, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0094] In yet another embodiment, the present invention is characterized by a method for treating or alleviating the severity of idiopathic pain in subjects, where idiopathic pain includes pain of fibromyalgia, and the method comprises administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0095] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of a pathological cough in a subject, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0096] In yet another embodiment, the present invention features a method for treating or reducing the severity of acute pain in a subject, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, acute pain includes acute postoperative pain.

[0097] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain from hernia repair, pain from aponeurosis resection, or pain from abdominal wall reconstruction) in subjects comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0098] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of pain in a patient undergoing aponeurosis resection, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0099] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of pain in a patient with hernia repair surgery, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] In yet another aspect, the present invention is characterized by a method for treating or reducing the severity of pain in patients undergoing abdominoplasty, comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0101] In yet another embodiment, the present invention features a method for treating or reducing the severity of visceral pain in a subject comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0102] In yet another embodiment, the present invention features a method for treating or reducing the severity of a neurodegenerative disease in a subject comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the neurodegenerative disease includes multiple sclerosis. In some embodiments, the neurodegenerative disease includes Pitt-Hopkins syndrome.

[0103] In yet another embodiment, the present invention is characterized by a method in which a subject is treated simultaneously with one or more additional therapeutic agents administered before or after treatment with an effective amount of a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0104] In another embodiment, the present invention is characterized by a method for inhibiting voltage-gated sodium channels in a biological sample, the method comprising contacting the biological sample with an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, the voltage-gated sodium channels are Na V It is 1.8.

[0105] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain and irritable bowel syndrome associated with multiple sclerosis, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, diabetic neuralgia - L-pathies, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain from hernia repair, pain from aponeurosis excision, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic erythema Erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoproliferative disorder, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induction The present invention is characterized by a method for treating or alleviating the severity of conditions in which the present invention is used, including: induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, renal colic, biliary tract disease, vascular lower extremity ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0106] In another aspect, the present invention relates to pain from femoral cancer, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, and pain. Neuromas with ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-lower limb, upper limb, or mastectomy), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain, renal pelvis and kidney Inflammation, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labor pains, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behçet's disease pain, painful steatosis, phlebitis pain, Guillain-Barré syndrome pain, painful leg and mobile toes, Haglung The present invention is characterized by a method for treating or alleviating the severity of conditions in which the present invention is used, including: Doe syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain, the method comprising administering an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0107] Compounds for use, pharmaceutically acceptable salts, and compositions In another embodiment, the present invention is characterized by the compound of the present invention for use as a pharmaceutical agent, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0108] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of inhibiting voltage-gated sodium channels in a subject. In another aspect, the voltage-gated sodium channel is Na V It is 1.8.

[0109] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in methods of treating or alleviating the severity of conditions in the following subjects: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from hernia repair, pain from aponeurosis resection, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmias.

[0110] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in methods of treating or alleviating the severity of conditions in the following subjects: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmias.

[0111] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of intestinal pain, including pain of inflammatory bowel disease, pain of Crohn's disease, or pain of interstitial cystitis.

[0112] In another embodiment, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in methods of treating or reducing the severity of neuropathic pain in subjects. In some embodiments, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the term "idiopathic small fiber neuropathy" shall be understood to include any small fiber neuropathy.

[0113] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in methods of treating or reducing the severity of neuropathic pain in subjects, including postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy, pain after spinal cord injury, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic headache.

[0114] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in methods of treating or reducing the severity of musculoskeletal pain in subjects. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0115] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of musculoskeletal pain, including osteoarthritis, back pain, cold pain, burn pain, or toothache.

[0116] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of inflammatory pain in subjects, the inflammatory pain including rheumatoid arthritis pain or vulvodynia.

[0117] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of inflammatory pain in subjects of rheumatoid arthritis.

[0118] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of idiopathic pain, wherein idiopathic pain includes pain of fibromyalgia.

[0119] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of a pathological cough in a subject.

[0120] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of acute pain in a subject. In some embodiments, acute pain includes acute postoperative pain.

[0121] In yet another aspect, the present invention is characterized by a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of postoperative pain (for example, pain from joint replacement surgery, pain from soft tissue surgery, pain from hernia repair surgery, pain from aponeurosis excision surgery, or pain from abdominal wall reconstruction surgery).

[0122] In another aspect, the present invention features the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of pain in patients undergoing aponeurosis resection.

[0123] In another aspect, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or reducing the severity of pain in a subject of hernia repair surgery.

[0124] In another aspect, the present invention features the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in methods of treating or reducing the severity of pain in patients undergoing abdominal wall reconstruction surgery.

[0125] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of visceral pain in a subject. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0126] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in methods of treating or reducing the severity of neurodegenerative diseases in subjects. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome.

[0127] In another embodiment, the present invention features a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof for use in a manner in which the subject is treated simultaneously with treatment by an effective amount of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, or with one or more additional therapeutic agents administered before or after such treatment. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0128] In another embodiment, the present invention features a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of inhibiting voltage-gated sodium channels in a biological sample, the method comprising contacting the biological sample with an effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another embodiment, voltage-gated sodium channels are Na V It is 1.8.

[0129] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonicis, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain and irritable bowel syndrome associated with multiple sclerosis, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, and diabetic neuropathy. Neuropathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain from hernia repair, pain from aponeurosis excision, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, all Systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoproliferative disorder, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy pain, sarcoidosis, spondylolysis, spondylolisthesis, The present invention is characterized by the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions, for use in methods of treating or alleviating the severity of conditions in which the following conditions are present: chemotherapy-induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, renal colic, biliary tract disease, vascular lower extremity ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0130] In another aspect, the present invention relates to pain from femoral cancer, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, and peripheral nerve injury. Painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-lower limb, upper limb, or mastectomy), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain Pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labor pains, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behçet's disease pain, painful steatosis, phlebitis pain, Guillain-Barré syndrome pain, painful leg and mobile toes The present invention is characterized by the compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating or reducing the severity of conditions in Haglund's syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0131] In another aspect, the present invention features compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use in methods of treating or reducing the severity of conditions in which the subject has trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary nerve disorder, radial nerve disorder, ulnar nerve disorder, brachial plexus disorder, thoracic nerve disorder, intercostal neuralgia, lumbosacral nerve disorder, ilioinguinal neuralgia, pudendal neuralgia, femoral nerve disorder, paresthesia of femoral pain, saphenous nerve disorder, sciatic nerve disorder, peroneal nerve disorder, tibial nerve disorder, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain after amputation surgery.

[0132] Pharmaceutical manufacturing In another aspect, the present invention provides the use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals.

[0133] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the inhibition of voltage-gated sodium channels. In another aspect, voltage-gated sodium channels are Na V It is 1.8.

[0134] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or alleviation of the severity of conditions in the following subjects: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from hernia repair, pain from aponeurosis resection, or pain from abdoplasty), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmias.

[0135] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or alleviation of the severity of conditions in the following subjects: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, hernia repair pain, aponeurosis resection pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmias.

[0136] In yet another aspect, the present invention provides the use of the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions described herein for the manufacture of agents for use in treating or alleviating the severity of intestinal pain, including pain of inflammatory bowel disease, pain of Crohn's disease, or pain of interstitial cystitis.

[0137] In yet another embodiment, the present invention provides compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity in subjects of neuropathic pain. In some embodiments, neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some embodiments, neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0138] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity of neuropathic pain in subjects, including postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radiculopathy, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuropathy, cancer chemotherapy-induced neuropathy, antiretroviral therapy-induced neuropathy, post-spinal cord injury pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal-autonomic neuropathy.

[0139] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity of musculoskeletal pain. In some embodiments, musculoskeletal pain includes osteoarthritis.

[0140] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity of musculoskeletal pain, including osteoarthritis, back pain, cold pain, burn pain, or toothache.

[0141] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of pharmaceuticals for use in the treatment or reduction of the severity of inflammatory pain in subjects of rheumatoid arthritis or vulvodynia.

[0142] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of pharmaceuticals for use in the treatment or reduction of the severity of inflammatory pain in subjects of rheumatoid arthritis.

[0143] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of pharmaceuticals for use in the treatment or reduction of the severity of idiopathic pain, wherein idiopathic pain includes pain of fibromyalgia.

[0144] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity of pathological cough in subjects.

[0145] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or alleviation of the severity of acute pain in subjects. In some embodiments, acute pain includes acute postoperative pain.

[0146] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or alleviation of the severity of postoperative pain in subjects (e.g., pain from joint replacement surgery, pain from soft tissue surgery, pain from hernia repair surgery, pain from aponeurosis resection surgery, or pain from abdominal wall reconstruction surgery).

[0147] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating or alleviating the severity of pain in patients with hernia repair surgery.

[0148] In yet another aspect, the present invention provides the use of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a drug for use in the treatment or reduction of the severity of pain in patients undergoing aponeurosis resection.

[0149] In yet another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in treating or alleviating the severity of pain in patients undergoing abdominal wall reconstruction surgery.

[0150] In yet another embodiment, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or alleviation of the severity of visceral pain in subjects. In some embodiments, visceral pain includes visceral pain resulting from abdominoplasty.

[0151] In other embodiments, the present invention features compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of agents for use in the treatment or reduction of the severity of neurodegenerative diseases. In some embodiments, neurodegenerative diseases include multiple sclerosis. In some embodiments, neurodegenerative diseases include Pitt-Hopkins syndrome.

[0152] In yet another embodiment, the present invention provides the use of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof for the manufacture of a drug to be used in combination with one or more additional therapeutic agents administered before or after treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0153] In another aspect, the present invention relates to acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, dysalgesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonicis, arrhythmia, motor disorders, neuroendocrine disorders, ataxia, central neuropathic pain and irritable bowel syndrome associated with multiple sclerosis, incontinence, pathological cough, visceral pain, osteoarthritis, postherpetic neuralgia, and diabetic neuropathy. Neuropathy, radiculopathy, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., pain from joint replacement, pain from soft tissue surgery, pain from hernia repair, pain from aponeurosis excision, or pain from abdominal wall reconstruction), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic cervical syndrome, fragility fracture, vertebral fracture, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, all Systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, venous osteopathy, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteoproliferative disorder, intervertebral disc degeneration / hernia pain, nerve root compression, facet joint syndrome, spinal surgery failure syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmic neuropathy pain, sarcoidosis, spondylolysis, spondylolisthesis, The present invention provides for the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the manufacture of agents used for the treatment or reduction of the severity of chemotherapy-induced oral mucositis, Charcot arthritis, temporomandibular joint disorder, painful total knee replacement, noncardiac chest pain, genital pain, renal colic, biliary tract disease, vascular lower extremity ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina pectoris, exercise-induced angina pectoris, palpitations, hypertension, or abnormal gastrointestinal motility.

[0154] In another aspect, the present invention relates to pain from femoral cancer, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, and peripheral nerve injury. Painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-lower limb, upper limb, or mastectomy), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain Pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labor pains, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behçet's disease pain, painful steatosis, phlebitis pain, Guillain-Barré syndrome pain, painful leg and mobile toes The present invention provides compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents to be used for the treatment or reduction of the severity of Haglund's syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina-induced pain.

[0155] In another aspect, the present invention provides the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the manufacture of agents for use in the treatment or reduction of the severity of pain following traumatic neuroma, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary nerve disorder, radial nerve disorder, ulnar nerve disorder, brachial plexus disorder, thoracic nerve disorder, intercostal neuralgia, lumbosacral nerve disorder, ilioinguinal neuralgia, pudendal neuralgia, femoral nerve disorder, paresthesia of femoral pain, saphenous nerve disorder, sciatic nerve disorder, peroneal nerve disorder, tibial nerve disorder, lumbosacral plexus disorder, stump pain of traumatic neuroma, or pain following amputation surgery.

[0156] Administration of compounds, pharmaceutically acceptable salts, and compositions In certain embodiments of the present invention, an "effective amount" of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective in treating or alleviating the severity of one or more of the conditions listed above.

[0157] The compounds, salts, and compositions produced by the methods of the present invention may be administered in any amount and via any route of administration that is effective in treating or alleviating one or more of the severities of painful or non-painful conditions listed herein. The exact amount required will vary among subjects depending on the species, age, and general condition of the subject, the severity of the condition, the specific drug, and its mode of administration. The compounds, salts, and compositions of the present invention may be formulated in unit dosage forms as needed for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically distinct drug unit that is appropriate for the subject being treated. However, it will be understood that the total daily dose of the compounds, salts, and compositions of the present invention should be determined by the attending physician within the bounds of sound medical judgment. A specific effective dose level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and its severity, the activity of the specific compound or salt used, the specific composition used; the subject's age, weight, general health, sex, and diet; the timing of administration, route of administration, and excretion rate of the specific compound or salt used; the duration of treatment; the agents used in combination with or concurrently with the specific compound or salt used; and similar factors well known in the medical technology. As used herein, the terms “subject” or “patient” mean an animal, preferably a mammal, and most preferably a human.

[0158] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisional, vaginally, intraperitoneally, topically (as powder, ointment, or droplets), orally or as a nasal spray to the cheek, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the present invention may be administered orally or parenterally once or twice a day at a dosage level of about 0.001 mg / kg to about 1000 mg / kg, which is effective in obtaining the desired therapeutic effect.

[0159] 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 include, for example, inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0160] Preparations for injection, such as sterile aqueous or oily suspensions for injection, may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile preparations for injection may also be sterile solutions, suspensions, or emulsions for injection in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (United States Pharmacopeia), and isotonic sodium chloride solution. Furthermore, sterile fixatives have traditionally been used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0161] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0162] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Depot formulations for injection are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The compound release rate can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0163] A composition for rectal or vaginal administration is preferably a suppository that can be prepared by mixing the compound or salt of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0164] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, carbonate It is mixed with calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0165] Similar types of solid compositions may also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology. They may optionally contain opacifying agents and may optionally be compositions that release the active ingredient in a delayed manner, only in or preferentially in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions may also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0166] The active compound or salt may also be in the form of microcapsules having one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in pharmaceutical formulation technology. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. These may optionally contain opacifiers and may optionally be compositions that release the active ingredient in a delayed manner, only in a specific part of the intestinal tract, or preferentially. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0167] Dosage forms for topical or transdermal administration of the compounds or salts of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. Furthermore, the present invention intends to utilize transdermal patches, which have the additional advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0168] Generally as described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compound is Na V1.8 is an inhibitor, and therefore does not wish to be bound by any particular theory, but the compound, salt, and composition are Na V 1.8 is particularly useful for treating or reducing the severity of diseases, conditions, or disorders in which activation or hyperactivity is involved. V 1.8 If the activation or hyperactivity of Na is involved in a particular disease, condition, or disorder, then the disease, condition, or disorder may also be Na V 1.8 A disease, condition, or disorder may be referred to as a mediated disease. Therefore, in another embodiment, the present invention is Na V 1.8 The present invention provides a method for treating or alleviating the severity of a disease, condition, or disorder in which activation or hyperactivity of the substance is involved in the disease state.

[0169] Na V The activity of the compounds used in the present invention as inhibitors of 1.8 may be assayed in accordance with methods generally described in International Publication No. WO2014 / 120808A9 and U.S. Publication No. 2014 / 0213616A1 (both of which are incorporated in their entirety by reference), the methods described herein, and other methods known and available to those skilled in the art.

[0170] Additional medications The compounds, salts, and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (treatments or procedures) used in a combination regimen will take into account the suitability of the desired therapeutic agent and / or procedure, as well as the desired therapeutic effect to be achieved. Naturally, the therapies used may achieve the desired effect against the same disorder (for example, the compounds of the present invention may be administered simultaneously with another agent used to treat the same disorder) or they may achieve different effects (for example, control of any adverse effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known to be appropriate for the disease or condition being treated. For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, e.g., etodolac, indomethacin, sulindac, tolmetine, naphthyl alkanones, e.g., nabumetone, oxicam, e.g., piroxicam, para-aminophenol derivatives, e.g., acetaminophen, propionic acid, e.g., fenoprofen, fluviprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamet, e.g., Examples include meclofenamic acid, mefenamic acid, and pyrazoles (e.g., phenylbutazone), or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, buprenorphine, butorphanol, dezosine, nalbufine, and pentazocine). Furthermore, non-pharmacological analgesic approaches may be used in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiological (spinal infusion, nerve block), neurosurgical (nerve decompression of CNS pathways), neurostimulation (percutaneous electroneural stimulation, spinal cord posterior column stimulation), physical therapy (physiotherapy, orthostatic devices, diathermy), or psychiatric (cognitive methods - hypnosis, biofeedback, or behavioral methods) approaches may also be used.Additional appropriate therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), 2011, and the Food and Drug Administration (website www.fda.gov), the entire contents of which are incorporated herein by reference.

[0171] In another embodiment, additional suitable therapeutic agents are selected from the following: (1) Opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyfene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbufine, pentazocine, or diferikephalin; (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, fluviprofen, ibuprofen (but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketrolac (but not limited to ketrolactromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimeslide, nitroflurbiprofen, orsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac; (3) Barbiturate sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mefobarbital, metalbital, methhexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamylal, or thiopental; (4) Benzodiazepines having a sedative effect, such as chlordiazepoxide, chlorazepic acid, diazepam, furazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) Histamine (H1) antagonists having a sedative effect, such as diphenhydramine, pyriramine, promethazine, chlorpheniramine, or chlorcyclidine; (6) Sedatives, such as glutethimide, meprobamate, methacaron, or dichlorphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline kinin, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), combination preparations of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel (NR2B antagonists, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-l-piperidinyl]-l-hydroxyethyl-3,4-dihydro-2(lH)-quinolinone); (9) Alpha-adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamide-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline; (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate; (12) Tachykinin (NK) antagonists, especially NK-3, NK-2, or NK-1 antagonists, for example, (alpha-R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazosino[2,1g][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S) -2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazole-3-one (MK-869), aprepitant, ranepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, dalifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, delacoxib, etoricoxib, or lumiracoxib; (15) Coal-tar analgesics, especially paracetamol; (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesolidazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, certindol, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, lacloprid, zotepine, bifepurnox, asenapine, lurasidone, amisulpride, paraperidone, palindore, eprivanserin, osanetan, limonabant, meclinertan, Miraxion®, or sarizotan; (17) Vanilloid receptor agonists (e.g., resiniferatoxin or cibamide) or antagonists (e.g., capsazepine, GRC-15300); (18) Beta-adrenaline, e.g., propranolol; (19) Local anesthetics, e.g., mexiletine; (20) Corticosteroids, e.g., dexamethasone; (21) 5-HT receptor agonists or antagonists, in particular 5-HT 1B / 1D Agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan; (22)5-HT 2A Receptor antagonists, e.g., R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) Cholinergic (nicotinic) analgesics, for example isopronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentador ER (Nucynta®); (25) PDE5 inhibitors, e.g., 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]Indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazine-l-yl-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazine-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(l-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidine-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one, 5-[2-ethoxy-5-(4-ethylpiperazine-l-ylsulfonyl)pyridine-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-ONE, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidine-l-yl]-N-(pyrimidine-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidine-5-yl)-N-[2-(l-methylpyrrolidine-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) Alpha-2-delta ligands, e.g., gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hepta-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- Proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hepta-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-one, C-[1-(1H-tetrazole-5-ylmethyl)-cycloheptayl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid; (27) Cannabinoids, e.g., KHK-6188; (28) Metabotropic glutamate subtype 1 receptor (mGluRl) antagonists; (29) Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, esitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiopine, ritoxetine, dapoxetine, nefazodone, sericlamine, and trazodone; (30) Norepinephrine reuptake inhibitors, e.g., maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensin, and biloxazine (Vivalan®), in particular selective norepinephrine reuptake inhibitors, e.g., reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-norepinephrine reuptake inhibitors, e.g., venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, e.g., S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitride; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- [Thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitride, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors, e.g., donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, e.g., N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridine-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridine-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, e.g., l-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057), or DPC-11870; (36) 5-lipoxygenase inhibitors, e.g., dileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) Sodium channel blockers, e.g., lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate; (38) Na V1.7 Blockers, e.g., XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112, and WO2011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012 / 196869); WO2012 / 112743 (US2012 / 245) 136); as disclosed in WO2012 / 125613 (US2012 / 264749), WO2012 / 116440 (US2014 / 187533), WO2011 / 026240 (US2012 / 220605), US8883840, US8466188, WO2013 / 109521 (US2015 / 005304), WO2020 / 117626, and CN111217776 (the entire contents of each application are incorporated herein by reference); (38a)Na V1.7 Blockers, e.g., (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methylphenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro Ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxyphenyl)methanone, 1-(4-benzhydrylpiperazine-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[ 3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonilicate, (4-isopropoxy-3-methylphenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl (L)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6- [Iyl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[1'-[ 4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-Piperidine]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-Bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide, or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone. (39) Na V 1.8 Blockers, e.g., PF-04531083, PF-06372865, and e.g., WO2008 / 135826 (US2009048306), WO2006 / 011050 (US2008312235), WO2013 / 061205 (US2014296313), US2013 / 0303535, WO2013 / 131018, US8466188, WO2013 / 114250(US2013 / 274243), WO2014 / 120808(US2014 / 213616), WO2014 / 120815(US2014 / 228371), WO20 14 / 120820(US2014 / 221435), WO2015 / 010065(US20160152561), WO2015 / 089361(US20150166589), WO2 019 / 014352(US2019 / 0016671), WO2018 / 213426, WO2020 / 146682, WO2020 / 146612, WO2020 / 014243, WO 2020 / 014246, WO2020 / 092187, WO2020 / 092667(US2020140411), WO2020 / 261114, WO2020 / 140959, WO20 Disclosed in 20 / 151728, WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN112479996 (WO2021 / 047622) (the entire contents of each application are incorporated herein by reference); (39a)Na V1.8 Blockers, e.g., 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2- Xo-1,2-dihydropyridine-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -Fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridine-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro Phenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridine-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridine-4- (Iyl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-2-oxopyridine-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 3-(4-Chloro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoxaline-2-Carboxamide, 4-(3-(4-(Trifluoromethoxy)phenoxy)Quinoxaline-2-Carboxamide)Picolinic Acid, 2-(2,4-Difluorophenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 2-(4-Fluoro-2-Methoxyphenoxy)-N-(3-Sulfamoylphenyl)Quinoline-3-Carboxamide, 3-(2,4-Difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-Carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridine-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N -(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamide)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamide)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-Bis(trifluoromethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamide) picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide) benzoic acid, 5-(4,5-Dichloromethyl 4-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamide) benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) benzoic acid, 4-(4, 5-Dichloro-2-(4-chloro-2-methylphenoxy)benzamide)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide) picolinic acid, 5-(4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamide) picolinic acid, 4-(4,5-Dichloro-2-(4-fluoro-2-methylphenoxy)benzamide)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamide) picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide) picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamide) benzoic acid, 5-(4,5-dichloro-2-(2,4-Difluorophenoxy)benzamide)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-s Sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methyl) Toxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2,4-Dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-Bis(trifluoromethyl)benzamide, 5-Chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 4,5-Dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-Fluoro-2-(4-fluoro-2-methylphenoxy)- N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(triduteromethoxy)-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-pheni, N-(3-carbamoyl-4-fluorophenyl)-3 -(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(triduteromethoxy)-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-fluorophenyl)-2,3,4-Trifluoro-6-[2-Methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-Carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy )phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2-(triduteromethoxy)-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-(trifluoro Oromethyl)benzamide, 5-[[2-fluoro-6-[2-(triduteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, 4-(2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide)picolinamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;, (40) Combined Na V 1.7 and Na V 1.8 Blockers, e.g., DSP-2230, Lohocla201, or BL-1021; (41) 5-HT3 antagonists, e.g., ondansetron; (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharmaceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, e.g., varenicline; (44) N-type calcium channel antagonists, e.g., Z-160; (45) Nerve growth factor antagonists, e.g., tannezumab; (46) Endopeptidase stimulants, e.g., senlevotase; (47) Angiotensin II antagonists, e.g., EMA-401; (48) Acetaminophen (but not limited to intravenous acetaminophen (e.g., Ofrmev®)); (49) Bupivacaine (including, but not limited to, bupivacaine liposome injection suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)), and (50) A combination of bupivacaine and meloxicam (e.g., HTX-011).

[0172] In one embodiment, additional suitable therapeutic agents are selected from V-116517, pregabalin, sustained-release pregabalin, ezogabine (Potiga®), ketamine / amitriptyline topical cream (Amiket®), AVP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

[0173] In another embodiment, additional suitable therapeutic agents are selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-yl)acetamide; N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridine-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazole-2-yl)methyl)oxetane-3-amine.

[0174] In another embodiment, additional therapeutic agents are selected from GlyT2 / 5HT2 inhibitors, e.g., Operanserin (VVZ149), TRPV modulators, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, EGR1 inhibitors, e.g., Brivoglide (AYX1), NGF inhibitors, e.g., tanezumab, facinumab, ASP6294, MEDI7352, Mu opioid agonists, e.g., cebranopadol, NKTR181 (oxycodegol), CB-1 agonists, e.g., NEO1940 (AZN1940), imidazoline 12 agonists, e.g., CR4056, or p75NTR-Fc modulators, e.g., LEVI-04.

[0175] In another embodiment, the additional therapeutic agent is oryceridine or ropivacaine (TLC590).

[0176] In another embodiment, the additional therapeutic agent is Na V 1.7 Blockers, e.g., ST-2427 or ST-2578, as disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and WO2022 / 036297 (the entire contents of each application are incorporated herein by reference). In some embodiments, additional therapeutic agents are Na disclosed in WO2020 / 072835. V 1.7 Blockers. In some embodiments, additional therapeutic agents are disclosed in WO2022 / 036297. V 1.7 It is an antiblocker.

[0177] In another embodiment, additional therapeutic agents include ASP18071, CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra®), Brivolizide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS-2031, MEDI7352, or XT-150.

[0178] In another embodiment, additional therapeutic agents include Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS-4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623, ETX-801, or ACD440.

[0179] In another embodiment, additional therapeutic agents include WO2021 / 257490, WO2021 / 257420, WO2021 / 257418, WO2020 / 014246, WO2020 / 092187, WO2020 / 092667, WO2020 / 261114, CN112457294, CN112225695, CN111808019, WO2021 / 032074, WO2020 / 151728, WO2020 / 140959, WO2022 / 037641, WO2022 These are compounds disclosed in / 037647, CN112300051, CN112300069, WO2014 / 120808, WO2015 / 089361, WO2019 / 014352, WO2021 / 113627, WO2013 / 086229, WO2013 / 134518, WO2014 / 211173, WO2014 / 201206, WO2016 / 141035, WO2021 / 252818, WO2021 / 252822, and WO2021 / 252820.

[0180] In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 086229. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2013 / 134518. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 211173. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2014 / 201206. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2016 / 141035. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252818. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252822. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2021 / 252820. In some embodiments, the additional therapeutic agent is a compound disclosed in WO2020 / 072835. In some embodiments, additional therapeutic agents are compounds disclosed in WO2022 / 036297.

[0181] In another embodiment, the additional therapeutic agent is Na as identified above.V 1.7 and Na V 1.8 These are sodium channel inhibitors (also known as sodium channel blockers), such as 1.8-blockers.

[0182] The amount of additional therapeutic agents present in the composition of the present invention may be less than or equal to the amount typically administered in a composition containing the therapeutic agent as the sole active agent. The amount of additional therapeutic agents in the currently disclosed compositions may range from about 10% to 100% of the amount typically present in a composition containing the agent as the sole therapeutic active agent.

[0183] The compounds and salts of the present invention, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents, and catheters. Therefore, in another embodiment, the present invention includes compositions for coating implantable devices, generally comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. In yet another embodiment, the present invention includes implantable devices coated with compositions comprising the compounds or salts of the present invention described above, as well as the classes and subclasses herein, and carriers suitable for coating such implantable devices. General preparations of suitable coatings and coated implantable devices are described in U.S. Patents 6,099,562, 5,886,026, and 5,304,121. The coatings are typically biocompatible polymer materials such as hydrogel polymers, polymethyldisiloxanes, polycaprolactones, polyethylene glycols, polylactic acid, ethylene vinyl acetates, and mixtures thereof. The coating may be further covered with a suitable top coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or a combination thereof, as needed, to impart sustained-release properties to the composition.

[0184] Another aspect of the present invention is a biological sample or subject in which Na V1.8 With regard to inhibiting activity, the method includes administering to a subject or contacting the biological sample with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0185] Na in biological samples V 1.8 Inhibition of activity is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena, and the comparative evaluation of novel sodium channel inhibitors.

[0186] Synthesis of the Compound of the Present Invention The compounds of the present invention can be prepared from known materials by the methods described in the examples, other similar methods, and other methods known to those skilled in the art. As those skilled in the art will understand, the functional groups of the intermediate compounds in the following methods may need to be protected by suitable protecting groups. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art. The use of protecting groups is described in detail in TGMWuts et al., Greene's Protective Groups in Organic Synthesis (4th ed. 2006).

[0187] Radiolabeled analogues of the compound of the present invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention. As used herein, the term “radiolabeled analogue of the compounds of the present invention” means a compound that is identical to the compounds of the present invention described herein, except that one or more atoms are replaced with radioisotopes of atoms present in the compounds of the present invention, including all embodiments thereof.

[0188] As used herein, the term “radioisotope” refers to an isotope of an element known to undergo spontaneous radioactive decay. Examples of radioisotopes include: 3 H, 14 C, 32 P, 35 S, 18 F, 36 Examples include Cl, as well as isotopes whose decay modes have been identified in the Table of Nuclides (January 1980) by VS Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory.

[0189] Radiolabeled analogs can be used in several beneficial ways, including various types of assays such as substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14 C) Labeled compounds can be useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection capabilities.

[0190] In another aspect, the present invention relates to pharmaceutically acceptable salts of radiolabeled analogs of compounds of the present invention, according to any of the embodiments described herein.

[0191] In another aspect, the present invention relates to a pharmaceutical composition comprising a radiolabeled analogue or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, in accordance with any of the embodiments described herein relating to the compound of the present invention.

[0192] In another aspect, the present invention relates to a method for inhibiting voltage-gated sodium channels in a subject, comprising administering an effective amount of a radiolabeled analog, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, in accordance with any of the embodiments described herein relating to the compounds of the present invention, and a method for treating or reducing the severity of various diseases and disorders, including pain.

[0193] In another aspect, the present invention relates to radiolabeled analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for use in relation to the compounds of the present invention, according to any of the embodiments described herein.

[0194] In another aspect, the present invention relates to radiolabeled analogues or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals, and the use of pharmaceutical compositions thereof, in accordance with any of the embodiments described herein relating to the compounds of the present invention.

[0195] In another embodiment, radiolabeled analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof may be used in combination therapy in relation to the compounds of the present invention, according to any of the embodiments described herein.

[0196] Listed embodiments Additional embodiments, features, and advantages of this disclosure will become apparent from the following detailed description and through the implementation of this disclosure. The compounds and methods of this disclosure may be described as embodiments of any of the following enumerated clauses. Any embodiment described herein can be used in conjunction with any other embodiment described herein, to the extent that the embodiments are not inconsistent with each other. 1. Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 2a However, N, N + -O - , or CR 2aAnd, X 3a However, N, N + -O - CR 3a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n And, X 4a However, N, N + -O - CR 4a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n And, X 5a However, N, N + -O - , or CR 5a And, X 6a However, N, N + -O - , or CR 6a And, Each R is independently H or C1-C6 alkyl. n is 0 or 1, R A However, it is either H or CH3. R 2a , R 3a , R 4a , R 5a , and R 6a Each of these is independently H, halo, C1-C6 alkyl, or C1-C6 haloalkyl. R 4b1 and R 4b2 One of them is OH, C1-C6 alkoxy, or C1-C6 haloalkoxy, and the other is H. R 5b1 and R 5b2 Each of these is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl. X 3c However, N or CR 3c And, X 4c However, N or CR 4c And, X5c However, N or CR 5c And, X 6c However, N or CR 6c And, R 2c However, H, OH, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), and the cycloalkyl is substituted with 1-2 halos as needed. L 1 However, it is a bond or O, L 2 However, it is a bond or C1-C6 alkylene, R 3c However, it is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 4c However, it is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 5c However, it is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, R 6c However, it is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl, However, X 2a , X 3a , X 4a , X 5a , and X 6a Two or fewer of these are N or N + -O - And, X 3a and X 4a At least one of them is N, N + -O - CR 3a , or CR 4a And, X 3c , X 4c , X5c, and X 6c A compound of formula (I), or a pharmaceutically acceptable salt thereof, provided that one or less of the elements is N. 2. The compound is of formula (IA) [ka] A compound as described in Clause 1, or a pharmaceutically acceptable salt thereof, having the above characteristics. 3. The compound is of formula (IA-1) [ka] A compound as described in Clause 1, or a pharmaceutically acceptable salt thereof, having the above characteristics. 4. The compound is of formula (IB) [ka] A compound as described in Clause 1, or a pharmaceutically acceptable salt thereof, having the above characteristics. 5. The compound is of formula (IB-1) [ka] A compound as described in Clause 1, or a pharmaceutically acceptable salt thereof, having the above characteristics. 6.X 2a However, CR 2a And R 2a A compound described in any one of clauses 1, 2, or 4, or a pharmaceutically acceptable salt thereof, wherein H is present. 7.X 3a However, N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n The compound described in any one of clauses 1 to 6, or a pharmaceutically acceptable salt thereof. 8.X 3a However, the compound described in Clause 7, or a pharmaceutically acceptable salt thereof, is N. 9.X 3a However, C-CH 1-n (R A )(OH)(CH2OH) n The compound described in Clause 7, or a pharmaceutically acceptable salt thereof, wherein n is 0. 10.X 3aHowever, C-CH 1-n (R A )(OH)(CH2OH) n The compound described in Clause 7, or a pharmaceutically acceptable salt thereof, wherein n is 1. 11.X 4a However, N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n The compound described in any one of clauses 1 to 8, or a pharmaceutically acceptable salt thereof. 12.X 4a However, the compound described in Clause 11, or a pharmaceutically acceptable salt thereof, is N. 13.X 4a However, C-CH 1-n (R A )(OH)(CH2OH) n The compound described in Clause 11, or a pharmaceutically acceptable salt thereof, wherein n is 0. 14.X 4a However, C-CH 1-n (R A )(OH)(CH2OH) n The compound described in Clause 11, or a pharmaceutically acceptable salt thereof, wherein n is 1. 15.X 3a and X 4a One of them is N, and the other is C-CONR2 or C-CH 1-n (R A )(OH)(CH2OH) n The compound described in any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof. 16.R 5b1 The compound described in any one of clauses 1 to 15, wherein the compound is a C1-C6 alkyl or a C1-C6 haloalkyl. 17.R 5b1 However, the compounds described in Clause 16, or pharmaceutically acceptable salts thereof, which are CH3 or CF3. 18.R 5b2 The compound described in any one of clauses 1 to 17, which is a C1-C6 alkyl or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 19.R 5b2However, the compounds described in Clause 18, or pharmaceutically acceptable salts thereof, which are CH3 or CF3. 20.R 2c A compound described in any one of clauses 1 to 19, wherein the compound is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, or a pharmaceutically acceptable salt thereof. 21.R 2c The compounds described in Clause 20, or pharmaceutically acceptable salts thereof, wherein the compound is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2. 22.R 2c However, the compounds described in Clause 21, or pharmaceutically acceptable salts thereof, which are CH3 or OCH3. 23.R 3c A compound described in any one of clauses 1 to 22, which is a halo or a C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 24.R 3c However, F is a compound as described in Clause 23, or a pharmaceutically acceptable salt thereof. 25.R 3c However, the compound described in Clause 23, or a pharmaceutically acceptable salt thereof, is CH3. 26.R 4c However, a compound that is a halo, as described in any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof. 27.R 4c However, F is a compound as described in Clause 26, or a pharmaceutically acceptable salt thereof. 28.R 5c A compound described in any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein H is present. 29.R 6c A compound described in any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, wherein H is present. 30.R 4b2 However, the compound described in any one of clauses 1 to 29, which is a C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 31.R 4b2However, the compounds described in Clause 30, or pharmaceutically acceptable salts thereof, which are OCH2CH3 or OCH3. 32.R 4b2 However, the compound described in Clause 31, which is OCH3, or a pharmaceutically acceptable salt thereof. 33.R 4b1 However, the compound described in any one of clauses 1 to 29, which is a C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof. 34.R 4b1 However, the compounds described in Clause 33, or pharmaceutically acceptable salts thereof, which are OCH2CH3 or OCH3. 35.R 4b1 However, the compound described in Clause 34, which is OCH3, or a pharmaceutically acceptable salt thereof. 36. A compound selected from Table A, or a pharmaceutically acceptable salt thereof. 37. A compound described in any one of clauses 1 to 36, which is in a non-salt form. 38. A pharmaceutical composition comprising a therapeutically effective amount of a compound described in any one of clauses 1 to 36 or a pharmaceutically acceptable salt thereof, or a compound described in clause 37, and one or more pharmaceutically acceptable carriers or vehicles. 39. A pharmaceutical composition comprising a compound described in any one of Clauses 1 to 32 or a pharmaceutically acceptable salt thereof, or a compound described in Clause 37, and one or more pharmaceutically acceptable carriers or vehicles. 40. A method for inhibiting voltage-gated sodium channels in a subject, comprising administering to the subject a compound described in any one of Clauses 1 to 36 or a pharmaceutically acceptable salt thereof, a compound described in Clause 37, or a pharmaceutical composition described in Clause 38 or 39. 41. Voltage-gated sodium channels, Na V 1.8 The method described in Clause 40. 42. A method for treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of clauses 1 to 36, a compound described in clause 37, or a pharmaceutical composition described in clause 38 or 39 to the subject. 43. The method according to Clause 42, wherein the method includes treating or reducing the severity in a subject with neuropathic pain. 44. The method according to Clause 43, wherein neuropathic pain includes postherpetic neuralgia. 45. The method according to Clause 43, wherein neuropathic pain includes small fiber neuropathy. 46. ​​The method according to Clause 43, wherein neuropathic pain includes idiopathic small-diameter fiber neuropathy. 47. The method according to Clause 43, wherein neuropathic pain includes diabetic neuropathy. 48. The method according to Clause 42, wherein diabetic neuropathy includes diabetic peripheral neuropathy. 49. The method according to Clause 42, wherein the method includes treating or reducing the severity of musculoskeletal pain in a subject. 50. The method according to Clause 49, wherein musculoskeletal pain includes pain of osteoarthritis. 51. The method according to Clause 42, wherein the method includes treating or reducing the severity of acute pain in an object. 52. The method according to Clause 51, wherein acute pain includes acute postoperative pain. 53. The method according to Clause 42, wherein the method includes treating or reducing the severity of postoperative pain in a subject. 54. Postoperative pain, including pain from aponeurosis excision, as described in Clause 53. 55. The method described in Clause 53, wherein postoperative pain includes pain from abdominal wall reconstruction. 56. Postoperative pain, including pain from hernia repair surgery, as described in Clause 53. 57. The method of Article 42, wherein the method includes treating or reducing the severity of visceral pain in a subject. 58. The method according to any one of the clauses 40 to 57, wherein the subject is treated simultaneously with, or concurrently with, treatment with one or more additional therapeutic agents administered before or after, treatment with a compound, a pharmaceutically acceptable salt, or a pharmaceutical composition. 59. Use as a pharmaceutical agent of any one of the compounds described in Clauses 1 to 36 or a pharmaceutically acceptable salt thereof, the compounds described in Clause 33, or the pharmaceutical compositions described in Clause 38 or 39. [Examples]

[0197] General method 1 The 1H NMR spectrum was obtained as a solution in a suitable deuterated solvent such as dimethyl sulfoxide-d6 (DMSO-d6).

[0198] Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC / MS analysis. LC / MS analysis was performed using a Waters Acquity UPLC BEH C8 column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002877) with a guard column (pn: 186003978) and a dual gradient run of 2–98% mobile phase B over 4.45 minutes. Mobile phase A = H2O (10 mM ammonium formate containing 0.05% ammonium hydroxide). Mobile phase B = acetonitrile. Flow rate = 0.6 mL / min, injection volume = 2 μL, and column temperature = 45°C.

[0199] X-ray powder diffraction analysis: X-ray powder diffraction (XRPD) analysis was performed in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc., Westborough, Massachusetts). The X-ray generator was operated with copper emission (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. The powder sample was placed on a 96-well sample holder with Mylar film and loaded into the instrument. The sample was scanned over a range of approximately 3° to approximately 40°²θ with a step size of 0.0131303° and a time of 49 seconds per step.

[0200] Abbreviation Unless otherwise stated or specified in the context, the following abbreviations should be understood to have the following meanings. [Table 2-1] [Table 2-2]

[0201] Example 1 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide(1) [ka] Steps 1 and 2: A solution of diethyl oxalate (17.40 mL, 128.1 mmol) and (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one (intermediate H) (20.0 g, 128.1 mmol) in THF (80.00 mL) was added over 1 hour to a stirred suspension of NaH (10.8 g, 270.0 mmol) in dry THF (140.0 mL) at a steady rate of gas generation and at a rate that maintained the internal temperature below 40°C. After complete addition, the mixture was heated overnight at 60°C. The reaction mixture was cooled to ambient temperature and poured into ice / water (400 ml, 20 vol). The measured pH of the solution was 11-12. The mixture was extracted twice with MTBE (5 vol, 100 ml). The resulting aqueous solution was poured into a 6 M HCl (25 vol, 500 ml) solution and confirmed to have a pH of 1. The mixture was extracted with MTBE (3 × 100 mL, 5 volumes). The combined extract was dried (MgSO4), filtered, and vacuum concentrated to obtain a brown oil, which was used directly in the next step. The oil was solubilized in pure EtOH (160 mL) and H2SO4 (1.4 mL, 26.26 mmol) was added. The reaction mixture was heated to reflux temperature for 3 hours. A further amount of H2SO4 (5.5 mL, 103.2 mmol) was added, and heating was continued overnight. The reaction mixture was cooled to ambient temperature and vacuum concentrated (30 mbar and 35°C) to obtain a brown oil. The crude oil was partitioned between NaHCO3 and DCM. The aqueous phase was further extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and vacuum concentrated (250 mbar, 32°C) to obtain a brown oily (R)-5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (30.3 g, 83%) containing 15.5 wt% DCM. 1 H NMR(400MHz,DMSO-d6)δ 6.70(s,1H),4.38(q,J=7.1Hz,2H),1.66(d,J=0.9Hz,3H),1.31(t,J=7.1Hz,3H)ppm.

[0202] Step 3: Boranedimethyl sulfide (20 mL of 2M solution, 40.00 mmol) was added dropwise over 3 minutes to a solution of (R)-5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (7.92 g, 33.25 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine (3.3 mL of 1M toluene solution, 3.30 mmol) in THF (150 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was quenched by adding 1M HCl solution and diluted with MTBE (150 mL). The total was separated, and the aqueous phase was extracted with MTBE (50 mL). The combined organic layers were dried and concentrated under vacuum in (MgSO4). The residue was passed through a silica (50g) plug, washed with MTBE (250mL), and the filtrate was purified by flash chromatography (120g SiO2, 0 to 100% MTBE in hexane) to obtain (4S,5R)-4-hydroxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (4.7g, 59%). 1 ¹H NMR (500MHz, chloroform-d) δ 6.00 (dd, J=2.8, 0.7Hz, 1H), 4.85 (d, J=2.8Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 1.54 (q, J=1.0Hz, 3H), 1.35 (t, J=7.1Hz, 3H) ppm; no alcohol OH groups were observed. ESI-MS m / z calculated value 240.06094, measured value 242.8 (M+1) + ;Retention time: 0.74 minutes.

[0203] Step 4: Proton-sponge® (1,8-bis(dimethylamino)naphthalene; 42 g, 196.0 mmol) and trimethyloxynium tetrafluoroborate (30 g, 202.8 mmol) were successively added to a solution of (4S,5R)-4-hydroxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (16.2 g, 67.45 mmol) in DCM (300 mL). The reaction mixture was stirred in the dark at ambient temperature for 3 days, then passed through an SCX-2 cartridge and washed with MTBE (500 mL). The combined organic layers were washed with 1 M HCl (10 × 50 mL). The combined aqueous extracts were back-extracted with MTBE (2 × 100 mL). The combined organic extracts were washed with brine. The solution was purified by flash chromatography (0 to 50% MTBE in SiO2 and hexane) to obtain (4S,5R)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (16.6 g, 80%). 1 H NMR(500MHz,chloroform-d)δ 6.06(t,J=2.1Hz,1H),4.46(t,J=2.1Hz,1H),4.30(qd,J=7.1,1.7Hz,2H), 3.43(d,J=1.7Hz,3H),1.66-1.49(m,3H),1.33(td,J=7.1,1.7Hz,3H)ppm.

[0204] Step 5: Silver nitrate (10.9 g, 64.17 mmol) and NIS (15.9 g, 70.67 mmol) were added under nitrogen to a stirred solution of (4S,5R)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (19.6 g, 64.00 mmol) in MeCN (200 mL). The reaction mixture was heated at 100 °C for 24 hours. The reaction mixture was cooled to ambient temperature and quenched by adding saturated Na2S2O3 aqueous solution (100 mL). The mixture was filtered, and the filtrate was diluted with MTBE (200 mL). The layers were separated. The aqueous layer was extracted with MTBE (100 mL). The combined organic layers were washed with saturated NaHCO3 solution (8 × 100 mL), water (20 mL), and brine (20 mL), dried, filtered through (MgSO4), and concentrated under vacuum. The residue was recrystallized from siRNA to obtain pale yellow needle-shaped (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (6 g). The mother liquor, still containing the product, was purified by flash chromatography (220 g SiO2, 0 to 30% MTBE in hexane) to obtain an additional 6.8 g of the product. A total of 12.8 g (53%) of (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate was obtained. 1 H NMR(500MHz,chloroform-d)δ 4.42-4.27(m,3H),3.64(s,3H),1.63(d,J=1.0Hz,3H),1.39(t,J=7.1,7.1Hz,3H)ppm.ESI-MS m / z Calculated value 379.97324, actual value 381.4 (M+1) + ;Retention time: 0.93 minutes.

[0205] Step 6: A mixture of (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (6 g, 15.79 mmol), (3,4-difluoro-2-methoxyphenyl)boronic acid (3.9 g, 20.75 mmol), Pd(PPh3)4 (990 mg, 0.8567 mol), and sodium carbonate (25 mL of 2 M aqueous solution, 50.00 mmol) in 1,4-dioxane (150 mL) was heated at 50°C for 2 hours, 70°C for 2 hours, and then at 100°C (reflux) for 16 hours. The reaction mixture was cooled to ambient temperature, acidified to pH 1, and partitioned between water (150 mL) and ethyl phosphate (300 mL). The layers were separated. The aqueous layer was extracted with ethyl phosphate. The combined organic layers were washed with water and brine, dried, filtered, and vacuum concentrated. The residue was diluted with EtOH (100 mL) and H2SO4 (900 μL, 16.88 mmol) was added. The mixture was heated under reflux for 3 hours. Purification by flash chromatography (SiO2, heptane with 0 to 35% ethyl phosphate) yielded (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (3.3 g, 53%). ESI-MS m / z calculated value 396.0996, measured value 395.5 (M-1). - ;Holding time: 1.03 minutes.

[0206] Step 7: A solution of (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate ethyl (330 mg, 0.83 mmol) in EtOH (15 mL) was circulated for 3.5 hours in an H cube fitted with a Pd / C cartridge. The reaction was carried out at a flow rate of 0.5 mL / min with hydrogen at 100 °C and 80 bar. The resulting solution was concentrated under vacuum to obtain crystalline solid (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate ethyl (304 mg, 92%). 1H NMR(500MHz,chloroform-d)δ 7.25-7.22(m,1H),6.85-6.78(m,1H),4.79(d,J=8.0Hz,1H),4.49(t,J=7.6,7.6Hz,1H ),4.01-3.92(m,6H),3.16(s,3H),1.54(s,3H),0.96(t,J=7.1,7.1Hz,3H)ppm.ESI-MS m / z calculated value 398.11526, measured value 399.6(M+1) + ;Holding time: 0.99 minutes.

[0207] Step 8: KOt-Bu (3.0 g, 26.74 mmol) was added at 0°C to a solution of (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate ethyl (3.4 g, 7.60 mmol) in THF (30 mL). The reaction mixture was stirred at 0°C for 5 minutes. The solution was acidified to pH 1 by adding 1 M HCl (50 mL). The mixture was extracted with ELISA (3 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried, filtered, and vacuum concentrated to obtain a pale yellow oily (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.81 g, 100%), which was used in the next step without further purification. ESI-MS m / z calculated value 370.08395, measured value 369.7 (M-1) - ;Holding time: 0.49 minutes.

[0208] Step 9: A solution of (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (130 mg, 0.35 mmol), methyl 4-aminopyridine-2-carboxylate (60 mg, 0.39 mmol), NEt3 (100 μL, 0.72 mmol), and T3P (50 wt% solution in ethyl acetate, 180 μL, 0.80 mmol) in isopropyl acetate (2 mL) was stirred in a sealed container at 120 °C for 1 hour. The reaction mixture was cooled to ambient temperature. The suspension was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered, and vacuum concentrated to obtain 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (100 mg, 56%). ESI-MS m / z calculated value 504.132, measured value 505.7 (M+1). + ;Holding time: 0.92 minutes.

[0209] Step 10: A solution of methyl 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinate (714 mg, 1.42 mmol) in methanol ammonia (7M, 10 mL) and MeOH (10 mL) was stirred at ambient temperature for 2.5 days. An additional amount of methanol ammonia (7M, 10 mL, 70.00 mmol) was added, and the reaction was stirred at ambient temperature for a further 24 hours. The mixture was concentrated under vacuum. The sample was purified by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm × 21.1 mm (gradient of MeOH from 15% to 22% over 6 mins, 85 mg / ml, 35 mg, then to 40% MeOH; 20 mM ammonia) on a Berger Instruments Minigram SFC instrument to obtain 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (1,470 mg, 68%) as a yellow solid. 1 H NMR(500MHz,chloroform-d)δ 8.58(s,1H),8.48(d,J=5.6Hz,1H),8.17(dd,J=5.5,2.1Hz,1H),7.94(d,J =2.1Hz,1H),7.91(s,1H),7.31-7.27(m,1H),6.97(td,J=9.3,7.6Hz,1H), 5.58(s,1H),5.08(d,J=11.6Hz,1H),4.02(d,J=2.5Hz,3H),3.95(dd,J=11 .8,4.9Hz,1H),3.87(d,J=4.9Hz,1H),3.02(s,3H),1.67(s,3H)ppm.ESI-MS m / z Calculated value: 489.13232, Measured value: 490.5 (M+1) + ;488.7(M-1) - ;Retention time: 3.08 minutes.

[0210] The following compounds were prepared using the method described in Example 1, except that step 4 was not required. In the case of compound 2, the conditions used in step 9 of the amide coupling were the same as those used in step 11 of Example 2. In the case of compound 3, pyridazine-4-amine was used as the amide coupling partner in step 9 instead of methyl 4-aminopyridine-2-carboxylate, and step 10 was not required. [Table 3]

[0211] The following compounds were prepared using the method described in Example 1, except that (4-fluoro-2-methoxy-3-methylphenyl)boronic acid was used as the coupling partner in step 6 of the Suzuki coupling, instead of (3,4-difluoro-2-methoxyphenyl)boronic acid. In step 9 of the amide coupling, pyridazine-4-amine was used as the coupling partner. Step 10 was unnecessary. [Table 4]

[0212] Compound 4 was analyzed by X-ray powder diffraction and determined to be amorphous (see Figure 1).

[0213] The following compounds were prepared using the method described in Example 1, except that (4-fluoro-2-methoxy-3-methylphenyl)boronic acid was used as the coupling partner in step 6 of the Suzuki coupling. Step 9 of the amide coupling was carried out at ambient temperature for 2 hours under conditions well known in the art: generation of highly reactive acylimidazolium ions from a combination of excess TCFH and 1-methylimidazole in acetonitrile as a solvent, and using excess methyl 4-aminopicolinate as the coupling partner. [Table 5]

[0214] The following compounds were prepared using the method described in Example 1, except that (4-fluoro-2-methoxy-3-methylphenyl)boronic acid was used as the coupling partner in step 6 of the Suzuki coupling. (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (intermediate C) was used as the coupling partner in step 9 of the amide coupling, and ethyl acetate was used as the solvent instead of isopropyl acetate. Step 10 was replaced with a deprotection step carried out overnight at 50°C using excess TFA in a 4:1 mixture of THF and water as the solvent. [Table 6]

[0215] The following compounds were prepared using the method described in Example 1, except that the Suzuki coupling step 6 was carried out over 50 minutes at 50°C in a 10:1 mixture of 1,4-dioxane and water as the solvent, with (3,4-difluoro-2-methylphenyl)boronic acid as the coupling partner, Pd(dppf)Cl2·DCM as the catalyst, and K3PO4 as the base. The hydrogenation step 7 was carried out over 48 hours using 19 bar of hydrogen in the presence of a Pearlman catalyst in ethanol as the solvent. The conditions used for the amide coupling step 9 were the same as those used in step 11 of Example 2, where NMP was used as the solvent in the second part of the reaction. [Table 7]

[0216] Example 2 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)picolinamide(8) [ka] Step 1: Acetyl chloride (9.4 mL, 132.2 mmol) was added at 0°C to a stirred solution of ethyl (S)-2-hydroxypropanoate (10 mL, 88.2 mmol) in DCM (45 mL). The mixture was heated to ambient temperature and stirred for 20 hours. The mixture was quenched with saturated NaHCO3 solution (40 mL) and extracted with DCM. The organic extract was dried with (Na2SO4), filtered, and concentrated under vacuum. Purification by flash chromatography yielded ethyl (S)-2-acetoxypropanoate (13.6 g, 96%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.06 (q, J=7.1Hz, 1H), 4.20 (q, J=7.1Hz, 2H), 2.13 (s, 3H), 1.48 (d, J=7.1Hz, 3H), 1.28 (t, J=7.1Hz, 3H) ppm.

[0217] Step 2: A solution of ethyl (S)-2-acetoxypropanoate (13.6 g, 84.91 mmol) in THF (400 mL) was added to a stirred solution of LiHMDS (204 mL of 1 M LiHMDS in THF, 204.0 mmol) in THF (400 mL) over 30 minutes at -78°C. The mixture was stirred at this temperature for 90 minutes and then poured into 30 mL of 2 M aqueous HCl. The layers were separated. The aqueous phase was extracted with ELISA, and the combined organic layers were washed with brine. The organic layers were concentrated under vacuum, redissolved in DCM, dried (Na2SO4), filtered, and concentrated under vacuum to obtain solid (S)-4-hydroxy-5-methylfuran-2(5H)-one (8 g, 83%), which was used in the next step without further purification. 1 H NMR(500MHz,DMSO-d6)δ 12.57(s,1H),4.88(s,1H),4.85(dq,J=6.7,0.9Hz,1H),1.34(d,J=6.7Hz,3H)ppm.

[0218] Step 3: A solution of bromine (3.7 mL, 71.82 mmol) in CHCl3 (450 mL) was added dropwise to a solution of (S)-4-hydroxy-5-methylfuran-2(5H)-one (7.8 g, 68.4 mmol) in CHCl3 (280 mL) at 0°C. Stirring was continued at this temperature until the reaction was complete. The formed precipitate was collected by filtration to obtain (S)-3-bromo-4-hydroxy-5-methylfuran-2(5H)-one (11.15 g, 85%). 1 1H NMR (500MHz, DMSO-d6): δ 4.99 (q, J=6.8Hz, 1H), 1.40 (d, J=6.8Hz, 3H) ppm; no alcohol OH groups were observed.

[0219] Step 4: Anhydrous trifuric acid (7.8 mL, 7.80 mmol, 1 M in DCM) was added at 0°C to a stirred solution of TPPO (4.5 g, 16.2 mmol) in DCM (27 mL). After stirring for 15 minutes, a precipitate formed. A solution of (S)-3-bromo-4-hydroxy-5-methylfuran-2(5H)-one (1.5 g, 7.77 mmol) and DIPEA (1.4 mL, 8.04 mmol) in DCM (40 mL) was added to the suspension. After the colorless precipitate dissolved, MeOH (380 μL, 9.38 mmol), followed by DIPEA (1.7 mL, 9.76 mmol), was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 20 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in EtOH (50 mL), and dichlorozinc (3.6 mL, 38.81 mmol) was added. The mixture was stirred for 2 hours. The precipitate was filtered off, and the filtrate was concentrated under vacuum to obtain (S)-3-bromo-4-methoxy-5-methylfuran-2(5H)-one (1.55 g, 96%). 1 ¹H NMR (500 MHz, chloroform-d) δ 4.78 (q, J=6.7 Hz, 1H), 4.34 (s, 3H), 1.47 (d, J=6.8 Hz, 3H) ppm.

[0220] Step 5: K2CO3 (2.8 g, 20.26 mmol), (3,4-difluoro-2-methoxyphenyl)boronic acid (926 mg, 4.93 mmol), and tetrakis(triphenylphosphine)palladium (715 mg, 0.62 mmol) were successively added to a degassed solution of (S)-3-bromo-4-methoxy-5-methylfuran-2(5H)-one (850 mg, 4.11 mmol) in 1,4-dioxane (20 mL) and water (4.2 mL). The mixture was flushed with nitrogen and heated at 80°C for 2 hours. The reaction mixture was cooled to ambient temperature, quenched with saturated NH4Cl solution (20 mL), and diluted with ELISA (20 mL). The layers were separated, and the aqueous phase was extracted with ELISA (20 mL). The combined organic phases were dried with (MgSO4), filtered, and concentrated under vacuum. The solution was purified by flash chromatography to obtain (S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methylfuran-2(5H)-one (600 mg, 54%). 1 H NMR(500MHz,chloroform-d)δ 6.98(ddd,J=8.7,5.8,2.1Hz,1H),6.91(ddd,J=9.5,8.7,7.2Hz,1H),4.86(q,J= 6.7Hz,1H),3.94(d,J=2.0Hz,3H),3.73(s,3H),1.54(d,J=6.7Hz,3H)ppm.ESI-MS m / z calculated value 270.07037, actual value 271.4(M+1) + ;Retention time: 2.58 minutes.

[0221] Step 6: Nickel chloride hexahydrate (510 mg, 2.15 mmol) and NaBH4 (406 mg, 10.73 mmol) were successively added at -40°C to a stirred solution of (S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methylfuran-2(5H)-one (580 mg, 2.146 mmol) in a mixture of MeOH (24 mL) and THF (4.6 mL). The resulting mixture was stirred for 15 minutes. The mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL). The layers were separated, and the aqueous phase was extracted with DCM (20 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated to obtain (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyldihydrofuran-2(3H)-one (575 mg, 98%). 1 H NMR(500MHz,chloroform-d)δ 7.12-7.07(m,1H),6.90(ddd,J=9.6,8.9,7.5Hz,1H),4.67(qd,J=6.5,3.5Hz,1H),4.30(d,J=5.2Hz,1 H),4.03(d,J=2.7Hz,3H),3.93(dd,J=5.2,3.6Hz,1H),2.98(s,3H),1.47(d,J=6.5Hz,3H)ppm.ESI-MS m / z calculated value 272.08603, actual value 273.5(M+1) + ;Retention time: 2.66 minutes.

[0222] Step 7: DIBAL (1M, 2.5 mL, 2,500 mmol) was added at -78°C to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyldihydrofuran-2(3H)-one (575 mg, 2,112 mmol) in DCM (8.5 mL). After stirring at -78°C for 1 hour, an additional amount of DIBAL (1M, 2.5 mL, 2,500 mmol) was added. Upon completion of the reaction, the mixture was quenched by adding saturated ammonium chloride aqueous solution (4 mL) and Rochelle salt solution (30% w / w, 4 mL). The mixture was stirred for 1 hour. The layers were separated, and the aqueous phase was extracted with DCM (10 mL). The combined organic layers were dried (MgSO4), filtered, and vacuum concentrated to obtain (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-ol (580 mg, 100%), which was used directly in the next step. ESI-MS m / z calculated value 274.10165, measured value 258.5 (M-OH) + ;Retention time: 2.34 minutes.

[0223] Step 8: DMAP (130 mg, 1.06 mmol) and acetic anhydride (880 mg, 8.62 mmol) were successively added at ambient temperature to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-ol (580 mg, 2.12 mmol) in DCM (6 mL). Upon completion of the reaction, the mixture was quenched by adding saturated sodium bicarbonate aqueous solution (6 mL). The mixture was stirred at ambient temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted with DCM (2 × 10 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography yielded (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-yl acetate (260 mg, 39%) as a mixture of epimers at the C2 position. ESI-MS m / z calculated value: 316.11224, measured value: 258.5 (M-OAc). +;Retention time: 2.94 minutes.

[0224] Step 9: TMSCN (280 μL, 2.10 mmol) and BF3.OEt2 (46.5% w / w, 330 μL, 1.24 mmol) were successively added dropwise to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-yl acetate (260 mg, 0.82 mmol) in DCM (8 mL) at -78°C. The reaction mixture was stirred at -78°C for 30 minutes and then warmed to ambient temperature. The mixture was quenched with saturated sodium bicarbonate aqueous solution. The aqueous layer was separated and extracted with DCM (3 × 10 mL). The combined organic extract was dried with (Na2SO4), filtered, and vacuum concentrated. The resulting oil was dissolved in DCM and filtered through a Celite pad. The liquid was vacuum concentrated. The residue was dissolved in a sodium methoxide solution (2.5 mL of 0.5 M sodium methoxide in MeOH, 1.250 mmol) and stirred overnight at ambient temperature. The reaction product was quenched by adding saturated citric acid aqueous solution. The mixture was stirred for 30 minutes. After complete hydrolysis, the reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM. The solution was washed with water (10 mL) and brine (10 mL). The combined organic extract was dried in (MgSO4), filtered, and concentrated under vacuum to obtain (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylate methyl (260 mg, 100%) as the main stereoisomer. 1 H NMR(500MHz,chloroform-d)δ 7.20(ddd,J=8.2,5.8,2.3Hz,1H),6.89(ddd,J=9.6,8.8,7.4Hz,1H),4.74(d,J=9.8Hz,1H),4.45(qd,J=6.4,3.1Hz,1H),4.06 -4.00(m,1H),3.96(d,J=1.9Hz,3H),3.68(s,3H),3.67(dd,J=4.5,2.8Hz,1H),3.02(s,3H),1.35(d,J=6.3Hz,3H)ppm.ESI-MS m / z calculated value 316.11224, actual value 317.4(M+1) + ;Holding time: 2.8 minutes.

[0225] Step 10: Potassium tert-butoxide (370 mg, 3.30 mmol) was added at ambient temperature to a stirred solution of (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylate methyl (260 mg, 0.82 mmol) in THF (3.2 mL). Upon completion of the reaction, the reaction product was quenched by adding saturated ammonium chloride aqueous solution (3 mL) and diluted with DCM (3 mL). The layers were separated, and the aqueous phase was extracted with DCM (5 mL). The aqueous phase was acidified with 1 M HCl until pH 0 and extracted with DCM (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated to obtain (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylic acid (220 mg, 89%) as a single enantiomer. 1 ¹H NMR (500MHz, chloroform-d) δ 7.14 (ddd, J=8.5, 5.8, 2.3Hz, 1H), 6.83 (td, J=9.3, 7.5Hz, 1H), 4.70 (d, J=10.3Hz, 1H), 4.37 (qd, J=6.3, 3.0Hz, 1H), 3.92 (dd, J=10.3, 4.3Hz, 1H), 3.90 (d, J=2.0Hz, 3H), 3.62 (dd, J=4.3, 3.0Hz, 1H), 2.96 (s, 3H), 1.29 (d, J=6.3Hz, 3H) ppm; no acid OH was observed. ESI-MS m / z calculated value 302.0966, measured value 301.4 (M-1) - ;Holding time: 1.51 minutes.

[0226] Steps 11 and 12: Oxalyl chloride (35 μL, 0.40 mmol) was added at 0°C to a stirred solution of (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylic acid (55 mg, 0.18 mmol) and DMF (1.5 μL, 0.019 mmol) in DCM (600 μL). The reaction mixture was heated to ambient temperature over 30 minutes and then vacuum concentrated. The residue, redissolved in DCM (300 μL), was added at 0°C to a stirred solution of 4-aminopyridine-2-carboxylate methyl (35 mg, 0.23 mmol) and NEt3 (35 μL, 0.25 mmol) in DCM (300 μL). The reaction mixture was heated to ambient temperature over 2 hours. The mixture was quenched by adding water and MeOH (2 mL) drop by drop and then vacuum concentrated. Purification by flash chromatography yielded 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)methyl picolinate (55 mg, 69%). ESI-MS m / z calculated value: 436.1446, measured value: 437.3 (M+1). + ;435.4(M-1) - ;Retention time: 2.77 minutes.

[0227] 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)methyl picolinate (55 mg, 0.126 mmol) was dissolved in methanol ammonia (7 M, 5 mL, 35.00 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum to obtain 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)picolinamide (8 mg, 140 mg, 50%). 1H NMR(500MHz,DMSO-d6)δ 10.41(s,1H),8.47(d,J=5.5Hz,1H),8.31(d,J=1.9Hz,1H),8.04(d,J=3.0Hz,1H),7.87(dd,J=5 .5,2.2Hz,1H),7.58(d,J=3.0Hz,1H),7.30(ddd,J=8.5,6.0,2.2Hz,1H),7.17(ddd,J=10.1,9.1, 7.8Hz,1H),4.74(d,J=10.1Hz,1H),4.50(qd,J=6.3,3.0Hz,1H),4.03(dd,J=10.1,4.4Hz,1H),3 .88(d,J=1.6Hz,3H),3.81(dt,J=4.7,3.2Hz,1H),2.98(s,3H),1.28(d,J=6.3Hz,3H)ppm.ESI-MS m / z calculated value 421.14493, actual value 422.5(M+1) + ;420.5(M-1) - ;Holding time: 2.62 minutes.

[0228] The following compounds were prepared using the method described in Example 2, except that different coupling partners were used in step 11 of the amide coupling process. For compound 9, rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-4-amine (intermediate D, first elution peak from chiral SFC separation) was used as the coupling partner in step 11 of the amide coupling process. For compound 10, rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-4-amine (intermediate E, second elution peak from chiral SFC separation) was used as the coupling partner in step 11 of the amide coupling process. Step 12 was replaced with a deprotection step using excess TFA in DCM as the solvent. [Table 8]

[0229] The following compounds were prepared using the method described in Example 2, except that rac-2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)pyridine-4-amine was used as the coupling partner in amide coupling step 11. Step 12 was unnecessary. The diastereoisomers from step 11 were separated by chiral SFC separation using a Daicel Chiralpak AS-H column, 5 μm particle size, 25 cm × 10 mm (10% MeOH, 20 mM NH3, 245 nm, 100 bar) on a Berger Instruments Minigram instrument. The final deprotection step was carried out using excess TFA in DCM as the solvent. [Table 9]

[0230] The following compounds were prepared using the method described in Example 2, with the exception that ethanol was used instead of methanol in step 4 of the O-alkylation of Hendrickson, and the second part of the step using ZnCl2 in EtOH was omitted. [Table 10]

[0231] The following compounds were prepared using the method described in Example 2, except that isopropanol was used instead of methanol in step 4 of the O-alkylation of Hendrickson, and part 2 of the step using ZnCl2 in EtOH was omitted. In the case of compound 15, methyl 5-aminopicolinate was used as the coupling partner in amide coupling step 11. [Table 11]

[0232] The following compounds were prepared using the method described in Example 2, except that isopropanol was used instead of methanol in step 4 of the O-alkylation of Hendrickson, and part 2 of the step using ZnCl2 in EtOH was omitted. For compound 16, (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (intermediate C) was used as the coupling partner in amide coupling step 11. For compound 17, 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-amine was used as the coupling partner in amide coupling step 11. In both cases, step 12 was replaced with a deprotection step carried out at 40-45°C using an excess of TFA in a 9:1 mixture of DCM and water as the solvent. [Table 12]

[0233] Example 3 rel-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide (18) and rel-4-((2S,3S,4R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide (19) [ka] Step 1: DMAP (3.5 g, 28.649 mmol), pyridine (22.005 g, 22.5 mL, 278.19 mmol), and acetic anhydride (32.460 g, 30 mL, 317.96 mmol) were continuously added at ambient temperature to a stirred solution of ethyl 2-hydroxy-2-methylpropanoate (25 g, 189.17 mmol) in DCM (125 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction product was quenched by adding saturated Na2CO3 solution (150 mL). The phases were separated, and the aqueous layer was extracted with DCM (500 mL). The combined organic extract was washed with aqueous CuSO4 solution (200 mL) and water (250 mL), dried, filtered, and vacuum concentrated to obtain pale green oily ethyl 2-acetoxy-2-methylpropanoate (25 g, 76%). 1 H NMR(400MHz,DMSO-d6)δ 4.08(q,J=7.04Hz,2H),2.00(s,3H),1.46(s,6H),1.22-1.15(t,J=7.00Hz,3H)ppm.

[0234] Step 2: A solution of ethyl 2-acetoxy-2-methylpropanoate (20 g, 114.81 mmol) in THF (100 mL) was cooled to -60°C. A solution of LiHMDS (200.00 mmol of 1 M in THF) was added dropwise over 20 minutes at a rate that kept the mixture below -60°C. The mixture was stirred at 0°C for 30 minutes. The reaction was quenched by adding water (250 mL), and the mixture was allowed to warm to ambient temperature. The mixture was acidified to approximately pH 1 by adding 1N HCl solution. DCM (500 mL) was added, and the layers were separated. The organic phase was dried (Na2SO4), filtered, and concentrated under vacuum to obtain an orange solid 4-hydroxy-5,5-dimethylfuran-2(5H)-one (12 g, 74%). 1 ¹H NMR (400MHz, DMSO-d6): δ 12.65 (s, 1H), 4.79 (s, 1H), 1.37 (s, 6H) ppm. ESI-MS m / z: Calculated value 128.0473, Measured value 129.1 (M+1). + ;Holding time: 0.70 minutes.

[0235] Step 3: NBS (25 g, 140.46 mmol) was added at ambient temperature to a stirred solution of 4-hydroxy-5,5-dimethylfuran-2(5H)-one (12 g, 85.47 mmol) in acetonitrile (480 mL). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum. It was purified by flash chromatography (SiO2, hexane with 20% ethyl phosphate) to obtain a grayish-white solid of 3-bromo-4-hydroxy-5,5-dimethylfuran-2(5H)-one (9 g, 51%). 1 ¹H NMR (400 MHz, chloroform-d): δ 1.48 (s, 6H) ppm; no alcohol OH groups were observed.

[0236] Step 4: K2CO3 (18.5 g, 133.86 mmol) and Me2SO4 (15.295 g, 11.5 mL, 121.26 mmol) were successively added to a stirred solution of 3-bromo-4-hydroxy-5,5-dimethylfuran-2(5H)-one (11 g, 53.13 mmol) in acetone (530 mL). The resulting mixture was stirred under argon at ambient temperature for 16 hours. The mixture was partitioned between water (100 mL) and ethyl acetate (500 mL). The organic layer was collected and concentrated under vacuum. It was purified by flash chromatography (SiO2, 4% ethyl acetate in hexane) to obtain a white solid of 3-bromo-4-hydroxy-5,5-dimethylfuran-2(5H)-one (11 g, 93%). 1 H NMR(400MHz,DMSO-d6)δ 4.31(s,3H),1.42(s,6H)ppm.

[0237] Step 5: K3PO4 (20 g, 94.22 mmol) was added to a stirred solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (11.9 g, 63.32 mmol) and 3-bromo-4-methoxy-5,5-dimethylfuran-2(5H)-one (7 g, 31.67 mmol) in DME (150 mL). The mixture was degassed with nitrogen gas for 20 minutes. PdCl2 (dtbpf) (2 g, 3.07 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. The mixture was filtered through a Celite pad. The filtrate was partitioned with water (200 mL). The layers were separated, and the aqueous phase was extracted with ELISA (500 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography (SiO2, hexane with 0 to 4% siRNA) yielded a grayish-white solid 3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethylfuran-2(5H)-one (7.13 g, 79%). 1 H NMR(400MHz,DMSO-d6)δ 7.24-7.15(m,2H),3.83(d,J=1.32Hz,3H),3.67(s,3H),1.49(s,6H)ppm.ESI-MS m / z Calculated value 284.086, Actual value 285.1(M+1) + ;Retention time: 2.08 minutes.

[0238] Step 6: Nickel chloride hexahydrate (3.7 g, 15.57 mmol) and NaBH4 (3 g, 79.30 mmol) were successively added at -40°C to a stirred solution of 3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethylfuran-2(5H)-one (4.4 g, 15.48 mmol) in a mixture of MeOH (175 mL) and THF (35 mL). After stirring the resulting mixture for 5 minutes, additional amounts of both nickel chloride hexahydrate (3.7 g, 15.57 mmol) and NaBH4 (3 g, 79.30 mmol) were added. Upon completion of the reaction, the mixture was quenched by adding NH4Cl solution (50 mL). The layers were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated to obtain a mixture of stereoisomers with rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyldihydrofuran-2(3H)-one (4.4g, 99%) as the main diastereoisomer, which was used in the next step without further purification. 1 H NMR(500MHz,chloroform-d)δ 7.04(ddd,J=9.1,5.8,2.3Hz,1H),6.89(ddd,J=9.6,8.9,7.4Hz,1H),4.47(d,J=5.8Hz,1H), 4.04(d,J=2.6Hz,3H),4.00-3.97(m,1H),2.96(s,3H),1.50(s,3H),1.49(s,3H)ppm.ESI-MS m / z calculated value 286.10165, actual value 287.5(M+1) + ;Retention time: 2.79 minutes.

[0239] Step 7: DIBAL (18 mL, 1 M in toluene solution, 18.00 mmol) was added dropwise at -78°C to a stirred solution of rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyldihydrofuran-2(3H)-one (4.4 g, 15.37 mmol) in DCM (60 mL). Upon completion of the reaction, the mixture was quenched by adding saturated ammonium chloride aqueous solution and Rochelle salt solution (30% w / w) (30 mL each). The mixture was stirred for 1 hour. The layers were separated, and the aqueous phase was extracted with DCM (2 × 30 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated to obtain rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyldihydrofuran-2-ol (4.3g, 97%) as a mixture of crystalline solid and stereoisomers, which was used in the next step without further purification. ESI-MS m / z calculated value 288.1173, measured value 271.4 (M-OH) + ;Retention time: 2.54 minutes.

[0240] Step 8: DMAP (910 mg, 7.45 mmol) and acetic anhydride (5.6 mL, 59.35 mmol) were successively added at ambient temperature to a stirred solution of a mixture of stereoisomers of rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-ol (4.3 g, 14.92 mmol) in DCM (45 mL). The reaction mixture was stirred for 16 hours, then quenched by adding saturated sodium bicarbonate aqueous solution (30 mL). The mixture was stirred at ambient temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted with DCM (20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The solution was purified by flash chromatography to obtain a mixture of stereoisomers of rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-yl acetate (3g, 61%), which was used directly in the next step. ESI-MS m / z calculated value: 330.12787, measured value: 271.4 (M-OAc).+ ;Holding time: 3.14 minutes.

[0241] Step 9: TMSCN (3.15 mL, 23.62 mmol) and BF3.OEt2 (46.5% w / w, 3.62 mL, 29.33 mmol) were continuously added dropwise at -78°C to a stirred solution of stereoisomers of rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-yl acetate (3 g, 9.08 mmol) in DCM (90 mL). The reaction mixture was stirred at -78°C for 30 minutes and then warmed to ambient temperature. The mixture was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL). The aqueous layer was separated and extracted with DCM (10 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated. The residue was dissolved in ELISA (30 mL). The solution was dried (MgSO4), filtered, and vacuum concentrated. The residue was dissolved in sodium methoxide solution (27.5 mL of 0.5 M sodium methoxide in methanol, 13.75 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture was quenched by adding saturated citric acid aqueous solution (1 mL). The mixture was vacuum concentrated, and the residue was dissolved in ELISA (10 mL) and brine (30 mL). The organic phase was separated, dried (MgSO4), filtered, and vacuum concentrated to obtain a mixture of stereoisomers with rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylate methyl (2.95 g, 98%) as the main diastereoisomer. ESI-MS m / z calculated value 330.12787, measured value 330.4 (M+1) + ;Holding time: 3.02 minutes.

[0242] Step 10: Potassium tert-butoxide (4 g, 35.65 mmol) was added at ambient temperature to a stirred solution of stereoisomers of rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylate methyl (2.95 g, 8.93 mmol) in THF (35 mL). Upon completion of the reaction, the mixture was quenched by adding water (20 mL) and diluted with DCM. The layers were separated, and the aqueous phase was extracted with DCM (20 mL). The aqueous phase was acidified to pH 0 with 1 M HCl and extracted with DCM (2 × 20 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated to obtain a mixture of stereoisomers, rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylic acid (2g, 71%), which was used directly in the next step. ESI-MS m / z calculated value 316.11224, measured value 315.4 (M-1) - ;Holding time: 1.68 minutes.

[0243] Steps 11, 12, and 13: Oxalyl chloride (60 μL, 0.69 mmol) was added at 0°C to a stirred solution of stereoisomers of rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylic acid (100 mg, 0.32 mmol) and DMF (2.5 μL, 0.032 mmol) in DCM (1.2 mL). The reaction mixture was heated to ambient temperature over 30 minutes and then concentrated under vacuum. The residue, redissolved in DCM (600 μL), was added at 0°C to a stirred solution of methyl 4-aminopyridine-2-carboxylate (60 mg, 0.39 mmol) and NEt3 (60 μL, 0.43 mmol) in DCM (600 μL). The reaction mixture was heated to ambient temperature over 2 hours. The mixture was quenched by adding saturated NH4Cl aqueous solution. The aqueous layer was separated and extracted with DCM (2 × 5 mL). The combined organic phase was dried (MgSO4), filtered, and vacuum concentrated. Purification by flash chromatography yielded a mixture of stereoisomers of rac-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)methyl picolinate, which was used directly in the next step. ESI-MS m / z calculated value 450.16025, measured value 451.4 (M+1) + ;449.5(M-1) - ;Retention time: 2.97 minutes.

[0244] A mixture of stereoisomers of rac-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)methyl picolinate was dissolved in methanol ammonia (7M, 5 mL, 35.00 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum to obtain a mixture of stereoisomers of rac-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide.

[0245] The enantiomers of rac-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide were separated by chiral SFC using a Minigram SFC instrument from Berger Instruments with a Lux i-Cellulose-5 column from Phenomenex, Inc., 5 μm particle size, 25 cm × 10 mm (25% MeOH, 20 mM NH3, 245 nm, 100 bar).

[0246] First eluted isomer (retention time = 4.93 min): rel-4-((2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide (18, 10 mg, 13%). 1 1H NMR (500MHz, DMSO-d6)δ 10.48(s,1H),8.46(dd,J=5.5,0.6Hz,1H),8.29(dd,J=2.2,0.6Hz,1H),8.04( d,J=2.8Hz,1H),7.82(dd,J=5.5,2.2Hz,1H),7.59(d,J=2.9Hz,1H),7.27-7.10 (m,2H),4.80(d,J=10.4Hz,1H),4.21(dd,J=10.4,4.9Hz,1H),3.92(d,J=1.4Hz ,3H),3.61(d,J=5.0Hz,1H),2.97(s,3H),1.38(s,3H),1.33(s,3H)ppm.ESI-MS m / z Calculated value: 435.16058, Measured value: 436.3 (M+1) + ;434.3(M-1) - ;Holding time: 2.80 minutes.

[0247] Second eluted isomer (retention time = 5.37 min): rel-4-((2S,3S,4R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxamide)picolinamide (19, 10 mg, 14%). 11H NMR (500MHz, DMSO-d6)δ 10.48(s,1H),8.46(dd,J=5.5,0.6Hz,1H),8.28(dd,J=2.2,0.6Hz,1H),8.03( d,J=2.8Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),7.63-7.54(m,1H),7.27-7.09(m ,2H),4.80(d,J=10.4Hz,1H),4.21(dd,J=10.4,5.0Hz,1H),3.92(d,J=1.6Hz, 3H),3.60(d,J=5.0Hz,1H),2.97(s,3H),1.38(s,3H),1.32(s,3H)ppm.ESI-MS m / z Calculated value: 435.16058, Measured value: 436.3 (M+1) + ;434.3(M-1) - ;Holding time: 2.80 minutes.

[0248] The following compounds were prepared using the method described in Example 3, except that rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-4-amine (intermediate D, first elution peak from chiral SFC separation) was used as the coupling partner in amide coupling step 11. Step 12 was not necessary. Chiral SFC separation step 13 was performed on a Waters Prep-100 SFC instrument using a Daicel Chiralpak IC column, 5 μm particle size, 25 cm × 20 mm (50% MeOH, 20 mM NH3). The final deprotection step was performed using excess TFA in DCM as the solvent. [Table 13]

[0249] Compound 21 was analyzed by X-ray powder diffraction and determined to be amorphous (see Figure 2).

[0250] The following compounds were prepared using the method described in Example 3, except that rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-4-amine (second elution peak from chiral SFC separation) was used as the coupling partner in amide coupling step 11. Step 12 was not necessary. Chiral SFC separation step 13 was performed on a Berger Instruments Minigram SFC instrument using a Daicel Chiralpak ID column, 5 μm particle size, 25 cm × 10 mm (12% MeOH, 20 mM NH3, 245 nm, 100 bar). The final deprotection step was performed using excess TFA in DCM as the solvent. [Table 14]

[0251] Example 4 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamide)picolinamide(24) [ka] Step 1: A mixture of (3,4-difluoro-2-methoxyphenyl)boronic acid (12.5 g, 66.51 mmol), 2-bromoethyl acetate (10 g, 58.68 mmol), K2CO3 (28 g, 200.6 mmol), and Cu2O (260 mg, 1.763 mmol) in toluene (200 mL) was flushed with nitrogen. Pd(PPh3)4 (2.2 g, 1.866 mmol) was added, and the reaction mixture was heated at 100 °C for 20 hours. The reaction mixture was quenched by adding water (50 mL). The mixture was diluted with ELISA (50 mL). The phases were separated. The organic layer was dried with (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography yielded 2-(3,4-difluoro-2-methoxyphenyl)ethyl acetate (10 g, 74%) with a purity of approximately 75%. ESI-MS m / z calculated value: 230.07545, measured value: 230.8 (M+1) + ;Retention time: 2.89 minutes.

[0252] Step 2: LiOH (2M, 20 mL, 40.00 mmol) was added at room temperature to a stirred solution of 2-(3,4-difluoro-2-methoxyphenyl)ethyl acetate (4 g, 17.38 mmol) in THF (50 mL). The reaction mixture was stirred at 50°C. Upon completion of the reaction, the mixture was diluted with DCM (30 mL). The aqueous phase was collected, acidified to pH 0 with 1N HCl, and extracted with DCM (2 × 20 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum to obtain a white solid 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (3.5 g, 100%). 1 ¹H NMR (500MHz, chloroform-d) δ 6.90 (ddd, J=8.7, 5.8, 2.1Hz, 1H), 6.83 (ddd, J=9.6, 8.7, 7.1Hz, 1H), 3.99 (d, J=2.4Hz, 3H), 3.64 (s, 2H) ppm; no acid OH was observed. ESI-MS m / z calculated value 202.04414, measured value 200.8 (M-1) - ;Holding time: 1.04 minutes.

[0253] Step 1': H2SO4 (3 mL, 56.28 mmol) was added to a stirred solution of (S)-2-hydroxy-3-methylbutanoic acid (15 g, 127.0 mmol) in MeOH (150 mL). The reaction mixture was heated under reflux for 3 hours. The mixture was concentrated under vacuum. The residue was dissolved in Et2O. The mixture was washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried, filtered, and concentrated under vacuum to obtain methyl (S)-2-hydroxy-3-methylbutanoate (11.6 g, 69%). 1 H NMR(500MHz,chloroform-d)δ 4.05(d,J=3.6Hz,1H),3.79(s,3H),2.66(br s,1H),2.07(heptd,J=6.9,3.6Hz,1H),1.02(d,J=6.9Hz,3H),0.86(d,J=6.9Hz,3H)ppm.

[0254] Step 3: Oxalyl chloride (3.75 mL, 42.99 mmol) was added dropwise at 0°C to a stirred solution of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (3.75 g, 18.55 mmol) and DMF (80 μL, 1.033 mmol) in DCM (80 mL). The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The mixture was concentrated under vacuum. The residue was taken into DCM (10 mL) and added to an ice-cold solution of (S)-2-hydroxy-3-methylbutanoate methyl (4.9 g, 37.08 mmol) in DCM (10 mL). The mixture was warmed overnight to ambient temperature. The reaction product was quenched by adding saturated NaHCO3 solution (10 mL) and diluted with DCM (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated. Purification by flash chromatography yielded (S)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3-methylbutanoate methyl (2.7 g, 46%). 1H NMR(500MHz,chloroform-d)δ 6.94(ddd,J=8.2,5.7,2.2Hz,1H),6.86-6.79(m,1H),4.86(d,J=4.6Hz,1H),3.97(d,J=2.3Hz,2H),3. 73(s,3H),3.71(s,3H),2.22(pd,J=6.9,4.6Hz,1H),0.97(d,J=6.9Hz,3H),0.93(d,J=6.9Hz,3H)ppm.

[0255] Step 4: A solution of (S)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3-methylbutanoate methyl (2.7 g, 8.536 mmol) in THF (75 mL) was added to a stirred solution of LiHMDS (22 mL of 1 M LiHMDS in THF, 22.00 mmol) in THF (75 mL) over 30 minutes at -78°C. The mixture was stirred at -78°C for 90 minutes. The reaction was quenched by pouring the contents of the flask into a 2N HCl solution (30 mL). The layers were separated. The aqueous phase was extracted with ELISA. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under vacuum to obtain (S)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-isopropylfuran-2(5H)-one (2.4 g, 99%), which was used in the next step without further purification. ESI-MS m / z calculated value: 284.08603, measured value: 284.8 (M+1) + ;283.0(M-1) - ;Holding time: 1.20 minutes.

[0256] Step 5: Anhydrous trifluic acid (8.5 mL, 1 M solution in DCM, 8.500 mmol) was added dropwise to a stirred solution of TPPO (4.9 g, 17.61 mmol) in DCM (40 mL) at 0°C. After stirring for 15 minutes, a precipitate formed. A solution of (S)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-isopropylfuran-2(5H)-one (2.4 g, 8.443 mmol) and DIPEA (1.5 mL, 8.612 mmol) in DCM (60 mL) was added to the suspension. After the colorless precipitate dissolved, methanol (750 μL, 18.51 mmol), followed by DIPEA (1.9 mL, 10.91 mmol), was added dropwise. The reaction mixture was heated to ambient temperature and stirred for 20 hours. The reaction mixture was concentrated under vacuum. Purification by flash chromatography yielded (S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxyfuran-2(5H)-one (1.1 g, 44%). ESI-MS m / z calculated value 298.10165, measured value 298.9 (M+1). + ;296.8(M-1) - ;Holding time: 3.05 minutes.

[0257] Step 6: Nickel chloride hexahydrate (530 mg, 2.230 mmol) and NaBH4 (420 mg, 11.10 mmol) were successively added at -40°C to a stirred solution of (S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxyfuran-2(5H)-one (660 mg, 2.213 mmol) in a mixture of MeOH (25 mL) and THF (5 mL). This procedure was repeated until the starting materials were completely consumed. A total of 3 equivalents of NiCl2.6H2O were added. Upon completion, the reaction mixture was quenched by adding a saturated ammonium chloride solution. The mixture was diluted with DCM and the phases were separated. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum to obtain (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxydihydrofuran-2(3H)-one (600 mg, 90%), which was used in the next step without further purification. 1H NMR(500MHz,chloroform-d)δ 7.11(ddd,J=8.4,5.7,2.3Hz,1H),6.91(td,J=9.2,7.4Hz,1H),4.29(d,J=4.5Hz,1H),4.04(d,J=2.6Hz,3H),4 .03-3.96(m,2H),2.85(s,3H),2.22(dq,J=10.0,6.7Hz,1H),1.14(d,J=6.7Hz,3H),0.94(d,J=6.7Hz,3H)ppm.

[0258] Step 7: DIBAL (2.4 mL, 1 M solution in toluene, 2.400 mmol) was added dropwise to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxydihydrofuran-2(3H)-one (600 mg, 1.998 mmol) in DCM (10 mL) under nitrogen at -78°C. Upon completion of the reaction, the mixture was quenched by adding saturated ammonium chloride solution and Rochelle salt solution (30% w / w). The resulting mixture was vigorously stirred at ambient temperature until clear phase separation was observed. The organic phase was separated, dried, filtered, and concentrated under vacuum to obtain (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-ol (460 mg, 76%), which was used in the next step without further purification. ESI-MS m / z calculated value: 302.13297, measured value: 285.9 (M-OH) + ;Retention time: 2.88 minutes.

[0259] Step 8: Acetic anhydride (500 μL, 5.299 mmol) was added at room temperature to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-ol (400 mg, 1.323 mmol) and DMAP (120 mg, 0.9823 mmol) in DCM (4 mL). Upon completion of the reaction, the mixture was quenched by adding saturated sodium bicarbonate solution (30 mL). The mixture was diluted with DCM (20 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic extracts were dried and concentrated under vacuum in (MgSO4). Purification by flash chromatography yielded (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-yl acetate (180 mg, 40%). ESI-MS m / z calculated value: 344.14352, measured value: 285.9 (M-OAc) + ;Retention time: 3.43 minutes.

[0260] Step 9: TMSCN (180 μL, 1.350 mmol) and BF3.OEt2 (200 μL, 1.621 mmol) were successively added dropwise to a stirred solution of (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-yl acetate (180 mg, 0.5227 mmol) in DCM (5.5 mL) at -78°C. The mixture was stirred at -78°C for 30 minutes and then warmed to ambient temperature. The reaction mixture was quenched by adding saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with DCM (3 × 30 mL). The combined organic extracts were dried with (Na2SO4), filtered, and vacuum concentrated. The residue was dissolved in DCM and filtered through a Celite pad. The liquid was vacuum concentrated. The residue was dissolved in sodium methoxide solution (1.6 mL of 0.5 M sodium methoxide in MeOH, 0.8000 mmol) and stirred overnight under nitrogen at ambient temperature. The reaction mixture was quenched by adding saturated citric acid solution. The mixture was stirred at room temperature. After complete hydrolysis, the mixture was extracted with DCM (2 × 30 mL). The organic extracts were combined, dried, filtered, and concentrated under vacuum to obtain (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylate methyl (150 mg, 83%), which was used in the next step without further purification. ESI-MS m / z calculated value 344.14352, measured value 334.9 (M+1) + ;Holding time: 3.35 minutes.

[0261] Step 10: Potassium tert-butoxide (200 mg, 1.782 mmol) was added at ambient temperature to a stirred solution of (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylate methyl (150 mg, 0.4356 mmol) in THF (2 mL). The mixture was stirred at ambient temperature. Upon completion of the reaction, the mixture was quenched by adding saturated ammonium chloride solution (3 mL) and diluted with DCM (3 mL). The aqueous layer was separated and extracted with DCM (5 mL). The aqueous extract was acidified to pH 0 with 1N HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried (MgSO4), filtered, and vacuum concentrated to obtain (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylic acid (121 mg, 84%). ESI-MS m / z calculated value: 330.12787, measured value: 330.9 (M+1). + ;329.0(M-1) - ;Holding time: 1.89 minutes.

[0262] Steps 11 and 12: Oxalyl chloride (70 μL, 0.802 mmol) was added to a stirred solution of (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylic acid (120 mg, 0.363 mmol) and DMF (4 μL, 0.052 mmol) in ice-cooled DCM (1.2 mL). The mixture was stirred and heated to ambient temperature for 30 minutes. The reaction mixture was vacuum concentrated. The solid was dissolved in DCM (700 μL), and the fresh solution was added to an ice-cooled solution of methyl 4-aminopyridine-2-carboxylate (70 mg, 0.4601 mmol) and Et3N (75 μL, 0.538 mmol) in DCM (700 μL). The mixture was stirred and heated to ambient temperature for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (2 mL) and extracted with DCM (2 × 5 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography yielded methyl 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamide)picolinate. ESI-MS m / z calculated value 464.1759, measured value 465.1 (M+1). + ;463.1(M-1) - ;Holding time: 3.24 minutes.

[0263] Methyl 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamide)picolinamide was dissolved in methanol ammonia (12 mL, 7 M solution in MeOH, 84.00 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum to obtain 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamide)picolinamide (24 mg, 78 mg, 43%). 1H NMR(500MHz,DMSO-d6)δ 10.45(s,1H),8.47(d,J=5.5Hz,1H),8.23(d,J=2.1Hz,1H),8.07(d,J=2.8Hz,1H),7.83 (dd,J=5.5,2.1Hz,1H),7.63(d,J=2.8Hz,1H),7.30(ddd,J=8.5,6.0,1.9Hz,1H),7.25-7 .15(m,1H),4.79(d,J=10.2Hz,1H),4.05(dd,J=10.2,3.8Hz,1H),3.90(d,J=1.5Hz,5H), 2.85(s,3H),2.04-1.90(m,1H),1.03(d,J=6.6Hz,3H),0.87(d,J=6.6Hz,3H)ppm.ESI-MS m / z calculated value 449.17624, actual value 450.0(M+1) + ;448.1(M-1) - ;Retention time: 3.07 minutes.

[0264] Example 5: 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide(25) [ka] Steps 1 and 2: A 1 L three-necked round-bottom flask equipped with a condenser and mechanical stirrer was filled with tetrahydrofuran (330 mL) and zinc powder (29.5 g, <10 μm, 4.136 mL, 451.14 mmol) under nitrogen. Trimethylsilyl chloride (3.681 g, 4.3 mL, 33.880 mmol) was added all at once, and the reaction mixture was heated at 60 °C for 1 hour, with the zinc powder mainly located in the lower third of the solution. A solution of tert-butyl 2-bromoacetate (65.68 g, 49.720 mL, 336.73 mmol) in tetrahydrofuran (30 mL) was added dropwise over 20 minutes, maintaining the internal temperature at 65–68 °C. The temperature was maintained at 67–68 °C for 1 hour. The reaction mixture was cooled to 40 °C and sparged with nitrogen for 10 minutes. During sparging, the temperature dropped to 31.5 °C. The reaction mixture was heated to 40°C, and an additional 125 mL of degassed tetrahydrofuran was added. Pd(dba)2 (4.57 g, 7.948 mmol) and XPhos (3.8 g, 7.971 mmol) were added. The reaction mixture was heated to 62°C, and a solution of 1-bromo-3,4-difluoro-2-methoxybenzene (50.14 g, 31.337 mL, 224.83 mmol) in 20 mL of tetrahydrofuran was added over 12 minutes, while maintaining the internal temperature below 70.5°C. The internal temperature was maintained at 68°C. After 90 minutes, the reaction mixture was cooled to 15°C and stirred overnight.

[0265] The reaction mixture was cooled to 0°C, 6N HCl solution (500 mL, 10 vols) was added, and the internal temperature was maintained below 15°C. The reaction mixture was heated to 55°C and stirred for 80 minutes. The reaction mixture was then cooled to ambient temperature. Heptane (500 mL) was added, the mixture was filtered on a Celite pad, and rinsed with heptane (300 mL, 6 vols) and MTBE (300 mL, 6 vols). The aqueous phase was extracted with MTBE (3 × 500 mL, 30 vols). The organic extracts were combined, washed with 1M sulfuric acid (500 mL, 10 vols) and brine (250 mL, 5 vols), dried, filtered, and vacuum concentrated. The residue was dissolved in MTBE (300 mL, 6 vols) and washed with 1.5N sodium hydroxide (400 mL, then 150 mL). The basic aqueous layer was cooled in an ice bath and acidified to pH 1 with 12M hydrochloric acid (150 mL, 3 vols). The aqueous layer was extracted with MTBE (250 mL, then 150 mL). The organic extracts were combined, washed with 15% sodium chloride aqueous solution (200 mL, 4 vols), dried (Na2SO4), and filtered. Activated carbon (5 g) was added to the solution and refluxed for 3 hours. The mixture was cooled overnight to ambient temperature. The mixture was filtered and concentrated under vacuum to obtain a yellowish-brown solid of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (39.55 g, 85%), which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 12.39(s,1H),7.15-7.03(m,2H),3.87(d,J=1.7Hz,3H),3.56(s,2H)ppm.ESI-MS m / z Calculated value 202.0442, Actual value 201.1(M-1) - ;Retention time: 2.33 minutes.

[0266] Step 1': (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (30 g, 189.8 mmol) was dissolved in MeOH (50 mL). Sulfuric acid (6 mL, 112.6 mmol) was added via syringe. The mixture was refluxed for 18 hours. MeOH was removed by distillation. The remaining mixture was poured into ice-cold water and extracted twice by DCM. The combined organic extracts were washed with saturated NaHCO3 solution, dried, filtered, and concentrated under vacuum to obtain (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionate methyl (28.7 g, 88%). 1 ¹H NMR (400 MHz, chloroform-d) δ 3.91 (s, 3H), 3.78 (s, 1H), 1.64-1.54 (m, 3H) ppm.

[0267] Step 3: Oxalyl chloride (6 mL, 68.78 mmol) was added dropwise at 0°C to a stirred solution of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (6 g, 29.68 mmol) and DMF (100 μL, 1.291 mmol) in DCM (100 mL). The solution was warmed to ambient temperature and stirred for 1 hour. The mixture was concentrated under vacuum. The residue was taken into DCM (10 mL) and added to an ice-cold solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionate methyl (4.4 g, 25.57 mmol) and triethylamine (7.8 mL, 55.96 mmol) in DCM (10 mL). The mixture was warmed overnight to ambient temperature. The reaction product was quenched by adding a saturated solution of ammonium chloride (50 mL) and diluted with DCM (50 mL). The aqueous phase was separated and extracted with DCM (20 mL). The combined organic extract was dried with (MgSO4), filtered, and vacuum concentrated. Purification by flash chromatography yielded (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate methyl (4.3 g, 41%). 1H NMR(500MHz,chloroform-d)δ 6.91(ddd,J=8.1,5.7,2.2Hz,1H),6.83(ddd,J=9.6,8.7,7.1Hz,1H),3.98( d,J=2.5Hz,3H),3.79(s,3H),3.70(s,2H),1.81(q,J=1.0Hz,3H)ppm.ESI-MS m / z calculated value 356.06833, retention time: 3.44 minutes.

[0268] Step 4: A solution of (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate methyl (1.48 g, 4.154 mmol) in THF (20 mL) was added at -78°C to a solution of LiHMDS (10 mL of 1 M LiHMDS in THF, 10.00 mmol) in THF (20 mL). The reaction mixture was stirred at -78°C for 5 hours. The solution was quenched by pouring the contents into a 2 M HCl solution. The mixture was diluted with ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The solution was purified by flash chromatography (SiO2, heptane with 0 to 100% ethyl phosphate) to obtain a yellow oily (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one (950 mg, 71%). 1 H NMR(400MHz,chloroform-d)δ 9.62(s,1H),7.82(ddd,J=9.2,5.7,2.5Hz,1H),7.11(td,J=9.2,7.5Hz,1H),4.00(d,J=1.0Hz,3H),1.79(q,J=1.1Hz,3H)ppm.ESI-MS m / z Calculated value 324.0421, actual value 325.1 (M+1) + ;323.1(M-1) - ;Retention time: 0.93 minutes.

[0269] Step 5: Ethanol (4 mL, 68.51 mmol) was added dropwise over 10 minutes under nitrogen to a mixture of DCC (2.71 g, 13.13 mmol) and CuCl (42 mg, 0.4242 mmol) cooled to 0°C. The reaction mixture was stirred at 0°C for 1 hour. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for a further 23 hours. The reaction mixture was concentrated under vacuum. It was purified by flash chromatography (SiO2, heptane with 0 to 100% ethyl isourea) to obtain a colorless oily 1,3-dicyclohexyl-2-ethyl isourea (2.1 g, 63%). 1 H NMR(400MHz,DMSO-d6)δ 4.78(d,J=8.2Hz,1H),3.94(q,J=7.0Hz,2H),3.28-3.17(m,1H),3.00(tt,J=9.6,3 .8Hz,1H),1.86-1.47(m,9H),1.36-0.98(m,11H),1.12(t,J=7.0Hz,3H)ppm.ESI-MS m / z calculated value 252.22017, actual value 253.3(M+1) + ;Holding time: 0.70 minutes.

[0270] A solution of 1,3-dicyclohexyl-2-ethyl-isourea (440 mg, 1.743 mmol) in 2-MeTHF (3 mL) was added to a degassed solution of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one (279 mg, 0.861 mmol) in 2-MeTHF (3 mL). The reaction mixture was heated overnight at 85°C. A white precipitate was filtered off. The mother liquor was concentrated under vacuum. It was purified by flash chromatography (SiO2, heptane with 0 to 40% ethyl phosphate) to obtain (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one (262 mg, 86%). 1H NMR(400MHz,chloroform-d)δ 7.02-6.88(m,2H),4.16-3.89(m,2H),3.92(d,J=2.0Hz,3H),1.76(q,J=1.0Hz,3H),1.23(t,J=7.0Hz,3H)ppm.ESI-MS m / z Calculated value 352.0734, actual value 353.1 (M+1) + ;Holding time: 1.02 minutes.

[0271] Step 6: Nickel chloride hexahydrate (65 mg, 0.274 mmol) and NaBH4 (53 mg, 1.401 mmol) were continuously added at -40°C to a stirred solution of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one (70 mg, 0.199 mmol) in a mixture of MeOH (2.5 mL) and THF (500 μL). The resulting mixture was stirred at -40°C for 15 minutes. Further amounts of both NiCl2.6H2O and NaBH4 were added to the reaction product. 19 The mixture was added until approximately 85% conversion was achieved, as indicated by 1F NMR. The reaction mixture was quenched by adding a saturated NH4Cl solution. The mixture was diluted with ethyl acetate, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The organic extracts were combined, dried, filtered, and concentrated under vacuum to obtain a mixture of stereoisomers with (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (60 mg, 85%) as the main diastereoisomer. 1 H NMR(400MHz,chloroform-d)δ 7.07-7.01(m,1H),6.97-6.88(m,1H),4.54-4.38(m,1H),4.07(d,J=6.1Hz,1H),4.06(d,J=2.9Hz, 3H),3.35-3.24(m,1H),2.95-2.78(m,1H),1.65(q,J=1.2Hz,3H),0.83(t,J=7.0Hz,3H)ppm.ESI-MS m / z calculated value 354.08905, actual value 354.1(M+1) + ;Holding time: 1.02 minutes.

[0272] Step 7: DIBAL (900 μL, 1 M in toluene, 0.900 mmol) was added dropwise at -78°C to a stirred solution of stereoisomers of (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (260 mg, 0.734 mmol) in DCM (9 mL). The reaction mixture was stirred at -78°C for 2 hours. The mixture was quenched by adding saturated ammonium chloride solution and Rochelle salt solution (30% w / w) (3 mL each). The mixture was diluted with DCM. The aqueous phase was separated and extracted with ELISA (2 × 20 mL). The combined organic extracts were dried (MgSO4), filtered, and vacuum concentrated. The compound was purified by flash chromatography (0 to 30% Â in SiO2 and heptane) to obtain (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (135 mg, 52%) as the main diastereoisomer. 1H NMR (400MHz, chloroform-d)δ 7.12(ddd,J=8.5,5.7,2.3Hz,1H),6.93-6.84(m,1H),5.86(dd,J=7.8,5.4Hz,1H),4.04(t,J=2.5Hz,1H),4.01(d,J=2.2Hz,3H),3.73(dd ,J=7.9,5.7Hz,1H),3.34-3.19(m,1H),3.07(d,J=5.5Hz,1H),2.97-2.86(m,1H),1.59(q,J=1.1Hz,3H),0.87(t,J=7.0Hz,3H)ppm.ESI-MS m / z Calculated value: 356.1047, Measured value: 309.1 (M-OH-Et) + ;Retention time: 0.96 minutes.

[0273] Step 8: DMAP (61 mg, 0.499 mmol) and acetic anhydride (155 μL, 1.643 mmol) were continuously added at ambient temperature to a stirred solution of a mixture of stereoisomers of (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (135 mg, 0.379 mmol) in DCM (2 mL). The reaction mixture was stirred overnight at ambient temperature. Upon completion of the conversion, the reaction product was quenched by adding saturated sodium bicarbonate solution. The aqueous phase was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with diluted HCl solution, dried, filtered, and vacuum concentrated to obtain a mixture of stereoisomers of (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (146 mg, 97%). ESI-MS m / z calculated value: 398.11526, measured value: 310.1 (M-OAc-Et) + ;Retention time: 1.06 minutes.

[0274] Step 9: TMSCN (154 mg, 1.552 mmol) and BF3.OEt2 (120 μL, 0.972 mmol) were continuously added dropwise at -78°C to a stirred solution of a mixture of stereoisomers of (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (150 mg, 0.377 mmol) in DCM (4.5 mL). The mixture was stirred at -78°C for 15 minutes, then warmed to ambient temperature. The mixture was stirred at ambient temperature for 30 minutes. The mixture was quenched by adding 2 M sodium carbonate solution (10 mL). The aqueous phase was separated and extracted with DCM (3 × approximately 5 mL). The combined organic extract was dried (MgSO4), filtered, and concentrated under vacuum. The residue was dissolved in sodium methoxide solution (7.5 mL of 0.5 M sodium methoxide in methanol, 3.750 mmol) and stirred at ambient temperature for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl solution. The mixture was diluted with ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic extract was dried (MgSO4), filtered, and concentrated under vacuum. It was purified by flash chromatography (SiO2, heptane with 0 to 50% ethyl acetate) to obtain (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbimidic acid (carbimidate)methyl (69 mg, 46%) as the main diastereoisomer. 1 1H NMR (400 MHz, chloroform-d)δ 7.72(s,1H),7.18(ddd,J=8.5,5.7,2.3Hz,1H),6.88(ddd,J=9.7,9.0,7.5Hz ,1H),4.82(d,J=11.4Hz,1H),3.94(d,J=2.2Hz,3H),3.83(d,J=5.1Hz,1H),3. 75(dd,J=11.4,5.0Hz,1H),3.60(s,3H),3.24(dq,J=8.9,6.9Hz,1H),2.82(d q,J=8.9,6.9Hz,1H),1.54(q,J=1.1Hz,3H),0.87(t,J=6.9Hz,3H)ppm.ESI-MS m / z Calculated value: 397.13126, Measured value: 398.2 (M+1)+ ;Retention time: 0.96 minutes.

[0275] Step 10: LiOH (1000 μL, 2000 mmol, 2M aqueous solution) was added to a solution of (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbimidomethyl (55 mg, 0.138 mmol) in THF (3 mL). The reaction mixture was stirred at 70°C for 2 hours. An additional 1 ml of 2M LiOH solution was added, and the reaction mixture was stirred at 80°C over the weekend. A further 1 ml of 2M LiOH was added, and the reaction mixture was heated at 100°C for 5 hours. The mixture was acidified with 1 M HCl solution. The resulting solution was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic extracts were dried (MgSO4) and vacuum concentrated to obtain a yellow oil and (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (41 mg, 77%) as the main diastereoisomer. 1 H NMR(400MHz,chloroform-d)δ 7.17(ddd,J=8.3,5.6,2.3Hz,1H),6.89(td,J=9.3,7.4Hz,1H),5.00(d,J=11.6Hz,1H),3.99(d,J=2.4Hz,3H),4.03-3.94(m,1H) ,3.90(d,J=5.0Hz,1H),3.28(dq,J=8.9,6.9Hz,1H),2.92-2.81(m,1H),1.58(q,J=1.1Hz,3H),0.87(t,J=7.0Hz,3H)ppm.ESI-MS m / z calculated value 384.0996, actual value 383.2(M-1) - ;Retention time: 0.58 minutes.

[0276] Step 11: Oxalyl chloride (15 μL, 0.172 mmol) was added at 0°C to a stirred solution of (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (40 mg, 0.104 mmol) and DMF (10 μL, 0.129 mmol) in DCM (1000 μL). The reaction mixture was heated to ambient temperature and stirred for 90 minutes. The mixture was concentrated under vacuum. The residue was dissolved in DCM (1000 μL). Methyl 4-aminopyridine-2-carboxylate (21.2 mg, 0.139 mmol) and Et3N (25 μL, 0.179 mmol) were successively added to the reaction mixture. After stirring the reaction mixture for 2 hours, it was quenched by adding MeOH. The mixture was concentrated under vacuum. The compound was purified by flash chromatography (4g SiO2, heptane with 0 to 100% ethyl phosphate) to obtain 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (10mg, 19%) as the main diastereoisomer. ESI-MS m / z calculated value: 518.14764, measured value: 519.2 (M+1). + ;517.2(M-1) - ;Retention time: 0.96 minutes.

[0277] Step 12: 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)methyl picolinate (10 mg, 0.019 mmol) was dissolved in methanol ammonia (1 mL, 7.000 mmol of a 7 M solution in MeOH) and stirred overnight at ambient temperature. The reaction mixture was concentrated under vacuum. The sample was purified by reverse-phase HPLC (MeCN in H2O containing 0.1% ammonium hydroxide, 19 ml / min + 1 ml / min of MeCN during column dilution injection) using a Waters X-bridge C18 column (150 × 19 mm, 5 μm particle size) to obtain 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinamide (25, 8 mg, 81%). 1 ¹H NMR (400MHz, methanol-d4) δ 8.47 (dd, J=5.5, 0.6Hz, 1H), 8.23 ​​(dd, J=2.1, 0.7Hz, 1H), 7.87 (dd, J=5.5, 2.2Hz, 1H), 7.29 (ddd, J=8.5, 5.7, 2.3Hz, 1H), 7.01 (ddd, J=9.9, 8.9, 7.6Hz, 1H), 5.06 (d, J=11.3Hz, 1H), 4.19 (dd, J=11.3, 5.0Hz, 1H), 4.07 (d, J=5.1Hz, 1H), 3.98 (d, J=1.9Hz, 3H), 3.38-3.33 (m, 1H), 2.97-2.85 (m, 1H), 1.61 (d, J=1.1Hz, 3H), 0.88 (t, J=7.0Hz, 3H) ppm; amides NH and NH2 were not observed. ESI-MS m / z calculated value 503.14795, measured value 504.2 (M+1) + ;502.2(M-1) - ;Holding time: 3.23 minutes.

[0278] Intermediate A 4-Fluoro-2-methoxy-3-methylphenyl)boronic acid [ka] Step 1: Isopropylamine (23.460 g, 34.5 mL, 396.89 mmol) was slowly added to a stirred solution of 3-fluoro-2-methylphenol (50 g, 396.42 mmol) in DCM (2.5 L). The reaction mixture was cooled to -78°C. NBS (70 g, 393.29 mmol) was added in small amounts over 2 hours and 10 minutes, and the mixture was stirred for a further 30 minutes. The mixture was heated to 25°C. 2N HCl (500 ml) was added, and the mixture was stirred for 15 minutes. The organic layer was separated and concentrated under vacuum, and the water bath was kept at 15°C. Hexane (500 ml) was added to the residue, and the mixture was stirred for 10 minutes. The mixture was filtered, the liquid was concentrated under vacuum, and the water bath was kept at 15°C to obtain a light brown oily 6-bromo-3-fluoro-2-methylphenol (73 g, 90%). 1 ¹H NMR (400 MHz, chloroform-d) δ 7.24-7.21 (m, 1H), 6.55 (t, J=8.8 Hz, 1H), 5.61 (s, 1H), 2.20 (s, 3H) ppm.

[0279] Step 2: Potassium carbonate (135 g, 976.80 mmol) was added at ambient temperature to a stirred solution of 6-bromo-3-fluoro-2-methylphenol (40 g, 195.10 mmol) in acetone (400 mL). The reaction mixture was stirred at 25°C for 10 minutes. Methyl iodide (39 g, 17.105 mL, 274.77 mmol) was added dropwise over 10 minutes, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the solid residue was washed with acetone (50 mL). The mother liquor was concentrated under reduced pressure at 15°C. Hexane (200 mL) was added, and the mixture was stirred for 15 minutes. The solid was collected and washed with hexane (8 mL). The mother liquor was concentrated under reduced pressure at 15°C. The mixture was purified by distillation (520 mmHg, 192-196°C) to obtain 1-bromo-4-fluoro-2-methoxy-3-methylbenzene (32.4 g, 76%). 1 ¹H NMR (400 MHz, chloroform-d) δ 7.33-7.30 (m, 1H), 6.72 (t, J=8.7 Hz, 1H), 3.80 (s, 3H), 2.23 (s, 3H) ppm.

[0280] Step 3: Iodine (50 mg, 0.1970 mmol) was added at 25°C to a stirred mixture of Mg shavings (5 g, 205.72 mmol) in THF (50 mL). The mixture was stirred until the reactant became a clear, pale yellow. 1-Bromo-4-fluoro-2-methoxy-3-methylbenzene (2.5 g, 11.4 mmol) was added dropwise at ambient temperature. Once the start of the reaction was observed, the remaining solution of 1-bromo-4-fluoro-2-methoxy-3-methylbenzene (22.5 g, 102.71 mmol) in THF (200 mL) was added dropwise. The mixture was stirred for 40 minutes. The reaction mixture was cooled to -78°C, and triisopropyl borate (64.385 g, 79 mL, 342.34 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with 2N HCl (25 ml) and stirred for 15 minutes. The mixture was diluted with water (125 ml) and extracted with ethyl acetate (2 × 250 ml). The organic layer was separated, washed with water (250 mL), dried, and concentrated under vacuum. Hexane (25 mL) was added to the residue at 0°C and the mixture was stirred for 5 minutes. The resulting solid was filtered, washed with 10 mL of chilled hexane, and dried to obtain (4-fluoro-2-methoxy-3-methylphenyl)boronic acid (11.5 g, 55%). 1 H NMR(400MHz,DMSO-d6)δ 7.96(br s,2H),7.32(t,J=8.0Hz,1H),6.88(t,J=8.7Hz,1H),3.75(s,3H),2.11(s,3H)ppm.

[0281] Intermediates B and C (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine and (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine [ka] Step 1: Cs2CO3 (100 g, 306.92 mmol) was added to a stirred solution of 2-chloro-5-nitropyridine (25 g, 157.69 mmol) and potassium vinyltrifluoroborate (25 g, 186.64 mmol) in a mixture of 2-MeTHF (250 mL) and water (25 mL). The mixture was degassed with argon for 5 minutes. Pd(dppf)Cl2.DCM (6.25 g, 7.65 mmol) was added, and the reaction mixture was degassed again with argon. The reaction mixture was stirred at 90°C for 6 hours. The mixture was concentrated under vacuum and partitioned between ethyl acetate (125 mL) and water (40 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (SiO2, 5 to 20% ethyl acetate in hexane) yielded a pale brown solid of 5-nitro-2-vinylpyridine (22 g, 90%). 1 ¹H NMR (400MHz, chloroform-d) δ 9.38 (s, 1H), 8.42 (dd, J=2.1, 8.5Hz, 1H), 7.46 (d, J=8.8Hz, 1H), 6.93-6.86 (m, 1H), 6.44 (d, J=17.36Hz, 1H), 5.74 (d, J=10.8Hz, 1H) ppm. ESI-MS m / z Calculated value 150.0429, Measured value 151.0 (M+1) + ;Holding time: 1.59 minutes.

[0282] Step 2: NMO (104 mL of 50% w / v aqueous solution, 443.89 mmol) and OsO4 (19 mL of 4% w / v aqueous solution, 2.989 mmol) were added to a stirred solution of 5-nitro-2-vinylpyridine (22 g, 146.53 mmol) in acetone (250 mL). The reaction mixture was stirred at ambient temperature for 3 hours. The acetone was removed by vacuum, and the mixture was partitioned with ethyl acetate (150 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (SiO2, 20 to 80% ethyl acetate in hexane) yielded a grayish-white solid rac-1-(5-nitropyridine-2-yl)ethane-1,2-diol (18 g, 67%). 1H NMR(400MHz,DMSO-d6)δ 9.29(br s,1H),8.60-8.57(m,1H),7.77(d,J=8Hz,1H),5.77(d,J=8Hz,1H),4.80(t,J=5 .6Hz,1H),4.73-4.71(m,1H),3.75-3.73(m,1H),3.59-3.56(m,1H)ppm.ESI-MS m / z calculated value 184.0484, actual value 185.1(M+1) + ;Holding time: 1.46 minutes.

[0283] Step 3: p-TsOH (30 mg, 0.028 mL, 0.174 mmol) and 2,2-dimethoxypropane (338.80 mg, 0.4 mL, 3.253 mmol) were added to a stirred solution of rac-1-(5-nitropyridine-2-yl)ethane-1,2-diol (295 mg, 1.602 mmol) in a mixture of 2-MeTHF (5 mL) and acetone (5 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with a solution of NaHCO3 (7 mL). The mixture was concentrated under vacuum and ethyl acetate (50 mL) was added. The mixture was dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (SiO2, 5 to 10% ethyl acetate in hexane) yielded a grayish-white solid rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (300 mg, 83%). 1 H NMR(400MHz,DMSO-d6)δ 9.33(br s,1H),8.63(dd,J=2.4,8.8Hz,1H),7.76(d,J=8Hz,1H),5.27(t,J=6.4Hz,1H) ,4.45(t,J=8Hz,1H),3.93-3.89(m,1H),1.46(s,3H),1.43(s,3H)ppm.ESI-MS m / z calculated value 224.0797, actual value 225.3(M+1) + ;Holding time: 3.24 minutes.

[0284] Step 4: Pd / C (10% by weight packed, wet, Degussa, 285 mg, 0.268 mmol) was added to a solution of rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (2 g, 8.920 mmol) in ethyl acetate (60 mL). The reaction mixture was degassed with argon for 5 minutes and stirred for 6 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under vacuum to obtain a pale yellow, gum-like rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (1.7 g, 98%). 1 H NMR(400MHz,DMSO-d6)δ 7.86(d,J=2Hz,1H),7.12(d,J=8.4Hz,1H),6.92(dd,J=2.4,8.4Hz,1H),5.30(s,2H),4.92(t,J =6.8Hz,1H),4.20(t,J=6.4Hz,1H),3.78(t,J=7.6Hz,1H),1.39(s,3H),1.35(s,3H)ppm.ESI-MS m / z calculated value 194.1055, actual value 195.2(M+1) + ;Holding time: 1.41 minutes.

[0285] Step 5: The enantiomers of rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (9 g, 46.34 mmol) were separated on a Waters Prep-100 SFC instrument using a Daicel Chiralpak IB column with a particle size of 5 μm and a size of 25 cm × 20 mm.

[0286] First eluted isomer (retention time = 0.90 min): (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (4.4 g, 49%). 1H NMR(400MHz,DMSO-d6)δ 7.86(dd,J=2.8,0.7Hz,1H),7.12(d,J=8.3Hz,1H),6.92(dd,J=8.3,2.8Hz,1H),5.29(s,2H),4.92(dd,J=7.4,6.4Hz, 1H),4.21(dd,J=8.0,6.4Hz,1H),3.79(dd,J=8.0,7.4Hz,1H),1.40(d,J=0.7Hz,3H),1.36(d,J=0.7Hz,3H)ppm.ESI-MS m / z calculated value 194.10553, actual value 195.2(M+1) + ;Holding time: 0.43 minutes.

[0287] Second eluted isomer (retention time = 1.09 min): (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine-3-amine (4.6 g, 51%). 1 H NMR(400MHz,DMSO-d6)δ 7.86(dd,J=2.8,0.7Hz,1H),7.12(d,J=8.3Hz,1H),6.92(dd,J=8.3,2.7Hz,1H),5.29(s,2H),4.97-4.88(m,1H), 4.21(dd,J=8.0,6.4Hz,1H),3.79(dd,J=8.0,7.4Hz,1H),1.40(d,J=0.7Hz,3H),1.36(d,J=0.7Hz,3H)ppm.ESI-MS m / z calculated value 194.10553, actual value 195.2(M+1) + ;Holding time: 0.43 minutes.

[0288] The following intermediates were prepared using the methods described for intermediates B and C, with the exception that 2-chloro-4-nitropyridine was used as the starting material. In step 4, a 1:1 mixture of siRNA and EtOH was used as the solvent. In step 5, purification was performed by chiral SFC using a Daicel Corporation Chiralpak ID column, 5 μm particle size, 25 cm × 20 mm on a Berger Instruments Minigram SFC instrument (22% MeOH, 20 mM NH3, 245 nm, 100 bar). [Table 15]

[0289] The following intermediates were prepared using the methods described for intermediates B and C, except that 2-chloro-4-nitropyridine and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane were used as starting materials in step 1. In step 4, a 1:1 mixture of siRNA and EtOH was used as the solvent. Step 5 was not performed. [Table 16]

[0290] intermediate G 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-amine [ka] Step 1: Lithium aluminum hydride (120 mL, 2M, 240.00 mmol) was added under argon at 0°C to a stirred suspension of methyl 5-aminopicolinate (21.05 g, 138.35 mmol) in dry THF (400 mL). The suspension was stirred overnight at ambient temperature and then heated at 90°C for 6 hours. The reaction mixture was left at room temperature for 30 hours and then cooled back to 0°C. The reaction mixture was quenched by sequentially adding water (9.3 mL, dropwise), 15% NaOH aqueous solution (9.3 mL), and then further water (28 mL). The white precipitate was filtered off while washing with additional THF (300 mL). The filtrate was concentrated under vacuum to obtain brown oily (5-aminopyridine-2-yl)methanol (16.1 g, 75%), which was used in the next step without further purification. 1 1H NMR (400MHz, DMSO-d6): δ 7.81 (d, J=2.7Hz, 1H), 7.06 (d, J=8.2Hz, 1H), 6.89 (dd, J=8.5, 2.5Hz, 1H), 5.11 (s, 2H), 4.34 (s, 2H) ppm; no alcohol OH groups were observed.

[0291] Step 2: Imidazole (1.97 g, 28.938 mmol) was added to a mixture of (5-aminopyridine-2-yl)methanol (3.65 g, 18.641 mmol) and tert-butylchlorodimethylsilane (3.41 g, 22.624 mmol) in THF (60 mL). The mixture was stirred at room temperature for 17 hours. The THF layer was decanted, the oily subphase was dissolved in water (20 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (10 mL), dried, filtered, and vacuum concentrated. The oily residue (5.8 g) was incorporated into a 1:1 mixture of ethyl acetate and heptane (30 mL). The precipitate was removed by filtration. The filtrate was vacuum concentrated. The compound was purified by flash chromatography (SiO2, heptane with 25-75% ethyl acetate) to obtain 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-3-amine (3.92 g, 81%), a white solid with a low melting point. 1 H NMR(400MHz,chloroform-d)δ 8.00(d,J=2.7Hz,1H),7.27-7.25(d,1H),7.02(d,J=2.7Hz,1H),4.72(s,2H),3.82-2.92(br s,2H),0.93(s,9H),0.08(s,6H)ppm.ESI-MS m / z calculated value 238.1501, measured value 239.5(M+1) + ;Retention time: 0.86 minutes.

[0292] Intermediate H (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one [ka] Step 1: A jacketed glass reactor, dried and placed under a nitrogen atmosphere, was packed with (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.0 kg, 6.3261 mol) and diethyl ether (10 L). Methyllithium lithium bromide complex (1.5 M, 5.1000 mol in 3.4 L of Et2O) was slowly added with gas generation and thermoformation. The reactor was cooled and the temperature was maintained at approximately 16°C. Then, methyllithium (containing lithium bromide) was added. 6.1Lの2.2MEt213.420 mol of iodine was slowly added to the mixture. After the addition of a total of 2 equivalents, gas generation stopped and the rate of addition decreased. The mixture was stirred overnight at ambient temperature. The reaction mixture was cooled to 0°C and transferred to an extraction flask containing a mixture of water (6 L), ice (2 L), and brine (2 L). The mixture was neutralized by adding citric acid (1.6 kg, 960.96 mL, 8.3280 mol) and stirred for 30 minutes. The aqueous phase was separated and extracted with diethyl ether (2 × 2.5 L). The combined organic layers were vacuum concentrated to approximately 2 L. The distillate was yellow and consisted of 0.8% w / w product. After further distillation, only 25 g of product was recovered from the distillate. The distillation residue was further concentrated at atmospheric pressure using a distillation setup with a Vigreux (30 cm high). Distillation was continued under reduced pressure (770 mbar), and the pressure was gradually reduced (to 200 mbar) in a cold trap between the collection flask and pump, which were cooled in ice. The mixed fraction was collected until the distillation temperature reached 71°C. The main fraction (590 g) was then collected until the distillation temperature dropped below 70°C. The combined mixed fraction was poured into brine and extracted with diethyl ether (3 × 75 mL). The combined organic layer was dried (Na₂SO₄), filtered, and concentrated at atmospheric pressure in the distillation setup. The product was distilled under reduced pressure (200 mbar) to obtain a colorless oily product (198 g). The collected mixed fraction was redistilled to obtain an additional product (44.25 g). All quantities of product were combined (857 g), dried by adding potassium carbonate (52 g), and allowed to stand for 6 hours. The water level was reduced to below a detectable level, and the mixture was filtered through a glass filter to obtain a colorless oily (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one (815 g, 83%) (815 g). 1 ¹H NMR (300 MHz, chloroform-d) δ 4.33 (s, 1H), 2.40 (d, J=1.1 Hz, 3H), 1.57 (d, J=1.1 Hz, 3H) ppm. 19 F NMR (282 MHz, chloroform-d) δ - 77.96 ppm.

[0293] Example 6 NaV E-VIPR assay for detecting and measuring inhibitory properties Sodium ion channels are voltage-gated proteins that can be activated by inducing membrane voltage changes through the application of an electric field. An electrical stimulation device and method of use, referred to as E-VIPR, are described in International Publication No. 2002 / 008748A3 and C.-J. Huang et al. Characterization of voltage-gated sodium channel blockers by electrical stimulation and fluorescence detection of membrane potential, 24 Nature Biotech. 439-46 (2006), both of which are incorporated in their entirety by reference. The device comprises a microtiter plate handler, an optical system for exciting coumarin dyes while simultaneously recording coumarin and oxonol emission, a waveform generator, a current or voltage-controlled amplifier, and a pair of parallel electrodes inserted into the assay plate wells. Under integrated computer control, the device delivers a user-programmed electrical stimulation protocol to cells in the wells of the microtiter plate.

[0294] 16-20 hours before performing the assay against E-VIPR, use human Na with full channel activity. VHEK cells expressing the 1.8 cleavage morphology were seeded at a density of 25,000 cells per well in 384-well microtiter plates pre-coated with Matrigel. Before seeding, 2.5–5% KIR2.1 Bacmam virus was added to the final cell suspension. HEK cells were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS (fetal bovine serum, eligible; Sigma #F4135), 1% NEAA (non-essential amino acids, Gibco #11140), 1% HEPES (Gibco #15630), 1% Pen-Strep (penicillin-streptomycin; Gibco #15140), and 5 μg / ml blastosidine (Gibco #R210-01). Cells were grown in aerated capped cell culture flasks at 90–95% humidity and 5% CO2.

[0295] Reagents and stock solutions:

[0296] Pluronic® F-127 (Sigma #P2443) at 100 mg / mL in dried DMSO

[0297] Compound plate: Corning 384-well polypropylene round-bottom #3656

[0298] Cell plate: 384-well tissue culture plate (Greiner #781091-2B)

[0299] 2.5–5% KIR 2.1 Bacmam virus (in-house produced), prepared as described in section 3.3 of JAFornwald et al., Gene Expression in Mammalian Cells Using BacMam, a Modified Baculovirus System, 1350 Methods in Molecular Biology 95-116 (2016). The entire content is incorporated by reference. The concentration used may depend on the viral titer of each batch.

[0300] 5 mM DiSBAC6(3), voltage-sensitive oxonol receptor in dry DMSO (CAS number 169211-44-3, 5-[3-(1,3-dihexylhexahydro-4,6-dioxo-2-thioxo-5-pyrimidinyl)-2-propene-1-ylidene]-1,3-dihexyldihydro-2-thioxo-4,6(1H,5H)-pyrimidinedione). The preparation of DiSBAC6(3) is similar to the preparation of DiSBAC4(3) described in Voltage Sensing by Fluorescence Resonance Energy Transfer in Single Cells, Gonzalez, JE and Tsien, RY (1995) Biophys. J. 69, 1272-1280.

[0301] 5 mM CC2-DMPE (ThermoFisher Scientific, catalog number K1017, CAS number 393782-57-5; tetradecanoic acid, 1,1'-[(1R)-1-[8-(6-chloro-7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-3-hydroxy-3-oxide-8-oxo-2,4-dioxa-7-aza-3-phosphaocto-1-yl]-1,2-ethanediyl]ester, a commercially available membrane-bound coumarin lipid FRET donor, was prepared in dry DMSO. See also Gonzalez, JE and Tsien, RY (1997) Chem. Biol. 4, 269-277, for an indicator of cell membrane potential improvement using fluorescence resonance energy transfer.

[0302] The voltage assay background suppression compound (VABSC-1) is prepared in H2O (89-363 mM, within the range used to maintain solubility).

[0303] Human serum (HS, Millipore #S1P1-01KL, or Sigma SLBR5469V and SLBR5470V as a 50% / 50% mixture, at the final assay concentration of 25%)

[0304] Bath 1 buffer: The water contains 160 mM (9.35 g / L) sodium chloride, 4.5 mM (0.335 g / L) potassium chloride, 10 mM (1.8 g / L) glucose, 1 mM (0.095 g / L) anhydrous magnesium chloride, 2 mM (0.222 g / L) calcium chloride, and 10 mM (2.38 g / L) HEPES.

[0305] Na / TMA Cl solution 1 buffer: The water contains 96 mM (5.61 g / L) sodium chloride, 4.5 mM (0.335 g / L) sodium chloride, 64 mM (7.01 g / L) tetramethylammonium (TMA)-Cl, 10 mM (1.8 g / L) glucose, 1 mM (0.095 g / L) anhydrous magnesium chloride, 2 mM (0.222 g / L) calcium chloride, and 10 mM (2.38 g / L) HEPES.

[0306] Hexyl dye solution (2x concentration): Bath 1 buffer containing 0.5% β-cyclodextrin (freshly prepared before each use, Sigma #C4767), 8 μM CC2-DMPE, and 2 μM DiSBAC6(3). The solution was prepared by adding 10% Pluronic® F127 stock in a volume equal to the total volume of CC2-DMPE and DiSBAC6(3). The preparation sequence was as follows: first, Pluronic® and CC2-DMPE were mixed, then DiSBAC6(3) was added, and then Bath 1 / β-cyclodextrin was added while stirring.

[0307] Compound-filled buffer (2x concentration): Na / TMA Cl bath 1 buffer containing 50% HS (omitted in experiments performed in the absence of human serum (HS)), 1 mM VABSC-1, 0.2 mg / ml BSA (bath 1), 9 mM KCl, and 0.625% DMSO.

[0308] Assay protocol (7 key steps): 1) To reach the final concentration in each well, 375 nL of each compound was pre-spotted onto polypropylene compound plates (in pure DMSO) in an 11-point dose-response, 3-fold dilution, from an intermediate stock concentration of 0.075 mM to 240-fold dilution of the desired final concentration, to obtain the highest dose of 300 nM final concentration in the cell plates. Vehicle control (pure DMSO) and positive control (established Na V 1.8 The inhibitor (25 μM final in DMSO) was manually added to the outermost column of each plate. The compound plates were repacked with 45 μL of compound packing buffer per well to obtain 240-fold dilutions of the compound after 1:1 transfer of the compound to cell plates (see Step 6). The final DMSO concentration in all wells during the assay was 0.625% (0.75% DMSO was added to the compound packing buffer for the 0.625% final DMSO concentration). This assay dilution protocol was modified to allow testing of higher dose ranges in the presence of HS or when the final assay volume was altered. 2) A hexyl dye solution was prepared. 3) Cell plates were prepared. On the day of the assay, the culture medium was aspirated, and the cells were washed three times with 80 μL of Bath-1 buffer, maintaining a residual volume of 25 μL in each well. 4) Dispense 25 μL of hexyl dye solution per well into the cell plate. Incubate the cells in the dark at room temperature or ambient conditions for 20 minutes. 5) 45 μL of compound-packed buffer was dispensed into each well of the compound plate. 6) The cell plates were washed three times with 80 μL of Bath-1 buffer per well, leaving a residual volume of 25 μL. Then, 25 μL per well was transferred from the compound plate to each cell plate. The mixture was incubated at room temperature / ambient conditions for 30 minutes. 7) Cell plates containing the compound were read on the E-VIPR using a current-controlled amplifier, and stimulation pulses were delivered using a symmetric biphase waveform. The user-programmed electrical stimulation protocol was 1.25–4 amperes, with a pulse width of 4 milliseconds (depending on electrode composition) delivered at 10 Hz for 10 seconds. A pre-stimulation recording was performed for 0.5 seconds for each well to obtain a non-stimulation intensity baseline. A post-stimulation recording of 0.5 seconds was performed following the stimulation waveform to examine relaxation to the resting state. All E-VIPR responses were measured at an acquisition rate of 200 Hz.

[0309] Data analysis: The data was analyzed and reported as a normalized ratio of emission intensity measured in the 460 nm and 580 nm channels. The response as a function of time was reported as a ratio obtained using the following formula.

number

[0310] The data is initial (R i ) and final (R f The values ​​were further reduced (i.e., normalized) by calculating the ratio. These were the average ratio values ​​for part or all of the pre-stimulation period and between sample points during the stimulation period. The fluorescence ratio (R) was then calculated. f / R i We calculated and reported it as a function of time.

[0311] Control responses were obtained by performing assays in the presence of a positive control and in the absence of a pharmacological agent (DMSO vehicle negative control). Responses to the negative (N) control and positive (P) control were calculated as described above. Next, compound antagonist activity A% was defined as follows:

number

[0312] Measured IC50 < 0.01 μM in the E-VIPR assay described above 50 Compounds with values ​​include 1, 4, 5, 7, 24, and 25.

[0313] The measured ICs of less than 0.1 μM and ≥ 0.01 μM in the E-VIPR assay described above. 50 Compounds with values ​​include 6 and 18.

[0314] Measured ICs less than 1 μM and ≥ 0.1 μM in the E-VIPR assay described above 50 Compounds with values ​​include 2, 8, 13, 14, 20*, and 22*.

[0315] IC50 or higher measured in the E-VIPR assay described above 50 Compounds with values ​​include 3, 9*, 10*, 11*, 12*, 15, 16, 17, 19*, 21*, and 23*.

[0316] The asterisk (*) following the compound number indicates, as described above, that the assay was performed in the presence of human serum.

[0317] As will be apparent to those skilled in the art, many modifications and variations of the embodiments described herein may be made without departing from their scope. Specific embodiments described herein are provided for illustrative purposes only. In a particular embodiment, for example, the following items are provided: (Item 1) Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, X 2a However, N, N + -O - , or CR 2a And, X 3a However, N, N + -O - CR 3a , C-CONR 2 , or C-CH 1-n (R A )(OH)(CH 2 OH) n And, X 4a However, N, N + -O - CR 4a , C-CONR 2 , or C-CH 1-n (R A )(OH)(CH 2 OH) n And, X 5a However, N, N + -O - , or CR 5a And, X 6a However, N, N + -O - , or CR 6a And, Each R independently corresponds to H or C 1 -C 6 It is alkyl, n is 0 or 1, R A However, H or CH 3 And, R 2a 、R 3a 、R 4a 、R 5a , and R 6a Each of them is independent: H, Haro, C 1 -C 6 Alkyl, or C 1 -C 6 It is a haloalkyl, R 4b1 and R 4b2 One of them is OH, C 1 -C 6 Alkoxy, or C 1 -C 6 It is a haloalkoxy, and the other is H. R 5b1 and R 5b2 Each of them is independent of H and C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or C 1 -C 6 It is a haloalkyl, X 3c However, N or CR 3c And, X 4c However, N or CR 4c And, X 5c However, N or CR 5c And, X 6c However, N or CR 6c And, R 2c However, H, OH, halo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenil, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, or -L 1 -L 2 -(C 3 -C 6 It is a cycloalkyl group, and the cycloalkyl group is optionally substituted with 1 to 2 halos. L 1 However, it is a bond or O, L 2 However, bond or C 1 -C 6 It is alkylene, R 3c However, H, Haro, C 1 -C 6 Alkyl, or C 1 -C 6 It is a haloalkyl, R 4c However, H, Haro, C 1 -C 6 Alkyl, or C 1 -C 6 It is a haloalkyl, R 5c However, H, Haro, C 1 -C 6 Alkyl, or C 1 -C 6 It is a haloalkyl, R 6c However, H, Haro, C 1 -C 6 Alkyl, C 1 -C 6 It is a haloalkyl, However, X 2a 、X 3a 、X 4a 、X 5a , and X 6a Two or fewer of these are N or N + -O - And, X 3a and X 4a At least one of them is N, N + -O- CR 3a , or CR 4a And, X 3c 、X 4c 、X 5c , and X 6c A compound, or a pharmaceutically acceptable salt thereof, provided that one or less of the following is N. (Item 2) The aforementioned compound is of formula (IA)

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Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X ２ａ However, N, N ＋ -O － , or CR ２ａ And, X ３ａ is N, N ＋ -O － C-R ３ａ C-CONR ２ or C-CH １－ｎ (R Ａ (OH)(CH ２ OH) ｎ and X ４ａ However, N, N ＋ -O － , C-R ４ａ C-CONR ２ , or C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ And, X ５ａ However, N, N ＋ -O － , or CR ５ａ And, X ６ａ However, N, N ＋ -O － , or CR ６ａ And, Each R independently becomes H or C １ -C ６ It is alkyl, n is 0 or 1, R Ａ However, H or CH ３ And, R ２ａ , R ３ａ , R ４ａ , R ５ａ , and R ６ａ These are H, Haro, and C, each operating independently. １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ４ｂ１ and R ４ｂ２ One of them is OH, C １ -C ６ Alkoxy, or C １ -C ６ It is a haloalkoxy, and the other is H. R ５ｂ１ and R ５ｂ２ H and C are independent of each other. １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ It is a haloalkyl, X ３ｃ However, N or C-R ３ｃ And, X ４ｃ However, N or C-R ４ｃ And, X ５ｃ However, N or C-R ５ｃ And, X ６ｃ However, N or C-R ６ｃ And, R ２ｃ However, H, OH, halo, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy or -L １ -L ２ - (C ３ -C ６ The cycloalkyl group is either unsubstituted or substituted with one or two halos. L １ However, it is a bond or O, L ２ However, bonding or C １ -C ６ It is alkylene, R ３ｃ However, H, Haro, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ４ｃ is H, halo, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, and R ５ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and R ６ｃ However, H, Haro, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, However, X ２ａ , X ３ａ , X ４ａ , X ５ａ , and X ６ａ Two or fewer of these are N or N ＋ -O － And, (1) X 3a is N, N + -O -, or C -R 3a, or (2) X 4a is N, N + -O -, or C -R 4a, or (3) X 3a is N, N + -O -, or C -R 3a, and X 4a is N, N + -O -, or C -R 4a, X ３ｃ , X ４ｃ , X ５ｃ , and X ６ｃ A compound, or a pharmaceutically acceptable salt thereof, provided that one or less of the following is N.

2. The aforementioned compound is of formula (I-A) 【Chemistry 2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

3. The aforementioned compound is of formula (I-A-1) 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

4. The aforementioned compound is of formula (I-B) 【Chemistry 4】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

5. The aforementioned compound is of formula (I-B-1) 【Transformation 5】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

6. X ２ａ However, CR ２ａ And R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

7. X ３ａ However, N, C-CONR ２ , or C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. X ３ａ However, C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

9. X ４ａ However, N, C-CONR ２ , or C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. X ４ａ However, C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

11. X ３ａ and X ４ａ One of them is N, and the other is C-CONR ２ or C-CH １－ｎ (R Ａ ) (OH) (CH ２ OH) ｎ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ５ｂ１ However, C １ -C ６ Alkyl, or C １ -C ６ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

13. R ５ｂ２ However, C １ -C ６ Alkyl, or C １ -C ６ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

14. R ２ｃ But, OH, Halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, or C １ -C ６ A compound according to claim 1, which is a haloalkoxy, or a pharmaceutically acceptable salt thereof.

15. R ３ｃ However, Halo, or C １ -C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

16. R ４ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a halo.

17. R ５ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

18. R ６ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein H is present.

19. R ４ｂ２ However, C １ -C ６ The compound according to claim 1, which is an alkoxy, or a pharmaceutically acceptable salt thereof.

20. R ４ｂ１ However, C １ -C ６ The compound according to claim 1, which is an alkoxy, or a pharmaceutically acceptable salt thereof. 【Request Item 21】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 A compound selected from, or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of claims 1 to 21, which is in a non-salt form.

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

24. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

25. A composition for use in a method of inhibiting voltage-gated sodium channels in a subject, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

26. The voltage-gated sodium channel, Na Ｖ The composition according to claim 25, wherein the ratio is 1.

8.

27. A composition for use in treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

28. The composition according to claim 27, wherein the method comprises treating one or more of the following: neuropathic pain, musculoskeletal pain, acute pain, postoperative pain, or visceral pain, or reducing the severity of the aforementioned in the subject.

29. The composition according to claim 28, wherein the method comprises treating musculoskeletal pain or reducing its severity in the subject thereof, and the musculoskeletal pain includes osteoarthritis pain.

30. The composition according to claim 28, wherein the method comprises treating acute pain or reducing the severity of the acute pain in the subject, and the acute pain includes acute postoperative pain.

31. The composition according to claim 28, wherein the method comprises treating postoperative pain or reducing the severity of the postoperative pain in the subject, and the postoperative pain includes pain from aponeurosis resection, pain from abdominal reconstruction, or pain from hernia repair.

32. The composition according to claim 28, wherein the method comprises treating neuropathic pain or reducing its severity in the subject thereof, and the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy.

33. The composition according to claim 32, wherein the diabetic neuropathy includes diabetic peripheral neuropathy.

34. The composition according to claim 25, wherein the subject is treated simultaneously with treatment by the composition, or with one or more additional therapeutic agents administered before or after such treatment.

35. A composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

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