Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators 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 TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 197,141, filed June 4, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. Nevertheless, there are many conditions in which pain persists beyond its usefulness or in which patients would benefit from pain inhibition. 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 the nerve and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for discrete nerve damage include nerve entrapment injury, such as pain after amputation surgery, postoperative nerve injury pain, and neuropathic back pain. Neuropathic pain is a major cause of disability worldwide, adversely affecting 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. VNav1.8 mediates the rapid upstroke of 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 an important and central role in pain signaling comes from (1) evaluation of the role Nav plays in normal physiology, (2) pathological conditions resulting from mutations in the Nav1.8 gene (SCN10A), (3) preclinical studies in animal models, and (4) the pharmacological actions of known Nav1.8 modulators. Furthermore, because Nav1.8 expression is restricted to peripheral neurons, particularly those that sense pain (e.g., dorsal root ganglion), Nav1.8 inhibitors are unlikely to be associated with the side effects commonly observed with other sodium channel modulators and the abuse liability associated with opioid therapy. Thus, targeting the biology underlying pain through selective Nav1.8 inhibition represents a novel approach to analgesic development that may address the urgent unmet need for safe and effective acute and chronic pain therapies (Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets Na V1.8 Sodium Channels. Mol. Interv., 2007.7(4):p.192-5), England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin. Investig. Drugs 17(12), p.1849-64(2008), Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p.50-56(2008). V Because of the role played by Na V Antagonists that reduce the current can prevent or reduce nerve signaling. V It has been suggested that voltage-gated sodium channels may potentially reduce pain in conditions where hyperexcitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful painkillers are V Local anesthetics such as lidocaine have been identified as inhibitors of the Na channel. V Other compounds that block pain by inhibiting the channel, such as carbamazepine, lamotrigine, and tricyclic antidepressants, which have been shown to be effective in reducing pain, have also been suggested to act by blocking sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na+ currents by antidepressant sertraline and paroxetine.J.Membr.Biol.222(2),p.79-90(2008)).

[0004] Na V form a subfamily of voltage-gated ion channels that mediate the regulation of Na V 1.1~Na V It contains nine isoforms designated 1.9. The tissue localization of the nine isoforms varies. V 1.4 is the primary sodium channel in skeletal muscle and is V 1.5 is the primary sodium channel in cardiac myocytes. Na V 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system and V 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but distinct in the details of their voltage-dependence and kinetic behavior (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397(2005)).

[0005] At the time of their discovery, Na V The 1.8 channel was identified as a likely target for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562):p.257-62). V1.8 has been shown to be a carrier of the sodium current that sustains action potential firing in small dorsal root ganglion (DRG) neurons in the action potentials of nociceptive sensory neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, + 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 injured neurons, such as those that cause neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na + Channel Na V 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6, Jarvis,MF,et al.,A-803467,a potent and selective Na V 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.Proc.Natl.Acad.Sci.USA,2007.104(20):p.8520-5, Joshi,SK,et al.,Involvement of the TTX-resistant sodium channel Na 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 The small DRG neurons in which Na1.8 is expressed contain nociceptors involved in pain signaling.V 1.8 mediates large amplitude action potentials in small neurons of the dorsal root ganglion (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na + Current, TTX-resistant Na + current,and Ca 2+ current in the action potentials of nociceptive sensory neurons.J.Neurosci.,2002.22(23):p.10277-90). Na V 1.8 is required for rapid repetitive action potentials in nociceptors and 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). V1.8 appears to be a driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21):p.8245-50). In some animal pain models, sodium V 1.8 mRNA expression levels have been shown to increase in DRG (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain, 135(Pt 2): p.359-75, Strickland, IT, et al., Changes in the expression of Na V 1.7,Na V 1.8 and Na V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain.Eur.J.Pain,2008.12(5):p.564-72, Qiu,F.,et al.,Increased expression of tetrodotoxin-resistant sodium channels Na V 1.8 and Na V 1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci.Lett.,512(2):p.61-6). The inventors have found that some voltage-gated sodium channel inhibitors, for example, have a poor therapeutic window (e.g., Na VWe have found that selective NaCl has limitations as a therapeutic agent due to its lack of isoform selectivity, low efficacy, and / or other reasons. V There remains a need to develop selective voltage-gated sodium channel inhibitors, such as 1.8 inhibitors. [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 aspect, the invention relates to a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0008] In another aspect, the invention relates to pharmaceutical compositions comprising a compound or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable carriers or vehicles.

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

[0010] In yet another aspect, the invention relates to a method of treating or lessening 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 a compound, pharma- ceutically acceptable salt, or pharmaceutical composition to the subject. [Brief description of the drawings]

[0011] [Figure 1] 1 shows an XRPD pattern characteristic of amorphous Compound 4. [Diagram 2] 1 shows an XRPD pattern characteristic of amorphous compound 21. [Diagram 3] 1 shows an XRPD pattern characteristic of amorphous compound 23. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X 2a is N,N + -O - , or CR 2a and X 3a is N,N + -O - , C.R. 3a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n and X 4a is N,N + -O - , C.R. 4a , C-CONR2, or C-CH 1-n (RA )(OH)(CH2OH) n and X 5a is N,N + -O - , or CR 5a and X 6a is N,N + -O - , or CR 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 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 CR 3c and X 4c is N or CR 4c and X 5c is N or CR 5c and X 6c is N or CR 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), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; 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; However, X 2a , X 3a , X 4a , X 5a , and X 6a Two or less of the following are N or N + -O - and X 3a and X 4a At least one of N, N + -O - , C.R. 3a , or CR 4a and X 3c , X 4c , X5c, and X 6c The condition is that at most one of is N.

[0013] For the purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thFurther, general principles of organic chemistry are identified in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

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

[0015] As described herein, the compounds of the present invention may include a number of variable groups (e.g., X 3a , R A , R 5b1 As one of skill in the art would recognize, the combinations of groups contemplated by the present invention are those that result in the formation of a stable or chemically feasible compound. The term "stable" in this context refers to a compound that does not change substantially when subjected to conditions that allow for their production, detection, and, optionally, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not change substantially when kept 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 depicted herein are intended to be understood as they would be understood by one of ordinary skill in the art. For example, with respect to formulae (I), (IA), (IA-1), (IB), and (IB-1), X 2a and X 3a are linked by a single bond, and X 5a and X 6aare linked by a double bond, and X 4c and X 5c are linked by a single bond, although the bond between these groups may be hidden by atom labels in the chemical structure. Using different styles, Formula I may be drawn as follows to show the bonds: [ka]

[0017] Additionally, a substituent designated in a chemical structure as "CF3" or "F3C" refers to a trifluoromethyl substituent, regardless of whether that depiction 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 straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, without unsaturation and having a specified number of carbon atoms, which is attached to the remainder of the molecule by a single bond. For example, a "C1-C6 alkyl" group is an alkyl group having from 1 to 6 carbon atoms.

[0020] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing one or more carbon-carbon double bonds and having a specified number of carbon atoms, which is attached to the remainder of the molecule by a single bond. For example, a "C2-C6 alkenyl" group is an alkenyl group having from 2 to 6 carbon atoms.

[0021] As used herein, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms having the specified number of carbon ring atoms, which is attached to the remainder of the molecule by a single bond. For example, a "C3-C8 cycloalkyl" group is a cycloalkyl group having from 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 of the alkyl group's hydrogen atoms are replaced by a halo group. For example, a "C1-C6 haloalkyl" group is an alkyl group having 1 to 6 carbon atoms, in which one or more of the alkyl group's hydrogen atoms are replaced by a halo group.

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

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

[0025] As used herein, the term "alkylene" refers to a divalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, without unsaturation and having a specified number of carbon atoms, which is attached to the remainder of the molecule by two single bonds. For example, a "C1-C6 alkylene" group is an alkylene group having from 1 to 6 carbon atoms.

[0026] As used herein, the term "optionally substituted" refers to a group that is unsubstituted or substituted with the substituent specified thereafter. For example, an "optionally substituted group with 1 to 2 halo" is either unsubstituted, substituted with one halo group, or substituted with two halo groups.

[0027] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Additionally, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are within the scope of the invention.

[0028] As used herein, in any chemical structure or formula, a straight, non-bold bond attached to a stereocenter of a compound, such as in the formula: [ka] Indicates that the configuration of a stereocenter is unspecified. The compound may have any configuration, or a mixture of configurations, at the stereocenter.

[0029] As used herein, in any chemical structure or formula, a bold or dashed straight bond attached to a stereocenter of a compound, such as in the formula: [ka] A bold or dashed linear bond indicates the relative stereochemistry of a chiral center relative to the other stereocenter to which it is attached.

[0030] As used herein, in any chemical structure or formula, a bold or dashed wedge shaped bond attached to a stereocenter of a compound, such as in the formula: [ka] A bold or dashed wedge shaped bond indicates the absolute stereochemistry of a stereocenter relative to the other stereocenter to which it is attached, as well as the relative stereochemistry of the stereocenter.

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

[0032] As used herein, the prefix "rel-" when used in reference to a chiral compound refers to a single enantiomer of unknown absolute configuration. In compounds having the "rel-" prefix, the (R) and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. 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 not necessarily 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 there may be isotopic variations between the constituent atoms of the molecule, when referring to a compound of the present invention. The term "compound" includes a collection of such molecules, regardless of the purity of a given sample that contains the collection of molecules. Thus, the term "compound" includes a collection of such molecules in pure form, in a mixture with one or more other substances (e.g., a solution, suspension, colloid, or pharmaceutical composition or dosage form), or in the form of a hydrate, solvate, or co-crystal.

[0034] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are randomly arranged such that there is no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally rather isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature that indicates the 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 sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are seen in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, a solid material may include an amorphous compound, for example, the solid material may be characterized by the lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline but is amorphous as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may be seen in the XRPD pattern of the solid material. For a representative comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. A solid material including an amorphous compound may be characterized by a broader temperature range of melting of the solid material, for example, compared to the range of melting of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may be used to characterize the crystalline or amorphous form.

[0035] In this specification and claims, unless otherwise specified, any atom not specifically designated as a specific 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 specific isotope of any compound of the present invention, no effort was made to enrich that atom in a specific isotope, and therefore, one skilled in the art will understand that such atom was likely present in about the natural abundance isotopic composition of the specified element.

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

[0037] As used herein in the specification and claims, "H" refers to hydrogen and includes any stable isotope of hydrogen, i.e. 1 Includes H and D. In the examples, when an atom is designated as "H," no attempt has been made to enrich that atom in a particular isotope of hydrogen, and thus, one of ordinary skill in the art will understand that such hydrogen atom was likely present in about the natural abundance isotopic composition of hydrogen.

[0038] As used herein, " 1 "H" refers to protium. When an atom in a compound of the invention, or a pharma- ceutically acceptable salt thereof, is designated as protium, protium is present at the designated position at least at the natural abundance concentration of protium.

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

[0040] In some embodiments, the compounds of the invention and pharma- ceutically acceptable salts thereof contain each constituent atom at about the natural abundance isotopic composition of the designated element.

[0041] In some embodiments, the compounds of the invention and their pharma- ceutically 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 designated element ("isotopically labeled" compounds and salts). Examples of stable isotopes that are commercially available and suitable for the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, e.g., 2 H, 13 C. 15 N, 18 O. 17 O, and 31 These include, but are not limited to, P.

[0042] The isotopically labeled compounds and salts can be used in a number of beneficial ways, including as medicines. In some embodiments, the isotopically labeled compounds and salts contain deuterium ( 2 H) labeled. 2 H) The labeled compounds and salts are therapeutically useful and non- 2 3H-labeled compounds have potential therapeutic advantages over H-labeled compounds. 2 H) Labeled compounds and salts may have higher metabolic stability compared to non-isotopically labeled ones due to the kinetic isotope effect described below. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which represents a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds and salts can be generally prepared by carrying out the procedures disclosed in the synthesis schemes, examples, and related descriptions, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0043] deuterium( 2H) labeled compounds and salts can manipulate the rate of oxidative metabolism of a compound through the primary kinetic isotope effect, which is the change in the rate of a chemical reaction resulting from the exchange of an isotope nucleus, which in turn is caused by a change in the ground state energy of the covalent bonds involved in the reaction. The exchange of a heavier isotope usually results in a lowering of the ground state energy of the chemical bond and therefore a decrease in the rate-limiting bond cleavage. If the bond cleavage occurs in or near a saddle point region along the configuration of a multi-product reaction, the product distribution ratio can change significantly. For example, if deuterium is attached to a carbon atom in a non-exchangeable position, k H / k D A rate difference of 2 to 7 is typical. For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated by reference in its entirety.

[0044] The concentration of an isotope (e.g., deuterium) incorporated at a given position in an isotopically labeled compound of the present invention or a pharma- ceutically acceptable salt thereof can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of the isotope.

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

[0046] In some embodiments, the present invention provides a compound of formula (IA) [ka] or a pharma- ceutically acceptable salt thereof, 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 is defined as set out above in relation to formula (I).

[0047] In some embodiments, the present invention provides a compound of formula (IA-1) [ka] or a pharma- ceutically acceptable salt thereof, 3a , X 4a , R 4b1 , R4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set out above in relation to formula (I).

[0048] In some embodiments, the present invention provides a compound of formula (IB) [ka] or a pharma- ceutically acceptable salt thereof, 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 is defined as set out above in relation to formula (I).

[0049] In some embodiments, the present invention provides a compound of formula (IB-1) [ka] or a pharma- ceutically acceptable salt thereof, 3a , X 4a , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 2c , R 3c , and R 4c is defined as set out above in relation to formula (I).

[0050] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), and (IB), or a pharma- ceutically acceptable salt thereof, wherein X 2a CR 2a and R2a is H.

[0051] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein X 3a is N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n In some embodiments, X 3a is N. In other embodiments, X 3a is C-CH 1-n (R A )(OH)(CH2OH) n and n is 0. In other embodiments, X 3a is C-CH 1-n (R A )(OH)(CH2OH) n and n is 1.

[0052] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein X 4a is N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n In some embodiments, X 4a is N. In other embodiments, X 4a is C-CH 1-n (R A )(OH)(CH2OH) n and n is 0. In other embodiments, X 4a is C-CH 1-n (R A )(OH)(CH2OH) n and n is 1.

[0053] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein X 3a and X 4a One of the groups is N and the other is C-CONR2 or C-CH 1-n (R A )(OH)(CH2OH) n It is.

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

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

[0056] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 5b2 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 5b2 is CH, CH(CH), or CF. In some embodiments, R 5b2 is CH(CH). In some embodiments, R 5b2 is CF3.

[0057] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R5b1 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 5b1 is H, CH, or CF. In some embodiments, R 5b1 is H. In some embodiments, R 5b1 is CH3.

[0058] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 4b1 is H or C1-C6 alkoxy. In some embodiments, R 4b1 is H or OCH. In some embodiments, R 4b1 is H. In some embodiments, R 4b1 is OCH3.

[0059] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 4b2 is OH, C-C alkoxy, or C-C haloalkoxy. 4b2 is OH. In some embodiments, R 4b2 is C1-C6 alkoxy. In some embodiments, R 4b2 is OCH, OCHCH, or OCH(CH). In some embodiments, R 4b2 is OCH3. In some embodiments, R 4b2 is OCH2CH3. In some embodiments, R 4b2 is OCH(CH3)2.

[0060] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 2cis OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. 2c is OH, Cl, CH, OCH, OCD, OCHCH, OCH(CH), OCHCHF, or OCHCHF. In some embodiments, R 2c is CH3 or OCH3. In some embodiments, R 2c is CH3. In some embodiments, R 2c is OCH3.

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

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

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

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

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

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

[0067] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 4b2 is C1-C6. In some embodiments, R 4b2 is OCH2CH3 or OCH3. In some embodiments, R 4b2 is OCH3.

[0068] In some embodiments, the present invention relates to a compound of any one of formulas (I), (IA), (IA-1), (IB), and (IB-1), or a pharma- ceutically acceptable salt thereof, wherein R 4b1 is C1-C6. In some embodiments, R 4b2 is OCH2CH3 or OCH3. In some embodiments, R 4b1 is OCH3.

[0069] In some embodiments, the present invention relates to a compound of any one of formulas (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 invention relates to a compound selected from Table A, or a pharma- ceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0071] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0072] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0073] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0074] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0075] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0076] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that term is used herein.

[0077] In some embodiments, the present invention provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof. In another embodiment, the invention relates to the aforementioned compounds in non-salt form. Such compounds are considered to be "compounds of the invention" as that 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 pharma- ceutically acceptable salts thereof that are inhibitors of voltage-gated sodium channels, and thus the compounds and pharma- ceutically acceptable salts thereof are useful for treating diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia. Thus, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise a compound as described herein, or a pharma- ceutically acceptable salt thereof, and optionally include a pharma- ceutically 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 agent is a sodium channel inhibitor.

[0079] As used herein, the term "pharmaceutically acceptable" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound of the invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, in admixture with one or more other substances (e.g., solution, suspension, or colloid), or in the form of a hydrate, solvate, or co-crystal. As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of voltage-gated sodium channels.

[0080] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts such as sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0081] As used herein, the pharma- ceutically acceptable compositions of the present invention additionally include pharma- ceutically acceptable carriers, adjuvants, or vehicles, including any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, appropriate for the particular dosage form desired, as used herein. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharma- ceutical acceptable compositions and known techniques for their preparation. The use of any conventional carrier medium is contemplated within the scope of the present disclosure, except insofar as it is incompatible with the compounds of the present invention, for example, by causing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component of the pharma- ceutical acceptable composition.Some examples of materials that may serve as pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate, etc.), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose, cellulose esters ... 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 solutions, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents; preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0082] In another aspect, the invention features a pharmaceutical composition including a compound of the invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0083] In another aspect, the invention features a pharmaceutical composition that includes a therapeutically effective amount of a compound, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or vehicles.

[0084] Uses of the Compounds and Pharmaceutically Acceptable Salts and Compositions In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject, the method including administering to the subject a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It's 1.8.

[0085] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., bunionectomy pain, herniorrhaphy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia in a subject, the method includes administering an effective amount of a compound, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0086] In yet another aspect, the invention features a method of treating or lessening the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia in a subject, the method includes administering an effective amount of a compound, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0087] In yet another aspect, the invention features a method of treating or lessening the severity of intestinal pain in a subject, where intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, the method includes administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

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

[0089] In yet another aspect, the invention features a method of treating or lessening the severity of neuropathic pain in a subject, including postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, medication-induced 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 cephalopathy, the method comprising administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0090] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the musculoskeletal pain comprises osteoarthritis.

[0091] In yet another aspect, the invention features a method of treating or lessening the severity of musculoskeletal pain in a subject, where musculoskeletal pain includes osteoarthritis, back pain, cold pain, burn pain, or dental pain, the method includes administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0092] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, where inflammatory pain includes rheumatoid arthritis pain or vulvodynia, the method includes administering an effective amount of a compound of the invention, a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof.

[0093] In yet another aspect, the invention features a method of treating or lessening the severity of inflammatory pain in a subject, including rheumatoid arthritis pain, the method including administering an effective amount of a compound of the invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0094] In yet another aspect, the invention features a method of treating or lessening the severity of idiopathic pain in a subject, including fibromyalgia pain, the method including administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0095] In yet another aspect, the invention features a method of treating or lessening the severity of pathological cough in a subject, the method comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0096] In yet another aspect, the invention features a method of treating or lessening the severity of acute pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, hi some aspects, the acute pain comprises acute post-operative pain.

[0097] In yet another aspect, the invention features a method of treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0098] In yet another aspect, the invention features a method of treating or lessening the severity of bunionectomy pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0099] In yet another aspect, the invention features a method of treating or lessening the severity of herniorrhaphy pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] In yet another aspect, the invention features a method of treating or lessening the severity of abdominoplasty pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0101] In yet another aspect, the invention features a method of treating or lessening the severity of visceral pain in a subject comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, hi some aspects, the visceral pain comprises abdominoplasty visceral pain.

[0102] In yet another aspect, the invention features a method of treating or reducing the severity of a neurodegenerative disease in a subject, comprising administering an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome.

[0103] In yet another aspect, the invention features a method in which a subject is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with an effective amount of a compound, pharma- ceutically acceptable salt, or pharmaceutical composition, hi some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0104] In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a biological sample, the method including contacting the biological sample with an effective amount of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. V It's 1.8.

[0105] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic neuropathic pain, and inflammatory bowel disorders. pain, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic esophagitis, erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced In one embodiment, the present invention relates to a method for treating or lessening the severity of chronic oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pubic pain, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastrointestinal motility in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmacologic acceptable salt thereof, or a pharmaceutical composition thereof.

[0106] In another aspect, the present invention provides a method for treating femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, pain Neuromas with ulcerative colitis, ectopic proximal and distal secretions, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic post-operative 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-resection of lower limb, upper limb, breast), intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain, renal pelvic pain inflammation, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labour pain, caesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute shingles pain, sickle cell disease, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful adiposity, phlebitis pain, Guillain-Barre syndrome pain, sore legs and moving toes, Haglun In one embodiment, the present invention relates to a method for treating or reducing the severity of chronic urinary incontinence, chronic urinary incontinence, chronic urinary incontinence syndrome, erythromelalgia pain, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus, or angina induced pain in a subject, the method comprising administering an effective amount of a compound of the present invention, a pharmacologic salt thereof, or a pharmaceutical composition thereof.

[0107] Compounds, Pharmacologically Acceptable Salts, and Compositions for Use - Patent application In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use as a medicament.

[0108] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a subject. V It's 1.8.

[0109] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method to treat or lessen the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0110] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0111] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of intestinal pain, including inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0112] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain includes diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase "idiopathic small fiber neuropathy" is understood to include any small fiber neuropathy.

[0113] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of treating or lessening the severity of neuropathic pain in a subject, wherein the neuropathic pain includes post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, medication-induced 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 cephalopathy.

[0114] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of musculoskeletal pain in a subject, hi some aspects, the musculoskeletal pain comprises osteoarthritis.

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

[0116] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, where the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0117] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of inflammatory pain in a subject, where inflammatory pain includes rheumatoid arthritis pain.

[0118] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity of idiopathic pain in a subject, where idiopathic pain includes fibromyalgia pain.

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

[0120] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of acute pain in a subject, hi some aspects, the acute pain comprises acute post-operative pain.

[0121] In yet another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0122] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of bunionectomy pain in a subject.

[0123] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of herniorrhaphy pain in a subject.

[0124] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of abdominoplasty pain in a subject.

[0125] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt, or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain comprises visceral pain due to abdominoplasty.

[0126] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome.

[0127] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method in which a subject is treated with an effective amount of one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with the compound, pharma- ceutically acceptable salt, or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0128] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method of inhibiting a voltage-gated sodium channel in a biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. V It's 1.8.

[0129] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic nephropathy, and chronic pain. neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, total Systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, The present invention features a compound of the present invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in a method for treating or lessening the severity in a subject of chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pudendal, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0130] In another aspect, the present invention provides a method for treating hip cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury. , painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic post-operative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after lower limb, upper limb, mastectomy), intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain , pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labour pain, caesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute shingles pain, sickle cell disease, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful adiposity, phlebitis pain, Guillain-Barre syndrome pain, sore legs and moving toes The present invention features a compound of the present invention, or a pharma- ceutical composition thereof, for use in a method for treating or reducing the severity in a subject of chronic urinary incontinence, chronic obstructive pulmonary disease, chronic urinary incontinence, chronic obstructive pulmonary disease (COPD), chronic urinary incontinence, chronic obstructive pulmonary disease (OPD), chronic obstructive pulmonary disease (COPD) 2 (APO) 2 (APO), chronic obstructive pulmonary disease ...

[0131] In another aspect, the invention features a compound of the invention, or a pharmacologic acceptable salt, or pharmaceutical composition thereof, for use in a method of treating or lessening the severity in a subject of trigeminal neuralgia, Botox-treated migraine, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus pathology, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or pain following amputation surgery.

[0132] Drug manufacturing In another aspect, the present invention provides the use of a compound of the invention, or a pharma- ceutically acceptable salt, or a pharmaceutical composition thereof, for the manufacture of a medicament.

[0133] In another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. V It's 1.8.

[0134] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain (e.g., herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

[0135] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, herniorrhaphy pain, bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, or cardiac arrhythmia.

[0136] In yet another aspect, the invention provides the use of a compound, pharma- ceutically acceptable salt, or pharmaceutical composition as described herein for the manufacture of a medicament for use in treating or reducing the severity of intestinal pain in a subject, wherein intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0137] In yet another aspect, the present invention provides a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject. In some aspects, the neuropathic pain comprises postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small fiber neuropathy. In some aspects, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy).

[0138] In yet another aspect, the invention provides use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain comprises post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation surgery, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, medication-induced 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 neuropathy.

[0139] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of musculoskeletal pain in a subject, hi some aspects, the musculoskeletal pain comprises osteoarthritis.

[0140] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity in a subject of musculoskeletal pain, including osteoarthritis, back pain, cold pain, burn pain, or dental pain.

[0141] In yet another aspect, the invention provides the use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

[0142] In yet another aspect, the invention provides the use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of inflammatory pain in a subject, wherein inflammatory pain includes rheumatoid arthritis pain.

[0143] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of idiopathic pain in a subject, wherein idiopathic pain includes fibromyalgia pain.

[0144] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of pathological cough in a subject.

[0145] In yet another aspect, the present invention provides the use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of acute pain in a subject, hi some aspects, acute pain comprises acute post-operative pain.

[0146] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain) in a subject.

[0147] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of herniorrhaphy pain in a subject.

[0148] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of bunionectomy pain in a subject.

[0149] In yet another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of abdominoplasty pain in a subject.

[0150] In yet another aspect, the invention provides the use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of visceral pain in a subject, hi some aspects, the visceral pain comprises visceral pain due to abdominoplasty.

[0151] In another aspect, the invention features a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of a neurodegenerative disease in a subject. In some aspects, the neurodegenerative disease comprises multiple sclerosis. In some aspects, the neurodegenerative disease comprises Pitt-Hopkins syndrome.

[0152] In yet another aspect, the invention provides the use of a compound of the invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concomitantly, prior to, or following treatment with the compound or pharmaceutical composition, hi some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0153] In another aspect, the present invention provides a method for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, algesic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, central neuropathic pain in multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis, post-herpetic neuralgia, diabetic nephropathy, and chronic pain. neuropathy, radicular pain, sciatica, back pain, unspecified chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain (e.g., joint replacement pain, soft tissue surgery pain, herniorrhaphy pain, bunionectomy pain, or abdominoplasty pain), cancer pain including chronic cancer pain and cancer breakthrough pain, stroke (e.g., central neuropathic pain after stroke), traumatic neck syndrome, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, total Systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteoporosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic osteophytosis, degenerative / herniated disc pain, radiculopathy, facet joint syndrome, failed spinal surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylodiscitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ophthalmopathic pain, sarcoidosis, spondylolysis, spondylolisthesis, The present invention provides a use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment or reduction of the severity of chemotherapy-induced oral mucositis, Charcot arthropathy, temporomandibular joint disorders, painful knee replacement surgery, non-cardiac chest pain, pubic area, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0154] In another aspect, the present invention provides a method for treating hip cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, splenic pain, IBS pain, chronic and acute headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV associated neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury. , painful neuromas, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic post-operative pain (e.g., after amputation, thoracotomy, cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after lower limb, upper limb, mastectomy), intractable pain, acute pain, acute post-operative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tenosynovitis, injury pain, movement pain, acute visceral pain , pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic pain, acute obstetric pain, labour pain, caesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute shingles pain, sickle cell disease, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful adiposity, phlebitis pain, Guillain-Barre syndrome pain, sore legs and moving toes The present invention provides a compound of the present invention, a pharmacologic agent, a medicament for use in treating or reducing the severity of chronic urinary incontinence, chronic urinary incontinence, chronic obstructive pulmonary disease (COPD), chronic urinary incontinence (COP), chronic obstructive pulmonary disease (OPD), chronic urinary incontinence syndrome (CUP), chronic obstructive pulmonary disease (OP), chronic obstructive pulmonary disease (COP ...

[0155] In another aspect, the present invention provides use of a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating or reducing the severity of trigeminal neuralgia, migraine treated with Botox, cervical spondylotic radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexus pathology, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioinguinal neuralgia, pudendal neuralgia, femoral neuropathy, dysesthesias of the thigh, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexus pathology, traumatic neuroma stump pain, 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 a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective to treat or reduce the severity of one or more of the conditions listed above.

[0157] The compounds, salts, and compositions according to the method of the present invention may be administered using any amount and any route of administration effective for treating or reducing the severity of one or more of the pain or non-pain disorders listed herein. The exact amount required will vary between subjects, depending on the species, age, and general condition of the subject, the severity of the condition, the specific drug, its mode of administration, and the like. The compounds, salts, and compositions of the present invention are optionally formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the subject to be treated. However, it will be understood that the total daily usage of the compounds, salts, and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular subject or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the particular compound or salt used, the particular composition used, the age, weight, general health, sex, and diet of the subject, the time of administration, route of administration, and rate of excretion of the particular compound or salt used, duration of treatment, drugs used in combination with or concomitantly with the particular compound or salt used, and similar factors well known in the medical arts. As used herein, the term "subject" or "patient" means an animal, preferably a mammal, and most preferably a human.

[0158] The pharma- ceutically acceptable compositions of the invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally as an oral or nasal spray, etc., depending on the severity of the condition being treated. In certain embodiments, the compounds, salts, and compositions of the invention may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.001 mg / kg to about 1000 mg / kg that are effective to obtain the desired therapeutic effect.

[0159] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound or salt, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0160] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions 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 (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0161] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0162] In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

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

[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 mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, carbonate, glycerol, d) glycerol, e) glycerol, f) glycerol, g ... Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0165] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0166] The active compound or salt may also be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound or salt may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is normal practice. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a delayed manner, in a certain part of the intestinal tract. 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 pharma- ceutically acceptable carrier and any necessary preservatives or buffers, as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0168] As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are V1.8 and therefore, without wishing to be bound by any particular theory, the compounds, salts and compositions are inhibitors of Na V It is particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation or overactivity of Na 1.8 is implicated in the disease, condition, or disorder. V Where activation or overactivity of 1.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be associated with Na V 1.8-mediated disease, condition, or disorder. V The present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or overactivity of 1.8 is implicated in the disease state.

[0169] Na V The activity of the compounds utilized in this invention as inhibitors of 1.8 may be assayed according to the methods generally described in International Publication No. WO2014 / 120808A9 and U.S. Publication No. 2014 / 0213616A1 (both of which are incorporated by reference in their entireties), the methods described therein, as well as other methods known and available to those of skill in the art.

[0170] Additional medications It will also be understood that the compounds, salts, and pharma- ceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts, and pharma- ceutically acceptable compositions can be administered simultaneously with, prior to, or after one or more other desired therapies or medical treatments. The particular combination of therapies (treatments or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agent and / or treatment, and the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve the desired effect for the same disorder (e.g., the compounds of the present invention can be administered simultaneously with another agent used to treat the same disorder), or can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are referred to as "as known 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, tolmetin, naphthyl alkanones, e.g., nabumetone, oxicams, e.g., piroxicam, para-aminophenol derivatives, e.g., acetaminophen, propionic acids, e.g., fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, salicylates, e.g., aspirin, choline magnesium trisalicylate, diflunisal, fenamates, e.g., , meclofenamic acid, mefenamic acid, and pyrazoles, e.g., phenylbutazone), or opioid (anesthetic) agonists (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-pharmacological analgesic approaches may be utilized in conjunction with the administration of one or more compounds of the present invention. For example, anesthesiology (spinal injection, nerve block), neurosurgery (neuroablation of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, spinal cord dorsal column stimulation), physical therapy (physiotherapy, orthotics, diathermy), or psychology (cognitive methods - hypnosis, biofeedback, or behavioral methods) approaches may also be utilized.Additional suitable therapeutic agents or approaches are generally described in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.) 2011, and the Food and Drug Administration (website at www.fda.gov), the entire contents of which are incorporated herein by reference.

[0171] In another embodiment, the additional suitable therapeutic agent is selected from the following: (1) an opioid analgesic, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including but not limited to intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including but not limited to ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac; (3) Barbiturates, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental; (4) benzodiazepines with sedative effects, such as chlordiazepoxide, clorazepate, diazepam, flazepam, lorazepam, oxazepam, temazepam, or triazolam; (5) Sedating histamine (H1) antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine; (6) Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone; (7) Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine; (8) NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation 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-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline; (10) Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline; (11) Anticonvulsants, such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate; (12) Tachykinin (NK) antagonists, in particular NK-3, NK-2, or NK-1 antagonists, such as (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,lg][l,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S) -2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); (13) Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropium chloride, darifenacin, solifenacin, temiverine, and ipratropium; (14) COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) Coal-tar painkillers, especially paracetamol; (16) Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan; (17) vanilloid receptor agonists (e.g., resiniferatoxin or civamide) or antagonists (e.g., capsazepine, GRC-15300); (18) beta-adrenergics, such as propranolol; (19) Local anesthetics, such as 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, such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) Cholinergic (nicotinic) analgesics, such as isoprenicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine; (24) Tramadol®, tramadol ER (Ultram ER®), IV tramadol, tapentadol ER (Nucynta®); (25) PDE5 inhibitors, such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',l':6,l]-pyrido[3,4-b ]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-l-yl-l-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,lf][l,2,4]triazin-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]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-l-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin- 7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l-methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; (26) Alpha-2-delta ligands, such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)- Proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; (27) Cannabinoids, such as KHK-6188; (28) 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, escitalopram, d,l-fenfluramine, femoxetine, ioxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; (30) noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors, such as reboxetine, in particular (S,S)-reboxetine; (31) Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; (32) Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyl disulfide; (33) Acetylcholinesterase inhibitors, for example, donepezil; (34) Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; (35) Leukotriene B4 antagonists, such as l-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870; (36) 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); (37) Sodium channel blockers, such as lidocaine, lidocaine + tetracaine cream (ZRS-201), or eslicarbazepine acetate; (38)Na V1.7 Blockers such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (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); those 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 of which are incorporated herein by reference; (38a)Na V1.7 Blockers, such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-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-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-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-methyl-pyridine-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-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, yl]-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-methyl-pyridine-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-methyl-phenyl)-[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'-Piperidinyl]-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, such as PF-04531083, PF-06372865, as well as, for example, 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 those disclosed in WO2021 / 032074, CN112390745, CN111808019, CN112225695, CN112457294, CN112300051, CN112300069, CN112441969, and CN112479996 (WO2021 / 047622), the entire contents of each of which are incorporated herein by reference; (39a)Na V1.8 Blockers, such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 5-chloro-2-(4 -fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)- 5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluoro phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl-d3)phenoxy)-N-(2-oxo-1,2-dihydropyridine-4-yl (4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamide)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-N-( 3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline- 2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)picolinic acid, 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide, 3-(4-fluorophenoxy)-N -(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide)benzoic acid, N-(4-cyanophenyl)-3-(4 -fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)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)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dic 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4, 5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5- Dichloro-2-(2,4-dimethoxyphenoxy)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)benzamido)picolinic acid, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methylphenyl)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-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl), N-(3-carbamoyl-4-fluorophenyl)-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluorophenyl)-3-(trifluoromethoxy)benzamide, -(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteromethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide, 4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-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-(trideuteromethoxy)-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 N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide, 4-(2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)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, such as DSP-2230, Lohocla201, or BL-1021; (41) 5-HT3 antagonists, such as ondansetron; (42) TPRV1 receptor agonists, such as capsaicin (NeurogesX®, Qutenza®), and pharma- ceutically acceptable salts and solvates thereof; (43) Nicotinic receptor antagonists, such as varenicline; (44) N-type calcium channel antagonists, such as Z-160; (45) Nerve growth factor antagonists, such as tanezumab; (46) Endopeptidase stimulators, such as senrebotase; (47) Angiotensin II antagonists, such as EMA-401; (48) Acetaminophen (including but not limited to intravenous acetaminophen (e.g., Ofirmev®)); (49) Bupivacaine (including but not limited to bupivacaine liposomal injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll), and transdermal bupivacaine (Eladur®)); and (50) Combination of bupivacaine and meloxicam (e.g., HTX-011).

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

[0173] In another embodiment, the additional suitable therapeutic agent is selected from N-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide; N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide; or 3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

[0174] In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, e.g., Operanserin (VVZ149), a TRPV modulator, e.g., CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, an EGR1 inhibitor, e.g., Brivoglide (AYX1), an NGF inhibitor, e.g., Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist, e.g., Cebranopadol, NKTR181 (Oxycodegol), a CB-1 agonist, e.g., NEO1940 (AZN1940), an imidazoline 12 agonist, e.g., CR4056, or a p75NTR-Fc modulator, e.g., LEVI-04.

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

[0176] In another embodiment, the additional therapeutic agent is Na V 1.7 blockers, such as ST-2427 or ST-2578, and those disclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, WO2020 / 072835, and WO2022 / 036297, the entire contents of each of which are incorporated herein by reference. In some embodiments, the additional therapeutic agent is a Na V In some embodiments, the additional therapeutic agent is a Na 1.7 blocker as disclosed in WO2022 / 036297. V It is a 1.7 blocker.

[0177] In another embodiment, the additional therapeutic agent is 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™), bribolidide, 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, the additional therapeutic agent is 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, the additional therapeutic agent is one or more of the following: 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 / 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, the additional therapeutic agent is a compound disclosed in WO2022 / 036297.

[0181] In another embodiment, the additional therapeutic agent is a NaV 1.7 and Na V Sodium channel inhibitors (also known as sodium channel blockers), such as 1.8 blockers.

[0182] The amount of additional therapeutic agent present in the compositions of the invention may be up to the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0183] The compounds and salts of the present invention or pharma- ceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Thus, in another aspect, the present invention includes compositions for coating implantable devices, comprising the compounds or salts of the present invention generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising the compounds or salts of the present invention generally as described above, and the classes and subclasses herein, and a carrier suitable for coating the implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart sustained release characteristics in the composition.

[0184] Another aspect of the invention is to detect Na in a biological sample or subject. VWith respect to inhibiting 1.8 activity, the method includes administering to a subject or contacting the biological sample with a compound of the present invention, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies obtained from mammals or extracts thereof, as well as blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

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

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

[0187] Radiolabeled Analogues of the Compounds of the Invention In another aspect, the present invention relates to radiolabeled analogues of the compounds of the present invention.As used herein, the term "radiolabeled analogues of the compounds of the present invention" refers to compounds that are identical to the compounds of the present invention described herein, including all embodiments thereof, except that one or more atoms are replaced with radioisotopes of the atoms present in the compounds of the present invention.

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

[0189] Radiolabeled analogs can be used in a number of 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 detectability.

[0190] In another aspect, the invention relates to a pharma- ceutically acceptable salt of a radiolabeled analog according to any of the embodiments described herein in relation to the compounds of the invention.

[0191] In another aspect, the invention relates to a pharmaceutical composition comprising a radiolabeled analog or a pharma- ceutically acceptable salt thereof according to any of the embodiments described herein in relation to the compounds of the invention, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0192] In another aspect, the invention relates to methods of inhibiting voltage-gated sodium channels in a subject, and methods of treating or lessening the severity of various diseases and disorders, including pain, comprising administering an effective amount of a radiolabeled analog, pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, according to any of the embodiments described herein in connection with the compounds of the invention.

[0193] In another aspect, the invention relates to radiolabeled analogs, pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use according to any of the embodiments described herein in connection with the compounds of the invention.

[0194] In another aspect, the invention relates to the use of a radiolabeled analogue, or a pharma- ceutically acceptable salt thereof, according to any of the embodiments described herein in relation to the compounds of the invention, for the manufacture of a medicament, and pharmaceutical compositions thereof.

[0195] In another aspect, the radiolabeled analogs, their pharma- ceutically acceptable salts, and pharmaceutical compositions thereof, may be used in combination therapy according to any of the embodiments described herein in connection with the compounds of the invention.

[0196] Enumerated Embodiments Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through the practice of the disclosure. The compounds and methods of the present disclosure can be described as embodiments of any of the following recited clauses. Any of the embodiments described herein can be used in conjunction with any other embodiment described herein to the extent that the embodiments are not mutually exclusive. 1. A compound of formula (I), [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 2a But, N, N + -O - , or CR 2aand X 3a But, N, N + -O - , C.R. 3a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n and X 4a But, N, N + -O - , C.R. 4a , C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n and X 5a But, N, N + -O - , or CR 5a and X 6a But, N, N + -O - , or CR 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 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 But N or CR 3c and X 4c But N or CR 4c and X5c But N or CR 5c and X 6c But N or CR 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), wherein the cycloalkyl is optionally substituted with 1 to 2 halo; 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; However, X 2a , X 3a , X 4a , X 5a , and X 6a Two or less of the following are N or N + -O - and X 3a and X 4a At least one of N, N + -O - , C.R. 3a , or CR 4a and X 3c , X 4c , X5c, and X 6c or a pharma- ceutically acceptable salt thereof, provided that not more than one of: 2. The compound has the formula (IA) [ka] 2. The compound according to clause 1, having the formula: 3. The compound has the formula (IA-1) [ka] 2. The compound according to clause 1, having the formula: 4. The compound has the formula (IB) [ka] 2. The compound according to clause 1, having the formula: 5. The compound has the formula (IB-1) [ka] 2. The compound according to clause 1, having the formula: 6.X 2a But, CR 2a and R 2a A compound according to any one of clauses 1, 2 or 4, wherein is H, or a pharma- ceutically acceptable salt thereof. 7.X 3a is N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n 7. The compound according to any one of clauses 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein: 8.X 3a is N, or a pharma- ceutically acceptable salt thereof. 9.X 3a But, C-CH 1-n (R A )(OH)(CH2OH) n and n is 0; or a pharma- ceutically acceptable salt thereof. 10.X 3aBut, C-CH 1-n (R A )(OH)(CH2OH) n and n is 1, or a pharma- ceutically acceptable salt thereof. 11.X 4a is N, C-CONR2, or C-CH 1-n (R A )(OH)(CH2OH) n 9. The compound according to any one of clauses 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein: 12.X 4a is N, or a pharma- ceutically acceptable salt thereof. 13.X 4a But, C-CH 1-n (R A )(OH)(CH2OH) n and n is 0; or a pharma- ceutically acceptable salt thereof. 14.X 4a But, C-CH 1-n (R A )(OH)(CH2OH) n and n is 1, or a pharma- ceutically acceptable salt thereof. 15.X 3a and X 4a One of the groups is N and the other is C-CONR2 or C-CH 1-n (R A )(OH)(CH2OH) n 15. The compound according to any one of clauses 1 to 14, wherein: 16.R 5b1 is C1-C6 alkyl or C1-C6 haloalkyl. 17.R 5b1 is CH3 or CF3, or a pharma- ceutically acceptable salt thereof. 18.R 5b2 is C1-C6 alkyl or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof. 19.R 5b2is CH3 or CF3, or a pharma- ceutically acceptable salt thereof. 20.R 2c or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 19, wherein is OH, halo, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; or a pharma- ceutically acceptable salt thereof. 21.R 2c 21. The compound according to clause 20, wherein is OH, Cl, CH3, OCH3, OCD3, OCH2CH3, OCH(CH3)2, OCH2CH2F, or OCH2CHF2, or a pharma- ceutically acceptable salt thereof. 22.R 2c is CH3 or OCH3, or a pharma- ceutically acceptable salt thereof. 23.R 3c is halo or C1-C6 alkyl, or a pharma- ceutically acceptable salt thereof. 24.R 3c is F, or a pharma- ceutically acceptable salt thereof. 25.R 3c is CH3, or a pharma- ceutically acceptable salt thereof. 26.R 4c 26. The compound according to any one of clauses 1 to 25, wherein is halo, or a pharma- ceutically acceptable salt thereof. 27.R 4c is F, or a pharma- ceutically acceptable salt thereof. 28.R 5c is H; or a pharma- ceutically acceptable salt thereof. 29.R 6c is H; or a pharma- ceutically acceptable salt thereof. 30.R 4b2 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 29, wherein is C1-C6 alkoxy; or a pharma- ceutically acceptable salt thereof. 31.R 4b2is OCH2CH3 or OCH3, or a pharma- ceutically acceptable salt thereof. 32.R 4b2 is OCH3, or a pharma- ceutically acceptable salt thereof. 33.R 4b1 or a pharma- ceutically acceptable salt thereof. The compound according to any one of clauses 1 to 29, wherein is C1-C6 alkoxy; or a pharma- ceutically acceptable salt thereof. 34.R 4b1 is OCH2CH3 or OCH3, or a pharma- ceutically acceptable salt thereof. 35.R 4b1 is OCH3, or a pharma- ceutically acceptable salt thereof. 36. A compound selected from Table A, or a pharma- ceutically acceptable salt thereof. 37. The compound according to any one of clauses 1 to 36, in non-salt form. 38. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of clauses 1 to 36 or a pharma- ceutically acceptable salt thereof, or a compound according to clause 37, and one or more pharma- ceutically acceptable carriers or vehicles. 39. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 32 or a pharma- ceutically acceptable salt thereof, or a compound according to clause 37, and one or more pharma- ceutically acceptable carriers or vehicles. 40. A method for inhibiting voltage-gated sodium channels in a subject, the method comprising administering to the subject a compound according to any one of clauses 1 to 36 or a pharma- ceutically acceptable salt thereof, a compound according to clause 37, or a pharmaceutical composition according to clause 38 or 39. 41. Voltage-gated sodium channels are V 1.8. The method according to claim 40, 42. A method for treating or reducing the severity in a subject of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia, comprising administering to the subject an effective amount of a compound according to any one of clauses 1 to 36 or a pharma- ceutically acceptable salt thereof, a compound according to clause 37, or a pharmaceutical composition according to clause 38 or 39. 43. The method of clause 42, wherein the method comprises treating or reducing the severity of neuropathic pain in a subject. 44. The method according to clause 43, wherein the neuropathic pain comprises postherpetic neuralgia. 45. The method of clause 43, wherein the neuropathic pain comprises small fiber neuropathy. 46. ​​The method of claim 43, wherein the neuropathic pain comprises idiopathic small fiber neuropathy. 47. The method according to clause 43, wherein the neuropathic pain includes diabetic neuropathy. 48. The method according to clause 42, wherein the diabetic neuropathy includes diabetic peripheral neuropathy. 49. The method of clause 42, wherein the method comprises treating or reducing the severity of musculoskeletal pain in a subject. 50. The method according to clause 49, wherein the musculoskeletal pain comprises osteoarthritis pain. 51. The method of clause 42, wherein the method comprises treating or reducing the severity of acute pain in a subject. 52. The method of claim 51, wherein the acute pain comprises acute post-operative pain. 53. The method of clause 42, wherein the method comprises treating or reducing the severity of post-operative pain in a subject. 54. The method of claim 53, wherein the postoperative pain comprises bunionectomy pain. 55. The method according to clause 53, wherein the postoperative pain comprises abdominoplasty pain. 56. The method according to clause 53, wherein the postoperative pain comprises herniorrhaphy pain. 57. The method of clause 42, wherein the method comprises treating or reducing the severity of visceral pain in a subject. 58. The method of any one of clauses 40-57, wherein the subject is treated with one or more additional therapeutic agents administered simultaneously with, prior to, or following treatment with the compound, pharma- ceutically acceptable salt, or pharmaceutical composition. 59. Use of a compound according to any one of clauses 1 to 36 or a pharma- ceutically acceptable salt thereof, a compound according to clause 33, or a pharmaceutical composition according to clause 38 or 39, as a medicament. EXAMPLES

[0197] Common methods 1 1 H NMR spectra were obtained as solutions in a suitable deuterated solvent such as dimethylsulfoxide-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 (2.1×5 mm, 1.7 μm particles) guard column (pn: 186003978) and a dual gradient run of 2 to 98% mobile phase B over 4.45 min. Mobile phase A=H2O (10 mM ammonium formate with 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 at room temperature in transmission mode 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 radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step.

[0200] Abbreviation Unless otherwise indicated, or unless otherwise dictated by context, the following abbreviations shall 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 h to a stirred suspension of NaH (10.8 g, 270.0 mmol) in dry THF (140.0 mL) at a rate to maintain a steady rate of gas evolution and an internal temperature below 40 °C. Upon complete addition, the mixture was heated at 60 °C overnight. 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 to confirm a pH of 1. The mixture was extracted with MTBE (3 x 100 mL, 5 volumes). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to give a brown oil which was used directly in the next step. The oil was solubilized in absolute EtOH (160 mL) and H2SO4 (1.4 mL, 26.26 mmol) was added. The reaction mixture was heated to reflux for 3 h. An additional 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 concentrated in vacuo (30 mbar and 35 °C) to give 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 concentrated in vacuo (250 mbar, 32 °C) to give ethyl (R)-5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (30.3 g, 83%) as a brown oil 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: Borane dimethylsulfide (20 mL of 2M, 40.00 mmol) was added dropwise over 3 min to a solution of (R)-ethyl 5-methyl-4-oxo-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (7.92 g, 33.25 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine (3.3 mL of a 1M solution in toluene, 3.30 mmol) in THF (150 mL). The reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched by the addition of 1M HCl solution and diluted with MTBE (150 mL). The mixture was separated and the aqueous phase was extracted with MTBE (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was passed through a plug of silica (50 g), washed with MTBE (250 mL), and the filtrate was purified by flash chromatography (120 g SiO, 0 to 100% MTBE in hexanes) to give ethyl (4S,5R)-4-hydroxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (4.7 g, 59%). 1 H NMR (500 MHz, chloroform-d) δ 6.00 (dd, J = 2.8, 0.7 Hz, 1H), 4.85 (d, J = 2.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.54 (q, J = 1.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm; no alcohol OH observed. ESI-MS m / z calculated 240.06094, found 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 trimethyloxinium tetrafluoroborate (30 g, 202.8 mmol) were added successively to a solution of ethyl (4S,5R)-4-hydroxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (16.2 g, 67.45 mmol) in DCM (300 mL). The reaction mixture was stirred at ambient temperature in the dark 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. Purification by flash chromatography (SiO2, 0 to 50% MTBE in hexanes) gave ethyl (4S,5R)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (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 to a stirred solution of ethyl (4S,5R)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (19.6 g, 64.00 mmol) in MeCN (200 mL) under nitrogen. The reaction was heated to 100° C. for 24 h. The reaction mixture was cooled to ambient temperature and quenched by the addition of saturated aqueous Na2S2O3 (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), brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from EtOAc to give ethyl (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (6 g) as pale yellow needles. The mother liquor, still containing the product, was purified by flash chromatography (220 g SiO2, 0 to 30% MTBE in hexanes) to give an additional 6.8 g of product. A total of 12.8 g (53%) of ethyl (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 ethyl (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (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 a 2M aqueous solution, 50.00 mmol) in 1,4-dioxane (150 mL) was heated at 50° C. for 2 h, 70° C. for 2 h, and then at 100° C. (reflux) for 16 h. The reaction mixture was cooled to ambient temperature, acidified to pH 1, and partitioned between water (150 mL) and EtOAc (300 mL). The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was diluted with EtOH (100 mL) and H2SO4 (900 μL, 16.88 mmol) was added. The mixture was heated at reflux for 3 h. Purification by flash chromatography (SiO2, 0 to 35% EtOAc in heptane) afforded ethyl (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.3 g, 53%). ESI-MS m / z calculated 396.0996, found 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 (330 mg, 0.83 mmol) in EtOH (15 mL) was circulated through an H-cube fitted with a Pd / C cartridge for 3.5 h. The reaction was carried out at 100° C. and 80 bar hydrogen with a flow rate of 0.5 mL / min. The resulting solution was concentrated in vacuo to give ethyl (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (304 mg, 92%) as a crystalline solid. 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, actual value 399.6(M+1) + ;Holding time: 0.99 minutes.

[0207] Step 8: KOt-Bu (3.0 g, 26.74 mmol) was added to a solution of ethyl (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (3.4 g, 7.60 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min. The solution was acidified to pH 1 by adding 1 M HCl (50 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to give (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.81 g, 100%) as a pale yellow oil which was used in the next step without further purification. ESI-MS m / z calculated 370.08395, found 369.7 (M-1). - ;Retention 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 EtOAc, 180 μL, 0.80 mmol) in isopropyl acetate (2 mL) was stirred at 120° C. for 1 h in a sealed vessel. The reaction mixture was cooled to ambient temperature. The suspension was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 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 504.132, found 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 methanolic ammonia (10 mL of 7 M, 70.00 mmol) and MeOH (10 mL) was stirred at ambient temperature for 2.5 days. An additional amount of methanolic ammonia (10 mL of 7 M, 70.00 mmol) was added and the reaction was stirred at ambient temperature for an additional 24 h. The mixture was concentrated in vacuo. Purification by chiral SFC using a Daicel (R,R)-Whelk-O1 column, 5 μm particle size, 25 cm×21.1 mm (gradient of 15% to 22% MeOH in 6 min, 85 mg / ml, 35 mg, then ramped to 40% MeOH; 20 mM ammonia) on a Berger Instruments Minigram SFC instrument gave 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 made using the methods described in Example 1, except that step 4 was not required. For compound 2, the conditions used for amide coupling step 9 were those used in step 11 of Example 2. For compound 3, pyridazin-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 compound was made 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, pyridazin-4-amine was used as the coupling partner. Step 10 was not required. [Table 4]

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

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

[0214] The following compound was made 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)pyridin-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 made using the method described in Example 1, except that the Suzuki coupling step 6 was carried out in a 10:1 mixture of 1,4-dioxane and water as solvent using (3,4-difluoro-2-methylphenyl)boronic acid as the coupling partner, Pd(dppf)Cl2·DCM as catalyst and K3PO4 as base at 50 °C for 50 min. The hydrogenation step 7 was carried out in the presence of Pearlman's catalyst in ethanol as solvent using 19 bar of hydrogen for 48 h. The conditions used for the amide coupling step 9 were 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 to a stirred solution of (S)-ethyl 2-hydroxypropanoate (10 mL, 88.2 mmol) in DCM (45 mL) at 0° C. The mixture was warmed to ambient temperature and stirred for 20 h. The mixture was quenched with saturated NaHCO3 solution (40 mL) and extracted with DCM. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography afforded (S)-ethyl 2-acetoxypropanoate (13.6 g, 96%). 1 H NMR (400 MHz, chloroform-d) δ 5.06 (q, J = 7.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.13 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm.

[0217] Step 2: A solution of (S)-ethyl 2-acetoxypropanoate (13.6 g, 84.91 mmol) in THF (400 mL) was added over 30 min at -78 °C to a stirred solution of LiHMDS (204 mL of 1 M in THF, 204.0 mmol) in THF (400 mL). The mixture was stirred at this temperature for 90 min and then poured into 2 M aqueous HCl (30 mL). The layers were separated. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine. The organic layer was concentrated in vacuo, redissolved in DCM, dried (Na2SO4), filtered and concentrated in vacuo to give (S)-4-hydroxy-5-methylfuran-2(5H)-one (8 g, 83%) as a solid, 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 give (S)-3-bromo-4-hydroxy-5-methylfuran-2(5H)-one (11.15 g, 85%). 1 H NMR (500MHz, DMSO-d6) δ 4.99 (q, J = 6.8Hz, 1H), 1.40 (d, J = 6.8Hz, 3H) ppm; no alcohol OH observed.

[0219] Step 4: Triflic anhydride (7.8 mL of 1 M in DCM, 7.80 mmol) was added to a stirred solution of TPPO (4.5 g, 16.2 mmol) in DCM (27 mL) at 0° C. After stirring for 15 min, 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) was added dropwise, followed by DIPEA (1.7 mL, 9.76 mmol). The reaction was allowed to warm to ambient temperature and stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOH (50 mL) and dichlorozinc (3.6 mL, 38.81 mmol) was added. The mixture was stirred for 2 h. The precipitate was filtered off and the filtrate was concentrated in vacuo to give (S)-3-bromo-4-methoxy-5-methylfuran-2(5H)-one (1.55 g, 96%). 1 H 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-methoxy-phenyl)boronic acid (926 mg, 4.93 mmol), and tetrakis(triphenylphosphine)palladium (715 mg, 0.62 mmol) were added successively 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 to 80 °C for 2 h. The reaction mixture was cooled to ambient temperature, quenched with saturated NH4Cl solution (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography gave (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 dichloride hexahydrate (510 mg, 2.15 mmol) and NaBH4 (406 mg, 10.73 mmol) were added successively 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) at -40 °C. The resulting mixture was stirred for 15 min. The mixture was quenched by adding saturated aqueous NH4Cl (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 concentrated in vacuo to give (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 (2.5 mL of 1M, 2.500 mmol) was added 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) at -78°C. After stirring for 1 h at -78°C, an additional amount of DIBAL (2.5 mL of 1M, 2.500 mmol) was added. Upon completion of the reaction, the mixture was quenched by adding saturated aqueous ammonium chloride solution (4 mL) and Rochelle's salt solution (30% w / w, 4 mL). The mixture was stirred for 1 h. The layers were separated and the aqueous phase was extracted with DCM (10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give (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 274.10165, found 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 added successively 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) at ambient temperature. Upon completion of the reaction, the mixture was quenched by adding saturated aqueous sodium bicarbonate (6 mL). The mixture was stirred at ambient temperature for 30 min. 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 in vacuo. Purification by flash chromatography gave (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 C2. ESI-MS m / z calculated 316.11224, found 258.5 (M-OAc). +;Retention time: 2.94 minutes.

[0224] Step 9: TMSCN (280 μL, 2.10 mmol) and BF3.OEt2 (330 μL of 46.5% w / w, 1.24 mmol) were added dropwise in succession 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 min and then warmed to ambient temperature. The mixture was quenched with saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with DCM (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting oil was dissolved in DCM and filtered through a pad of Celite. The liquor was concentrated in vacuo. The residue was dissolved in sodium methoxide solution (2.5 mL of 0.5 M in MeOH, 1.250 mmol) and stirred at ambient temperature overnight. The reaction was quenched by adding saturated aqueous citric acid. The mixture was stirred for 30 min. After complete hydrolysis, the reaction mixture was concentrated in vacuo and the residue was dissolved in DCM. The solution was washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give methyl (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylate (260 mg, 100%) as the major 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 to a stirred solution of methyl (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxylate (260 mg, 0.82 mmol) in THF (3.2 mL) at ambient temperature. Upon completion of the reaction, the reaction was quenched by adding saturated aqueous ammonium chloride (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 x 10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give (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 H NMR (500 MHz, chloroform-d) δ 7.14 (ddd, J = 8.5, 5.8, 2.3 Hz, 1H), 6.83 (td, J = 9.3, 7.5 Hz, 1H), 4.70 (d, J = 10.3 Hz, 1H), 4.37 (qd, J = 6.3, 3.0 Hz, 1H), 3.92 (dd, J = 10.3, 4.3 Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 3.62 (dd, J = 4.3, 3.0 Hz, 1H), 2.96 (s, 3H), 1.29 (d, J = 6.3 Hz, 3H) ppm; no acid OH observed. ESI-MS m / z calcd 302.0966, found 301.4 (M-1). - ;Holding time: 1.51 minutes.

[0226] Steps 11 and 12: Oxalyl chloride (35 μL, 0.40 mmol) was added 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) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 30 min and concentrated in vacuo. The residue, redissolved in DCM (300 μL), was added to a stirred solution of methyl 4-aminopyridine-2-carboxylate (35 mg, 0.23 mmol) and NEt3 (35 μL, 0.25 mmol) in DCM (300 μL) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 2 h. The mixture was quenched by the addition of water and MeOH (2 mL) dropwise and concentrated in vacuo. Purification by flash chromatography gave 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamido)methyl picolinate (55 mg, 69%). ESI-MS m / z calculated 436.1446, found 437.3 (M+1). + ;435.4(M-1) - ;Retention time: 2.77 minutes.

[0227] Methyl 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)picolinate (55 mg, 0.126 mmol) was dissolved in methanolic ammonia (5 mL of 7 M, 35.00 mmol) and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyltetrahydrofuran-2-carboxamide)picolinamide (8, 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 made using the method described in Example 2, except that different coupling partners were used in the amide coupling step 11, and in the case of compound 9, rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (intermediate D, first eluting peak from chiral SFC separation) was used as the coupling partner in the amide coupling step 11. In the case of compound 10, rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (intermediate E, second eluting peak from chiral SFC separation) was used as the coupling partner in the amide coupling step 11. Step 12 was replaced with a deprotection step using excess TFA in DCM as the solvent. [Table 8]

[0229] The following compounds were made using the method described in Example 2, except that rac-2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)pyridin-4-amine was used as the coupling partner in the amide coupling step 11. Step 12 was not required. 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 made using the method described in Example 2, except that ethanol was used instead of methanol in Hendrickson O-alkylation step 4 and the second step using ZnCl in EtOH was not required. [Table 10]

[0231] The following compounds were made using the method described in Example 2, except that isopropanol was used instead of methanol in Hendrickson O-alkylation step 4, and the second step using ZnCl2 in EtOH was not necessary. For compound 15, methyl 5-aminopicolinate was used as the coupling partner in the amide coupling step 11. [Table 11]

[0232] The following compounds were made using the method described in Example 2, except that isopropanol was used instead of methanol in Hendrickson's O-alkylation step 4, and the second step using ZnCl2 in EtOH was not necessary. For compound 16, (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (Intermediate C) was used as the coupling partner in the amide coupling step 11. For compound 17, 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine was used as the coupling partner in the amide coupling step 11. In both cases, step 12 was replaced by a deprotection step carried out at 40-45° C. using excess 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 added successively to a stirred solution of ethyl 2-hydroxy-2-methylpropanoate (25 g, 189.17 mmol) in DCM (125 mL) at ambient temperature. The reaction mixture was stirred for 16 h at ambient temperature. The reaction 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 extracts were washed with aqueous CuSO4 (200 mL) and water (250 mL), dried (MgSO4), filtered, and concentrated in vacuo to give ethyl 2-acetoxy-2-methylpropanoate (25 g, 76%) as a light green oil. 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 mL of 1 M in THF, 200.00 mmol) was added dropwise over 20 min at a rate that kept the mixture below -60°C. The mixture was stirred at 0°C for 30 min. The reaction was quenched by adding water (250 mL) and the mixture was allowed to warm to ambient temperature. The mixture was acidified to pH approx. 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 in vacuo to give 4-hydroxy-5,5-dimethylfuran-2(5H)-one (12 g, 74%) as an orange solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 4.79 (s, 1H), 1.37 (s, 6H) ppm. ESI-MS m / z calculated 128.0473, found 129.1 (M+1) + ;Holding time: 0.70 minutes.

[0235] Step 3: NBS (25 g, 140.46 mmol) was added to a stirred solution of 4-hydroxy-5,5-dimethylfuran-2(5H)-one (12 g, 85.47 mmol) in acetonitrile (480 mL) at ambient temperature. The reaction mixture was stirred for 16 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (SiO2, 20% EtOAc in hexanes) afforded 3-bromo-4-hydroxy-5,5-dimethylfuran-2(5H)-one (9 g, 51%) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ 1.48 (s, 6H) ppm; no alcohol OH observed.

[0236] Step 4: K2CO3 (18.5 g, 133.86 mmol) and Me2SO4 (15.295 g, 11.5 mL, 121.26 mmol) were added sequentially 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 at ambient temperature under argon for 16 h. The mixture was partitioned between water (100 mL) and EtOAc (500 mL). The organic layer was collected and concentrated in vacuo. Purification by flash chromatography (SiO2, 4% EtOAc in hexanes) afforded 3-bromo-4-hydroxy-5,5-dimethylfuran-2(5H)-one (11 g, 93%) as a white solid. 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 min. PdCl2(dtbpf) (2 g, 3.07 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. The mixture was filtered through a pad of Celite. The filtrate was partitioned with water (200 mL). The layers were separated and the aqueous phase was extracted with EtOAc (500 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 4% EtOAc in hexanes) afforded 3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethylfuran-2(5H)-one (7.13 g, 79%) as an off-white solid. 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 dichloride hexahydrate (3.7 g, 15.57 mmol) and NaBH4 (3 g, 79.30 mmol) were added successively 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) at -40 °C. The resulting mixture was stirred for 5 min, after which additional amounts of both nickel dichloride 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 x 50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a mixture of stereoisomers with rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyldihydrofuran-2(3H)-one (4.4 g, 99%) as the major 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 to a stirred solution of a mixture 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) at −78° C. Upon completion of the reaction, the mixture was quenched by adding saturated aqueous ammonium chloride and Rochelle's salt solution (30% w / w) (30 mL each). The mixture was stirred for 1 h. The layers were separated and the aqueous phase was extracted with DCM (2×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyldihydrofuran-2-ol (4.3 g, 97%) as a crystalline solid and a mixture of stereoisomers which was used in the next step without further purification. ESI-MS m / z calculated 288.1173, found 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 added successively 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) at ambient temperature. The reaction mixture was stirred for 16 h and then quenched by the addition of saturated aqueous sodium bicarbonate (30 mL). The mixture was stirred at ambient temperature for 30 min. The layers were separated and the aqueous phase was extracted with DCM (20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography afforded a mixture of stereoisomers of rac-(3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-yl acetate (3 g, 61%), which was used directly in the next step. ESI-MS m / z calculated 330.12787, found 271.4 (M-OAc).+ ;Holding time: 3.14 minutes.

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

[0242] Step 10: Potassium tert-butoxide (4 g, 35.65 mmol) was added to a stirred solution of a mixture of stereoisomers of methyl rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylate (2.95 g, 8.93 mmol) in THF (35 mL) at ambient temperature. 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 x 20 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give rac-(2R,3R,4S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5,5-dimethyltetrahydrofuran-2-carboxylic acid (2 g, 71%) as a mixture of stereoisomers, which was used directly in the next step. ESI-MS m / z calculated 316.11224, found 315.4 (M-1). - ;Retention time: 1.68 minutes.

[0243] Steps 11, 12, and 13: Oxalyl chloride (60 μL, 0.69 mmol) was added to a stirred solution of a mixture 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) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 30 min and concentrated in vacuo. The residue, redissolved in DCM (600 μL), was added 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) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 2 h. The mixture was quenched by the addition of saturated aqueous NH4Cl. The aqueous layer was separated and extracted with DCM (2 x 5 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography afforded 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 450.16025, found 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 methanolic ammonia (5 mL of 7 M, 35.00 mmol) and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give 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 Phenomenex, Inc. Lux i-Cellulose-5 column, 5 μm particle size, 25 cm×10 mm on a Berger Instruments Minigram SFC instrument (25% MeOH, 20 mM NH, 245 nm, 100 bar).

[0246] First eluting 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 H 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 eluting 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%). 1H 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 compound was made using the method described in Example 3, except that rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (Intermediate D, first eluting peak from chiral SFC separation) was used as the coupling partner in amide coupling step 11. Step 12 was not required. Chiral SFC separation step 13 was performed using a Daicel Chiralpak IC column, 5 μm particle size, 25 cm×20 mm on a Waters Prep-100 SFC instrument (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 FIG. 2).

[0250] The following compound was made using the method described in Example 3, except that rel-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-4-amine (second eluting peak from chiral SFC separation) was used as the coupling partner in amide coupling step 11. Step 12 was not required. Chiral SFC separation step 13 was performed using a Daicel Chiralpak ID column, 5 μm particle size, 25 cm×10 mm on a Berger Instruments Minigram SFC instrument (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), ethyl 2-bromoacetate (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 to 100 °C for 20 h. The reaction was quenched by adding water (50 mL). The mixture was diluted with EtOAc (50 mL). The phases were separated. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography gave ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate (10 g, 74%) with approximately 75% purity. ESI-MS m / z calculated 230.07545, observed 230.8 (M+1) + ;Retention time: 2.89 minutes.

[0252] Step 2: LiOH (20 mL of 2M, 40.00 mmol) was added to a stirred solution of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate (4 g, 17.38 mmol) in THF (50 mL) at room temperature. 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 in vacuo to give 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (3.5 g, 100%) as a white solid. 1 H NMR (500 MHz, chloroform-d) δ 6.90 (ddd, J = 8.7, 5.8, 2.1 Hz, 1H), 6.83 (ddd, J = 9.6, 8.7, 7.1 Hz, 1H), 3.99 (d, J = 2.4 Hz, 3H), 3.64 (s, 2H) ppm; no acid OH observed. ESI-MS m / z calculated 202.04414, found 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 to reflux for 3 h. The mixture was concentrated in vacuo. The residue was dissolved with Et2O. The mixture was washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 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 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) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 1 h. The mixture was concentrated in vacuo. The residue was taken up in DCM (10 mL) and added to an ice-cold solution of (S)-methyl 2-hydroxy-3-methylbutanoate (4.9 g, 37.08 mmol) in DCM (10 mL). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by the addition of 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, concentrated in vacuo, and purified by flash chromatography to give methyl (S)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3-methylbutanoate (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)-methyl 2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3-methylbutanoate (2.7 g, 8.536 mmol) in THF (75 mL) was added over 30 min at −78° C. to a stirred solution of LiHMDS (22 mL of 1 M in THF, 22.00 mmol) in THF (75 mL). The mixture was stirred at −78° C. for 90 min. 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 EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give (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 284.08603, observed 284.8 (M+1) + ;283.0(M-1) - ;Holding time: 1.20 minutes.

[0256] Step 5: Triflic anhydride (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 min, 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) was added dropwise followed by DIPEA (1.9 mL, 10.91 mmol). The reaction was allowed to warm to ambient temperature and stirred for 20 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography gave (S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxyfuran-2(5H)-one (1.1 g, 44%). ESI-MS m / z calculated 298.10165, found 298.9 (M+1). + ;296.8(M-1) - ;Holding time: 3.05 minutes.

[0257] Step 6: Nickel dichloride hexahydrate (530 mg, 2.230 mmol) and NaBH4 (420 mg, 11.10 mmol) were added successively 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) at -40 °C. This procedure was repeated until the starting material was completely consumed. A total of 3 equivalents of NiCl2.6H2O were added. Upon completion, the reaction mixture was quenched by adding saturated ammonium chloride solution. The mixture was diluted with DCM and the phases were separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give (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's salt solution (30% w / w). The resulting mixture was vigorously stirred at ambient temperature until a clear phase separation was observed. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo to give (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: 302.13297, found: 285.9 (M-OH) + ;Retention time: 2.88 minutes.

[0259] Step 8: Acetic anhydride (500 μL, 5.299 mmol) was added 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) at room temperature. 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 (MgSO4) and concentrated in vacuo. Purification by flash chromatography gave (3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-yl acetate (180 mg, 40%). ESI-MS m / z calculated: 344.14352, found: 285.9 (M-OAc) + ;Holding time: 3.43 minutes.

[0260] Step 9: TMSCN (180 μL, 1.350 mmol) and BF3.OEt2 (200 μL, 1.621 mmol) were added dropwise successively 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 min and allowed to warm to ambient temperature. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with DCM (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and filtered through a pad of Celite. The solution was concentrated in vacuo. The residue was dissolved in sodium methoxide solution (1.6 mL of 0.5 M in MeOH, 0.8000 mmol) and stirred at ambient temperature under nitrogen overnight. 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 (MgSO4), filtered and concentrated in vacuo to give methyl (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylate (150 mg, 83%), which was used in the next step without further purification. ESI-MS m / z calculated 344.14352, found 334.9 (M+1). + ;Holding time: 3.35 minutes.

[0261] Step 10: Potassium tert-butoxide (200 mg, 1.782 mmol) was added to a stirred solution of methyl (2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxylate (150 mg, 0.4356 mmol) in THF (2 mL) at ambient temperature. 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 x 10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give (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 330.12787, found 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 DCM (1.2 mL) cooled in an ice bath. The mixture was stirred and allowed to warm to ambient temperature over 30 min. The reaction mixture was concentrated in vacuo. The solid was dissolved in DCM (700 μL) and the fresh solution was added to an ice-cold 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 allowed to warm to ambient temperature over 2 h. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (2 mL) and extracted with DCM (2 x 5 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography gave methyl 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamido)picolinate. ESI-MS m / z calculated 464.1759, found 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)picolinate was dissolved in methanolic ammonia (12 mL, 7 M solution in MeOH, 84.00 mmol) and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give 4-((2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-isopropyl-4-methoxytetrahydrofuran-2-carboxamide)picolinamide (24, 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 charged with tetrahydrofuran (330 mL) and zinc dust (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 in one portion and the reaction mixture was heated to 60 °C for 1 h, with the zinc dust being primarily 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 min, maintaining the internal temperature at 65-68 °C. The temperature was maintained at 67-68 °C for 1 h. The reaction mixture was cooled to 40 °C and sparged with nitrogen for 10 min. The temperature dropped to 31.5 °C during sparging. The reaction mixture was warmed to 40° C. and additional degassed tetrahydrofuran (125 mL) 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 tetrahydrofuran (20 mL) was added over 12 min, keeping the internal temperature below 70.5° C. The internal temperature was maintained at 68° C. After 90 min, the reaction mixture was cooled to 15° C. and stirred overnight.

[0265] The reaction mixture was cooled to 0° C. and 6N HCl solution (500 mL, 10 vol) was added, keeping the internal temperature below 15° C. The reaction mixture was heated to 55° C. and stirred for 80 min. The reaction mixture was then cooled to ambient temperature. Heptane (500 mL) was added and the mixture was filtered over a pad of celite and rinsed with heptane (300 mL, 6 vol) and MTBE (300 mL, 6 vol). The aqueous phase was extracted with MTBE (3×500 mL, 30 vol). The organic extracts were combined, washed with 1M sulfuric acid (500 mL, 10 vol) and brine (250 mL, 5 vol), dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in MTBE (300 mL, 6 vol) 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 12 M hydrochloric acid (150 mL, 3 volumes). The aqueous layer was extracted with MTBE (250 mL, then 150 mL). The organic extracts were combined, washed with 15% aqueous sodium chloride (200 mL, 4 volumes), dried (Na2SO4), and filtered. Activated charcoal (5 g) was added to the solution, which was refluxed for 3 hours. The mixture was cooled to ambient temperature overnight. The mixture was filtered and concentrated in vacuo to give 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (39.55 g, 85%) as a tan solid, 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 h. MeOH was evaporated. The remaining mixture was poured into ice-cold water and extracted twice with DCM. The combined organic extracts were washed with saturated NaHCO3 solution, dried (MgSO4), filtered and concentrated in vacuo to give (R)-methyl 3,3,3-trifluoro-2-hydroxy-2-methylpropionate (28.7 g, 88%). 1 H 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 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) at 0° C. The solution was warmed to ambient temperature and stirred for 1 h. The mixture was concentrated in vacuo. The residue was taken up in DCM (10 mL) and added to an ice-cold solution of (R)-methyl 3,3,3-trifluoro-2-hydroxy-2-methylpropionate (4.4 g, 25.57 mmol) and triethylamine (7.8 mL, 55.96 mmol) in DCM (10 mL). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by the addition of 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 extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography afforded methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (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)-methyl 2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (1.48 g, 4.154 mmol) in THF (20 mL) was added to a solution of LiHMDS (10 mL of 1 M in THF, 10.00 mmol) in THF (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 5 h. The solution was quenched by pouring the contents into a 2M HCl solution. The mixture was diluted with EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 100% EtOAc in heptane) afforded (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one (950 mg, 71%) as a yellow oil. 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 min to a mixture of DCC (2.71 g, 13.13 mmol) and CuCl (42 mg, 0.4242 mmol) cooled to 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h. The ice bath was removed and the reaction mixture was stirred at ambient temperature for an additional 23 h. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 100% EtOAc in heptane) afforded 1,3-dicyclohexyl-2-ethylisourea (2.1 g, 63%) as a colorless oil. 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 at 85° C. overnight. The white precipitate was filtered off. The mother liquor was concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 40% EtOAc in heptane) gave (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 dichloride hexahydrate (65 mg, 0.274 mmol) and NaBH4 (53 mg, 1.401 mmol) were added sequentially 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) at −40° C. The resulting mixture was stirred for 15 min at −40° C. Additional amounts of both NiCl2.6H2O and NaBH4 were added until the reaction was complete. 19 Addition was continued until F NMR indicated that approximately 85% conversion had been reached. The reaction mixture was quenched by addition of saturated NH4Cl solution. The mixture was diluted with EtOAc and the phases were separated. The aqueous phase was extracted twice with EtOAc. The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give 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 major 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, 1M in toluene solution, 0.900 mmol) was added dropwise 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)dihydrofuran-2(3H)-one (260 mg, 0.734 mmol) in DCM (9 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 h. The mixture was quenched by adding saturated ammonium chloride solution and Rochelle's salt solution (30% w / w) (3 mL each). The mixture was diluted with DCM. The aqueous phase was separated and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 30% EtOAc in heptane) afforded (3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (135 mg, 52%) as the major 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 added successively 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 complete conversion, the reaction 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 dilute HCl solution, dried (MgSO4), filtered and concentrated in vacuo to give 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 398.11526, found 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 added dropwise in succession 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) at −78° C. The mixture was stirred at −78° C. for 15 min and then allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 30 min. The mixture was quenched by the addition of 2 M sodium carbonate solution (10 mL). The aqueous phase was separated and extracted with DCM (3×approximately 5 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in sodium methoxide solution (7.5 mL of 0.5 M in methanol, 3.750 mmol) and stirred at ambient temperature for 2 h. The reaction was quenched by adding saturated NH4Cl solution. The mixture was diluted with EtOAc and water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 0 to 50% EtOAc in heptane) afforded methyl (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbimidate (69 mg, 46%) as the major diastereoisomer. 1 H NMR (400MHz, 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 of 2M aqueous solution, 2.000 mmol) was added to a solution of methyl (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbimide (55 mg, 0.138 mmol) in THF (3 mL). The reaction mixture was stirred at 70° C. for 2 h. An additional amount of 2M LiOH solution (1 ml) was added and the reaction mixture was stirred at 80° C. over the weekend. Another 1 ml of 2M LiOH was added and the reaction was heated at 100° C. for 5 h. The mixture was acidified with 1M HCl solution. The resulting solution was partitioned between water and EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give 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 major 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 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) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 90 min. The mixture was concentrated in vacuo. 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 added successively to the reaction mixture. The reaction was stirred for 2 h before being quenched by the addition of MeOH. The mixture was concentrated in vacuo. Purification by flash chromatography (4 g SiO2, 0 to 100% EtOAc in heptane) gave methyl 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)picolinate (10 mg, 19%) as the major diastereoisomer. ESI-MS m / z calculated 518.14764, found 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 methanolic ammonia (1 mL of a 7 M solution in MeOH, 7.000 mmol) and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo. Purification by reverse phase HPLC (MeCN in HO with 0.1% ammonium hydroxide, 19 ml / min column dilution + 1 ml / min MeCN) using a Waters X-bridge C18 column (150 x 19 mm, 5 μm particle size) gave 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 H NMR (400 MHz, methanol-d4) δ 8.47 (dd, J = 5.5, 0.6 Hz, 1H), 8.23 ​​(dd, J = 2.1, 0.7 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.29 (ddd, J = 8.5, 5.7, 2.3 Hz, 1H), 7.01 (ddd, J = 9.9, 8.9, 7.6 Hz, 1H), 5.06 (d, J = 11.3 Hz, 1H), 4.19 (dd, J = 11.3, 5.0 Hz, 1H), 4.07 (d, J = 5.1 Hz, 1H), 3.98 (d, J = 1.9 Hz, 3H), 3.38-3.33 (m, 1H), 2.97-2.85 (m, 1H), 1.61 (d, J = 1.1 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H) ppm; no amide NH or NH2 observed. ESI-MS m / z calculated 503.14795, found 504.2 (M+1). + ;502.2(M-1) - ;Retention 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 added slowly 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 portionwise over 2 h 10 min and the mixture was stirred for an additional 30 min. The mixture was warmed to 25°C. 2N HCl (500 ml) was added and the mixture was stirred for 15 min. The organic layer was separated and concentrated in vacuo, keeping the water bath at 15°C. Hexane (500 ml) was added to the residue and the mixture was stirred for 10 min. The mixture was filtered and the liquor was concentrated in vacuo, keeping the water bath at 15°C to give 6-bromo-3-fluoro-2-methylphenol (73 g, 90%) as a light brown oil. 1 H 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: To a stirred solution of 6-bromo-3-fluoro-2-methylphenol (40 g, 195.10 mmol) in acetone (400 mL) was added potassium carbonate (135 g, 976.80 mmol) at ambient temperature. The reaction mixture was stirred for 10 min at 25 °C. Methyl iodide (39 g, 17.105 mL, 274.77 mmol) was added dropwise over 10 min and the mixture was stirred for 16 h at 25 °C. 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 min. The solid was collected and washed with hexane (8 ml). The mother liquor was concentrated under reduced pressure at 15 °C. Purification by distillation (520 mmHg, 192-196 °C) gave 1-bromo-4-fluoro-2-methoxy-3-methylbenzene (32.4 g, 76%). 1 H 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 to a stirred mixture of Mg turnings (5 g, 205.72 mmol) in THF (50 mL) at 25° C. The mixture was stirred until the reaction turned a clear light yellow color. 1-Bromo-4-fluoro-2-methoxy-3-methylbenzene (2.5 g, 11.4 mmol) was added dropwise at ambient temperature. Once the initiation 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 min. 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 allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of 2N HCl (25 ml) and stirred for 15 minutes. The mixture was diluted with water (125 ml) and extracted with ethyl acetate (2 x 250 ml). The organic layer was separated, washed with water (250 mL), dried (Na2SO4) and concentrated in vacuo. 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 give (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)pyridin-3-amine and (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine [ka] Step 1: Cs2CO3 (100 g, 306.92 mmol) was added to a stirred solution of 2-chloro-5-nitro-pyridine (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 min. 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 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate (125 mL) and water (40 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 5 to 20% ethyl acetate in hexanes) gave 5-nitro-2-vinylpyridine (22 g, 90%) as a light brown solid. 1 H NMR (400 MHz, chloroform-d) δ 9.38 (s, 1H), 8.42 (dd, J = 2.1, 8.5 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.93-6.86 (m, 1H), 6.44 (d, J = 17.36 Hz, 1H), 5.74 (d, J = 10.8 Hz, 1H) ppm. ESI-MS m / z calculated 150.0429, found 151.0 (M+1). + ;Holding time: 1.59 minutes.

[0282] Step 2: NMO (104 mL of a 50% w / v aqueous solution, 443.89 mmol) and OsO4 (19 mL of a 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 for 3 h at ambient temperature. The acetone was removed in vacuo and the mixture was partitioned with ethyl acetate (150 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 20 to 80% ethyl acetate in hexanes) afforded rac-1-(5-nitropyridin-2-yl)ethane-1,2-diol (18 g, 67%) as an off-white solid. 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-nitropyridin-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 h. The reaction mixture was quenched with a solution of NaHCO3 (7 mL). The mixture was concentrated in vacuo and ethyl acetate (50 mL) was added. The mixture was dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (SiO2, 5 to 10% ethyl acetate in hexanes) afforded rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (300 mg, 83%) as an off-white solid. 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 wt% loaded, 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 min and stirred under a balloon atmosphere of hydrogen for 6 h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give rac-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (1.7 g, 98%) as a pale yellow gum. 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)pyridin-3-amine (9 g, 46.34 mmol) were separated by using a Chiralpak IB column from Daicel, 5 μm particle size, 25 cm×20 mm on a Waters Prep-100 SFC instrument.

[0286] First eluting isomer (retention time = 0.90 min): (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-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 eluting isomer (retention time = 1.09 min): (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-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, except that 2-chloro-4-nitropyridine was used as the starting material. In step 4, a 1:1 mixture of EtOAc 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 EtOAc and EtOH was used as the solvent. Step 5 was not performed. [Table 16]

[0290] intermediate G 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine [ka] Step 1: Lithium aluminum hydride (120 mL of 2M, 240.00 mmol) was added to a stirred suspension of methyl 5-aminopicolinate (21.05 g, 138.35 mmol) in dry THF (400 mL) under argon at 0° C. The suspension was stirred overnight at ambient temperature and then heated at 90° C. for 6 h. The reaction was left at room temperature for 30 h after which it was cooled back down to 0° C. The reaction was quenched by sequentially adding water (9.3 mL, dropwise), 15% aqueous NaOH (9.3 mL), and then more water (28 mL). The white precipitate was filtered off, washing with additional THF (300 mL). The filtrate was concentrated in vacuo to give (5-aminopyridin-2-yl)methanol (16.1 g, 75%) as a brown oil, which was used in the next step without further purification. 1 H 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 observed.

[0291] Step 2: Imidazole (1.97 g, 28.938 mmol) was added to a mixture of (5-aminopyridin-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 h. The THF layer was decanted and the oily lower phase 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 (Na2SO4), filtered and concentrated in vacuo. The oily residue (5.8 g) was taken up in a 1:1 mixture of ethyl acetate and heptane (30 mL). The precipitate was removed by filtration. The filtrate was concentrated in vacuo. Purification by flash chromatography (SiO2, 25-75% ethyl acetate in heptane) afforded 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine (3.92 g, 81%) as a low melting white solid. 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, actual 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 nitrogen, was charged 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 (3.4 L of 1.5 M in EtO, 5.1000 mol) was added slowly with gas evolution and heat formation. The reactor was cooled to maintain a temperature of approximately 16° C. Then, the methyllithium with lithium bromide ( 6.1Lの2.2MEt213.420 mol in O was added slowly. After a total of 2 equivalents had been added, gas evolution ceased and the rate of addition was reduced. The mixture was stirred overnight at ambient temperature. The reaction mixture was cooled to 0° C. and transferred to an extraction flask with 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 min. The aqueous phase was separated and extracted with diethyl ether (2×2.5 L). The combined organic layers were concentrated in vacuo to approximately 2 L. The distillate was yellow in color 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 in a distillation setup using a Vigreux (30 cm height) at atmospheric pressure. The distillation was continued at reduced pressure (770 mbar) and the pressure was gradually reduced (to 200 mbar) with a collection flask cooled in ice and a cold trap between the pump and the setup. Mixed fractions were 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 fractions were poured into brine and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated at normal pressure in a distillation setup. The product was distilled at reduced pressure (200 mbar) to give the product (198 g) as a colorless oil. The collected mixed fractions were redistilled to give further product (44.25 g). All portions of the product were combined (857 g) and dried by adding potassium carbonate (52 g) and left for 6 hours. The water level dropped below detectable levels and the mixture was filtered through a glass filter to give (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one (815 g, 83%) as a colorless oil (815 g). 1 H 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 (282MHz, chloroform-d) δ-77.96ppm.

[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 by applying an electric field. An electrical stimulation instrument, called E-VIPR, and methods of use are described in WO 2002 / 008748 A3 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 by reference in their entirety. The instrument comprises a microtiter plate handler, optics for exciting the coumarin dye while simultaneously recording coumarin and oxonol emission, a waveform generator, a current or voltage controlled amplifier, and a pair of parallel electrodes that are inserted into the assay plate wells. Under integrated computer control, the instrument delivers user-programmed electrical stimulation protocols to cells within the wells of the microtiter plate.

[0294] 16–20 h before performing the assay for E-VIPR, culture human NaCl with intact channel activity. VHEK cells expressing a truncated form of KIR2.1.8 were seeded in microtiter 384-well plates pre-coated with Matrigel at a density of 25,000 cells per well. 2.5-5% KIR2.1 Bacmam virus was added to the final cell suspension before seeding into the cell plates. HEK cells were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS (fetal bovine serum, qualified; 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 blasticidin (Gibco #R210-01). Cells were grown in vented cap 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 dry DMSO

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

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

[0299] 2.5-5% KIR 2.1 Bacmam virus (produced in-house), 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 contents of which are incorporated by reference. The concentration used may depend on the virus titer of each batch.

[0300] 5 mM DiSBAC6(3), voltage-sensitive oxonol receptor (CAS number 169211-44-3, 5-[3-(1,3-dihexylhexahydro-4,6-dioxo-2-thioxo-5-pyrimidinyl)-2-propen-1-ylidene]-1,3-dihexyldihydro-2-thioxo-4,6(1H,5H)-pyrimidinedione) in dry DMSO. The preparation of DiSBAC6(3) is similar to that 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] A commercially available membrane-bound coumarin lipid FRET donor, CC2-DMPE (ThermoFisher Scientific, Cat. No. K1017, CAS No. 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-phosphaoct-1-yl]-1,2-ethanediyl] ester), was prepared at 5 mM in dry DMSO. See also Improved Indicator of Cell Membrane Potential Using Fluorescence Resonance Energy Transfer, Gonzalez, JE and Tsien, RY (1997) Chem. Biol. 4, 269-277.

[0302] Prepare voltage assay background suppressing compound (VABSC-1) in HO (89-363 mM, range used to maintain solubility)

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

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

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

[0306] Hexyl dye solution (2x concentration): Bath 1 buffer containing 0.5% β-cyclodextrin (made fresh before each use, Sigma #C4767), 8 μM CC2-DMPE, and 2 μM DiSBAC6(3). The solution was made by adding 10% Pluronic® F127 stock in a volume equal to the combined volume of CC2-DMPE and DiSBAC6(3). The order of preparation was to first mix Pluronic® and CC2-DMPE, then add DiSBAC6(3), then add Bath 1 / β-cyclodextrin while mixing.

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

[0308] Assay protocol (7 critical steps): 1) 375 nL of each compound was pre-spotted (in pure DMSO) onto polypropylene compound plates at 240x the desired final concentration from an intermediate stock concentration of 0.075 mM in an 11-point dose response, 3-fold dilution to reach a final concentration in each well, resulting in the highest dose at 300 nM final concentration in the cell plate. A vehicle control (pure DMSO), and a positive control (established Na V 1.8 inhibitors (25 μM final in assay in DMSO) were manually added to the outermost column of each plate, respectively. The compound plate was back-loaded with 45 μL compound loading buffer per well, resulting in a 240-fold dilution of compound after 1:1 compound transfer to the cell plate (see step 6). The final DMSO concentration of all wells in the assay was 0.625% (for a final DMSO concentration of 0.625%, compound loading buffer was supplemented with 0.75% DMSO). This assay dilution protocol was adjusted to allow for testing of a higher dose range in the presence of HS or if the final assay volume was changed. 2) A hexyl dye solution was prepared. 3) Cell plates were prepared: On the day of the assay, the 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) 25 μL of the hexyl dye solution was dispensed per well into the cell plate. The cells were incubated in the dark at room temperature or ambient conditions for 20 minutes. 5) 45 μL per well of compound loading buffer was dispensed into the compound plate. 6) The cell plate was washed 3 times with 80 μL per well of Bath-1 buffer, 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 compounds were read on the E-VIPR using a current-controlled amplifier to deliver stimulus wave pulses using a symmetric biphasic waveform. The user-programmed electrical stimulation protocol was 1.25-4 amps with a 4 ms pulse width (depending on electrode composition) delivered at 10 Hz for 10 seconds. Pre-stimulus recordings were performed for 0.5 seconds for each well to obtain a non-stimulus intensity baseline. The stimulus waveform was followed by a 0.5 second post-stimulus recording to examine relaxation to the resting state. All E-VIPR responses were measured at an acquisition rate of 200 Hz.

[0309] Data Analysis: Data was analyzed and reported as a normalized ratio of emission intensities measured in the 460 nm and 580 nm channels. Responses as a function of time were reported as ratios obtained using the following formula:

number

[0310] The data is the initial (R i ) and the final (R f ) ratios. These were the average ratio values ​​between sample points during some or all of the pre-stimulation period and during the stimulation period. The fluorescence ratios (R f / R i ) was calculated and reported as a function of time.

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

number

[0312] Measured IC of less than 0.01 μM in the E-VIPR assay described above 50 Compounds having values ​​include 1, 4, 5, 7, 24, and 25.

[0313] Measured IC of less than 0.1 μM and greater than or equal to 0.01 μM in the E-VIPR assay described above 50 Compounds having values ​​include 6 and 18.

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

[0315] Measured IC of 1 μM or greater 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] An "*" following the compound number indicates that the assay was performed in the presence of human serum, as described above.

[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 the scope thereof. The specific embodiments described herein are provided for illustrative purposes only.

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein X ２ａ is N, N ＋ -O － or C-R ２ａ wherein 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 is N, N ＋ -O － 、C-R ４ａ 、C-CONR ２ 、or C-CH １－ｎ (R Ａ )(OH)(CH ２ OH) ｎ and X ５ａ is N, N ＋ -O － or C-R ５ａ wherein X ６ａ is N, N ＋ -O － or C-R ６ａ wherein Each R is independently H or C １ -C ６ is alkyl, n is 0 or 1, R Ａ is H or CH ３ and R ２ａ 、 R ３ａ 、 R ４ａ 、 R ５ａ 、 and R ６ａ are each independently H, halo, C １ -C ６ alkyl, or C １ -C ６ haloalkyl, and R ４ｂ１ and R ４ｂ２ one of which is OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and the other is H, R ５ｂ１ and R ５ｂ２ are each independently H, C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C １ -C ６ haloalkyl, and X ３ｃ is N or C—R ３ｃ wherein X ４ｃ is N or C—R ４ｃ and X ５ｃ is N or C—R ５ｃ wherein X ６ｃ is N or C—R ６ｃ and R ２ｃ is H, OH, halo, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -L １ -L ２ -(C ３ -C ６ cycloalkyl), where the cycloalkyl is optionally substituted with 1 to 2 halos, L １ is either a bond or O, L ２ is a linking or C １ -C ６ alkylene, R ３ｃ is H, halo, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, and 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 is H, halo, C １ -C ６ alkyl, C １ -C ６ haloalkyl, and However, X ２ａ X ３ａ X ４ａ X ５ａ and X ６ａ Among them, two or less 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 is X ３ｃ , X ４ｃ , X ５ｃ , and X ６ｃ A compound, or a pharmaceutically acceptable salt thereof, provided that one or less of them is N.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-A) 【Chemical 2】

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-A-1)

4. [Chemical 3] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-B)

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I-B-1) [Chemical Formula 4]

6.

7.

8. 【Chemical Formula 5】

9.

10. X ２ａ is C—R ２ａ and R ２ａ is H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. X ３ａ is 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.

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

13. X ４ａ is 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.

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

15. X ３ａ and X ４ａ one of which 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.

16. R ５ｂ１ is C １ -C ６ alkyl, optionally CH ３ , or C １ -C ６ haloalkyl, optionally CF ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C-C alkyl, optionally CH, or C-C haloalkyl, optionally CF.

17. R ５ｂ２ is C １ -C ６ alkyl, optionally CH ３ , or C １ -C ６ haloalkyl, optionally CF ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. R ２ｃ is OH, halo, optionally Cl, C １ -C ６ alkyl, optionally CH ３ , C １ -C ６ alkoxy, optionally OCH ３ , OCD ３ , OCH ２ CH ３ , OCH(CH ３ ), ２ , or C １ -C ６ haloalkoxy, optionally OCH ２ CH ２ F, or OCH ２ CHF ２ and is the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. R ３ｃ is halo, optionally F, or C １ -C ６ alkyl, optionally CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is as defined above.

20. R ４ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is halo and optionally F. A compound selected from, or a pharmaceutically acceptable salt thereof. R ５ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

22. R ６ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H. The compound according to any one of claims 1 to 21, in non-salt form. R ４ｂ２ is C １ -C ６ alkoxy, optionally OCH ２ CH ３ or OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is

23. R ４ｂ１ is C １ -C ６ alkoxy, optionally OCH ２ CH ３ or optionally OCH ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

21. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.

24. A pharmaceutical composition comprising the compound according to 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-dependent sodium channels in a subject, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

26.

27. A composition for use in a method of treating or reducing the severity of chronic pain, visceral 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 in a subject, the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

28. ​ wherein the voltage-dependent sodium channel is Na Ｖ The composition according to claim 25, wherein it is 1.

8. ​ ​ ​ The composition according to claim 27, wherein the method comprises treating one or more of neuropathic pain, musculoskeletal pain, optionally osteoarthritic pain, acute pain, optionally acute postoperative pain, postoperative pain, optionally pain after aponeurotomy, or optionally pain after abdominoplasty, or optionally pain after hernia suture, or visceral pain, or reducing the severity thereof in the subject.

29. The composition according to claim 28, wherein the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy, optionally diabetic peripheral neuropathy.

30. The composition according to claim 25, wherein the subject is treated with one or more additional therapeutic agents administered concomitantly with, prior to, or after treatment with the composition.

31. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

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