EA041031B1 - DEUTERATED PYRIDONAMIDES AND THEIR PRODRUGS AS SODIUM CHANNELS MODULATORS - Google Patents

Description

Cross-reference to related applications

This application claims priority under U.S. Provisional Application No. 62/507172, filed May 16, 2017, and U.S. Provisional Application No. 62/547,718, filed August 18, 2017, both of which are incorporated by reference in their entirety. completeness.

State of the art

Pain is a defense mechanism that allows healthy animals to avoid tissue damage and prevent further damage to damaged tissue. However, there are many conditions in which pain persists beyond its usefulness or where patients would benefit from pain suppression. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves. (Dieleman, J.P., 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 generalized metabolic nerve injury and pain caused by discrete nerve injury. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries include pain following amputation, post-surgical pain due to nerve injury, and injuries from nerve entrapment such as neuropathic back pain.

Voltage-gated sodium channels (NaV) are involved in the transmission of pain signals. NaVs are biological mediators of electrical signals because they provide a rapid increase in the action potential of many types of excitable cells (eg, neurons, skeletal myocytes, cardiomyocytes). Evidence for a role for these channels in normal physiology, pathological conditions resulting from mutations in sodium channel genes, preclinical studies in animal models, and the clinical pharmacology of known agents that modulate sodium channels all point to a central role for NaV in pain sensation (Rush, AM and TR Cummins, Painful Research: Identification of a Small Molecule Inhibitor that Selectively Targets Na _V 1.8 Sodium Channels, Mol Interv, 2007. 7(4), p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin Investig Drugs, 17(12), p. 1849-64 (2008); Krafte, DS and Bannon, AW, Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8(1), p. 50-56 (2008)). Na _V mediate a rapid increase in the action potential of many excitable cell types (eg, neurons, skeletal myocytes, cardiomyocytes) and thus are involved in the initiation of signaling in these cells. (Hille, Bertil, Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role of Na _V in the initiation and propagation of neural signals, antagonists that reduce NaV currents can prevent or reduce neural signals, and NaV channels are considered potential targets for pain reduction in conditions where there is hyperexcitability (Chahine, M., Chatelier, A., Babich, O., and Krupp, JJ, Voltage-gated sodium channels in neurological disorders, CNS Neurol Disord Drug Targets, 7(2), pp. 144-58 (2008)). Several clinically used analgesics have been identified as NaV channel inhibitors. Local anesthetics such as lidocaine block pain by inhibiting NaV channels, and other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective in reducing pain are also thought to act by inhibiting sodium channels (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action, Eur J. Pain 6 Suppl A, pp. 3-9 (2002); Wang, GK, Mitchell, J., and Wang, SY, Block of persistent late Na ⁺ currents by antidepressant sertraline and paroxetine J Membr Biol 222(2) pp 79-90 (2008)).

NaVs form a subfamily of the voltage-gated ion channel superfamily and include nine isoforms, designated Na _V 1.1-Na _V 1.9. Localizations of nine isoforms in tissues differ. Na _V 1.4 is the main skeletal muscle sodium channel and Na _V 1.5 is the main cardiomyocyte sodium channel. NaV 1.7, 1.8 and 1.9 are mainly localized in the peripheral nervous system, while Na _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 are similar, but differ in the specifics of their voltage-gated and kinetic properties (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)).

Since their discovery, Na _V 1.8 channels have been identified as potential targets for analgesia (Akopian, AN, L. Sivilotti, and JN Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 1996. 379(6562) , pp. 257-62). NaV1.8 has since been shown to be a sodium current carrier that maintains an action potential firing small neurons DRG (Blair, NT and B.P. 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). NaV1.8 is involved in spontaneous firing in damaged neurons, such as neurons like those that control neuropathic pain (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 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.

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Acad. sci. USA, 2007. 104(20), p. 8520-5; Joshi, SK, et al., Involvement of the TTX-resistant sodium channel Na _V 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain, 2006. 123(1-2), p. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na _V 1.8. Pain, 2002. 95(1-2), p. 143-52; Dong, XW, et al., Small interfering RNA-mediated selective knockdown of Na( _V )1.8 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., 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). Small DRG neurons expressing Na _V 1.8 include nociceptors involved in the transmission of pain signals. Na _V 1.8 mediates large amplitude action potentials in small dorsal root ganglion neurons (Blair, NT and B.P. 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), pp. 10277-90). NaV1.8 is required for fast repetitive action potentials in nociceptors and for spontaneous activity of damaged neurons (Choi, JS and SG Waxman, Physiological interactions between NaV1.7 and NaV1.8 sodium channels: a computer simulation study. J Neurophysiol. 106(6) , p. 3173-84 Renganathan, M., T. R. Cummins, and S. G. Waxman, Contribution of Na(V)1.8 sodium channels to action potential electrogenesis in DRG neurons, J Neurophysiol., 2001. 86(2), p. 629 -40 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), pp. 921-6). In depolarized or damaged DRG neurons, Na _V 1.8 appears to be the driving force behind 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), pp. 8245-50). In some animal models of pain, Na _V 1.8 mRNA expression levels have been shown to be increased in DRGs (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibers contributes to painful diabetic neuropathy in rats. Brain 135 (Pt 2), pp. 359-75 Strickland, IT, et al., Changes in the expression of Na _V 1.7, Na _V 1.8 and Na _V 1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain, Eur J. Pain, 2008. 12(5), pp. 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), pp. 61-6.

The main disadvantage of some of the known Na _V inhibitors is their poor therapeutic window, and this is probably a consequence of the lack of isoform selectivity. Since Na _V 1.8 is mainly restricted to neurons that sense pain, it is unlikely that selective Na _V 1.8 blockers will cause the side effects seen with non-selective Na _V blockers. Accordingly, there remains a need to develop additional NaV channel modulators, preferably those that are more potent and selective for Na _V 1.8, with increased metabolic stability, increased solubility, and fewer side effects.

A class of pyridonamide compounds that can be used as Na _V 1.8 sodium channel inhibitors has been described in International Publication No. WO 2014/120808 A9 and US Publication No. 2014/0213616 A1, and prodrugs of these compounds have been described in International Publication No. WO 2015/ 089361 A1 and US Publication No. 2015/0166589 A1, all of which are incorporated by reference in their entirety. These pyridonamide compounds overcome some of the shortcomings of previous Na _V 1.8 inhibitors, but further improvements can still be made.

The essence of the invention

In one aspect, the invention relates to a compound of formula I o or a pharmaceutically acceptable salt thereof, wherein R is H or CH2OPO(OH)2.

In another aspect, the invention relates to a compound of formula I which is

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or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound of formula I which is

In another aspect, the invention relates to a compound of formula I which is

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound of formula I which is

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

In yet another aspect, the invention relates to a method for inhibiting a voltage-gated sodium channel in a subject by administering a compound of Formula I, a pharmaceutically acceptable salt, or a pharmaceutical composition to the subject.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of various diseases, disorders or conditions in a subject, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., bursectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence, abnormal cough, and cardiac arrhythmia, by administering to the subject a compound of formula I, pharmaceutically acceptable salt or pharmaceutical composition.

Brief description of the figures

In FIG. 1 is a graph of the percentage of compounds 7 and 10 remaining over time when incubated in the presence of rat liver microsomes.

In FIG. 2 is a graph of the percentage of compounds 7 and 10 remaining over time when incubated in the presence of dog liver microsomes.

In FIG. 3 is a graph of the percentage of compounds 7 and 10 remaining over time when incubated in the presence of monkey liver microsomes.

In FIG. 4 is a graph of the percentage of compounds 7 and 10 remaining over time when incubated in the presence of human liver microsomes.

In FIG. 5 is a graph of the plasma concentration of compounds 7 and 10 remaining over time after intravenous administration to male Sprague Dawley rats.

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Detailed description

In one aspect, the invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein R is H or CH2OPO(OH)2.

In another aspect, the invention relates to a compound of formula I which is

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound of formula I which is

In another aspect, the invention relates to a compound of formula I which is

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound of formula I which is

The compound of formula I in which R is CH ₂ OPO(OH) ₂ and its pharmaceutically acceptable salts are prodrugs of the parent compound in which R is H.

As used herein, the term prodrug refers to compounds and salts that are drug precursors that, after administration and absorption, release the drug in vivo through a specific metabolic process. Typically, a prodrug has less biological activity than its parent drug. The prodrug may also improve the physical properties of the parent drug and/or may improve the overall efficacy of the drug, for example, by reducing drug toxicity and adverse effects by controlling drug absorption, blood levels, metabolic distribution, and cellular uptake.

As used herein, the term parent compound or parent drug substance refers to a biologically active substance that is released as a result of the enzymatic action of a metabolic or catabolic process or chemical process after administration of a prodrug. The parent compound may also be the starting material for the preparation of its corresponding prodrug.

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

As used herein, the term compounds of the invention refers to compounds of formula I and all of their variants described herein.

As used herein, the term compound, when referring to compounds of the invention, refers to a set of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecules. The term compound includes such a set of molecules, regardless of the purity of the sample containing the set of molecules. Thus, the term compound includes such a set of molecules, either alone or in admixture (eg, solution, suspension, or colloid) with one or more other substances.

In the description and in the claims, unless otherwise indicated, any atom not specifically designated as a particular isotope in any compound of the invention is intended to represent any stable isotope of the specified element. In the examples where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort has been made to enrich that atom in a particular isotope, and therefore one of ordinary skill in the art will appreciate that such an atom is most likely expected to be present in the natural isotopic composition. the specified element.

As used herein, the term stable, when referring to an isotope, means that the isotope does not undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes for which no decay type has been identified from V.S. Shirley & S.M. Lederer, Isotops Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

As used herein in the specification and claims, H refers to hydrogen and includes the stable isotope of hydrogen. In the examples where the atom is designated H, no effort has been made to enrich that atom with a particular hydrogen isotope, and therefore one skilled in the art will appreciate that such a hydrogen atom is most likely to be present in the natural hydrogen isotopic composition.

As used herein, D and d both refer to deuterium ( ² H).

In some embodiments, the compounds of the invention and their pharmaceutically acceptable salts comprise one or more atoms having an atomic mass or mass number that is different from the atomic mass or mass number of the most common isotope of said element (isotopically labeled compounds and salts). Examples of stable isotopes that are commercially available and suitable for the invention include, without limitation, isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, such as ² H, ¹³ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, and ³¹ P, respectively.

Isotopically labeled compounds and salts can be used in a number of successful ways, including as medicines. In some embodiments, the isotopically labeled compounds and salts are labeled with deuterium ( ² H). Deuterium ( ² H) labeled compounds and salts are therapeutically useful with potential therapeutic advantages over non- ² H labeled compounds. In general, deuterium ( ² H) labeled compounds and salts may have higher metabolic stability compared to with those not labeled with isotopes, due to the kinetic isotope effect described below. Higher metabolic stability directly leads to increased in vivo half-life or lower dosages, which in most cases represents the preferred embodiment of the present invention. Isotopically labeled compounds and salts can generally be prepared by carrying out the methods disclosed in the synthetic schemes, examples and associated description, replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

Compounds and salts labeled with deuterium ( ² H) can regulate the rate of oxidative metabolism of the compound through a primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction that occurs as a result of the exchange of isotopic nuclei, which, in turn, is caused by a change in the ground state energies of the covalent bonds involved in the reaction. The exchange of a heavier isotope generally results in a decrease in the ground state energy for a chemical bond and thus causes a decrease in the rate-limiting bond breaking. If bond breaking occurs at or near the saddle point along the multi-product reaction coordinate, the distribution ratios of the products can be significantly changed. To explain: if the deuterium is bound to the carbon atom in an unchangeable position, the differences in the rate k _H /k _D =2-7 are typical. For further discussion, see the review by SL Harbeson and RD Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011,

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46, 403-417, incorporated by reference in its entirety.

The concentration of an isotope (eg, deuterium) included at a given position of an isotopically labeled compound of the invention, or a pharmaceutically acceptable salt thereof, can be determined by an isotopic enrichment factor. The term isotopic enrichment factor as used herein means the ratio between the abundance of an isotope at a given position in an isotopically labeled compound (or salt) and the natural abundance of the isotope.

When an atom in a compound of the invention or a pharmaceutically acceptable salt thereof is designated deuterium, such compound (or salt) has an isotopic enrichment factor for that atom of at least 3000 (45% deuterium inclusion). In some embodiments, the isotopic enrichment factor is at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 ( 75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusions), at least 6600 (99% deuterium inclusion) or at least 6633.3 (99.5% deuterium inclusion).

In some embodiments, positions not specifically designated as D, d, or deuterium in the compounds of the invention are understood to contain hydrogen in their natural isotopic composition.

Salts, compositions, uses, composition, administration and additional agents.

Pharmaceutically acceptable salts and compositions.

The present invention relates to compounds and pharmaceutically acceptable salts thereof which are voltage gated sodium channel inhibitors and thus the present compounds and pharmaceutically acceptable salts thereof may be used in the treatment of diseases, disorders and conditions including, but not limited to, chronic pain. , bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (eg, bursectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie syndrome - Tuta, urinary incontinence, abnormal cough or cardiac arrhythmia. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein the compositions comprise a compound described herein, or a pharmaceutically acceptable salt thereof, and optionally contain a pharmaceutically acceptable carrier, additive, or vehicle. In some embodiments of the invention, these compositions, in addition, optionally contain one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

The term pharmaceutically acceptable salt refers to those salts that are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reaction, and the like. and commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt of a compound of this invention includes any non-toxic salt which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof. As used herein, the term inhibitory active metabolite or residue means that the metabolite or residue is also a voltage-gated sodium channel inhibitor.

Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in this field, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, 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, salts of valeric acid, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C ₁ .4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutical

- 6 041031 acceptable salts include, when necessary, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

In some embodiments, a pharmaceutically acceptable salt of a compound

F has the formula:

O

F where X denotes -PO(OH)O ^- M ⁺ , -PO(O') ₂ -2M ⁺ or -PO(O') 2 -D ²⁺ ;

M ⁺ is a pharmaceutically acceptable monovalent cation;

D ²⁺ is a pharmaceutically acceptable divalent cation.

The term monovalent cation (M ⁺ ) refers to a cation that carries one unit of positive charge. Monovalent cations include ammonium (eg N(R ⁹ )4 where R ⁹ is H or C1-C ₄ alkyl), alkali metal ions such as sodium, lithium and potassium ions, dicyclohexylamine ion and N-methyl ion. -D-glucamine. It should be noted that if there is a definition of 2M ⁺ , each of M ⁺ can be the same or different.

The term divalent cation (D ²⁺ ) refers to a cation carrying two units of positive charge. Divalent cations include alkaline earth metal ions such as calcium and magnesium ions, as well as divalent aluminum ions.

The terms monovalent cation and divalent cation include amino acid cations such as monovalent or divalent ions of arginine, lysine, ornithine, and so on. The basic nitrogen-containing groups may be protonated or may be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl-, diethyl-, dibutyl-; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide, etc.

Pharmaceutically acceptable compositions of the invention further comprise a pharmaceutically acceptable carrier, additive or vehicle, which as used herein includes any and all solvents, diluents or other liquid carriers, dispersions or suspension additives, surface active agents, isotonic agents , thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, suitable for the particular dosage form desired. In a review by Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various carriers useful in formulating pharmaceutically acceptable compositions and known methods for their preparation. Except where any conventional carrier medium is not compatible with the compounds of the invention, for example, in the event of producing any undesirable biological effect or otherwise adversely interacting with any other component(s) of a pharmaceutically acceptable composition, it is intended that their use is within the scope of this invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut butter,

- 7 041031 cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and, in addition, in accordance with the opinion of the compiler, colorants, releasing agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

The use of compounds and pharmaceutically acceptable salts and compositions.

In another aspect, the invention relates to a method for inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na _V 1.8.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (for example, pain during bursectomy or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence, abnormal cough or cardiac arrhythmia, which consists in administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, bursectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia, which consists in administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In still another aspect, the invention relates to a method for treating or alleviating the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, wherein said method comprises administering an effective amount a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of neuropathic pain in a subject, which comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, neuropathic pain includes postherpetic neuralgia or idiopathic small fiber neuropathy. As used herein, the expression idiopathic small fiber neuropathy should be understood to include any small fiber neuropathy.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of neuropathic pain in a subject, where neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain , painful neuroma; traumatic neuroma; Morton's neuroma; pinched nerve injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; trauma of the nerve roots avulsion, trauma of the brachial plexus; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain following spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia, wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of musculoskeletal pain in a subject, which comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, musculoskeletal pain includes osteoarthritis pain.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of musculoskeletal pain in a subject, where the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burning pain or toothache, and where the method consists in administering

- 8 041031 an effective amount of the compound according to the invention, its pharmaceutically acceptable salt or its pharmaceutical composition.

In yet another aspect, the invention provides a method for treating or alleviating the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis or vulvodynia pain, and wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention provides a method for treating or alleviating the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain, and wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention provides a method for treating or alleviating the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain, and wherein said method comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of a pathological cough in a subject, which method consists in administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of a subject of acute pain, which consists in the introduction of an effective amount of the compounds according to the invention, its pharmaceutically acceptable salt or its pharmaceutical composition. In some aspects, acute pain includes acute postoperative pain.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of postoperative pain (e.g., bursectomy pain or abdominoplasty pain) in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of bursectomy pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method for treating or alleviating the severity of abdominoplasty pain in a subject, comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the invention relates to a method of treating or alleviating the severity of visceral pain in a subject, which comprises administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some aspects, visceral pain includes visceral pain from abdominoplasty.

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

In another aspect, the invention relates to a method for inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na _V 1.8.

In another aspect, the invention relates to a method of treating or alleviating the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epileptic conditions, neurodegenerative disorders in a subject , psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, difficult-to-treat pain, nociceptive pain, breakthrough pain, postoperative pain (eg, bursectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, craniocerebral and trauma, amyotrophic lateral sclerosis, stress caused by angina pectoris, exercise-induced angina pectoris, palpitations, hypertension, or gastrointestinal motility disorder, which consists in administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the invention relates to a method for treating or ameliorating pain in a subject from hip cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;

- 9 041031 spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; pain in the temporomandibular joint; chronic visceral pain, abdominal pain; pain in the pancreas; pain IBS; chronic and acute headache; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; damage to peripheral nerves; painful neuromas; ectopic proximal and distal discharges; radiculopathy; neuropathic pain caused by chemotherapy; neuropathic pain caused by radiotherapy; pain after mastectomy; central pain; pain in spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; difficult-to-treat pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical back pain; neck pain; tendinitis; traumatic pain; pain during physical exertion; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, heart pain; pelvic pain, pain in renal colic, acute obstetric pain, labor pain; pain during caesarean section; acute inflammatory pain, burning pain, traumatic pain; acute intermittent pain, endometriosis; acute pain in shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behcet's disease; adipose dolorosa; phlebitis pain; pain in Guillain-Barré syndrome; painful legs-moving toes syndrome; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; diseases of the bladder and genitourinary system; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; general pain, paroxysmal intense pain, itching, tinnitus or pain caused by angina pectoris, which consists in administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Compounds, pharmaceutically acceptable salts and compositions for use.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use as a medicine.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of inhibiting a voltage-gated sodium channel in a subject. In another aspect, the voltage-gated sodium channel is Na _V 1.8.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (eg, bursectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence, abnormal cough, or cardiac arrhythmia.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, bursectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of intestinal pain in a subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or pain with interstitial cystitis.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia or idiopathic small fiber neuropathy. As used herein, the phrase idiopathic small fiber neuropathy should be understood to include any small fiber neuropathy.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, neuropathy

- 10 041031 trigeminal nerve pain, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; pinched nerve injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; trauma of the nerve roots avulsion, trauma of the brachial plexus; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain includes osteoarthritis pain.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain , burning pain or toothache.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis or vulvodynia pain.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of an abnormal cough in a subject.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating severe pain in a subject of acute pain. In some aspects, acute pain includes acute postoperative pain.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating postoperative pain (eg, bursectomy pain or tummy tuck pain) in a subject.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of bursectomy pain in a subject.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating the severity of abdominoplasty pain in a subject.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating visceral pain in a subject. In some aspects, visceral pain includes visceral pain from abdominoplasty.

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

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method for inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. . In another aspect, the voltage-gated sodium channel is Na _V 1.8.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or attenuating

- 11 041031 severity in the subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression , bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain headache, neck pain, severe pain, difficult-to-treat pain, nociceptive pain, breakthrough pain, postoperative pain (eg, bursectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress, challenge exercise-induced angina pectoris, palpitations, hypertension, or gastrointestinal motility.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in a method of treating or alleviating pain from hip cancer in a subject; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; pain in the temporomandibular joint; chronic visceral pain, abdominal pain; pain in the pancreas; pain IBS; chronic and acute headache; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; damage to peripheral nerves; painful neuromas; ectopic proximal and distal discharges; radiculopathy; neuropathic pain caused by chemotherapy; neuropathic pain caused by radiotherapy; pain after mastectomy; central pain; pain in spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; difficult-to-treat pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical back pain; neck pain; tendinitis; traumatic pain; pain during physical exertion; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, heart pain; pelvic pain, pain in renal colic, acute obstetric pain, labor pain; pain during caesarean section; acute inflammatory pain, burning pain, traumatic pain; acute intermittent pain, endometriosis; acute pain in shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behcet's disease; adipose dolorosa; phlebitis pain; pain in Guillain-Barré syndrome; painful legs-moving toes syndrome; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; diseases of the bladder and genitourinary system; urinary incontinence, pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II; general pain, paroxysmal intense pain, itching, tinnitus or pain caused by angina pectoris.

Manufacturing of medicines.

In another aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament.

In another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in voltage-gated sodium channel inhibition. In another aspect, the voltage-gated sodium channel is Na _V 1.8.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (eg, bursectomy pain or abdominoplasty pain), visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence, abnormal cough, or cardiac arrhythmia.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, bursectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

In yet another aspect, the invention relates to the use of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, in the manufacture of a medicament for use in the treatment or alleviation of a subject's bowel pain, where the bowel pain includes pain from inflammatory bowel disease, pain from Crohn's disease, or pain from interstitial cystitis.

In yet another aspect, the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of neuropathic pain in a subject. In some aspects, neuropathic pain includes postherpetic neuralgia or idiopathic small fiber neuropathy.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or alleviation of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; pinched nerve injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; trauma of the nerve roots avulsion, trauma of the brachial plexus; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or alleviation of musculoskeletal pain in a subject. In some aspects, musculoskeletal pain includes osteoarthritis pain.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or alleviation of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, pain in the back, cold pain, burning pain or toothache.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis or vulvodynia pain.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or alleviation of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or alleviation of a subject's pathological cough.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of acute pain in a subject. In some aspects, acute pain includes acute postoperative pain.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or amelioration of postoperative pain (e.g., bursectomy pain or abdominoplasty pain) in a subject.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or amelioration of bursectomy pain in a subject.

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of abdominoplasty pain in a subject.

- 13 041031

In yet another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or alleviation of visceral pain in a subject. In some aspects, visceral pain includes visceral pain from abdominoplasty.

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

In another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for use in the treatment or amelioration of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, pain difficult to treat, nociceptive pain, breakthrough pain and, postoperative pain (eg, bursectomy pain or abdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, angina stress, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility -intestinal tract.

In another aspect, the invention relates to the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment or amelioration of pain from hip cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; pain in the temporomandibular joint; chronic visceral pain, abdominal pain; pain in the pancreas; pain IBS; chronic and acute headache; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathy; damage to peripheral nerves; painful neuromas; ectopic proximal and distal discharges; radiculopathy; neuropathic pain caused by chemotherapy; neuropathic pain caused by radiotherapy; pain after mastectomy; central pain; pain in spinal cord injury; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; difficult-to-treat pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical back pain; neck pain; tendinitis; traumatic pain; pain during physical exertion; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernia; chest pain, heart pain; pelvic pain, pain in renal colic, acute obstetric pain, labor pain; pain during caesarean section; acute inflammation, burning pain, traumatic pain; acute intermittent pain, endometriosis; acute pain in shingles; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinus pain; toothache; pain in multiple sclerosis (MS); pain in depression; pain in leprosy; pain in Behcet's disease; adipose dolorosa; phlebitis pain; pain in Guillain-Barré syndrome; painful legs-moving toes syndrome; Haglund's syndrome; pain in erythromelalgia; pain in Fabry disease; diseases of the bladder and genitourinary system; urinary incontinence; pathological cough; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS) type I; complex regional pain syndrome (CRPS) type II; general pain, paroxysmal intense pain, itching, tinnitus or pain caused by angina pectoris.

Administration of pharmaceutically acceptable salts and compositions.

In some embodiments, an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is an amount effective to treat or ameliorate one or more of the conditions listed above.

Compounds, salts, and compositions according to the method of the invention may be administered using any amount and by any route of administration effective to treat or reduce the severity of one or more of the pain or non-pain syndromes listed herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, route of administration, and the like. The compounds, salts and compositions of the invention are preferably formulated in unit dosage form for ease of administration and dosage uniformity. The expression unit dosage form, as used herein, refers to a physically discrete unit of an agent suitable for the subject to be treated. It is understood, however, that the total daily use of the compounds, salts and compositions of the invention will be decided by the attending physician within the framework of sound medical judgement. The specific effective dose 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; specific composition used; age, body 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 or simultaneously with the particular compound or salt used, and like factors well known in medicine. The term subject or patient as used herein means an animal, preferably a mammal, and most preferably a human.

Pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (for example, via powders, ointments or drops), buccally, as an oral or nasal spray, or the like, in depending on the severity of the condition being treated. In some embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at doses of about 0.001 to about 100 mg/kg, or about 0.01 to about 50 mg/kg of the subject's body weight per day, one or more times per day, effectively to obtain the desired therapeutic effect.

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

Injectable preparations, for example sterile injectable aqueous or oily suspensions, can be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or vehicle, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as the solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

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

In order to prolong the action of the compounds of the invention, it is often desirable to delay the absorption of the compounds upon subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The uptake rate of a compound depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form of a compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microcapsule 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 release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable compositions are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

- 15 041031

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

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

Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form 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 field. They may optionally contain opacifying agents and may also be formulated in which they release the active ingredient(s) only or preferably in a certain part of the intestinal tract, optionally with a delay. Examples of drug-incorporated excipient compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compound or salt may also be in microencapsulated form with one or more of the excipients mentioned above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be made with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is usually the case, additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be formulated in which they release the active ingredient(s) only or preferably in a certain part of the intestinal tract, optionally with a delay. Examples of drug-incorporated excipient compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound or salt of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic composition, ear drops and eye drops are also considered to be within the scope of this invention. In addition, the invention contemplates the use of transdermal patches, which have the added benefit of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dosing the compound in a suitable medium. Absorption enhancers can also be used to increase skin penetration of the compound. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described above, the compounds of the invention can be used as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds are Na _V 1.8 inhibitors and thus, without wishing to be bound by any particular theory,

The compounds, salts and compositions are particularly useful for treating or reducing the severity of a disease, condition or disorder where Na _V 1.8 activation or hyperactivity is involved in the disease, condition or disorder. When Na _V 1.8 activation or hyperactivity is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a Na _V 1.8 mediated disease, condition or disorder. Accordingly, in another aspect, the invention relates to a method of treating or reducing the severity of a disease, condition or disorder in which Na _V 1.8 activation or hyperactivity is associated with a disease state.

The activity of the compound used in this invention as an inhibitor of Na _V 1.8 can be analyzed according to the methods described mainly in International Publication No. WO 2014/120808 A9 and US Publication No. 2014/0213616 A1, both of which are incorporated by reference. in its entirety, by the methods described herein, and by other methods known and available to a person skilled in the art.

Additional Therapeutic Agents.

It should also be understood that the compounds, salts and pharmaceutically acceptable compositions of the invention can be used in combination therapy, i. compounds, salts and pharmaceutically acceptable compositions can be administered simultaneously, before or after one or more other desired therapeutic or medical procedures. The specific combination of treatments (therapeutics or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapeutic agents used may achieve the desired effect in the same disorder (for example, a compound of the invention may be administered simultaneously with another agent used to treat the same disorder), or they may achieve different effects (for example, suppression of any side effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known to be suitable for the disease or condition being treated. Examples of additional therapeutic agents include, for example, but not limited to, non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones such as nabumetone; oxicams such as piroxicam; para-aminophenol derivatives such as acetaminophen; propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; salicylates such as aspirin, magnesium choline trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone) or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocin, nalbuphine and pentazocine). In addition, non-drug analgesic approaches may be used in combination with the administration of one or more compounds of the invention. For example, anesthetic (intraspinal infusion, neuronal block), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiotherapy (physiotherapy, orthopedic devices, diathermy) or psychological (cognitive methods-hypnosis) approaches with biological feedback or behavioral methods. 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 on the Food and Drug Administration website, www.fda.gov, the full contents of which are included in this document by reference.

In another embodiment, additional therapeutic agents are 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 or pentazocine;

(2) non-steroidal anti-inflammatory drug (NSAID) such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen , olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

(4) a sedative benzodiazepine such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

(5) a histamine (H1) antagonist with a sedative effect, such as diphenhydramine, pyrylamine, promethazine, chlorpheniramine or chlorcyclizine;

- 17 041031 (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

(7) a musculoskeletal relaxant such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

(8) NMDA receptor antagonist, eg dextromethorphan ((+)-3-hydroxy-M-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4 -(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), morphine/dextromethorphan combination, topiramate, neramexane, or perzinfotel, including an NR2B antagonist, such as ifenprodil, traxoprodil, or (-)-(R) -6-{2-[4-(3-fluorophenyl)-4hydroxy-1-piperidinyl]}-1-hydroxyethyl-3,4-dihydro-2(1 H)-quinolinone;

(9) an alpha-adrenergic such as doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2- yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant such as desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant such as carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), or valproate;

(12) a tachykinin (NK) antagonist, in particular an NK-3, NK-2 or NK-1 antagonist, for example (alpha R,9R)-7-[3,5-bis-(trifluoromethyl)benzyl]-8.9 ,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7Н[ 1,4]diazocin[2,1-g] [1,7]-naphthyridine-6-13-dione (TAK-637 ),

5-[[(2R,3S)-2-[(1R)-1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]1,2 -dihydro-3I-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or

3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenylpiperidine (2S,3S);

(13) a muscarinic receptor antagonist such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a selective COX-2 inhibitor such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal tar analgesic, in particular paracetamol;

(16) antipsychotic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserine, iloperidone, perospirone, rakloprid, zotepine bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindrone, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (eg, resinferatoxin or civamide) or a vanilloid receptor antagonist (eg, capsazepine, GRC-15300);

(18) a beta-adrenergic agent such as propranolol;

(19) a local anesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, in particular a 5-HT _1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22) a 5-HT _2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

(23) a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4(3-pyridinyl)-3-butene-1-amine (RJR-2403), (R)- 5-(2-azetidinylmethoxy)-2-chloropyridine (AWT-594) or nicotine;

(24) Tramadol®, tramadol ER (Ultram ER®), tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor such as

5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2', 1':6,1]pyrido [3,4-b]indole-1,4-dione (IC-351 or tadalafil),

2-[2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1f] [1,2,4]triazine- 4-on (vardenafil),

5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3d]pyrimidine-7- He,

5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7Hpyrazolo[4,3-d]pyrimidine-7- He,

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6dihydro-7H-pyrazolo[4,3-d ]pyrimidin-7-one,

4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2ylmethyl)pyrimidine-5-carboxamide,

- 18 041031

3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2- yl)ethyl]-4-propoxybenzenesulfonamide;

(26) alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (1[alpha], 3[alpha],5[alpha])(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S, 5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4- (3-fluorobenzyl)proline,

[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,

3-(1-aminomethylcyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,

С-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-aminomethyl-5 -methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5- dimethylheptanoic acid and (3S,4R,5R)-3-amino-4,5-dimethyloctanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) a metabotropic glutamate receptor subtype (mGluRl) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepine , dapoxetine, nefazodone, cericlamine and trazodone;

(30) norepinephrine (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropirone, bupropirone metabolite hydroxybupropirone, nomifensine and viloxazine (Vivalan®), especially a selective norepinephrine reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

(31) a dual-acting serotonin-norepinephrine reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such as

S-[2-[(1-iminoethyl)amino]ethyl]-1-homocysteine,

S-[2-[(1-iminoethyl)amino]ethyl]-4,4-dioxo-1-cysteine,

S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-1-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5 -heptenoic acid,

2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S-pyridinecarbonitrile,

2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2- chloro-5-(trifluoromethyl)phenyl]thio]-5-triazolebutanol,

2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,

2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,

N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462 or guanidinoethyl disulfide;

(33) an acetylcholinesterase inhibitor such as dopenesil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such as

N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4methylbenzenesulfonamide or

4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

(35) leukotriene B4 antagonist; such as

-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)cyclopentanecarboxylic acid (CP-105696),

5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057) or

DPC-11870;

(36) a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1 -methyl-2quinolone (ZD-2138) or

- 19 041031

2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

(37) a sodium channel blocker such as lidocaine, lidocaine plus tetracaine cream (ZRS-201), or eslicarbazepine acetate;

(38) a Na _V 1.7 blocker such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 and such as those described in WO 2011/140425 (US 2011/306607); WO 2012/106499 (US2012196869); WO 2012/112743 (US 2012245136); WO 2012/125613 (US 2012264749), WO 2012/116440 (US 2014187533), WO 2011026240 (US 2012220605), US 8883840, US 8466188 or WO 2013/109521 (US 2015005) are incorporated into each application in its entirety4 links.

(38a) a Na _V 1.7 blocker such as (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl)-(4-isopropoxy-3methylphenyl) methanone,

2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethylspiro[3,4dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone,

[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl](4-isobutoxy-3- methoxyphenyl) methanone,

1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxyphenyl)-[2-methyl-6-( trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine1,4'-piperidine]-1'-yl]methanone,

[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl](5-isopropoxy-6- methyl-2-pyridyl)methanone, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2a] pyrazin-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-methylphenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-

1,4'-piperidine]-1'-yl]methanone,

2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methylspiro[3,4-dihydropyrrolo[1,2-а]pyrazine- 1,4'-piperidine]-6-yl]ethanone,

2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-3,3-dimethylspiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1, 4'-piperidine]-6-yl]ethanone,

2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methylspiro[3,4-dihydropyrrolo[1,2a]pyrazine-1,4'-piperidine]-6- yl]ethanone, (4-isopropoxy-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1' -yl] methanone,

2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine ]-6-yl]ethanone,

1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4 '-piperidine]-6-yl]-2,2,2-trifluoroethanone,

[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'-piperidin]-1'-yl][3-methoxy-4- [(1 R)-1-methylpropoxy]phenyl]methanone,

2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methylpyridine-2-carbonyl)-2,4-dimethylspiro[3,4dihydropyrrolo[1,2-а]pyrazine-1,4' -piperidine]-6-yl]ethanone,

1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'piperidin]-6-yl]-2 ,2-dimethylpropan-1-one, (4-isopropoxy-3-methylphenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-а]pyrazine-1,4'- piperidine]-1 '-yl] methanone,

[2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-1,4'piperidine]-1'-yl]-[4-(3,3,3 -trifluoropropoxymethyl)phenyl]methanone,

4-bromo-M-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxyphenyl)-[2-methyl-6 -(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2a]pyrazin-1,4'-piperidin]-1'-yl]methanone;

(39) a Na _V 1.7 blocker such as PF-04531083, PF-06372865 and such as those described in WO 2008/135826 (US 2009/048306), WO 2006/011050 (US 2008/312235), WO 2013/061205 (US 2014/296313) WO 2014/120820 (US 2014221435), WO 2015/010065 (US 2016/0152561) and WO 2015/089361 (US 2015/0166589), the entire content of each application is incorporated herein by reference;

(39a) Na _V 1.7 blocker such as

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-(2-oxo-1,2-dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-M -(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-M-(2-oxo-1,2-dihydropyridine -4-yl)benzamide,

4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-M-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,

- 20 041031

2-(4-fluoro-2-methoxyphenoxy)-M-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,

N-(2-oxo-1,2-dihydro-pyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)(benzαmide,

2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,

5-chloro-2-(4-fluoro-2-methoxyphenoxy)-M-(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)-M- (2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4- yl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-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)-M-(2 -oxo-1,2-dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2-hydroxybenzyl)oxy)-M-(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)(benzαmid, N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide.

In one embodiment, the compound is 3-(4-fluoro-2-methoxyphenoxy)-M-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-fluorophenoxy)-K- (3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(4-chloro-2-methoxyphenoxy)-M- (3-sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl) quinoline-3-carboxamide, 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4-difluorophenoxy)-K-(3-sulfamoylphenyl)quinoxaline- 2-carboxamide, K-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide, K-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2- carboxamide, 3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid, 3 -(4-fluoro-2-methoxyphenoxy)-N-(2-ok co-2,3-dihydro-1H-benzo[d]imidazo-5-yl)quinoxaline-2carboxamide,

3-(4-fluoro-2-methoxyphenoxy)-M-(pyridin-4-yl)quinoxalin-2-carboxamide, 3-(4-fluorophenoxy)-K-(3-sulfamoylphenyl)quinoxalin-2-carboxamide, K- (3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4- (3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4, 5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis-(trifluoromethyl)benzamido)picolinic acid, 4-( 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis-(trifluoromethyl)benzamido)picolinic acid , 4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic acid , 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy) benzamido)picolinic acid, 4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid, 4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl) benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido )benzoic acid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy) benzamido)picolinic acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido) picolinic acid, 5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid, 5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido) picolinic acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid , 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl) benzamide, 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl) benzamide, 2-(2-chloro-4-fluorophenoxy)-K-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide,

- 21 041031

2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-( trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfαmoylphenyl)benzαmide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-( 3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fluoro-2-methylphenoxy) -N-(3-sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis-(trifluoromethyl)benzamide, 2-(4-fluoro-2- methylphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis-(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide, 2-( 4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide , 4,5-dichloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide,

2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl) benzamide, 2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide or N(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl) benzamide;

(40) a combined Na _V 1.7 and Na _V 1.8 blocker such as DSP-2230 or BL-1021;

(41) a 5-HT3 antagonist such as ondansetron;

(42) a TPRV1 receptor agonist such as capsaicin (NeurogesX®, Qutenza®); and its pharmaceutically acceptable salts and solvates;

(43) a nicotinic receptor antagonist such as varenicline;

(44) an N-type calcium channel antagonist such as Z-160;

(45) a nerve growth factor antagonist such as tanezumab;

(46) an endopeptidase stimulator such as senrebotaz;

(47) an angiotensin II antagonist such as EMA401;

In one embodiment, additional appropriate therapeutic agents are selected from V-116517, pregabalin, controlled release pregabalin, esogabine (Potiga®), topical cream containing ketamine and amitriptyline (Amiket®), AVP-923, perampanel (E- 2007), ralfinamide, bupivacaine transdermally, (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561, or ARC-4558.

In another embodiment, additional appropriate therapeutic agents are 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

-((4-(4-(trifluoromethoxy)phenyl)-III-imidazol-2-yl)methyl)oxetan-3-amine.

In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker), such as the Na _V 1.7 and Na _V 1.8 blockers above.

The amount of additional therapeutic agent present in the compositions of the present invention will be no more than the amount that would normally be included in compositions containing only the active agent as a therapeutic agent. The amount of additional therapeutic agent in the compositions described herein may vary from about 10% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

The compounds of the present invention, or pharmaceutically acceptable compositions thereof, may also be included in coating compositions for implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. Accordingly, in another aspect, the invention includes a composition for coating an implantable device comprising a compound or salt of the invention described generally above, as well as in the classes and subclasses herein, and a carrier suitable for coating said implantable device. In yet another aspect, the invention includes a coated implantable device with a composition comprising a compound or salt of the invention described generally above, as well as in the classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and a general description of the preparation of coated implantable devices are described in US Pat. The coatings may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart composition characteristics.

- 22 041031 controlled release.

Another aspect of the present invention relates to the inhibition of Na _V 1.8 activity in a biological sample or subject, wherein the method comprises administering to the subject a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting said biological entity with a compound of the invention, a pharmaceutically acceptable salt thereof, or its pharmaceutical composition. The term biological sample as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal, or extracts thereof; and blood, saliva, urine, feces, seminal fluid, tears or other body fluids or extracts thereof.

Inhibition of Na _V 1.8 activity in a biological sample is used for a variety of purposes known to those skilled in the art. Examples of such tasks include, but are not limited to, the study of sodium channels in biological and pathological processes and the comparative evaluation of novel sodium channel inhibitors.

Examples

General ways.

1H NMR spectra (400 MHz) were obtained as solutions in an appropriate deuterated solvent such as dimethylsulfoxide-d ₆ (DMSO-d ₆ ).

Compound purity, retention time, and electrospray mass spectrometry (ESI-MS) data were determined by LC/MS analysis using two methods: method A and method B.

LC/MS method A.

LC/MS analysis was performed using a Waters Acquity Ultra Performance LC system by reverse phase UPLC using an Acquity UPLC WEN C18 column (30 x 2.1 mm, particle size 1.7 µm) from Waters (pn: 186002349) and eluting with mobile phase B with double gradient 1-99% for 1.2 min. Mobile phase A = H ₂ O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.5 ml/min, injection volume = 1.5 μl, column temperature = 60°C.

LC/MS method B.

LC/MS analysis was performed using a Waters Acquity Ultra Performance LC system by reverse phase UPLC using an Acquity UPLC WEN C18 column (50 x 2.1 mm, particle size 1.7 µm) from Waters (pn: 186002350) and eluting with mobile phase B with double gradient 1-99% for 3.0 min. Mobile phase A = H ₂ O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 ml/min, injection volume = 1.5 μl, column temperature = 60°C.

Abbreviations.

Unless otherwise indicated, or unless the context otherwise requires, the following abbreviations shall have the following meanings.

NMR - nuclear magnetic resonance, MHz - megahertz, DMSO - dimethyl sulfoxide, ESI-MS - electrospray mass spectrometry, m/z - mass-to-charge ratio, LC/MS - liquid chromatography/mass spectrometry, LC/MS-MS - tandem liquid chromatography-mass spectrometry, UHPLC - ultra-high-performance liquid chromatography, ml - milliliters, min - minutes, hour - hour, hours, μl - microliters, mm - milliliters, μm - micrometers, THF - tetrahydrofuran, n-BuLi - n-butyllithium, DCM - dichloromethane, T3P - propylphosphinic acid anhydride, TEA - triethylamine, 2-MeTHF - 2-methyltetrahydrofuran, AcOH, HOAc - acetic acid, DABCO - 1,4-diazabicyclo[2.2.2]octane, DCE - 1.2 -dichloroethane, DMF - N,N-dimethylformamide,

- 23 041031

Bu4NI - tetrabutylammonium iodide,

EtOAc - ethyl acetate, iso-PrOH - isopropyl alcohol, g - grams,

M - molar (concentration), mmol - millimoles, mg - milligrams, n. - normal (concentration), aq. - water, ppm - ppm, E-VIPR - voltage stimulation/ion probe reader, HEK - human fetal kidney, KIR2.1 - internal potassium ion channel rectifier 2.1, DMEM - Dulbecco's Modified Needle medium, FBS - fetal bovine serum, NEAA - non-essential amino acids ,

HEPES - 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid,

DiSBAC6(3) - bis-(1,3-dihexyl-thiobarbituric acid)trimethinoxonol, CC2-DMPE - chlorocoumarin-2-dimyristoyl phosphatidylethanolamine, VABSC-1 - composition for stress analysis background suppression, HS - human serum, l - liter ( s), BSA - bovine serum albumin, nl - nanoliters, ms - millisecond, Hz - Hertz, nm - nanometer,

NADPH - nicotinamide adenine dinucleotide phosphate, reduced form, ACN - acetonitrile, mM - millimolar (concentration), μM - micromolar (concentration),

HPLC/MS/MS - tandem high performance liquid chromatography/mass spectrometry, IS - internal standard,

HPLC - High Performance Liquid Chromatography, MRM - Multiple Reaction Monitoring, ESI - Electrospray Ionization,

LLOQ - lower limit of quantitation,

AUCall is the area under the plasma drug concentration versus time curve from the moment of drug administration (time zero) to the last time point with the measured drug concentration,

AUCo- _OT is the area under the plasma drug concentration-time curve versus the time of drug administration (time zero) extrapolated to infinity of time,

Co - concentration immediately after intravenous administration (at zero time),

Cl - clearance,

V _SS - volume of distribution at steady state, t ₁ / ₂ - half-life,

SD - standard deviation, %CV - coefficient of variation,

D5W - 5% dextrose in water,

PK - pharmacokinetics, rpm - number of revolutions per minute.

Example 1

2-(4-Fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (10)

Synthesis

2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)- 24 041031 benzamide (10) is described in International Publication No. WO 2014/ 120808 A9 and US Publication No. 2014/0213616 A1, both of which are incorporated by reference in their entirety.

Example 2

(4-(2-(4-Fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrophosphate (20)

The synthesis of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (20) is described in International Publication No. WO 2015/089361 A1 and US Publication No. 2015/0166589 A1, both of which are incorporated by reference in their entirety.

Example 3

2-(4-Fluoro-2-(methyl-d ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7)

2-(4-Fluoro-2-(methyl-d ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7) was synthesized as shown in scheme 1. Trideuteriomethylation of 1-fluoro-4-methoxy-benzene (1) gave 4-fluoro-1-methoxy-2-(methyl-d ₃ )benzene (2), which was demethylated to give 4-fluoro-2- (methyl-d ₃ )phenol (3). Separately, condensation of 2-fluoro-4-(trifluoromethyl)benzoic acid (4) with 2-methoxypyridine-4-amine gave 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (5 ), which was demethylated to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4(trifluoromethyl)benzamide (6). 2-Fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (6) was treated with 4-fluoro-2-(methyl-b ₃ )phenol (3) in the presence of a base with obtaining 2-(4-fluoro-2-(methyld ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7). Detailed experimental procedures and analytical data are given below.

Scheme 1

Synthesis of compound 7

Preparation of 4-fluoro-2-(methyl-b ₃ )phenol (3).

To a solution of 1-fluoro-4-methoxybenzene (1) (1.02 g, 8.09 mmol) in THF (10 ml) was added n-BuLi (2.38 g 2 5 M in hexane, 8.75 mmol), keeping the internal temperature below -5°C. The solution was allowed to warm to room temperature and then stirred for 1 h. The mixture was cooled to 0° C. and treated dropwise with iodomethane-b ₃ (1.30 g,

- 25 041031

8.97 mmol, incl. 99.5% D) while maintaining the internal temperature above 5°C. The reaction mixture was allowed to reach room temperature and stirred for 45 minutes. The reaction mixture was diluted with diethyl ether and cold water and the layers were separated. The aqueous layer was extracted with more ether and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel (0-10% ethyl acetate/hexane) gave 4-fluoro-1-methoxy-2-(methyl-d ₃ )benzene (2) (160 mg, 14%).

1H NMR (400 MHz, DMSO-d6) δ 7.03-6.97 (m, 1H), 6.95 (dd, J=8.4, 3.2 Hz, 1H), 6.90 (dd, J=8.9, 4.8 Hz, 1H), 3.76 (s, 3H) ppm

LC/MS retention time (method A): 0.60 min (1 minute run).

_{BBr 3} (2.3 ml 1 M in dichloromethane, 2.3 mmol). The reaction mixture was removed from the ice bath, allowed to reach room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude 4-fluoro-2-(methyl-d ₃ )phenol (3) (125 mg, 87%) which was directly used in the next reaction. LC/MS retention time (method A): 0.43 min (1 minute run).

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (6).

A solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (4) (5.0 g, 24 mmol) in 2-methyltetrahydrofuran (30 ml) at 40°C was treated with a solution of T3P (23 ml of 50% w/v. in ethyl acetate, 36 mmol), then pyridine (5.7 g, 5.8 ml, 72 mmol), triethylamine (7.3 g, 10 ml, 72 mmol) and 2-methoxypyridine-4-amine (3.3 g , 26 mmol). The reaction mixture was heated at 40° C. for 16 hours. Water (50 ml) was added and the mixture was stirred. The resulting layers were separated and the organic layer was washed with 50 ml of 0.1N. HCl, 50 ml 10% KOH, and 50 ml brine. The solution was dried over sodium sulfate, filtered and evaporated to give 2-fluoro-N-(2-methoxy-4pyridyl)-4-(trifluoromethyl)benzamide (5) (7.1 g, 94%).

ESI-mS m/z calc. 314.07, found 315.2 (M+1)+.

LC/MS retention time (method B): 1.21 min (3 min run).

¹ H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.14-8.07 (m, 1H), 7.96-7.88 (m, 2H), 7.76 (dd, J=8.1, 1.6 Hz, 1H), 7.22 (d, J=4.7 Hz, 2H), 3.85 (s, 3H) ppm.

To a suspension of 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (5) (6.44 g, 20.5 mmol) in acetic acid (39 ml) was added HBr in acetic acid (25 ml 33% w/v, 103 mmol) and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to 28° C. and treated with toluene (15 ml). The mixture was stirred for 10 min, filtered and the resulting solid washed with toluene (15 ml) and dried in vacuo at 40° C. to give 3.42 g of product. Second (0.35 g) and third (0.40 g) batches of product were obtained by subsequent filtration of the mother liquor and washing of the resulting solid with toluene (15 ml). The solids were combined to give 2-fluoro-N-(2-oxo-N-pyridin-4-yl)-4(trifluoromethyl)benzamide (6) (4.17 g, 70%).

ESI-MS m/z calc. 300.05, found 301.1 (M+1) ⁺ .

LC/MS retention time (method B): 1.05 min (3 min run).

1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 10.86 (s, 1H), 7.96-7.87 (m, 2H), 7.76 (dd, J=8.2, 1.6 Hz, 1H), 7.48 (dd, J=7.1, 1.8 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.56 (dd, J=7.2, 2.1 Hz, 1H) ppm

Preparation of 2-(4-fluoro-2-(methyl-d ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7).

2-Fluoro-K-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (6) (265 mg, 0.883 mmol), K ₂ CO ₃ (366 mg, 2.645 mmol) and 4 -fluoro-2-(methyl-d ₃ )phenol (3) (125 mg, 0.968 mmol) was combined in anhydrous DMSO (2.5 ml) and heated at 75°C for 16 h. The reaction mixture was diluted with water (10 ml), filtered and the resulting solid was washed with water (10 ml) and air dried. The solid was slurried in isobutyl acetate and filtered to give the desired product as an off-white solid (200 mg). The mother liquor was concentrated and purified by silica gel chromatography (1-15% methanol/dichloromethane) to give an additional 60 mg of product. Two batches were dissolved in dichloromethane, the solvent was concentrated and the resulting solid was air dried to give 2-(4-fluoro-2-(methyl-d ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridine-4- yl)-4(trifluoromethyl)benzamide (7) (260 mg, 72%).

ESI-MS m/z calc. 409.11, found 410.2 (M+1) ⁺ .

LC/MS retention time (method B): 1.59 min (3 min run).

1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.61 (s, 1H), 7.88-7.78 (m, 1H), 7.60 (dt, J= 8.1, 1.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.22 (ddd, J=9.2, 2.5, 1.0 Hz, 1H ), 7.12-7.07 (m, 2H), 6.97 (d, J=1.6 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H) ppm

Example 4

(4-(2-(4-Fluoro-2-(methyl-d ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl

- 26 041031 dihydrophosphate (13)

(4-(2-(4-Fluoro-2-(methyl-th ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (13) was synthesized as shown in Scheme 2. Chloromethylation of 2-(4-fluoro-2-(methyld ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7) chloromethyl chloroformate gave N-[1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl]-2-[4-fluoro-2-(methyl-d ₃ )phenoxy]-4(trifluoromethyl)benzamide ( 11), which was then treated with di-tert-butoxyphosphoryloxypotassium to give di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-b ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2 -oxopyridin-1(2H)-yl)methyl)phosphate (12). Hydrolysis of compound 12 gave (4-(2-(4-fluoro-2-(methylb ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (13). Detailed experimental procedures and analytical data are given below.

Scheme 2

Synthesis of compound 13

Preparation of N-[1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl]-2-[4-fluoro-2-(methyl-d ₃ )phenoxy]-4(trifluoromethyl)benzamide (11 ).

To a suspension of 2-(4-fluoro-2-(methyl-d ₃ )phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (7) (1, 9 g, 4.642 mmol) in DCE (20 ml) and DMF (1 ml) was added DABCO (265 mg, 2.362 mmol). Chloromethyl chloroformate (620 µl, 6.972 mmol) was added dropwise to the slurry over 5 min. The mixture was stirred at 60° C. for 1 hour. The light yellow slurry was cooled to room temperature and diluted with water (50 ml) and DCM (50 ml). The organic phase was separated and the aqueous phase was extracted with DCM (50 ml). The combined organic phases were washed with brine. The organic phase was dried over MgSO ₄ , filtered through Celite and concentrated to give N-[1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl]-2-[4-fluoro-2-(methyl- d ₃ )phenoxy]-4-(trifluoromethyl)benzamide (11) (2.1 g, 99%). The product was used in the next step without further purification.

ESI-MS m/z calc. 457.08957, found 458.1 (M+1)+;

LC/MS retention time (method B): 2.06 min (3 min run).

Preparation of di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-b ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2oxopyridin-1(2H)-yl)methyl)phosphate ( 12).

Into a suspension of N-[1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl]-2-[4-fluoro-2-(methyl-d ₃ )phenoxy]-4(trifluoromethyl)benzamide ( 11) (2.1 g, 4.587 mmol) in EtOAc (25 ml) was added tetrabutylammonium iodide (30 mg, 0.08122 mmol), then di-tert-butoxyphosphoryloxypotassium (1.3 g, 5.236 mmol) and the mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched by pouring into ice water (50 ml) and diluted with EtOAc (100 ml). The organic phase was separated and washed with brine. The aqueous phases were extracted with EtOAc (100 ml) and the combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified using reverse phase chromatography (50-100% water/ACN) to give di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-b ₃ )phenoxy)-4(trifluoromethyl )benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (12) (1.75 g, 60%).

ESI-MS m/z calc. 631.21497, found 632.2 (M+1)+;

LC/MS retention time (method B): 2.25 min (3 min run).

Preparation of (4-(2-(4-fluoro-2-(methyl-b ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridine-1 (2H)

- 27 041031 yl) methyl dihydrogen phosphate (13).

To a mixture of di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-d ₃ )phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl )phosphate (12) (1.5 g, 2.375 mmol) in isopropanol (9 ml) and water (3 ml) was added HOAc (4.5 ml). The mixture was heated at 70° C. for 4.5 hours. The mixture was concentrated to approximately 2 ml oil and diluted with 10 ml ACN to give a cloudy solution which was then diluted with 10 ml isopropanol. The solvent was concentrated to approximately 2 ml, which gave a granular solid. The solid was collected using a medium fritted funnel and washed 3 times with 5 ml of acetone. The solid product was dried in air for 15 min, then in a vacuum oven at 40°C for 16 h to obtain (4-(2-(4-fluoro-2-(methyl-d ₃ )phenoxy)-4(trifluoromethyl )benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (13) (150 mg, 12%).

ESI-MS m/z calc. 519.0898, found 520.0 (M+1)+;

LC/MS retention time (method B): 1.99 min (3 min run).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.51 (s, 2H), 10.75 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.61 (dd, J=7.2, 1.7 Hz, 2H), 7.22 (dd, J=9.3, 2.5, 1.0 Hz, 1H), 7.15-7.06 (m , 2H), 6.98 (d, J=1.5 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.44 (dd, J=7.6, 2, 3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) ppm

Example 5

Assessing the conversion of prodrug to parent compound: in vitro hepatocyte assay.

Materials.

Cryopreserved human hepatocytes and cryopreserved hepatocyte repair medium (CHRM™) were purchased from Life Technologies (Carlsbad, CA). Gibco™ Leibovitz's L-15 medium was purchased from Fisher Scientific (Waltham, MA).

Ways.

mM stock solutions containing compound 20 and compound 13 were prepared in DMSO. Equal volumes of two 10 mM stock solutions were mixed to form a combined stock solution containing compound 20 and compound 13 at concentrations of 5 mM each. The 5 mM combined stock solution was diluted to a concentration of 50 µM of each compound in DMSO (50 µM combined stock solution). Cryopreserved human hepatocytes were thawed in CHRM™ medium and prepared in suspension in incubation medium (L-15 medium supplemented with glucose, HEPES buffer and NaHCO ₃ ) at a final cell concentration of 0.625 million cells/ml. In a 48-well plate, 1 μl of 50 μM combined stock solution and then 199 μl of hepatocyte suspension (0.625 million cells/ml) was added to each well.

The plate was covered and incubated at 37° C. in a light shaking incubator (50 rpm). Reactions were quenched at 0, 0.25, 0.5, 1, and 2 h by adding 200 µl of ice-cold quench solution (ACN:MeOH:0.1% aqueous formic acid, 2:2:1) containing an internal standard ( n=3 at each moment of time). The quenched samples were centrifuged and the supernatants were analyzed for the amount of compound 20 and compound 13 remaining and the amount of compound 10 and compound 7 formed by LC-MS/MS analysis. LC-MS/MS analysis was performed using a Phenomenex Luna C8 column (3 µm, 2 mm diameter, 30 mm length, at room temperature) eluting with a gradient consisting of mobile phases consisting of 0.1% formic acid in water and 0 1% formic acid in acetonitrile, at a total flow rate of 0.6 ml/min and a total run time of 4.5 minutes. Analytes were recorded using electrospray ionization (ESI) MS/MS in multiple reaction monitoring (MRM) mode. The injection volume was 10 μl.

Results.

When Compound 20 and Compound 13 samples incubated with human hepatocytes were analyzed by LC-MS/MS, the peaks corresponding to Compound 20 and Compound 13 rapidly decreased with a concomitant increase in the peaks corresponding to 10 and Compound 7, indicating rapid conversion of Compound 20 and compound 13 to compound 10 and compound 7, respectively. The time t _1/2 of compound 20 and compound 13 in human hepatocytes was <0.5 h. 1.

- 28 041031

Table 1

Percentage of compound 20 and compound 13,

E-VIPR assay to detect and measure the inhibitory properties of _NaV .

Sodium ion channels are voltage-gated proteins that can be activated to cause changes in membrane voltage by applying electrical fields. An electrical stimulation device and methods of using it, referred to as E-VIPR, are described in International Publication No. 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 device contains a device for processing microtiter plates, an optical system for excitation of the coumarin dye while recording the emission of coumarin and oxonol, a signal generator, an amplifier with current or voltage control, and parallel pairs of electrodes that are inserted into the wells of the analytical plate. Under the control of a built-in computer, this instrument transmits user-programmed electrical stimulus protocols to the cells in the wells of a microtiter plate.

16-20 hours prior to E-VIPR assay, HEK cells expressing human Na _V 1.8 were plated in 384-well plates (Greiner #781091-1B) pre-coated with Matrigel at a density of 25,000 cells/well. 5% KIR2.1 vaccine virus was added to the final cell suspension prior to seeding into cell plates. HEK cells were grown in DMEM (exact composition specific to each cell type and Na _V subtype) supplemented with 10% FBS (fetal bovine serum specified; Sigma #F4135), 1% NEAA (non-essential amino acids, Life Tech #11140), 1 % HEPES (Life Tech #15630), 1% Pen-Strep (penicillin-streptomycin; Life Tech #15640) and 5 μg/ml blasticidin (Gibco #R210-01). Cells were cultured in flasks with a ventilated cap at 95% humidity and 5% CO2.

Reagents and stock solutions: 100 mg/ml Pluronic F-127 (Sigma #P2443) in dry DMSO.

Compound Application Plates: Corning 384-well Polypropylene Round Bottom #3656.

Cell culture plates: 384-well plates treated with Greiner tissue culture #781091-1B.

5% KIR 2.1 Bacmam virus (in-house produced) prepared as described in section 3.3 of J.A. Fornwald et al., Gene Expression in Mammalian Cells Using BacMam, a Modified Baculovirus System, 1350 Methods in Molecular Biology, 95-116 (2016), the entire content of which is incorporated by reference.

mM DiSBAC ₆ (3) (voltage-gated oxonol acceptor) (Aurora #00-100-010) in dry DMSO.

mM CC2-DMPE (membrane-bound coumarin phospholipid donor FRET) (Aurora #00-100-008) in dry DMSO.

mM VABSC-1 in H2O.

Human serum (HS, Millipore #S1P1-01KL, lot #2706671A).

Buffer Bath1:

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 l), calcium chloride 2 mM (0.222 g/l), HEPES 10 mM (2.38 g/l) in water.

Buffer Na/TMA Cl Bath1:

Sodium chloride 96 mM (5.61 g/l), potassium 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.

Hexyl Dye Solution (Hexyl Dye Solution) (2X):

Bath1 buffer containing 0.5% β-cyclodextrin (prepared before use, Sigma #C4767), 8 μM CC2-DMPE and 2 μM DiSBAC ₆ (3). A solution was prepared by adding a volume of 10% Pluronic F127 stock solution equal to the combined volumes of CC2-DMPE and DiSBAC ₆ (3). The order of preparation was as follows: Pluronic and CC2-DMPE were first mixed, then DiSBAC ₆ (3) was added with swirling, and then Bath1/β-cyclodextrin was added.

Compound Addition Buffer (2X): Na/TMA Cl Bathl Buffer containing HS 50% (not present in

- 29 041031 experiments performed without HS), VABSC-1 1 mM, BSA 0.2% (in Bath-1), KCl 9 mM, DMSO 0.75%.

Study protocol.

1) 400 nL of test compound (Compound 7 or Compound 13) was preloaded (in pure DMSO) onto polypropylene plates to apply compound at 400x desired final concentration, 11-point dose response, 3-fold dilution, resulting in a maximum dose was 3 μM final concentration in the cell culture plate. Vehicle control (pure DMSO) and positive control (compound 10 (for compound 7 assay) or compound 20 (for compound 13 assay), 25 μM final in DMSO assay) were manually added to the outermost columns of each plate, respectively. The compound application plates were filled with 80 μl/well compound addition buffer resulting in a 400-fold dilution of the compound after transferring the compound 1:1 to the cell culture plate (step 6). The final DMSO concentration for all wells in the assay was 0.625% (0.75% DMSO was added to compound addition buffer to a final DMSO concentration of 0.625%).

2) Get a solution of Hexyl Dye.

3) Cell culture plates were prepared. On the day of analysis, 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) Hexyl Dye solution was dispensed into cell culture plates at 25 µl/well. Cells were incubated for 20 min at room temperature or under ambient conditions in the dark.

5) Addition buffer was dispensed into cell culture plates at 80 µl/well.

6) Cell culture plates were washed three times with 80 µl per well with Bath-1 buffer, leaving 25 µl residual volume. Then, 25 µl/well from the compound application plate was transferred to each cell culture plate. The mixture was incubated for 30 minutes at room temperature/ambient conditions.

7) The plate was read on the E-VIPR using a current controlled amplifier to deliver stimulus waveforms using the following protocol: 1.25 A biphasic waveform with 2.5 ms pulse width, 10 Hz for 10 s at a scan rate of 200 Hz. To obtain the initial values of unstimulated intensities, registration was performed for 0.5 s before the stimulating effect. The stimulus signal followed the post-stimulus recording for 0.5 s to study relaxation at rest.

Data analysis.

The data were analyzed and presented as normalized ratios of the radiation intensity measured in the 460 and 580 nm channels. The answer as a function of time was presented as a ratio obtained using the following formula:

R(t)= (intensity _{460 nm} ) _ (intensity _{580 nm} )

The data were further processed by calculating the ratio of initial (Ri) and final (Rf) indicators. They are average ratios during the partial or full pre-stimulation period and at sampling time points during the stimulation period. The fluorescence ratio (Rf/Ri) was then calculated and presented as a function of time.

Response control values were obtained by performing assays in the presence of a positive control (compound 10 or compound 20) and in the absence of pharmacological agents (negative DMSO vehicle control). The negative (N) and positive (P) control responses were calculated as above. Antagonist A compound activity score was determined as follows:

XN

A \u003d.... x 100

P-N where X denotes the reaction coefficient of the test compound.

Using this method of analysis, dose-response curves were constructed and IC ₅₀ and max. % activity.

Results.

IC ₅₀ values and max. % activity determined for compound 7 and compound 13 are given in table. 2 and 3, respectively.

table 2

IC ₅₀ and max. % activity of compound 7 in the E-VIPR assay

Navl.8 IC50 (µM) Max. % Navi.8 activity (%) 0.35 98

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Table 3

IC50 and max. % activity of compound 13 in the E-VIPR assay

Na _v 1.8 1C ₅₀ (µM) Max. % activity Na _v 1.8 (%) 1.2 99

Example 7

Assessment of metabolic stability: in vitro microsomal analysis.

Materials.

Rat, dog, monkey and human liver microsomes (20 mg/ml) were purchased from Xenotech, LLC (Lenexa, KS). P-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl ₂ ), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.

Methods. 10 mM stock solutions containing test compound (compound 10 or compound 7) were prepared in DMSO. 10 mM stock solutions were diluted to 100 μM in DMSO. To each clustered polypropylene tube was added 190.7 µl of 100 mM phosphate buffer, pH 7.4, followed by 2.5 µl of liver microsomes (20 mg/ml, rat, dog, monkey or human), followed by a 2 µl aliquot of 100 µl of test compound and the mixture were preheated for 10 min. Reactions were initiated by adding 4.8 μl of pre-warmed NADPH solution (100 mM in 100 mM phosphate buffer). The final reaction volume was 200 µl and contained 0.25 mg/ml rat, dog, monkey or human liver microsomes, 1.0 µl test compound, and 2.4 mM NADPH in 0.1 µl potassium phosphate buffer, pH 7.4 . The reactions were incubated at 37°C and the reactions were quenched after 0, 15, 30 and 60 min by adding 200 µl of ice-cold quench solution (ACN:MeOH:0.1% formic acid in water 2:2:1) containing internal standard, n=3 at time. The tubes were centrifuged and the supernatants were analyzed for the amount of test compound remaining by LC-MS/MS. The HPLC system included a Phenomenex Luna C8 column, 3 μm, 2 mm in diameter and 30 mm long, gradient elution with a mobile phase of 0.1% formic acid in water or in acetonitrile. Analytes were recorded using MS/MS with electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The injection volume was 10 μl.

Results.

The percentage of compounds 7 and 10 remaining at each time point during incubation with rat, dog, monkey and human liver microsomes is shown in FIG. 1 (rat), 2 (dog), 3 (monkey), and 4 (human). The data are also presented in Table. 4a (rat), 4b (dog), 4c (monkey), and 4d (human).

Table 4a

Rat liver microsome data for compounds 7 and 10

Time Compound 10 (% remaining) Compound 7 (% remaining) 0 min 100 100 15 minutes 108 109 30 min 102 105 60 min 87.4 92.2

Table 4b

Dog liver microsome data for compounds 7 and 10

Time Compound 10 (% remaining) Compound 7 (% remaining) 0 min 100 100 15 minutes 85.9 86.1 30 min 85.4 85.8 60 min 85.7 87.5

- 31 041031

Table 4c

Rat monkey liver microsome data for compounds 7 and 10

Time Compound 10 (% remaining) Compound 7 (% remaining) 0 min 100 100 15 minutes 96.4 97.0 30 min 92.4 93.3 60 min 91.4 92.5

table 4d

Human liver microsome data for compounds 7 and 10

Time Compound 10 (% remaining) Compound 7 (% remaining) 0 min 100 100 15 minutes By 109 30 min 105 105 60 min 106 106

Example 8

Pharmacokinetic study in vivo.

General methods.

Plasma concentrations of test compounds were determined using tandem high performance liquid chromatography/mass spectrometry (HPLC/MS/MS). The test compounds together with the internal standard (IS) were extracted from plasma (20 μl) by direct precipitation of proteins with acetonitrile (plasma/acetonitrile ratio 1:25). After centrifugation, the extract supernatant (10 µl) was injected into the LC/MS/MS system. The HPLC system included a Phenomenex Luna C8 column, 3 μm, 2 mm diameter x 75 mm length, gradient elution with a mobile phase of 0.1% formic acid in water or in acetonitrile. Analytes were recorded using MS/MS with electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The lower limit of quantification (LLOQ) was 1.00 ng/mL. The linear range of the assay ranged from 1 to 3000 ng/mL. The analysis error was within 20% of the nominal values.

Samples of the composition of dosed cassettes of the studied compounds were analyzed by a similar HPLC/MS/MS method after dilution first with DMSO and then with zero plasma with a final dilution factor of 1000 times.

The plasma concentration-time profiles of the test compounds were analyzed by non-compartmental pharmacokinetic methods using the Watson software version 7.4.2 (Thermo Scientific). Were determined pharmacokinetic parameters such as AUCall, AUC _{0 -/} . C ₀ , Cl, V _SS and t _1/2 .

Descriptive statistics of plasma concentrations and estimates of pharmacokinetic parameters were calculated including mean, standard deviation (SD), and coefficient of variation (%CV) using Microsoft Excel 2010.

Rat study IV.

Male Sprague Dawley rats (n=3) were given a single bolus dose of Compounds 7 and 10 intravenously via cannula inserted into the jugular vein. The nominal dose of each compound was 0.5 mg/kg. The solution for cassette dosing was prepared in D5W with additives. Animals had free access to food and water before and after dosing. Blood samples (approximately 0.25 ml each) were collected via a pre-dose carotid catheter and at 0 (pre-dose), 5, 10 min, 0.25, 0.5, 1, 2, 4, 8 , 12, 24 hours after dosing. Each blood sample was collected in a tube kept on wet ice and containing potassium EDTA as an anticoagulant. Plasma was separated and stored at about 70° C. until analysis.

Plasma samples and dosing solutions were analyzed using tandem liquid chromatography-mass spectrometry (LC/MS/MS) to determine the concentrations of compounds 7 and 10 with a lower limit of quantitation (LLOQ) of 1.00 ng/ml. Mean plasma concentrations of compounds 7 and 10 are shown in FIG. 5 and also presented in tabular form in table. 5.

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Claims (21)

Table 5 Intravenous administration to rats, plasma concentration (ng/ml) versus time (hours) Time watch) Compound 10 (ng/ml) Compound 7 (ng/ml) 0.083 391 420 0.167 349 399 0.25 316 371 0.5 239 301 1 174 256 2 111 208 4 51.6 154 8 14.3 91.3 12 4.27 47.6 24 7.57 Plasma concentration versus time data were subjected to a non-compartmental pharmacokinetic (PK) analysis. The results of this analysis are presented in table. 6. Measured doses of compounds 7 and 10 are also shown in table. 6. To determine the measured dose of each compound, the dosage formulation (50 μl) was aliquoted into a cluster tube at the time of dosing. Then 450 µl of DMSO was added to the tube to dilute 10 times. The diluted dosing solution was then added to control rat plasma at a 100-fold dilution. The resulting plasma sample was analyzed together with plasma samples taken from rats administered compounds using the same LC/MS/MS method. Table 6 Pharmacokinetic data from an intravenous study in rats Dose (mg/kg) Measured dose (mg/kg) Anal nt Co (µg/mL) AUC _a n (µg*h/ml) AUCo_ _w (µg*h/ml) 11/2 (h) C1 ( ml/min/kg) Vss (l/kg) 0.5 0.560 10 0.245 0.415 0.422 2.2 22.1 3.4 0.5 0.464 7 0.211 0.937 0.961 4.4 8.07 3.0 As shown in Table. 6, compound 7 has a lower clearance in rats and a longer t _1/2 time than compound 10. Many modifications and variations of the embodiments described herein can be made without departing from the scope, as will be apparent to those skilled in the art. The specific embodiments described herein are provided by way of example only. CLAIM 1. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is H or CH ₂ OPO(OH) ₂ . 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is - 33 041031 3. The compound according to claim 1, where the compound of formula I is 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is 5. The compound according to claim 1, where the compound of formula I is 6. A pharmaceutical composition containing a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to claim 1, 2 or 4 or a compound according to claim 3 or 5 and one or more pharmaceutically acceptable carriers or excipients. 7. A method for inhibiting a voltage-gated sodium channel in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt according to claim 1, 2 or 4, a compound according to claim 3 or 5, or a pharmaceutical composition according to claim 6. 8. The method of claim 7 wherein the voltage-gated sodium channel is Na _V 1.8. 9. A method of treating or alleviating the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, or visceral pain in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt according to paragraphs. 1, 2 or 4, a compound according to claim 3 or 5 or a pharmaceutical composition according to claim 6. 10. The method of claim 9, wherein the method comprises treating or alleviating the severity of neuropathic pain in a subject. 11. The method of claim 10, wherein the neuropathic pain includes postherpetic neuralgia. 12. The method of claim 10 wherein the neuropathic pain includes idiopathic small fiber neuropathy. 13. The method of claim 10 wherein the neuropathic pain includes diabetic neuropathy. 14. The method of claim 9, wherein the method comprises treating or alleviating the subject's musculoskeletal pain. 15. The method of claim 14 wherein the musculoskeletal pain includes osteoarthritis pain. 16. The method of claim 9, wherein the method comprises treating or alleviating the severity of the subject's acute pain. 17. The method of claim 16 wherein the acute pain includes acute postoperative pain. 18. The method of claim 9, wherein the method comprises treating or alleviating the severity of postoperative pain in a subject. 19. The method of claim 18 wherein the postoperative pain includes bursectomy pain. 20. The method of claim 18, wherein the postoperative pain includes tummy tuck pain. 21. The method of claim 9, wherein the method comprises treating or alleviating the severity of visceral pain in -