Oxazolidone-derived compounds and their use in the treatment of chronic and acute pain

Abstract

The present disclosure relates to oxazolidone-derived compounds (of formulas I, II, III and IV) and their use as pharmaceutical agent in the treatment, prevention or reduction of both acute and chronic pain. The mode of action disclosed herein allows oxazolidone and oxazolidone analogue compounds to act as analgesic through reduction of hyperactive firing of pain sensing neurons. Related to their high efficacy in the treatment of pain, these compounds are expected to selectively target voltage-activated K+ currents expressed in the small diameter dorsal root neurons (sdDRGns). Such findings, together with those showing that oxazolidone and oxazolidone analogue compounds act as activity dependent blockers also lead to very reduced side-effects. The results disclosed herein show that oxazolidone and oxazolidone analogue compounds described herein are a viable alternative to the already existing pharmaceutical compounds used in the treatment of pain.

Description

TITLEOXAZOLIDONE-DERIVED COMPOUNDS AND THEIR USE IN THE TREATMENT OF CHRONIC AND ACUTE PAINTECHNICAL FIELD

[0001] The present disclosure relates to oxazolidone-derived compounds and their use as analgesic agents for the treatment, prevention, and / or reduction of chronic pain and acute pain.BACKGROUND

[0002] Acute pain usually arises suddenly, and the cause is specific. It is sharp in quality. Acute pain commonly does not last longer than three to six months. It goes away when there is no longer an underlying cause for the pain. A person may then go on with life as usual. Examples of the possible causes of acute pain include surgery, broken bones, dental work, bums and cuts, labour and childbirth.

[0003] Chronic pain is defined as pain persisting for more than three months or beyond the natural recovery time. Pain signals keep firing in the nervous system, even without physiological stimuli, for weeks, months or years. It arises in many medical conditions, including for example diabetes, arthritis, migraine, fibromyalgia, cancer, back pain, shingles, sciatica, trigeminal neuralgia and previous trauma or injury.

[0004] Chronic pain may cause disability significantly interfering with a person's quality of life and causing a huge negative impact on society. It affects 21% of the world's population (1.5 billion people) and has enormous economic costs associated. In the United States of America (USA) alone, in 2010, it was estimated that $560- 635 billion were spent in salary losses and low productivity, and health care costs. With the increasing aged population, the demand for adequate and better pain management therapies is on the rise. Although there are effective and safe analgesics for mild pain, treatments for moderate and severe chronic pain are, in most cases, ineffective and cause limiting and noxious side effects.

[0005] Therefore, the major problem for patients of most types of chronic pain is the inexistence of a truly adequate pharmaceutical treatment, at least without inflicting important limiting side-effects. For example, against situations of moderate to severe pain levels, opioid derivatives do alleviate pain but co-inflict important noxious effects like habituation, addiction and loss of drive or motivation. The use of opioids became anepidemical problem in several countries, with increasing addiction situations and a heavy burden for society. For example, in the USA, the number of deaths related to opioids use is much greater than the number of deaths caused by illicit drugs. Other kinds of drugs that are used for treating chronic pain, including antidepressants, antiepileptic drugs, and non-steroidal anti-inflammatory drugs (NSAIDs), are either not efficient or also cause relevant side-effects. Ion channel modulators are also examples of more recent treatments for moderate to severe pain and are closer to the pharmacological context of the present disclosure. Ion channels are key proteins present in neuronal membranes that shape electrical signalling, and thus control pain signals in nerves. Neurons involved in pain sensing (nociception) located in the peripheral nervous system include those that have their cell bodies located in the nervous ganglia (dorsal root ganglia-DRG) outside the spinal cord (or trigeminal ganglia-TG, in the head). Such nociceptive fibers are the first peripheral nerve sensors involved in the physiological pathway that leads to the brain perception of pain. In terms of currently available therapies involving ion channel modulation for the treatment of pain, there are only two cases already in the market. Notwithstanding, they are only partially effective or still cause relevant side effects, due to the type of ion channel being modulated. More specifically, they are topic capsaicin, a Transient Receptor Potential Cation channel subfamily V member 1 (TRPV1) channel agonist and intrathecal injection of ziconotide (Prialt®), an N-type voltage-gated calcium channel blocker, obtained from a marine cone snail. The latter acts not peripherally, but centrally. New products currently under clinical development (in the pipeline of several biotechnology and pharmaceutical companies but which have not been approved for commercialization) include new opioids with certain modifications (making them less addictive) and other ion channel modulators tackling ion channels known to be involved in pain (e.g. ion channels such as other TRPVs, voltage-gated sodium channels Navi.7 and Navi.8). To the date of the present submission, a new Navi.8 channel blocker, VX- 548, an oral, highly selective inhibitor of NaVl .8, has been tested in clinical trials of postoperative pain evaluating the efficacy and safety of VX-548 in persons who had acute pain after abdominoplasty or bunionectomy. To date, results are encouraging for acute pain although its use for chronic pain remains to be demonstrated, further highlighting the need for other strategies.

[0006] As far as it is currently known from the prior art, there are only two agents acting on a K+ channel that are currently under non-clinical or clinical trials for pain treatment. First, there is the anticonvulsant retigabine (Phase II), which attenuates nociceptivebehaviours in rat models of persistent and neuropathic pain. Retigabine works primarily as a K+ channel opener - that is, by activating a certain family of voltage-gated potassium (Kv7 / M) channels in the brain. Second, another channel modulator, BL-7050 (in pre- clinical phase, which is based on the molecular structure of diclofenac (a NSAID), binds to and stabilizes the body’s potassium channels, controlling their hyper-excitability (by keeping it open) and preventing the occurrence of pain by keeping the channels open for the outflow of K+.

[0007] Despite substantial pharmaceutical research, there is still a need for more and better, clinically approved, ion channels specific blockers / potentiators / modulators, and for drugs acting on other promising targets such as ASICs, KCNQ(l-4), P2Xx, TRPVx, TREK-x, and HCNx, to improve patients’ lives who are left with no alternative besides pharmaceutical drugs with heavy side-effects. .SUMMARY

[0008] In one embodiment, the present disclosure provides oxazolidone-derived compounds and their use as analgesics for the treatment, prevention, or reduction of chronic pain and acute pain. Without wanting to be bound by theory, in some embodiments, the present disclosure differentiates from the existing solutions not only by its chemical nature but also by its mode of action. More specifically, the disclosure provides new compounds that reduce the activity of the nociceptive fibers with bioactive molecules, by which brain perception of pain is predicted to be blocked or attenuated. The latter supposedly works in a manner that may not affect brain functioning, because these compounds may act in the peripheral portion of pain signalling pathway, prior to the central nervous system.

[0009] Any embodiment or embodiment described herein may be combined with any other embodiment or embodiment as disclosed herein. While the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present disclosure, which is defined by the scope of the appended claims, other embodiments, advantages, and modifications are within the scope of the following embodiments.

[0010] Embodiment 1. A compound of formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture,tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0011] (Formula I);

[0012] (Formula II);

[0013] (Formula III); and

[0014] (Formula IV); and wherein

[0015] - represents a carbon-carbon single bond or a carbon-carbon double bond;

[0016] X is selected from C, CH, or N;

[0017] Q is selected from O, NH or N-CH3

[0018] R1, R2, R3are independently selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0019] D is selected from C, CH;

[0020] One of A and E is H and the other is selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine -(CH2)n-R5, wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine.

[0021] Embodiment 2. The compound of formula I according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0022] X is C;

[0023] Q is O;

[0024] R1is H or CH3;

[0025] R2is H or CH3;

[0026] R3is H, CH3alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;

[0027] D is C or CH:

[0028] E is H; and

[0029] A is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0030] Embodiment 3. The compound of formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is N;Q is O;R1is H or CH3;R2is H or CH3;R3is H or alkyl [excluding only when for -(CH)n-CH3n=l , 2, 4, 5, 6 or 9 and A is benzene], aryl (except benzene when A is -(CH)n-CH3with n=l, 2, 4, 5, 6 or benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or - (CH2)n-R4wherein R4is selected from aryl [except when for-(CH3)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H; andA is alkyl [excluding only for when -(CH)n-CH3 n=l, 2, 4, 5, 6 or 9 or when R3is benzene], aryl [excluding benzene when R1and R2are both H and R3is methyl or (CH)n-CH3 with n= 2, 4, 6 or R3is also benzene], furan, imidazole, isoxazole, anisole [excluding when R3is also anisole], pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or - (CH2)2-CH3], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0031] Embodiment 4. The compound of formula I according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0032] X is N;

[0033] Q is N-CH3;

[0034] R1is H or CH3;

[0035] R2is H or CH3;

[0036] R3is H, CH3 (except for when R1and R2are H and A is benzene or anisole; or for when A is -CH2-R5and R5is benzene), alkyl | except for when -(CH2)n-CH3 with n=2, 4, 6 and A is benzene; or for when -(CH2)4-CH3 and A is anisole], aryl (except benzene when A is benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for- (CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;

[0037] D is CH;

[0038] E is H; and

[0039] A is aryl [except for benzene when R1and R2are both H and R3is methyl or (CH)n- CH3 with n= 2, 4, 6], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, alkyl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(CH2)2-CH3], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine

[0040] Embodiment 5. The compound of formula I according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0041] X is N;

[0042] Q is NH;

[0043] R1is H or CH3;

[0044] R2is H or CH3;

[0045] R3is H, CH3 (except for when R1and R2are H and A is benzene or anisole; or for when A is -CH2-R5and R5is benzene), alkyl [except for when -(CH2)n-CH3 with n=2, 4,6 and A is benzene; or for when -(CH2)4-CH3 and A is anisole], aryl (except benzene when A is benzene or anisole or -CH2-R5and Rsis benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for-(CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;

[0046] D is CH;

[0047] E is H; and

[0048] A is aryl [except for benzene when R1and R2are both H and R3is methyl or (CH)n- CH3 with n= 2, 4, 6], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, alkyl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(CHih-CHsi or when for -CH2-RSwith and R3is alkyl -(CHzh-CH? or R3is is benzene and R is NH|, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine;

[0049] Embodiment 6. The compound of formula I according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0050] X is N;

[0053] R2is H or CH3;

[0054] R3is H or alkyl [excluding only when for -(CH)n-CH3 n=l, 2, 4, 5, 6 or 9 and A is benzene], aryl (except benzene when A is (CH)n-CH3 with n=l, 2, 4, 5, 6 or benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for-(CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;

[0055] D is CH;

[0056] E is H;and

[0057] A is alkyl [excluding only for when -(CH)n-CH3n=l, 2, 4, 5, 6 or 9 or when R3is benzene], aryl [excluding benzene when R1and R2are both H and R3is methyl or (CH)n- CH3with n= 2, 4, 6 or R3is also benzene], furan, imidazole, isoxazole, anisole [excluding when R3is also anisole], pyridine, pyrimidine, piperidine;

[0058] Embodiment 7. The compound of formula II according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0059] X is N;

[0060] Q is O;

[0061] R1is H or CH3;

[0062] R2is H or CH3;

[0063] R3is - (CH2)n-R4wherein R4is selected from aryl [except when for-(CH3)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;

[0064] D is CH;

[0065] E is H; and

[0066] A is -(CH2)n-R5; wherein R5is selected from aryl [except benzene when for -CH2- R5, R1and R2are both H and R3is methyl -or -(CH2)2-CH3], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0067] Embodiment 8. The compound of formula III according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0068] X is N;

[0069] Q is O;

[0070] R1is H or CH3;

[0071] R2is H or CH3;

[0072] R3is H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine or pyrimidine, piperidine or -(CH2)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine.

[0073] D is CH;

[0074] E is H; and

[0075] A is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-Rs; wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0076] Embodiment 9. The compound of formula IV according to embodiment 1, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein

[0077] X is N;

[0078] Q is O;

[0079] R1is H or CH3;

[0080] R2is H or CH3;

[0081] R3is H, alkyl or aryl, furan, imidazole, isoxazole, anisole, pyridine or pyrimidine, piperidine or -(CH3)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine.

[0082] D is CH;

[0083] E is H; and

[0084] A is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0085] Embodiment 10: The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound is selected from the compounds of formula V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XVIII, XIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, XLIV, XLV, XL VI, XL VII, XL VIII as follows:

[0086] Embodiment 11: The compound of embodiment 10, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound is selected from the compounds of formula VI, XII and XV as follows:

[0087] Embodiment 12. A compound of formula I, II, III or IV, according to any one of embodiments 1 to 9, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof,, for use in the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.

[0088] Embodiment 13. The compound for use of embodiment 12, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof , wherein the pain is chronic pain including, but not limited to, at least one of the following: neuropathic pain, nociceptive pain psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, postoperative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, and pain associated with osteoarthritis.

[0089] Embodiment 14. A compound of formula I, II, III or IV, according to any one of embodiments 1 to 11 , and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for use as an antiepileptic orantiseizure agent in a subject in need thereof.

[0090] Embodiment 15. The compound for use according to any one of embodiments 12 to 14, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the subject is a warm-blooded vertebrate, preferably a mammal, more preferably a human.

[0091] Embodiment 16. The compound for use according to any one of embodiments 12 to 15, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound or a pharmaceutically acceptable salt or prodrug thereof, is used in a therapeutic dose ranging from 3 to 6 mg / kg body weight as the peak blood concentration, if by intravenous administration, or from 1 to 300 mg / Kg of body weight, preferably a dose ranging from 30 to 100 mg / Kg body weight by any route of administration, preferably by oral administration.

[0092] Embodiment 17. The compound for use according to any one of embodiments 12 to 15, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound or a pharmaceutically acceptable salt or prodrug thereof, is used in a therapeutic dose ranging from 0.1 to 20 mg / Kg of body weight, preferably a dose ranging from 3 to 6 mg / Kg body weight by any route of administration, preferably by intravenous administration.

[0093] Embodiment 18. A pharmaceutical composition comprising at least one compound according to formula I, II, III or IV, according to any one of claims 1 to 11, and / or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, and a pharmacologically acceptable diluent or carrier.

[0094] Embodiment 19. A method of method of treating, preventing, or lessening theseverity of pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I, II, III or IV according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof.

[0095] Embodiment 20. The method according to embodiment 19, wherein the pain is a chronic pain including, but not limited to, at least one of the following: neuropathic pain, nociceptive pain psychogenic or somatogenic pain, diabetic neuropathic pain, postherpetic pain, low -back pain, radiculopathy pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, and pain associated with osteoarthritis.

[0096] Embodiment 21. A method of treatment of epilepsy or seizures in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula I, II, III and or IV according to any one of claims 1 to 11 , and / or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, to the subject.

[0097] Embodiment 22. The method according to embodiments 19 to 21, wherein the therapeutically effective dose ranges from 10 to 300 mg / kg of body weight, preferably from 30 to 60 mg / kg body weight as the peak blood concentration, by any route of administration, preferably by oral administration.

[0098] Embodiment 23. The method according to embodiments 19 to 21, wherein the therapeutically effective dose ranges from 0.1 to 20 mg / kg of body weight, preferably from 3 to 6 mg / kg body weight as the peak blood concentration, by any route of administration, preferably by intravenous administration.

[0099] Embodiment 24. The compound according to embodiments 1 through 23, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof,, wherein the compound, pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, is isolated or synthetically produced.

[0100] Embodiment 25. Use of a compound of formula I, II, III or IV, according to any one of Claims 1 to 11, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.

[0101] Embodiment 26. A compound of formula I, II, III or IV, according to any one of Claims 1 to 11 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for use in the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.BRIEF DESCRIPTION OF THE DRAWINGS

[0102] For easier understanding of this application, figures are provided that represent some of the preferred forms of implementation which nevertheless are not intended to limit the technique disclosed herein.

[0103] FIG. 1 illustrates the formulas of 44 of the compounds, which are examples of the compounds of formulas I to IV, most of which were tested (see Table I).

[0104] FIG. 2A, FIG. 2B, FIG. 2C and FIG. 2D illustrate the effects of compound V (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 2A shows ’spontaneous activity’ recorded before and during the treatment of compound V ; FIG. 2B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / lms to 1 nA) recorded before and during the treatment of compound V ; FIG. 2C shows action potentials evoked by a depolarizing current injection of 450 pA, 1000 ms duration, before and after the treatment compound V; FIG. 2D shows the number of action potentials plotted against current injections (0 to 500pA, in 50 pA increments, 1000 ms duration, every 60 s); values taken before (squares: ‘control’) and during treatment of compound V (circles).

[0105] FIG. 3 A, FIG. 3B, FIG. 3C and FIG. 3D illustrate the effects of compound VI (30 p VI) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 3 A shows ’spontaneous activity’ recorded before and during the treatment of compound VI; FIG. 2B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound V ; FIG. 2C shows action potentials evoked by a depolarizing current injection of 500 pA, 1000 ms duration) before and after the treatment compound VI; FIG. 2D shows the number of action potentials were plotted against current injections (-50 to 500pA, in 50 pA increments, 1000 ms duration, every 60 s) ; values taken before (squares: ‘control’) and during treatment of compound VI (circles).

[0106] FIG. 4A, FIG. 4B, FIG. 4C and FIG. 4D illustrate the effects of compound VII (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 4A shows ’spontaneous activity’ recorded before and during thetreatment of compound VII; FIG. 4B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound VII; FIG. 4C shows action potentials evoked by a depolarizing current injection of 120 pA, 1000 ms duration) before and after the treatment compound VII; FIG. 4C shows the number of action potentials plotted against current injections (- 80 to 470pA, in 50 pA increments, 1000 ms duration, every 60 s) ; values taken before (squares: ‘control’) and during treatment of compound VII (circles).

[0107] FIG. 5 A, FIG. 5B, FIG. 5C and FIG. 5D illustrate the effects of compound VIII (30 p VI) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 5B shows ’spontaneous activity’ recorded before and during the treatment of compound VII; (B) evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound VIII; FIG. 5C shows action potentials evoked by a depolarizing current injection of 100 pA, 1000 ms duration) before and after the treatment compound VIII; FIG. 5D shows the number of action potentials plotted against current injections (-50 to 400pA, in 50 pA increments, 1000 ms duration, every 60 s) ; values taken before (squares: ‘control’) and during treatment of compound VIII (circles).

[0108] FIG. 6A, FIG. 6B, FIG. 6C and FIG. 6D illustrate the effects of compound IX (30 p VI) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 6A shows ’spontaneous activity’ recorded before and during the treatment of compound IX; FIG. 6B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to 1 nA) recorded before and during the treatment of compound IX; FIG. 6C shows action potentials evoked by a depolarizing current injection of 200 pA, 1000 ms duration) before and after the treatment compound IX; FIG. 6D shows the number of action potentials plotted against current injections (-30 to 420pA, in 50 pA increments, 1000 ms duration, every 60 s) ; values taken before (squares: ‘control’) and during treatment of compound IX (circles).

[0109] FIG. 7A, FIG. 7B, FIG. 7C and FIG. 7D illustrate the effects of compound X (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 7A shows ’spontaneous activity’ recorded before and during the treatment of compound X; FIG. 7B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound X; FIG. 7C shows action potentials evoked by a depolarizing current injection of 400 pA, 1000 ms duration) before and after the treatment compound X; FIG. 7D shows the number of action potentials plotted against current injections (0 to 400pA, in 50 pA increments, 1000 ms duration, every 60 s) ; values taken before (squares: ‘control’) and during treatment of compound X (circles).

[0110] FIG. 8A, FIG. 8B, FIG. 8C and FIG. 8D illustrate the effects of compound XI (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 8 A shows ’spontaneous activity’ recorded before and during the treatment of compound XI; FIG. 8B showsevoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound XI; FIG. 8C shows action potentials evoked by a depolarizing current injection of 100 pA, 1000 ms duration) before and after the treatment compound XI; FIG. 8D shows the number of action potentials plotted against current injections (-50 to 400pA, in 50 pA increments, 1000 ms duration, ever}' 60 s); values taken before (squares: ‘control’) and during treatment of compound XI (circles).

[0111] FIG. 9A, FIG. 9B, FIG. 9C and FIG. 9D illustrate the effects of compound XII (30 p VI) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 9A shows ’spontaneous activity’ recorded before and during the treatment of compound XII; FIG. 9B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to 1 nA) recorded before and during the treatment of compound XII; FIG. 9C shows action potentials evoked by a depolarizing current injection of 200 pA, 1000 ms duration) before and after the treatment compoundXII; FIG. 9D shows the number of action potentials plotted against current injections (- 50 to 450pA, in 50 pA increments, 1000 ms duration, every 60 s); values taken before (squares: ‘control’) and during treatment of compound XII (circles).

[0112] FIG. 10A, FIG. 10B, FIG. IOC and FIG. 10D illustrate the effects of compoundXIII (30 M) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 10A shows ’spontaneous activity’ recorded before and during the treatment of compound XIII; FIG. 10B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound XIII; FIG.10C shows action potentials evoked by a depolarizing current injection of 200 pA, 1000 ms duration) before and after the treatment compound XIII; FIG. 10D shows the number of action potentials plotted against current injections (0 to 500pA, in 50 pA increments, 1000 ms duration, every 60 s); values taken before (squares: ‘control’) and during treatment of compound XIII (circles).

[0113] FIG. 11 A, FIG. 11B, FIG. 11C and FIG. 11D illustrate the effects of compoundXIV (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cell configuration). FIG. 11A shows ’spontaneous activity’ recorded before and during the treatment of compound XIV; FIG. 1 IB shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound XIV; FIG. 11C shows action potentials evoked by a depolarizing current injection of 200 pA, 1000 ms duration) before and after the treatment compound XIV; FIG. 1 ID shows the number of action potentials plotted against current injections (-30 to 370pA, in 50 pA increments, 1000 ms duration, every 60 s); values taken before (squares: ‘control’) and during treatment of compound XIV (circles).

[0114] FIG. 12A, FIG. 12B, FIG. 12C and FIG. 12D illustrate the effects of compoundXV (30 pM) on the membrane potential, i.e. voltage signals, recorded from small diameter Dorsal Root Ganglia neurons (sdDRGns) under current-clamp (whole-cellconfiguration). FIG. 12A shows ’spontaneous activity’ recorded before and during the treatment of compound XV; FIG. 12B shows evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA) recorded before and during the treatment of compound XV; FIG.12C shows action potentials evoked by a depolarizing current injection of 150 pA, 1000 ms duration) before and after the treatment compound XV; FIG.12D shows the number of action potentials plotted against current injections (- 50 to 500pA, in 50 pA increments, 1000 ms duration, every 60 s); values taken before (squares: ‘control’) and during treatment of compound XV (circles).

[0115] FIG. 13A and FIG. 13B illustrate the effect of the compound of formula V (30 p VI) on voltage activated currents recorded from sdDRGns. FIG. 13 A: In sdDRGns, voltage-activated outward potassium (K+) currents were evoked by a depolarizing step to +20 mV (holding potential of -70 mV) preceded by a hyperpolarizing pre-pulse to -120 mV. Currents were better fit by the sum of two exponential functions, thus revealing two components (here termed Islow and Ifast) whose time constants were rfast ~75 ms and rslow -595 ms. FIG. 13B: Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula V (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -820 ms).

[0116] FIG. 14 illustrates the effect of the compound of formula VI (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula VI (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -1100 ms).

[0117] FIG. 15 illustrates the effect of the compound of formula VII (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula VII (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -520 ms).

[0118] FIG. 16 illustrates the effect of the compound of formula VIII (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula VIII (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -714 ms).

[0119] FIG. 17 illustrates the effect of the compound of formula IX (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula IX (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -1100 ms).

[0120] FIG. 18 illustrates the effect of the compound of formula X (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula X (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -150 ms).

[0121] FIG. 19 illustrates the effect of the compound of formula XI (30 pM) on voltage activated currents recorded from sdDRGns. Typical voltage activated K+ current traces recorded before and in the presence of the compound of formula XI (30 pM); lower trace corresponding to the current subtraction, fit with a single-exponential function (time constant r -393 ms).

[0122] FIG. 20A, FIG. 20B, FIG. 20C, FIG. 20D, FIG. 20E, FIG. 20F and FIG. 20G show typical effects of compounds of formulas V, VI, VII, VIII, X and XI, respectively, on the voltage dependence of steady-state of inactivation of the K+ currents recorded from small diameter neurons isolated from a dorsal-root ganglion. FIG. 20A shows an example of current traces elicited during a command pulse to +10 mV (600 ms) preceded by a series pre-pulses of 1040 ms duration, ranging from -140 to +10 mV in a 10 mv step increments; traces in the left were obtained before and those on the right, during theapplication of compound V (30 pM). FIG. 20B, FIG. 20C, FIG. 20D, FIG. 20E, FIG- 20F and FIG. 20G illustrate the current / voltage relationships where current peak amplitudes (obtained in examples such as the one illustrated in FIG. 20 A are plotted against the potentials of the pre-pulse used in the voltage protocol in FIG. 20A’ (bullets in black relate to control-CCI; open bullets, during treatment with each compound). FIG. 20B refers to an example experiment with compound V, FIG. 20C, to compound VI, FIG. 20D, to compound VII, FIG. 20E, to compound VIII, FIG. 20F, to compound X and FIG. 20G, to compound XI. One may observe a shift to hyperpolarized values during the treatments with all the compounds. The relationships were better fit with the sum of two Boltzmann functions showing that in most cases, both conditions show two components. In fact, the Vh parameters (voltage of half maximum current) of the Boltzmann equation showed more hyperpolarized values when during treatment with all compounds.

[0123] FIG. 21 illustrates behavioral readouts as measures of pain during treatment with compounds V on a Neuropathic pain rat model CCI (chronic constriction injury). Typical experiments using a group of Wistar rats subjected to four unilateral sciatic nerve constrictions. Values refer to the mechanical sensitivity to stimulation using calibrated von Frey Filaments, and consequently reflecting hyperalgesia when hypersensitive (black filled markers - ipsilateral, operated leg; Open markers - contralateral, uninjured leg). Dotted line refers to the average value of the ipsilateral paw prior to surgery. (A) Induction of the model showing that 3 days after operation, the mechanical sensitivity of the ipsilateral limb increases markedly, whereas the one associated with the contralateral leg remained relatively unchanged, similar to baseline values. This tendency is maintained during 31 days after surgery, 28 in the case presented, day that treatment with Oxazolidone compounds were performed (circle with dotted line). (B) Effect of intravenous injection of compound V, 28 days after the surgery(estimated plasma concentration of 40 pg / ml) on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]x 100.

[0124] FIG. 22 illustrates behavioral readouts as measures of pain during treatment with compound VI on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of intravenous injection of compound VI (estimated plasma concentration of 80 pg / ml, injected 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain- related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]x 100.

[0125] FIG. 23 illustrates behavioral readouts as measures of pain during treatment with compound VII on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of intravenous injection of compound VII (estimated plasma concentration of 80 pg / ml, injected 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain- related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]x 100.

[0126] FIG. 24 illustrates behavioral readouts as measures of pain during treatment with compound VIII on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of intravenous injection of compound VIII (estimated plasma concentration of 80 pg / ml, injected 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0127] FIG. 25 illustrates behavioral readouts as measures of pain during treatment with compound IX on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of intravenous injection of compound IX (estimated plasma concentration of 80 pg / ml, injected 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain- related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]x 100.

[0128] FIG. 26 illustrates behavioral readouts as measures of pain during treatment with compound XI in a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of intravenous injection of compound XI (estimated plasma concentration of 80 g / ml, injected 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain- related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]x 100.

[0129] FIG. 27 illustrates behavioral readouts as measures of pain during treatment with oral administration of the compound VI on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of oral administration (p.o. administration by gavage) of compound VI (estimated plasma concentration of 1 ug / ml, administered 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0130] FIG. 28 illustrates behavioral readouts as measures of pain during treatment with oral administration of the compound VIII on a Neuropatic pain rat model CCI (Chronic constriction injury). Effect of oral administration (p.o. administration by gavage) of compound VIII (estimated plasma concentration of 1 pg / ml, administered 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0131] FIG. 29 illustrates behavioral readouts as measures of pain during treatment with compound XII on a Neuropathic pain rat model CCI (Chronic constriction injury). Effect of oral administration (p.o. administration by gavage) of compound XII (estimated plasma concentration of 1 pg / ml, administered 21 or 28 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0132] FIG. 30 illustrates behavioral readouts as measures of pain during treatment with compound VI on a model of post-operative pain (POP). Effect of oral administration (p.o. administration by gavage) of compound VI (estimated plasma concentration of 1 pg / ml, administered 1-2 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0133] FIG. 31 illustrates behavioral readouts as measures of pain during treatment with compound XII on a model of post-operative pain (POP). Effect of oral administration (p.o. administration by gavage) of compound XII (estimated plasma concentration of 1 pg / ml, administered 1-2 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[ (Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0134] FIG. 32 illustrates behavioral readouts as measures of pain during treatment with compound XIII on a model of post-operative pain (POP). Effect of oral administration (p.o. administration by gavage) of compound XIII (estimated plasma concentration of 1 pg / ml, administered 1-2 days after surgery, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0135] FIG. 33 illustrates behavioral readouts as measures of pain during treatment with compound VI on a model of inflammatory pain (CFA). Effect of intravenous injection of compound VI (estimated plasma concentration of 80 pg / ml, injected 3 or 8 days after induction, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0136] FIG. 34 illustrates behavioral readouts as measures of pain during treatment withcompound XII on a model of inflammatory pain (CFA). Effect of intravenous injection of compound XII (estimated plasma concentration of 80 pg / ml, injected 3 or 8 days after induction, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0137] FIG. 35 illustrates behavioral readouts as measures of pain during treatment with compound XXXVIII on a model of osteoarthritis induced pain (Mono-iodoacetate, MIA, model). Effect of intravenous injection of compound XXXVIII (estimated plasma concentration of 80 pg / ml, injected 7 or 14 days after induction, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0138] FIG. 36 illustrates behavioral readouts as measures of pain during treatment with compound XII on a model of osteoarthritis induced pain (Mono-iodoacetate, MIA, model). Effect of intravenous injection of compound XII (estimated plasma concentration of 80 pg / ml, injected 7 or 14 days after induction, on the mechanical sensitivity of the ipsilateral leg (Black bullets). The data of the contralateral limb is also shown, remaining unaltered. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0139] FIG. 37 illustrates behavioral readouts as measures of pain during treatment with compound VI on a model of chemotherapy-induced peripheral neuropathy (CIPN).Effect of intravenous injection of compound VI (estimated plasma concentration of 80 pg / ml), injected 6 weeks after induction, on the mechanical sensitivity of the hind leg (Black bullets). The data of the same limb before induction (or from treated SHAM animals) is also shown. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0140] FIG. 38 illustrates behavioral readouts as measures of pain during treatment with VI on a model of orofacial pain (ION-CCI). Effect of intravenous injection of compound VI (estimated plasma concentration of 80 pg / ml), injected 21 or 28 days after induction, on the mechanical sensitivity of the hairy skin surrounding the mystacial vibrissae (Black bullets). The data of the same area before induction (or from treated SHAM animals) is also shown. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.

[0141] FIG. 39 illustrates behavioral readouts as measures of pain during treatment with VI on a model of gastrointestinal inflammatory bowel disease (IBD) induced pain. Effect of intravenous injection of compound VI (estimated plasma concentration of 80 pg / ml), injected 3 or 10 days after induction, on the mechanical sensitivity applied to the abdominal area. (Black bullets). The data of the same area before induction (or from treated SHAM animals) is also shown. Data is presented in %MPE, in which MPE is the maximum possible reduction in pain-related behaviour that may be achieved with the intervention. The formula for calculating the percentage of MPE is: Percentage of MPE=[(Effect with Treatment-Baseline Effect) / (MPE-Baseline Effect]xl00.DETAILED DESCRIPTION

[0142] DEFINITIONS

[0143] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the Specification.

[0144] As used in this Specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0145] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”.

[0146] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include A and B; A or B; A (alone): and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0147] The terms “e.g.,” and “i.e.,” as used herein, are used merely by way of example, without limitation intended, and should not be construed as referring only those items explicitly enumerated in the specification.

[0148] The terms “or more,” “at least,” “more than,” and the like, e.g., “at least one” are understood to include but not be limited to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142,143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000,2000, 3000, 4000, 5000, or more than the stated value. Also included is any greater number or fraction in between.

[0149] Conversely, the term “no more than” includes each value less than the stated value. For example, “no more than 100” includes 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89,88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65,64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41,40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17,16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, and 0. Also included is any lesser number or fraction in between.

[0150] The terms “plurality,’' “at least two,” “two or more,” “at least second,” and the like, are understood to include but not limited to at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107,108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125,126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000,3000, 4000, 5000, or more. Also included is any greater number or fraction in between.

[0151] Throughout the specification the word “comprising,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. The term "consisting of" excludes any element, step, or ingredient not specified in the claim. In re Gray, 53 F.2d 520, 11 USPQ 255 (CCPA 1931); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) ("consisting of" defined as "closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith"). The term “consisting essentially of’ limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed disclosure.

[0152] Unless specifically stated or evident from context, as used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “approximately” may mean within one or more than one standard deviation per the practice in the art. “About” or “approximately” may mean a range of up to 10% (i.e., ±10%). Thus, “about” may be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001% greater or less than the stated value. For example, about 5 mg may include any amountbetween 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, the terms may mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition.

[0153] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to be inclusive of the value of any integer within the recited range and, when appropriate, fractions thereof (such as one-tenth and one- hundredth of an integer), unless otherwise indicated.

[0154] Units, prefixes, and symbols used herein are provided using their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0155] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related.

[0156] “Individual, “subject,” and “patient” are used interchangeably and can refer to a human or non-human.

[0157] A “therapeutically effective amount,” “effective dose,” “effective amount,” or “therapeutically effective dosage” of a therapeutic agent, e.g. compounds or “agents” described in the specification, is any amount that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. Such terms may be used interchangeably. The ability of a therapeutic agent to promote disease regression may be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. Therapeutically effective amounts and dosage regimens may be determined empirically by testing in known in vitro or in vivo (e.g., animal model) systems.

[0158] As used herein, unless otherwise indicated, the term “prevent” or “preventing” refer to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., pain related / associated disorder) resulting in a decrease in the probability that the subject will develop the condition. As used herein, the terms “prophylactic agent” and“prophylactic agents” refer to any agent(s) which can be used in the prevention of a condition or one or more symptoms thereof and / or which prevents or impedes the onset, development, progression and / or severity of a condition. In some or any embodiments, the term “prophylactic agent” includes a compound provided herein. In some or any other embodiments, the term “prophylactic agent” does not refer a compound provided herein. In some or any embodiments, the agent is administered prophylactically, for example before surgery to prevent or impede the onset, duration, progression and / or severity of pain (e.g., post surgical pain). As used herein, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a condition, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

[0159] The terms “lower, ’’“reduced, ’’“reduction, ’’“decrease,” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount. However, for avoidance of doubt, “lower, ’’“reduced, ’’“reduction, “decrease,” or “inhibit” means a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (i.e., absent level as compared to a reference sample), or any decrease between 10-100% as compared to a reference level.

[0160] The terms “increased, ’’“increase, ’’“enhance,” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased, ’’“increase, ’’“enhance,” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3 -fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0161] The term "combination" refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present disclosure and a combination partner (e.g., another drug as explained below, also referred to as "therapeutic agent" or "agent") may be administered independently at the same time or separately withintime intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms "coadministration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0162] The term "administering" as used herein refers to the physical introduction of a composition including a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering may also be performed, for example, once, a plurality of times, and / or over one or more extended periods and may be a therapeutically effective dose or a subtherapeutic dose.

[0163] The term "pharmaceutically acceptable salt" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this disclosure includes any nontoxic salt that, upon administration to a subject, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitory active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a K+channel. 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 compound of this disclosure include those derived from suitable inorganic and organic acids and bases. In one embodiment, the term refers to a salt form of one or more of the compounds or prodrugs described herein which are presented to increase the solubility of the compound in the gastric or gastroenteric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such aspotassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts may be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4- phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc. Additional examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Cl-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0164] The terms "subject" and "patient" as used herein refer any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such asnon-human primates, mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., e.g., for veterinary medical use and guinea pigs. In some embodiments, the subject is a human. The terms, "subject" and "patient" are used interchangeably herein.

[0165] The term "treatment" as used herein refers to any treatment of a condition or disease in a subject and may include: (i) preventing the disease or condition from occurring in the subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, z.e., arresting its development; relieving the disease or condition, z.e., causing regression of the condition; or (iii) ameliorating or relieving the conditions caused by the disease, z.e., symptoms of the disease. Treatment could be used in combination with other standard therapies or alone. Treatment or "therapy" of a subject also includes any type of intervention or process performed on, or the administration of an agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.

[0166] The term “small molecule” as used herein refers to a molecule having molar mass of 5000 g / mol or less, 1000 g / mol or less, 950 g / mol or less, 900 g / mol or less, 850 g / mol or less, 800 g / mol or less, 750 g / mol or less, 700 g / mol or less, 650 g / mol or less, 600 g / mol or less, 550 g / mol or less, 500 g / mol or less, 450 g / mol or less, 400 g / mol or less, 350 g / mol or less, 300 g / mol or less, 250 g / mol or less, or 200 g / mol or less.

[0167] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. The same rule applies for any other ranges described herein, even if the values within the range are not specifically called out in this disclosure.

[0168] The terms “alkyl,” “alkyl unit,” and “alkyl group” as used interchangeably herein refer to a saturated monovalent hydrocarbon radical comprising one to twelve carbon atoms (C1-C12). Alkyl groups may be linear, branched, or cyclic. Alkyl groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkyl group comprises one to eight carbon atoms (C1-C8). In some embodiments, an alkyl group comprises one to six carbon atoms (C1-C6). In someembodiments, an alkyl group comprises one to four carbon atoms (C1-C4). In some embodiments, a cyclic alkyl group comprises three to six carbon atoms (C3-C6). Nonlimiting examples of substituted and unsubstituted linear, branched, or cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4- dimethyl ami nobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethyl, and trifluoropropyl.

[0169] The terms “alkylene,” “alkylene unit,” and “alkylene group” as used interchangeably herein refer to a saturated divalent hydrocarbon radical comprising one to twelve carbon atoms (C1-C12). Alkylene groups may be linear, branched, or cyclic. Alkylene groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkylene group comprises one to eight carbon atoms (Cl- C8). In some embodiments, an alkylene group comprises one to six carbon atoms (C1-C6). In some embodiments, an alkylene group comprises one to four carbon atoms (C1-C4). Non-limiting examples of alkylene groups include methylene and ethylene.

[0170] The terms “alkenyl,” “alkenyl unit,” and “alkenyl group” as used interchangeably herein refer to a monovalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site of unsaturation (i.e., an sp2 carbon-carbon double bond). Alkenyl groups may be linear, branched, or cyclic. Alkenyl groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkenyl group comprises two to six carbon atoms (C2-C6). In some embodiments, an alkenyl group comprises two to four carbon atoms (C2-C4). Alkenyl groups may have E or Z orientations. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1 -propenyl, iso-propenyl, and 2-chloroethenyl.

[0171] The terms “alkenylene,” “alkenylene unit,” and “alkenylene group” as used interchangeably herein refer to a divalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site of unsaturation (e.g., an sp2 carbon-carbon double bond). Alkenylene groups may be linear, branched, or cyclic. Alkenylene groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkylene group comprises two to six carbon atoms (C2-C6). In some embodiments, an alkylene group comprises two to four carbon atoms (C2-C4). alkylenegroups may have E or Z orientations. Non-limiting examples of alkenyl groups include ethenylene (also called vinylene).

[0172] The terms "alkynyl," “alkynyl unit,” and “alkynyl group” as used interchangeably herein refer to a monovalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site of unsaturation (i.e., an sp carbon-carbon triple bond). Alkynyl groups may be linear or branched. Alkynyl groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkynyl group comprises two to six carbon atoms (C2-C6). In some embodiments, an alkynyl group comprises two to four carbon atoms (C2-C4). Non- limiting examples of alkynyl groups include ethynyl.

[0173] The terms "alkynylene," “alkynylene unit,” and “alkynylene group” as used interchangeably herein refer to a divalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site of unsaturation (i.e., an sp carbon-carbon triple bond). Alkynylene groups may be linear or branched. Alkynylene groups may be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkynylene group comprises two to six carbon atoms (C2-C6). In some embodiments, an alkynylene group comprises two to four carbon atoms (C2-C4). Nonlimiting examples of alkynylene groups include ethynylene.

[0174] The terms “aryl,” “aryl unit,” and “aryl group” as used interchangeably herein refer to a monovalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6-C20) that is derived by removing a hydrogen atom from an aromatic ring. Aryl groups can be unsubstituted, or they can substituted with one or more substituents as described elsewhere herein. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fhiorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4- difluorophenyl, 2-hydroxyphenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-phenoxyphenyl, 3 -phenoxyphenyl, 4- phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3-methylsulfonylphenyl, 4- methylsulfonylphenyl, 3 -aminophenyl, 3 -methylaminophenyl, 3-(2- hydroxyethoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1- naphthyl and 2-naphthyl.

[0175] The terms “arylene,” “arylene unit,” and “arylene group” as used interchangeably herein refer to a divalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6- C20) that is derived by removing two hydrogen atoms from an aromatic ring. Arylene groups can be unsubstituted, or they can be substituted with one or more substituents as described elsewhere herein. Non- limiting examples of arylene groups include phenylene.

[0176] The terms “heterocycle,” “heterocyclyl,” “heterocyclic unit,” and “heterocyclic group” as used interchangeably herein refer to a saturated or partially unsaturated ring system comprising 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom chosen from nitrogen, oxygen, phosphorous, and sulfur. A heterocyclic group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein. In some embodiments, a heterocyclic group comprises 3 to 10 atoms. In some embodiments, a heterocyclic group comprises 3 to 7 atoms. In some embodiments, a heterocyclic group is monocyclic. In some embodiments, a heterocyclic group is bicyclic. In some embodiments, a heterocyclic group comprises fused rings. Non-limiting examples of unsubstituted and substituted heterocyclic groups include pyrrolidinyl, N- methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3- hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl.

[0177] The terms “heteroaryl,” “heteroaryl unit,” and “heteroaryl group” as used interchangeably herein refer to a monovalent aromatic radical comprising one or more 5-, 6-, or 7-membered rings and comprising one or more heteroatoms independently chosen from nitrogen, oxygen, phosphorous, and sulfur. A heteroaryl group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein. In some embodiments, a heteroaryl group comprises 5 to 20 atoms. In some embodiments, a heteroaryl group comprises 5 to 9 atoms. In some embodiments, a heteroaryl group comprises 5 atoms. In some embodiments, a heteroaryl group comprises 6 atoms. In some embodiments, a heteroaryl group comprises 7 atoms. In some embodiments, a heteroaryl group is monocyclic. In some embodiments, a heteroaryl group is bicyclic. In some embodiments, a heteroaryl group comprises fused rings. Non-limiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-l,2,4-oxadiazolyl, 3-phenyl-l,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and lH-pyrrolo[2,3-b]pyridinyl.

[0178] The term “substituted” as used herein refers to the replacement of one or more hydrogen atoms on one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group with one or more substituents. On a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group, any number of hydrogen atoms may be replaced by substituents. Non-limiting examples of substituents that replace a single hydrogen atom include halogen, hydroxyl, and amino. Non-limiting examples of substituents that replace two hydrogen atoms include carbonyl. Non-limiting examples of substituents that replace three hydrogen atoms include cyano.

[0179] Non-limiting examples of substituents that can substitute for hydrogen atoms on one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group include:

[0180] 1. C1-C6 linear, branched, or cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl sec -butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0181] 2. C2-C8 linear, branched, or cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1 -propenyl, and iso-propenyl;

[0182] 3. C2-C8 linear or branched alkynyl groups, non-limiting examples of which include ethynyl;

[0183] 4. substituted or unsubstituted aryl groups, non-limiting examples of which include phenyl, 2-fluorophenyl, 3 -methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4- difluorophenyl, 3 -hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3- methylsulfonylphenyl, 4- trifluoromethylphenyl, 3 -isopropylphenyl, 1 -naphthyl, and 2- naphthyl;

[0184] 5. substituted or unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3 -methoxy pyrrolidinyl;

[0185] 6. substituted or unsubstituted heteroaryl groups; non-limiting examples of which include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl,isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-l,2,4-oxadiazolyl, 3-phenyl- 1,2,4- oxadiazolyl, indolyl, benzothiazolyl, and lH-pyrrolo[2,3-b]pyridinyl;

[0186] 7. (CRaRb)zORc, non-limiting examples of which include OH, OCH3,OCH2OH, and OCH2CH3;

[0187] 8. (CRaRb)zN(Rc)(Rd), non-limiting examples of which include NH2,NHCH3, N(CH3)2, CH2NH2, CH2NHCH3, and CH2N(CH3)2;

[0188] 9. a halogen atom, non-limiting examples of which include a fluorine atom (F) and a chlorine atom ( Cl).

[0189] 10. (CRaRb)zCN;

[0190] 11. (CRaRb)zNO2;

[0191] 12. -CHxXy, wherein X is a halogen atom and x + y sum to 3, non-limiting examples of which include CH2F, CHF2, and CF3;

[0192] 13. (CRaRb)zC(O)Rc, non-limiting examples of which include COCH3,COCH2CH3, and CH2COCH3;

[0193] 14. (CRaRb)zC(O)ORc, non-limiting examples of which include

[0194] -CO2H, CO2CH3. CO2CH2CH3, and CH2CO2CH3;

[0195] 15. (CRaRb)zC(O)N(Rc)(Rd), non-limiting examples of which includeCONH2, CONHCH3, CON(CH3)2, CH2CONH2, CH2CONHCH3, andCH2CON(CH3)2;

[0196] 16. (CRaRb)zSO2Rc; non-limiting examples of which include SO2H,SO2CH3, CH2SO2H, CH2SO2CH3, SO2C6H5, and CH2SO2C6H5; and

[0197] 17. (CRaRb)zSO3Rc; non-limiting examples of which include SO3H,SO3CH3, CH2SO3H, CH2SO3CH3, SO3C6H5, and CH2SO3C6H5;

[0198] wherein each of Ra and Rb is independently chosen from hydrogen and substituted or unsubstituted C1-C6 linear, branched, or cyclic alkyl, each of Rc and Rd is independently chosen from hydrogen, substituted or unsubstituted Cl -C6 linear, branched, or cyclic alkyl, and aryl, or wherein Rc and Rd together form a ring system comprising 3 to 7 atoms, and z is chosen from 0, 1, 2, 3, and 4.

[0199] Compounds of the disclosure may contain one or more chiral centers. Compounds of the disclosure thus may exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including, as non-limiting examples, diastereomers, enantiomers, and mixtures thereof (including, as a non-limiting example, racemic mixtures) form parts of the disclosure. Crystalline forms of the compounds, salts, and prodrugs of the disclosure are also within the scope of the claims.

[0200] As used herein, unless otherwise indicated, the term “delayed release” mean that the composition dissolves, melts, disintegrates, liquefies, etc. in a targeted area of the gastrointestinal tract such that substantially all of the a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof no longer remains in a formulation, composition, or dosage form. Delayed release compositions include sustained release compositions, gastro-retentive compositions, targeted release compositions (e.g. colonic -release compositions, or compositions that target the ileosecal valve, etc.), extended release compositions and / or combinations thereof. As used herein, unless otherwise indicated, the term “extended release composition” means that the composition is a dosage form that releases a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof over an extended period of time after administration. This allows a reduction in dosing frequency compared to immediate release compositions.

[0201] As used herein, unless otherwise indicated, the term “isolated and purified” means at least 95 percent pure (for example, at least 96% pure, at least 97% pure, at least 98% pure, or even at least 99% pure: or at least 95%, 96%, 97%, 98%, 99% to 100% by weight), as measured, for example, by chromatographic purity using HPLC.

[0202] COMPOUNDS AND METHODS OF USE

[0203] In one embodiment, the present application provides oxazolidone-derived compounds and their use as analgesics for the treatment of chronic and acute pain. Through an approach using electrophysiology and pharmacology, as well in vivo efficacy studies, a novel pharmaceutical application regarding an analgesic effect is disclosed herein.

[0204] In sharp contrast to the existing therapeutic drugs, the analgesic compounds disclosed herein will be positioned as a breakthrough in pain management due to their novel mode of action, predicted effectiveness in humans, target specificity, and reduced side-effects. Without being bound by theory, the disclosure provides that, in one embodiment, a mode of action for at least some of the compounds of the disclosure involves a strong inhibitory effect of neuronal excitability in nociceptive c-fiber cells, mainly via an inhibition of voltage activated slow currents, which underlies a peripheric analgesic effect.

[0205] In one embodiment, the disclosure provides that the effects of the compounds on excitability and on the slow voltage-activated currents, reveal interesting interaction withthe target-channels) it is a channel-inactivation-state dependent blockage, thus an activitydependent blockage, (b) it involves a change of the inactivation state of the channel, and, (c) it acts on a set of Kv channels underlying Islow. In one embodiment, the disclosure provides that this mode of action explains why and how the oxazolidone analogue compounds are solely effective in body limbs / body parts with injured / affected nerves. Indeed, the disclosure provides oxazolidone-derived compounds that do not alter nociceptive and sensorial scores in unaffected body limbs / body parts.

[0206] In one embodiment, the disclosure relates to the use of oxazolidone-derived compounds as analgesics for the treatment of chronic and acute pain. Thus, in the context of the present application, the compounds referred to ’’oxazolidone-derived compounds” are illustrated by the compounds of formula I, II, III or IV below: whereinX, Q, Rl, R2, R3, A, D and E are defined in the embodiments 1 to 7, listed in the SUMMARY of the disclosure. For example, they are the compounds of formula I, II, III or IV

[0207] wherein

[0208] - represents a carbon-carbon single bond or a carbon-carbon double bond;

[0209] X is selected from C, CH, or N;

[0210] Q is selected from O, NH or N-CH3

[0211] R1, R2, R3are independently selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;

[0212] D is selected from C, CH;One of A and E is H and the other is selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine -(CH2)n-Rs, wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, anisole, pyridine, pyrimidine, piperidine.

[0213] The aspects and embodiments described herein include the recited compounds as well as a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, mixture, prodrug, or combination thereof. Included herein, if chemically possible, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure at a particular atom, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.

[0214] In one embodiment, the present patent application discloses robust evidence that these compounds may be used in the management of pain, obtained from several technical approaches, including ex vivo neuronal preparations, animal models of pain, behavioural readouts of pain, in silica approaches, in vitro toxicity tests and, whole-cell current-clamp and voltage-clamp recordings.

[0215] In one embodiment, the disclosure provides that a competitive advantage of oxazolidone-derived compounds over other compounds used in pain therapy, including those acting on ion channels, may lie in one of six characteristics that, although interrelated, may be summarized as (1) Ease of Production; (2) Mode of Action; (3) Specificity7; (4) Administration; (5) Toxicity; and (6) Effectiveness.1- Ease of production: Oxazolidone-derived compounds are small molecules, synthesizable using basic chemistry synthesis approaches.2- Mode of action and the location and nature of their cellular target: oxazolidone- derived compounds reduce pain-induced neuronal hyperexcitability. In one embodiment, this is, likely by acting on Kv channels expressed in snDRGsresponsible for the slow delayed rectifying current, which modulate pain signalling and propagation towards the brain.3- Specificity: Administering oxazolidone-derived compounds does not result in any loss of sensorial and nociceptive capacities and nociception of the uninjured limbs / body parts, a feature that relates to its mode of action, for example, to the fact that compound interaction with the target (ion-channel) it is an activity- dependent effect.4- Administration: The Oxazolidone-derived compounds of the present application are easily administrated. In the animal models used to test the oxazolidone-derived compounds, intravenous (i.v.) and oral (p.o.) administration were used with success regarding its analgesic effect.5- Toxicity: Based on the toxicological experiments performed, there are no signs of any toxicity or side effects on the systems tested and described below. This is likely due to the fact that there is little or no effect in the central nervous system. Given that the effect is mainly in the peripheral nervous system, brain- derived toxicity / side effects are unlikely.6- Effectiveness: Oxazolidone-derived compounds are effective on mitigating pain in a number of pain models, including acute and neuropathic chronic pain, acute and long-term inflammatory pain (nociceptive pain), orofacial chronic pain and diabetic neuropathic chronic pain. Such results anticipate a wide range of possible clinical applications. Although also effective in acute / short-term pain, oxazolidone-derived compounds are particularly effective on long-term I chronic forms of pain.

[0216] SYNTHESIS OF THE COMPOUNDS OF THE DISCLOSURE

[0217] The compounds of the disclosure may be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. Exemplary methods for synthesising the compounds of the disclosure are described else where in the DetailedDescription and in the Examples.

[0218] COMPOSITIONS

[0219] Accordingly, the disclosure provides that the compounds of the disclosure may be prepared through any chemical process and provided alone or in compositions. In some embodiments, the compositions are pharmaceutically acceptable compositions. In some embodiments, the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, 22nd Edition (Sep. 15, 2022) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com 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 oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminium 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, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator. In a specific embodiment andin this context, the term “pharmaceutically acceptable carrier or diluent” may mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0220] In another embodiment, the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the disclosure features 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.

[0221] The composition may include a solubilizing agent. The solubilizing agent may include a solvent or solvent system for Oxazolidone-derived compounds, and this solvent system, itself including one or more solvents, may form the bulk of the medium in which the Oxazolidone-derived compounds is dissolved. Regardless of the nature of the solubilizing agent and whether it includes one or more solvents, a sufficient quantity of the solubilizing agent is present to solubilize essentially all of the Oxazolidone-derived compounds. The solubilizing agent must be pharmaceutically acceptable when present in an amount needed to solubilize the Oxazolidone-derived compounds. For example, the solubilizing agent should not be toxic to nor cause excessive irritation of tissues lining the nasal cavity. In an embodiment, the solvent may be water, alcohol, or a combination thereof. In another embodiment, the solvent may be water.

[0222] The composition optionally further includes a receptivity agent. The term “receptivity agent” herein means an agent that, when included in a pharmaceutical composition administered to a subject, is capable of mitigating an undesirable response to the composition at or in proximity to the locus of administration in or on the subject. Specifically, when the locus of administration is intranasal, such undesirable responses that may be mitigated may include an involuntary or reflex response such as sneezing, excessive nasal drip or irritation of nasal tissues, and / or a cognitive response, such as to unpleasant taste or odor. A cognitive response may include a conscious or subconscious decision to reduce or end use of the composition, and may thus affect patient compliance. A receptivity agent may mitigate one or more such undesirable responses.

[0223] In some embodiments, the receptivity agent includes an organoleptic enhancing agent. Illustrative examples of organoleptic enhancing agents include natural and / orsynthetic sweeteners, flavorants, aromatics, taste-masking compounds, or combinations thereof.

[0224] In some embodiments, an organoleptic enhancing agent included as a receptivity agent includes a sweetener. Illustrative sweeteners include saccharin, aspartame, neotame, cyclamates, glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, hydrogenated isomaltulose, lactitol, sorbitol, mannitol, trehalose, maltodextrin, polydextrose, glycerin, erythritol, maltol, acesulfame, acesulfame potassium, alitame, neohesperidin dihydrochalcone, stevioside, thaumatin, sugars, or combinations thereof.

[0225] In an embodiment, the receptivity agent includes an agent that may inhibit sneezing, i.e., an anti -sternutatory agent.

[0226] The pharmaceutical composition optionally further includes one or more pharmaceutically acceptable ingredients, for example, ingredients useful as carriers, preservatives, diluents, stabilizers, pH modulating agents, etc. According to an embodiment, the composition includes at least one preservative. Preservatives may have antimicrobial activity and / or may serve as antioxidants. Illustrative preservatives include but are not limited to butylated hydroxytoluene, butylated hydroxyanisole, or combinations thereof.

[0227] Where the composition is formulated in an aqueous medium, it may include one or more tonicity modulating agents, for example in an amount that renders the composition substantially isotonic. For example, a saline solution may form the basis of such a composition.

[0228] Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. In some or any embodiments, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6.197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613.358; and 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in some or any embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known tothose of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus, encompassed herein are unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release. All controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0229] In some embodiments, the composition is a delayed release composition. In some embodiments, the delayed release composition can comprise any stabilizing amount of a cation (e.g., metal cation). Any suitable cation(s) can be included in the composition, for example, any suitable metal cation or organic cation. In some embodiments, the composition comprises a metal cation selected from calcium, potassium, magnesium, zinc, aluminium, iron, tin, manganese, chromium, cobalt, nickel, barium, sodium, or a combination or mixture thereof. In some embodiments, the composition comprises a metal cation selected from calcium, potassium, magnesium, zinc, aluminum, manganese, chromium, cobalt, nickel, barium, sodium, or a combination or mixture thereof. In some embodiments, the composition comprises a metal cation selected from aluminum, calcium, potassium, sodium, magnesium, manganese, zinc, or a combination or mixture thereof. In some embodiments, the composition comprises a metal cation selected from calcium, magnesium, manganese, zinc, or a combination or mixture thereof. In some embodiments,the composition comprises a divalent metal cation. In some embodiments, the composition comprises a divalent metal cation selected from A13+, Ca2+, Mg2+, Zn2+, Mn2+, or a combination or mixture thereof. In some embodiments, the composition comprises Mg2+. In some embodiments, the composition comprises Ca2+. In some embodiments, the composition comprises Zn2+. In some embodiments, the composition comprises A13+.

[0230] Moreover, the metal cation can be added to the composition in any suitable form, for example any pharmaceutically acceptable salt with any appropriate counterion. Suitable metal salts include, for example, calcium chloride, calcium carbonate, calcium acetate, magnesium chloride, magnesium acetate, zinc acetate, zinc chloride, or mixtures thereof. In some embodiments, the composition comprises calcium chloride, magnesium chloride, zinc acetate, or any combination or mixture thereof. In some embodiments, the composition comprises calcium chloride. In some embodiments, the composition comprises magnesium chloride. In some embodiments, the composition comprises zinc acetate. Suitable organic cations include, for example, ammonium hydroxide, D-arginine, L-arginine, t-butylamine, calcium acetate hydrate, calcium carbonate, calcium DL-malate, calcium hydroxide, choline, ethanolamine, ethylenediamine, glycine, L-histidine, L-lysine, magnesium hydroxide, N-methyl-D-glucamine, L-ornithine hydrochloride, potassium hydroxide, procaine hydrochloride, L-proline, pyridoxine, L-serine, sodium hydroxide, DL- tryptophan, tromethamine, L-tyrosine, L-valine, carnitine, taurine, creatine malate, arginine alpha ketoglutarate, ornithine alpha ketoglutarate, spermine acetate, spermidine chloride, or combinations or mixtures thereof. In some embodiments, the organic cation is selected from the group consisting of N-methyl D-glucamine, choline, arginine, lysine, procaine, tromethamine (TRIS), spermine, N-methyl-morpholine, glucosamine, N,N- bis(2-hydroxyethyl) glycine, diazabicycloundecene, creatine, arginine ethyl ester, amantadine, rimantadine, ornithine, taurine, and citrulline, or any combination or mixture thereof.

[0231] In some embodiments, the composition comprises (i) between 0.1 and 30 wt. % of a polymer, (ii) a sterically hindered primary amine (e.g., an amino acid) in a molar ratio of primary amine to a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof between 150:1 and 10:1, and (iii) a cation (e.g., a metal cation) in a molar ratio of cation to a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof between 60:1 and 40: 1.

[0232] In some embodiments, the polymer acts as both a stabilizer, protective coating, or as a film forming agent within the delayed release composition. In some embodiments, thedelayed release composition comprises a molar ratio of polymer (e.g., PVP or PVA) to a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof between 80:1 and 300:1, for example, between 100:1 and 200: 1, between 110: 1 and 190:1, or even between 120:1 and 180:1. In some embodiments, the delayed release composition comprises a molar ratio of polymer (e.g., PVP or PVA) to a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof greater than about 80:1, for example, greater than about 100: 1 , or even greater than about 120: 1. In some embodiments, the delayed release composition comprises a weight ration of polymer (e.g., PVP or PVA) to a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof between 10:1 and 300: 1, for example, between 80:1 and 200: 1, between 100:1 and 180:1, or even between 110:1 and 150: 1. In some embodiments, the delayed release composition comprises a weight ration of polymer (e.g., PVP or PVA) to compound of the dislosure between 100:1 and 500:1, for example, between 200:1 and 400:1, between 250:1 and 350:1, or even between 300:1 and 350:1.

[0233] Suitable polymers for inclusion in the delayed release compositions are, for example, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl alcohol low peroxide (PVA-LP), hydroxylpropyl methyl cellulose (HPMC), hydroxylpropyl cellulose (HPC), methyl cellulose, methacrylate polymers, cyclodextrin, dextrin, dextran, polyacrylic acid, chitosan, guar gum, xanthan gum, polyethylene oxide (e.g., polyethylene polypropylene oxide), poly (sodium vinylsulfonate), polyethylene glycol, poly (arginine), poly carbophil, polyvinyl pyrrolidone-co-vinyl acetate, a poloxamer (e.g., Plutonic® products available from BASF), alginate, trehalose, sucrose, inulin, or a combination or mixture thereof. In some embodiments, the composition comprises a polymer selected from PVP, PVA, methacrylate polymers, cyclodextrin, dextran, polyacrylic acid, chitosan, guar gum, xanthan gum, polyethylene oxide, polyethylene glycol, poly(arginine), poly carbophil, polyvinyl pyrrolidone-co-vinyl acetate, a poloxamer, or a combination or mixture thereof. In some embodiments, the composition comprises PVP, PVA, polyethylene oxide, or a mixture thereof. In some embodiments, the composition comprises PVP, PVA, or a mixture thereof. In some embodiments, the composition comprises PVP. In some embodiments, the composition comprises PVA.

[0234] In some embodiments, the composition comprises two or more stabilizing agents. For example, the composition can include a stabilizing amount of a polymer and a stabilizing amount of a sterically hindered primary amine. Moreover, the composition can include a stabilizing amount of a polymer and a stabilizing amount of a cation (e.g., metalcation). In addition, the composition can include a stabilizing amount of a sterically hindered primary amine and a stabilizing amount of a cation (e.g., metal cation). In some embodiments, the composition comprises a stabilizing amount of a polymer, a stabilizing amount of a sterically hindered primary amine, and a stabilizing amount of a cation (e.g., metal cation).

[0235] In some embodiments, the delayed release composition comprises a stabilizing amount of P VP and a stabilizing amount of an amino acid selected from histidine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a mixture thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or a mixture thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of histidine.

[0236] In some embodiments, the delayed release composition comprises a stabilizing amount of PVP and a stabilizing amount of a cation (e.g., metal cation). In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of a divalent metal cation. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Mg2+, Ca2+, Zn2+ or a salt thereof or a combination or mixture thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Ca2+ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Mg2+ or a salt thereof. In some embodiments, the composition comprises a stabilizing amount of PVP and a stabilizing amount of Zn2+ or a salt thereof.

[0237] In some embodiments, the delayed release composition comprises a stabilizing amount of an amino acid selected from histidine and a stabilizing amount of a divalent metal cation selected from Mg2+, Ca2+, Zn2+ or a salt thereof or a combination or mixture thereof. In some embodiments, the delayed release composition comprises (i) a stabilizing amount of PVP or PVA, (ii) a stabilizing amount of histidine, and (iii) a stabilizing amount of Mg2+, Ca2+, Zn2+ or a salt thereof or a combination or mixture thereof.

[0238] The delayed release composition (e.g., delayed release tablet) may also comprise any one or more filling agents. Suitable filling agents include, but are not limited to, starch, calcium carbonate, calcium sulfate, hydroxylpropylmethyl cellulose, fructose, methylcellulose, dextrates, dextrose, dextran, lactitol, maltose, sucrose, sorbitol, isomalt, pregelatinized starch, dicalcium phosphate, microcrystalline cellulose, mannitol, gelatin, trehalose, erythritol, maltitol, lactose, glucose, or a combination thereof, or a mixture thereof. In some embodiments, the filling agent is isomalt. In some embodiments, the filling agent is gelatin. In some embodiments, the filling agent is mannitol. In some embodiments, the filling agent is pregelatinized starch. In some embodiments, the filling agent is microcrystalline cellulose.

[0239] The delayed release composition (e.g., delayed release tablet) can comprise any suitable concentration of filling agent. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 0.1-99% by weight, relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 1-95 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 10-90 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 20- 90 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 25-85 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 30-80 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 40-70 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 10-60 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, for example, the composition comprises one or more filling agents in a concentration of 20-50 wt. % of filling agent(s), relative to the total weight of the composition. In some embodiments, the composition comprises one or more filling agents in a concentration of at least 20 wt. %, for example, at least 40 wt. %, at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, or at least 90 wt. %, relative to the total weight of the composition.

[0240] In some embodiments, the delayed release composition (e.g., delayed release film) comprises one or more plasticizers. Suitable plasticizers include, but are not limited to, polyethylene glycol, propylene glycol, glycerin, glycerol, monoacetin, diacetin, triacetin,dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl titrate, tributyl citrate, triethyl citrate, triethyl acetyl citrate, castor oil, acetylated monoglycerides, sorbitol or combinations thereof. In exemplary embodiments, the concentration of the plasticizer in the formulation may be about 0 to about 30 wt. %, for example, about 1 to about 20 wt. %, about 0 to about 10 wt. %, about 1 to about 5 wt. %, or even 0 to about 4 wt. %.

[0241] In some embodiments, the delayed release composition comprises a film forming agent, a water-soluble polymer, a pH sensitive polymer, biodegradable polymer, or combination thereof. Water soluble, pH sensitive, or biodegradable polymers that may be used in the orally dissolving formulations of the present invention include, but are not limited to, cellulose derivatives, synthetic polymers polyacrylates and natural gums. For example, the water soluble polymers used in the orally dissolving formulations of the present invention may include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, amylose, dextran, casein, pullulan, gelatin, pectin, agar, carrageenan, xanthan gum, tragacanth, guar gum, acacia gum, arabic gum, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, cyclodextrin, carboxyvinyl polymers, sodium alginate, poly aery lie acid, methylmethacrylate or mixtures thereof. In exemplary embodiments, the concentration of the water-soluble polymer in the formulation may be about 20% to about 90% (by weight), preferably between about 40% to about 80% (by weight).

[0242] In some embodiments, the pH sensitive polymer is Eudagrit® L100 that has a threshold pH (also called dissolution pH) of 6.0. In some embodiments, the pH sensitive polymer is Eudagrit® S100 that has a threshold pH of 7.0. In some embodiments, the pH sensitive polymer is Eudagrit® L-30D that has a threshold pH of 5.6. In some embodiments, the pH sensitive polymer is Eudagrit® FS 30D that has a threshold pH of 6.8. In some embodiments, the pH sensitive polymer is Eudagrit® L100-55 that has a threshold pH of 5.5. In some embodiments, the pH sensitive polymer is Polyvinyl acetate phthalate that has a threshold pH of 5.0. In some embodiments, the pH sensitive polymer is Hydroxypropylmethylcellulose phthalate that has a threshold pH of 4.5-4.8. In some embodiments, the pH sensitive polymer is Hydroxypropylmethylcellulose phthalate 50 that has a threshold pH of 5.2. In some embodiments, the pH sensitive polymer is Hydroxypropylmethylcellulose phthalate 55 that has a threshold pH of 5.4. In someembodiments, the pH sensitive polymer is Cellulose acetate trimelliate that has a threshold pH of 4.8. In some embodiments, the pH sensitive polymer is Cellulose acetate phthalate that has a threshold pH of 5.0. In some embodiments the delayed release composition comprises a combination of the pH sensitive polymers mentioned above.

[0243] One skilled in the art, with the benefit of this disclosure, will understand that other components may be included to enhance one or more properties of the delayed release composition. In some embodiments, for example, the delayed release compositions may include one or more disintegrants, lubricants, anti-caking additives, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents, and / or coloring agents.

[0244] Suitable disintegrants include, for example, agar-agar, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, and mixtures thereof. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

[0245] Suitable lubricants include, for example, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL® 200, W.R. Grace Co., Baltimore, MD USA), a coagulated aerosol of synthetic silica (Evonik Degussa Co., Plano, TX USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, MA USA), and mixtures thereof.

[0246] Suitable anti-caking additives include, for example, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, glyceryl, and mixtures thereof.

[0247] Suitable anti-microbial additives that may be used, e.g., as a preservative for the a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof compositions, include, for example, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, cresol, chlorobutanol, dehydroacetic acid, ethylparaben, methylparaben, phenol, phenylethyl alcohol, phenoxyethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymol, and mixtures thereof.

[0248] The composition may also comprise any suitable pharmaceutically acceptable carrier or medium. Suitable pharmaceutically acceptable carriers include, for example, any solvents, dispersants, pH buffering agents, coatings, absorption promoting agents, controlled release agents, and one or more inert excipients (e.g., filling agents, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents), or the like. In addition, the compositions can contain any desired additional components, additives, and / or species, for example, surface active additives, dispersing additives, humectants, suspending agents, solubilizers, buffering agents, disintegrants, preservatives, colorants, flavorants, and the like. In some embodiments, the composition comprises one or more ion species that interact with the compounds of the disclosure.

[0249] The composition can contain any stabilizing amount of a polymer. In some embodiments, the composition comprises between 1 and 25% by weight of a polymer, relative to the total weight of the composition. In some embodiments, the composition comprises between 1 and 10% by weight of a polymer, relative to the total weight of the composition. In some embodiments, the composition comprises between 2 and 4% by weight of a polymer, relative to the total weight of the composition. In some embodiments, the composition comprises between 0.01 and 5 wt. % of a polymer. In some embodiments, the composition comprises between 0.1 and 4 wt. % of a polymer. In some embodiments, the composition comprises about 0.71 wt. % of a polymer. In some embodiments, the composition comprises about 3.59 wt. % of a polymer.

[0250] In some embodiments, a compound of the disclosure, prodrugs, or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 2,000 pg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 1 ,000 pg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 500 pg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 250 pg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 100 pg. In some embodiments, a compound of the disclosure,prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 50 pg.

[0251] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 5,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 3,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 250 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 100 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 50 mg.

[0252] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 250 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 100 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceuticallyacceptable) salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 50 mg.

[0253] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 250 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 100 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 50 mg.

[0254] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 250 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 100 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 50 mg.

[0255] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in anamount from about 50 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 250 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 100 mg.

[0256] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 500 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 250 mg.

[0257] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 1,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 500 mg.

[0258] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 500 mg to 2,000 mg. In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount from about 500 mg to 1,000 mg.

[0259] In some embodiments, a compound of the disclosure, prodrug, and / or(pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount sufficient to administer about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 10 pg, about 15 pg, about 20 pg, about 25 pg, about 30 pg, about 35 pg, about40 pg, about 45 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg, about 125 pg, about 150 pg, about 175 pg, about 200 pg, about 225 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, about 800 pg, about 850 pg, about 900 pg, about 1,000 pg, about 1,100 pg, about 1,200 pg, about 1,300 pg, about 1,400 pg, about 1,500 pg, about 1,6 >00 pg, about 1,700 pg, about 1,800 pg, about1,900 pg, about 2,000 pg, about 2,100 pg, about 2,200 pg, about 2,300 pg, about 2,400 pg, about 2,500 pg, about 2,600 pg, about 2,700 pg, about 2,800 pg, about 2,900 pg, about 3,000 pg, about 3,100 pg, about 3,200 pg, about 3,300 pg, about 3,400 pg, about 3,500 pg, about 3,600 pg, about 3,700 pg, about 3,800 pg, about 3,900 pg, about 4,000 pg, about 4,100 pg, about 4,200 pg, about 4,300 pg, about 4,400 pg, about 4,500 pg, about 4,600 pg, about 4,700 pg, about 4,800 pg, about 4,900 pg, 5,000 pg, about 5,100 pg, about 5,200 pg, about 5,300 pg, about 5,400 pg, about5,500 pg, about 5,600 pg, about5,700 pg, about 5,800 pg, about 5,900 pg, or about 6,000 pg per kilogram of body weight of the subject.

[0260] In some embodiments, a compound of the disclosure, prodrug, and / or (pharmaceutically acceptable) salt thereof is present in a pharmaceutical composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, about 1,800 mg, about 1,900 mg, about 2,000 mg, about 2,100 mg, about 2,200 mg, about 2,300 mg, about 2,400 mg, about 2,500 mg, about 2,600 mg, about 2,700 mg, about 2,800 mg, about 2,900 mg, about 3,000 mg, about 3,100 mg, about 3,200 mg, about 3,300 mg, about 3,400 mg, about 3,500 mg, about 3,600 mg, about 3,700 mg, about 3,800 mg, about 3,900 mg, about 4,000 mg, about 4,100 mg, about 4,200 mg, about 4,300 mg, about 4,400 mg, about 4,500 mg, about 4,600 mg, about 4,700 mg, about 4,800 mg, about 4,900 mg, or about 5,000 mg.

[0261] In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0. 1 mg / mL to about 500 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg / mL to about 50 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg / mL to about 5 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg / mL to about 2 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg / mL to about 1 mg / mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0. 1 mg / mL to about 0.5 mg / mL.

[0262] Parenteral Dosage Forms

[0263] In some or any embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects' natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. In some or any embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0264] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some or any embodiments, suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0265] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.

[0266] Transdermal, Topical & Mucosal Dosage Forms

[0267] Also provided are transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington: The Science and Practice of Pharmacy: Pharmaceutical Press; 22 edition (Sep. 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.

[0268] As will be clear from the disclosure herein, the pharmaceutical composition is useful for administration to subjects of a variety of species, particularly mammalian species, more particularly to human subjects.

[0269] EXEMPLARY METHODS OF USE

[0270] In another embodiment, the disclosure features a method of inhibiting one or more voltage-activated potassium channels in a subject comprising administering to the subject a compound of the disclosure or a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof.

[0271] In one embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of chronic pain including, but not limited to, at least one of the following: neuropathic pain, nociceptive pain psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, postoperative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short- term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain,phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, and pain associated with osteoarthritis

[0272] In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, idiopathic pain, postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain), visceral pain, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof.

[0273] In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of cancer pain (nerve pain, bone pain, soft tissue pain, phantom pain, referred pain, somatic pain, visceral pain), cancer chemotherapy induced neuralgia, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. Additional examples of cancer pain syndromes include: (1) pain syndromes associated with tumor infiltration (headache, cranial neuralgias, Glossopharyngeal neuralgia, Trigeminal neuralgia, Brachial plexopathy, Celiac plexopathy, Lumbosacral plexopathy, Sciatica Hepatic enlargement, Bone pain, Gastrointestinal obstruction, (2) pain syndromes associated with cancer therapy such as postchemotherapy pain syndromes (Peripheral neuropathy, Perineal pain, Steroid pseudorheumatism, Aseptic necrosis of bone, Headache, Mononeuropathy), postsurgical pain syndromes (Postmastectomy pain, Postradical neck dissection pain, Postthoracotomy pain, Phantom limb and stump pain), postradiation pain syndromes (Radiation fibrosis of brachial plexus, Radiation fibrosis of lumbosacral plexus, Radiation myelopathy, Radiation-induced peripheral nerve tumors), and Acute herpetic and postherpetic neuralgia.

[0274] The term “cancer,” as used herein, may be used to describe a solid tumor, metastatic cancer, or non-metastatic cancer. In certain embodiments, the cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, tongue, or uterus.

[0275] The cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cellcarcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary' and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary' serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary’ carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w / squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; ley dig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma. malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblasticfibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant: ependymoma; astrocytoma; protoplasmic astrocytoma: fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; hodgkin's disease; hodgkin's; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0276] In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain, irritable bowel syndrome, endometriosis, polycyctic ovarian disease, salpingitis, cervicitis or interstitial cystitis pain wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In some embodiments, the neuropathic pain comprises post-herpetic neuralgia, small fiber neuropathy, diabetic neuropathy, or idiopathic small-fiber neuropathy. In some embodiments, the neuropathic pain comprises diabetic neuropathy (e.g., diabetic peripheral neuropathy). As used herein, the phrase “idiopathic small- fiber neuropathy” shall be understood to include any small fiber neuropathy. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsioninjury; complex regional pain syndrome, drug therapy induced neuralgia, anti-retroviral therapy induced neuralgia, HIV-induced neuropathy; post spinal cord injury pain, spinal stenosis pain, small fiber neuropathy, idiopathic small- fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of musculoskeletal pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In some embodiments, the musculoskeletal pain comprises osteoarthritis pain. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain, ankylosing spondylitis or vulvodynia wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises reflex sympathetic dystrophy pain, wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical compositionthereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of pathological cough wherein said method comprises administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of acute pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the acute pain comprises acute post-operative pain. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post-thoracotomy pain, postmastectomy pain, haemorrhoidectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of bunionectomy pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of shoulder arthroplasty pain or shoulder arthroscopy pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of herniorrhaphy pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of abdominoplasty pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of visceral pain comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In some embodiments, the visceral pain comprises visceral pain from abdominoplasty. In some embodiments, thevisceral pain is selected from the group consisting of general abdominal pain, diverticular disease, pain associated with irritable bowel syndrome (IBS), chronic or acute radiation proctopathy (also referred to as radiation proctitis), rectal pain, chronic proctalgia, proctalgia fugax, anal pain, chronic anal fissure, post-operative anal pain, overactive bladder syndrome, stress incontinence, interstitial cystitis, bladder pain syndrome, pain associated with cancer, pain associated with gastrointestinal tract neoplasms, general pelvic pain, endometriosis, orchialgia, chronic prostatitis, prostatodynia, vulvodynia, urethra] syndrome, penile pain, perianal pain, ulcerative colitis, ulcerative proctitis, and Crohn's disease.

[0277] In yet another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of a neurodegenerative disease comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In some embodiments, the neurodegenerative disease comprises multiple sclerosis. In some embodiments, the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS). In yet another embodiment, the disclosure features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is a sodium channel inhibitor.

[0278] In another embodiment, the disclosure features a method of inhibiting a voltage- activated potassium channel in a biological sample comprising contacting the biological sample with an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of acute pain, sub-acute and chronic pain, nociplastic pain, arthritis, migraine, cluster headaches, tension headaches, and all other forms of headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, unspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain (e.g., joint replacement pain, soft tissue surgery pain, post- thoracotomy pain, post-mastectomy pain, herniorrhaphy pain, bunionectomy pain or abdominoplasty pain), stroke (e.g., post stroke central neuropathic pain), chronic widespread pain, disc degeneration / herniation pain,radiculopathy, bums, carpal tunnel syndrome, Paget’s disease pain, spinal canal stenosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy induced oral mucositis, Charcot neuropathic osteoarhropathy, temporo-mandibular joint disorder, painful joint arthroplasties, non-cardiac chest pain, pudendal neuralgia, renal colic, biliary tract diseases, vascular leg ulcers, pain in Parkinson’s disease, pain in Alzheimer’s disease, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of femur cancer pain; non- malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; medication-overuse headache; trauma-induced acute or chronic headache; opioid withdrawal pain; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; hereditary sensory neuropathy; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; persistent / chronic post- surgical pain (e.g., post amputation, post-thoracotomy, post- cardiac surgery), postmastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; phantom pain (e.g., following removal of lower extremity, upper extremity, breast); intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury7pain; exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory pain, bum pain, trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anaemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Bane pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence, pathological cough; hyperactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRTS), type I, complex regional pain syndrome (CRPS) type II; widespread pain, paroxysmal extreme pain, pruritus, tinnitus,or angina-induced pain, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof. In another embodiment, the disclosure features a method of treating, preventing, or lessening the severity in a subject of trigeminal neuralgia, migraines treated with botox, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbrosacral radiculopathy, iliolingual neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain or postamputation pain, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition thereof.

[0279] In another embodiment, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament in the treatment, prevention, or lessening of severity of one or more pain conditions recited above.

[0280] In certain embodiments of the disclosure, an “effective amount” of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating, preventing, or lessening the severity of one or more of the conditions recited above.

[0281] In certain embodiments, the preferred dosage ranges from 0. 1 to 20 mg / kg of body weight, preferably a doses ranging from 3 to 6 mg / kg body weight. In some embodiments, the dosage is from 1 mg / kg to 10 mg / kg, 2 mg kg / to 8 mg / kg, 2 mg / kg to 6 mg / kg, 2 mg / kg to 4 mg / kg, or 6 mg / kg to 8 mg / kg. In some aspects, the agent is administered in a dosage amount of at least 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg or more. In certain embodiments, it is contemplated that doses in the range from 10 mg / kg to 200 mg / kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 pg / kg, mg / kg, pg / day, or mg / day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and / or on multiple days, weeks, or months. In certain embodiments, the effective dose of the pharmaceutical composition is one which can provide a blood level of about 1 pM to 150 pM. In another embodiment, the effectivedose provides a blood level of about 4 pM to 100 pM; or about 1 pM to 100 pM; or about 1 pM to 50 pM; or about 1 pM to 40 pM; or about 1 pM to 30 pM; or about 1 pM to 20 pM; or about 1 pM to 10 pM; or about 10 pM to 150 pM; or about 10 pM to 100 pM; or about 10 pM to 50 pM; or about 25 pM to 150 pM; or about 25 pM to 100 pM; or about 25 pM to 50 pM; or about 5 pM to 150 pM; or about 50 pM to 100 pM (or any range derivable therein). In other embodiments, the dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or 100 pM or any range derivable therein. In certain embodiments, the therapeutic agent that is administered to a subject is metabolized in the body to a metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent. It will be understood by those skilled in the art and made aware that dosage units of pg / kg or mg / kg of body weight can be converted and expressed in comparable concentration units of pg / ml or mM (blood levels), such as 4 pM to 100 pM. It is also understood that uptake is species and organ / tissue dependent.

[0282] In one embodiment, the oxazolidone-derived compounds of the disclosure may be used for pharmacological use in warm-blooded vertebrates, particularly humans, in doses that, after administration, achieve a final peak concentration ranging from 2 pg / ml blood (0.3 mg / Kg body weight) to 42 pg / ml blood (20 mg / Kg body weight), for example following oral administration. In one embodiment, the dose ranges from 0.1 pg / ml blood to 1 pg / ml blood; 1 pg / ml blood to 10 pg / ml blood; 10 pg / ml blood to 20 pg / ml blood; 20 pg / ml blood to 50 pg / ml blood; 50 pg / ml blood to 100 pg / ml blood; 100 pg / ml blood to 500 pg / ml blood; 500 pg / ml blood to 1000 pg / ml blood.

[0283] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a compositionprovided herein, not all of the dosages need be the same. In some or any embodiments, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0284] The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.

[0285] Accordingly, the compounds, and salts and prodrugs thereof, and compositions, according to the method of the disclosure, may be administered using any amount and any route of administration effective for treating, preventing, or lessening the severity of one or more of the pain or non-pain diseases recited 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, its mode of administration, and the like. The compounds, salts and prodrugs thereof, and compositions of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. The pharmaceutically acceptable compositions of this disclosure may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the disclosuremay be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective 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 salt, the 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 (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0286] The injectable formulations may be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of the compounds of the disclosure, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of thecompound in biodegradable polymers such as polylactide-poly glycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compound or salt of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as 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 glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding 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 comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients 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 excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceutical formulating art. 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 comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. Tn the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0287] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. In some or any embodiments, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0288] The compositions and compounds of the disclosure may be formulated to be compatible with their intended route of administration. In some or any embodiments, routes of administration include, but are not limited to, parenteral, e.g., intrathecal, epidural, local or regional for peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical (including administration to the eye, and in some embodiments to the cornea), transmucosal, intra-tumoral, intra-synovial, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral,intranasal, or topical (including administration to the eye, and in some embodiments to the cornea) administration to human beings. In a specific embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection

[0289] Dosage forms for topical or transdermal administration of a compound or salt of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate may be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. In some or any embodiments, dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0290] As described generally above, the compounds of the disclosure are useful as inhibitors of voltage- activated K+ channels. Thus, without wishing to be bound by any particular theory, the compounds, salts and prodrugs thereof, and compositions are particularly useful for treating, preventing, or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of K+ channel(s) is implicated in the disease, condition, or disorder. When activation or hyperactivity of a K+ channel is implicated in aparticular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “K+-channel-mediated disease, condition or disorder.” Accordingly, in another embodiment, the disclosure provides a method for treating, preventing, or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of K+ channel(s) is implicated in the disease state.

[0291] The activity of a compound utilized in this disclosure as an inhibitor of K+ channels may be assayed according to methods described generally in the Examples of this application, and other methods known and available to one of ordinary skill in the art.

[0292] ADDITIONAL THERAPEUTIC AGENTS

[0293] In some or any embodiments, a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agent. As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, and / or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder. The two or more agents may be administered sequentially and / or concurrently.

[0294] Accordingly, it will be appreciated that the compounds, salts, prodrugs, and pharmaceutically acceptable compositions of the disclosure may be employed in combination therapies, that is, the compounds, salts, prodrugs, and pharmaceutically acceptable compositions may be administered concurrently with, prior to, and / or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and thedesired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthyl alkanones such as Nabumetone; oxicams such as Piroxicam; paraaminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen. Ibuprofen, Ketoprofen. Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the disclosure. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods- hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0295] In some embodiments, the additional therapeutic agent is a chemotherapeutic, immunotherapeutic, or other cancer therapeutic. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylol melamine; nitrogen mustards such aschlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine: elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; Polysaccharide K (PSK); razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOLTM, Bristol-Myers Squibb) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylomi thine (DMFO); retinoic acid derivatives such as TargretinTM (bexarotene), PanretinTM, (alitretinoin); ONTAKTM (denileukin diftitox); esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In some embodiments, compositions comprising the compounds, saltsand prodrugs thereof, and compositions disclosed herein may be administered in conjunction with an anti-hormonal agent that acts to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide. leuprolide. and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Combinations of chemotherapeutic agents are also administered where appropriate, including, but not limited to CHOP, i.e., Cyclophosphamide (Cytoxan®), Doxorubicin (hydroxy doxorubicin), Vincristine (Oncovin®), and Prednisone, R-CHOP (CHOP plus Rituximab), and G-CHOP (CHOP plus obinutuzumab). Additional therapeutic agents include PD-1 inhibitors such as nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), Cemiplimab (Libtayo), pidilizumab (CureTech), and atezolizumab (Roche), and PD-L1 inhibitors such as atezolizumab, durvalumab, and avelumab. Additional therapeutic agents suitable for use in combination (before, after, and / or concurrently with the administration of the compounds, salts, prodrugs, compositions of the disclosure) with the compositions and methods disclosed herein include, but are not limited to, ibrutinib (IMBRUVICA®), ofatumumab (ARZERRA®), rituximab (RITUXAN®), bevacizumab (AVASTIN®), trastuzumab (HERCEPTIN®), trastuzumab emtansine (KADCYLA®), imatinib (GLEEVEC®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), catumaxomab, ibritumomab, ofatumumab, tositumomab, brentuximab, alemtuzumab, gemtuzumab, erlotinib, gefitinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, lestaurtinib, axitinib, cediranib, lenvatinib, nintedanib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, lestaurtinib, ruxolitinib, pacritinib, cobimetinib, selumetinib, trametinib, binimetinib, alectinib, ceritinib, crizotinib, aflibercept, adipotide, denileukin diftitox, mTOR inhibitors such as Everolimus and Temsirolimus, hedgehog inhibitors such as sonidegib and vismodegib, CDK inhibitors such as CDK inhibitor (palbociclib), inhibitors of GM-CSF, CSF1, GM-CSFR, or CSF1R, in addition to anti-thymocyte globulin, lenzilumab and mavrilimumab. Other immunotherapies that may be used in combination with the compounds, salts, prodrugs, and compositions of the disclosure include T cell therapies.

[0296] In some embodiments, additional appropriate therapeutic agents are antiinflammatory agents. Anti-inflammatory agents or drugs include, but are not limited to, steroids and glucocorticoids (including betamethasone, budesonide, dexamethasone, hydrocortisone acetate, hydrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone), nonsteroidal anti-inflammatory drugs (NSAIDS) including aspirin, ibuprofen, naproxen, methotrexate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamide and mycophenolate. Exemplary NSAIDs include ibuprofen, naproxen, naproxen sodium, Cox-2 inhibitors, and sialylates. Exemplary analgesics include acetaminophen, oxycodone, tramadol of proporxyphene hydrochloride. Exemplary glucocorticoids include cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, or prednisone. Exemplary biological response modifiers include molecules directed against cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors, such as the TNF antagonists, (e.g., etanercept (ENBREL®), adalimumab (HUMIRA®) and infliximab (REMICADE®), chemokine inhibitors and adhesion molecule inhibitors. The biological response modifiers include monoclonal antibodies as well as recombinant forms of molecules. Exemplary DMARDs include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine, Gold (oral (auranofin) and intramuscular), and minocycline.

[0297] In some embodiments, additional appropriate therapeutic agents are selected from cytokines, such as lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N- methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor (HGF); fibroblast growth factor (FGF); prolactin; placental lactogen; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors (NGFs) such as NGF-beta; platelet-growth factor; transforming growth factors (TGFs) such as TGF-alpha and TGF-beta; insulin-like growth factor-I and -II; erythropoietin (EPO, Epogen®, Procrit®); osteoinductive factors; interferons such as interferon-alpha, beta, and -gamma; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte- CSF (G-CSF); interleukins (ILs) such as IL-1, IL-lalpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; IL-15, a tumor necrosis factor such as TNF-alpha or TNF-beta; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture, and biologically active equivalents of the native sequence cytokines.

[0298] In another embodiment, additional appropriate therapeutic agents are selected from the following: (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, pentazocine, or difelikefalin; (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen (including without limitation intravenous ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac (including without limitation ketorolac tromethamine (e.g., Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, i.v. meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; COX-2 inhibitor; (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental; (4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; (5) a histamine (Hl) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; (6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

[0400] (8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2-[4- (3-fluorophenyl)-4-hydroxy-l- piperidinyl]-l-hydroxyethyl- 3,4-dihydro-2(lH)-quinolinone; (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5- methane-sulfonamido-1, 2,3,4- tetrahydroisoquinolin-2-yl)-5- (2-pyridyl) quinazoline;(10) a tricyclic antidepressant, e.g. desiprainine, imipramine, amitriptyline or nortriptyline;(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate; (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]- 8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H- [l,4]diazocino[2,l-g][l,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]-l,2- dihydro-3H-l,2,4- triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2- methoxy-5-(trifluoromethoxy)phenyl]- methylamino]-2-phenylpiperidine (2S,3S); (13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (15) a coal-tar analgesic, in particular paracetamol; (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300); (18) a beta-adrenergic such as propranolol; (19) a local anesthetic such as mexiletine; (20) a corticosteroid such as dexamethasone; (21) a 5-HT receptor agonist or antagonist, particularly a 5-HTlB / lDagonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; (22) a 5-HT2Areceptor antagonist such as R(+)-alpha-(2,3-dimethoxy- phenyl)-l-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907); (23) a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine; (24) Tramadol®, Tramadol ER (Ultram ER®), i.v. Tramadol, Tapentadol ER (Nucynta®); (25) a PDE5 inhibitor, such as 5-[2-ethoxy-5-(4-methyl-l- piperazinyl-sulphonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3- d]pyrimidin-7-one (sildenafil), (6R,12aR)- 2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2',r:6,l]-pyrido[3,4-b]indole- 1,4-dione (IC-351 or tadalafil) , 2- [2-ethoxy-5 -(4-ethyl-piperazin-l-yl-l-sulphonyl)-pheny 1] -5 -methyl-7- propyl- 3H-imidazo[5,l-f][l,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3- ethyl-2-(l- ethyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)- 3-ethyl-2-(l-isopropyl-3-azetidinyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4- ethylpiperazin-l-ylsulphonyl)pyridin- 3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H- pyrazolo[4,3- d]pyrimidin-7-one, 4- [(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]-N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(l- methyl-7-oxo-3-propyl-6,7- dihydro-lH- pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide; (26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (l[alpha],3[alpha],5[alpha])(3-amino-methyl- bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid,(25.45)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6- (aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl-cyclohexylmethyl)- 4H-[l,2,4]oxadiazol-5-one, C-[l-(lH-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(35.45)-(1- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5- methyl-octanoic acid, (3R,4R,5R)-3- amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)- 3-amino-4,5-dimethyl-octanoic acid; (27) a cannabinoid such as KHK-6188; (28) metabotropic glutamate subtype 1 receptor (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, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)- reboxetine; (31) a dual serotonin-noradrenaline 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-[(l- iminoethyl)amino]ethyl]- L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2- [(1- iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l- iminoethyl)amino]-5- heptenoic acid, 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-thiazolyl)-butyl]thio]-S-chloro-S- pyridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5- thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio] -5 -thiazolebutanol, 2- [ [ (1R , 3 S)-3 -amino-4- hydroxy-l-(5 - thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(lR,3S)-3-amino-4- hydroxy-l-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3- chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide; (33) an acetylcholinesterase inhibitor such as donepezil; (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6- dimethyl- 1H- imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(15)-l- ({ [5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid; (35) a leukotriene B4 antagonist; such as l-(3-biphenyl-4-ylmethyl-4-hydroxy- chroman-7-yl)- cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)-3-[6- (4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870; (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3, 4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-l-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3- pyridylmethyl)-!, 4-benzoquinone (CV-6504); (37) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream (ZRS-201) or eslicarbazepine acetate; (38) a NaV1.7 blocker, such as XEN-402, XEN403, TV-45070, PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074 (Vixotrigine), BIIB-095, ASP-1807, DSP- 3905, OLP-1002, RQ- 00432979, FX-301, DWP-1706, DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in W02011 / 140425 (US2011 / 306607); WO2012 / 106499 (US2012196869); WO2012 / 112743 (US2012245136);WO2012 / 125613 (US2012264749), WG2012 / 116440 (US2014187533), W02011026240 (US2012220605), US8883840, US8466188, W02013 / 109521 (US2015005304), CN111217776, W02020 / 1 17626, WO2021 / 252822, WO2021 / 252818, WO2021 / 252820, WO2014 / 201173, WO2012 / 125973, WO2013 / 086229, WO2013 / 134518,WG2014 / 201206, or W02016 / 141035 the entire contents of each application hereby incorporated by reference; (38a) a NaV1.7 blocker such as (2-benzylspiro[3,4- dihydropyrrolo[l,2-a]pyrazine-l,4’- piperidine]- l'-yl)-(4-isopropoxy-3-methyl- phenyl)methanone, 2,2,2-trifluoro-l-[l'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[l,2- a]pyrazine-l ,4'- piperidine]-6-yl]ethanone, [8-fluoro-2-methyl-6-(trifhioromethyl)spiro[3,4-dihydropyrrolo[l,2- a]pyrazine-l,4'-piperidine]-l'-yl]-(4- isobutoxy-3-methoxy-phenyl)methanone, 1 -(4-benzhydrylpiperazin- l-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4’-piperidine]-r- yl]methanone, [8-fluoro-2- methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[l ,2- a]pyrazine-l ,4'-piperidine]-l'-yl]-(5-isopropoxy- 6-methyl-2-pyridyl)methanone, (4- isopropoxy-3-methyl-phenyl)-[2-methyl-6-( 1 , 1 ,2,2,2- pentafluoroethyl)spiro[3,4- dihydropyrrolo[l,2-a]pyrazine-l,4’-piperidine]-r-yl]methanone, 5-[2-methyl- 4-[2- methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[ 1 ,2-a]pyrazine- 1 ,4'-piperidine]- 1 carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6- (trifluoromethyl)spiro[3 ,4- dihydro-2H-pyrrolo[ 1 ,2-a]pyrazine- 1 , 4' -piperidine]- 1'- yl]methanone, 2,2,2-trifluoro-l-[l’-[3-methoxy-4- [2-(trifluoromethoxy)ethoxy]benzoyl]- 2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine- 1,4' -piperidine]- 6-yl]ethanone, 2,2,2- trifluoro-l-[r-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-l-[l'-(5- isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine- 1 ,4’-piperidine]-6- yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6- (trifluoromethyl)spiro| 3,4- dihydropyrrolol 1 ,2-a]pyrazine- 1 ,4'-piperidine |- 1 yl]methanone, 2,2,2-trifluoro- 1 - [ 1 '-(5- isopentyloxypyridine-2-carbonyl)-2,4-dimethyl- spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4’-piperidine]- 6-yl]ethanone, l-[(3S)-2,3- dimethyl-r-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[l,2- a]pyrazine-l,4'-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-r-yl]-[3- methoxy-4-[(lR)-l- methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-l-[l'-(5- isopropoxy-6-methyl-pyridine-2-carbonyl)- 2,4-dimethyl-spiro[3,4-dihydropyrrolo[l,2- a]pyrazine-l,4’-piperidine]-6-yl]ethanone, l-[l'-[4-methoxy-3- (trifluoromethyl)benzoyl]- 2-methyl-spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]-6-yl]-2,2- dimethyl- propan-l-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4- dihydropyrrolo[l,2-a]pyrazine-l,4’-piperidine]-r-yl]methanone, [2-methyl-6-(l- methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[l,2-a]pyrazine-l,4'-piperidine]- l’-yl]-[4-(3,3,3- trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4- bromophenyl)-3-[(l-methyl-2-oxo-4- piperidyl)sulfamoyl]benzamide or (3-chloro-4- isopropoxy-phenyl)-[2-methyl-6-(l,l,2,2,2- pentafluoroethyl)spiro[3,4- dihydropyrrolo[l,2-a]pyrazine-l,4’-piperidine]-r-yl]methanone. (39) a NaV1.8 blocker, such as PF-04531083, PF-06372865 and such as those disclosed in WO2008 / 135826 (US2009048306), W02006 / 011050 (US2008312235), WO2013 / 061205,(US2014296313), US20130303535, W02013131018, US8466188, W02013114250(US2013274243), W02014 / 120808 (US2014213616), W02014 / 120815 (US2014228371) WO2014 / 120820 (US2014221435), WO2015 / 010065 (US20160152561), WO2015 / 089361 (US20150166589), WO2019 / 014352 (US20190016671), WO2018 / 213426, W02020 / 146682, WO2020 / 146612, W02020 / 014243, W02020 / 014246, W02020 / 092187, W02020 / 092667(US2020140411), W02020 / 144375, W02020 / 261114, W02020 / 140959, WO2020 / 151728, WO2021 / 032074, WO2021 / 047622 (CN 112479996),WO2021 / 257490, WO / 2021 / 257420, WO2021 / 257418, WO2022 / 263498,WO2022 / 235558, WO2022 / 235859, CN112390745, CN111808019, CN112225695,CN112457294, CN112300051, CN112300069, CN112441969, and CN114591293, the entire contents of each application hereby incorporated by reference; (39a) a NaV1.8 blocker such as 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 4,5-dichloro-2-(4-fluorophenoxy)-N- (2-oxo- 1 ,2-dihydropyridin-4- yl)benzamide, 4,5-dichloro-2-(3-fluoro-4- methoxyphenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4- yl)benzamide, 2-(4-fluoro-2- methoxyphenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, N- (2-oxo-l,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-4- (perfluoroethyl)benzamide, 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-l,2- dihydropyridin-4- yl)benzamide, N-(2-oxo-l ,2-dihydropyridin-4-yl)-2-(4- (trifluoromethoxy)phenoxy)-5- (trifluoromethyl)benzamide, 2-(4-fluoro-2- methylphenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 2-(2- chloro-4-fluorophenoxy)-N-(2-oxo- 1 ,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2- dihydropyridin-4- yl)benzamide, 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)benzamide, 5- chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-l,2- dihydropyridin-4-yl)benzamide, 2-((5-fluoro-2- hydro xybenzyl)oxy)-N-(2-oxo- 1,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo- 1 ,2- dihydropyridin-4-yl)- 2-(o-tolyloxy)-5-(trifluoromethyl)benzamide, 2-(2,4-difluorophenoxy)-N-(2-oxo- 1 ,2- dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide, N-(2-oxo- 1 ,2-dihydropyridin-4-yl)- 2-(2- (trifluoromethoxy )phenoxy)-5-(trifluoromethyl)benzamide, 2-(4-fluorophenoxy)-N- (2-oxo- 1 ,2- dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide, 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-lH- pyridin-4-yl)-4-(trifluoromethyl)benzamide, [4-[[2-(4-fluoro-2- methyl-phenoxy)-4- (trifluoromethyl)benzoyl]amino]-2-oxo- 1 -pyridyl]methyl dihydrogen phosphate, 2-(4-fluoro-2-(methyl- d3)phenoxy)-N-(2-oxo- 1,2-dihydropyridin- 4-yl)-4-(trifluoromethyl)benzamide, (4-(2-(4-fluoro-2-(methyl- d3)phenoxy)-4- (trifluoromethyl)benzamido)-2-oxopyridin-l(2H)-yl)methyl dihydrogen phosphate, 3-(4- fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide, 3- (2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, 3-(2- chloro-4-methoxyphenoxy)-N- (3-sulfamoy]phenyl)quinoxaline-2-carboxamide, 3-(4- chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2- carboxamido)picolinic acid, 2-(2,4- difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 2- (4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide, 3-(2,4- difluorophenoxy)- N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3- sulfamoylphenyl)-2-(4- ( trifluoromethoxy )phenoxy)quinoline-3-carboxamide, N-(3- sulfamoylphenyl)-3-(4- (trifluoromethoxy )phenoxy)quinoxaline-2-carboxamide, 3-(4- chloro-2-methylphenoxy)-N-(3- sulfamoylphenyl)quinoxaline-2-carboxamide, 5-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2- carbox amido)picolinic acid, 3-(4-fluoro-2- methoxyphenoxy)-N-(2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)quinoxaline-2- carboxamide, 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- yl)quinoxaline-2- carboxamide, 3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide, N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, N-(4- carbamoylphenyl)- 3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide, 4-(3-(4- (trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid, N-(4- cyanophenyl)-3-(4-fluoro-2- methoxyphenoxy)quinoxaline-2-carboxamide, 5-(4,5- dichloro-2-(4-fluoro-2- methoxyphenoxy )benzamido)picolinic acid, 5-(2-(2,4- dimethoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(4,5-dichloro-2- (4-fluoro-2- methoxyphenoxy )benzamido)benzoic acid, 5-(2-(4-fluoro-2- methoxyphenoxy)-4,6- bis(trifluoromethyl)benzamido)picolinic acid, 4-(2-(4-fluoro-2- methoxyphenoxy)-4- (perfluoroethyflbenzamido)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 - (trifluoromethy l)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)-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)benzamide, 2-(2-chloro-4-fhiorophenoxy)-5-(difhioromethyl)-N-(3- sulfamoylphenyljbenzamide, 2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2- methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide, 5-chloro-2-(4-fluoro-2- methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2,4-dichloro-6-(4-fhioro-2-methylphenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 2-(4-fhioro-2-methylphenoxy)-N-(3- sulfamoylphenyl)-4,6- bis(trifluoromethyl)benzamide, 5-chloro-2-(2-chloro-4- fluorophenoxy)-N-(3- sulfamoylphenyl)benzamide, 2-(4-fluoro-2-methoxyphenoxy)-N- (3-sulfamoylphenyl)-4- ( trifluoromethoxy )benzamide, 2-(4-fluoro-2-methoxyphenoxy)- N-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide, 4,5-dichloro-2-(4- fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(4- fluoro-2-methoxyphenoxy)-4- (perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide, 5-fluoro-2-(4-fluoro-2- methylphenoxy)-N-(3-sulfamoylphenyl)benzamide, 2-(2-chloro-4-fluorophenoxy)-4- cyano-N-(3- sulfamoylphenyl)benzamide, N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- [2-methoxy-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro- phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide, 4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]- 3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, 4-[[3-chloro-2-fluoro-6-[2- methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, 4- [[2- fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro- phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzamide, 4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2- carboxamide, N-(3- carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4- fluoro-phenyl)-2-fluoro-6-[2-methyl-4- (trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2- methoxy-4-(trifluoromethoxy)phenoxy|benzamide, N-(2-carbamoyl-4-pyridyl)-3-fluoro- 5- [2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4- carboxamide, 4-[[6-[2- (difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- (trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro- phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3- trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, N-(4-carbamoyl-3-fluoro- phenyl)-2-fluoro-6- [2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide, 4-[[2-fluoro-6-[2- (trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(l , 1 ,2,2,2-pentafluoroethyl)benzamide, 4- [ [4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4- trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4- fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzamide, 4-[[4- cyclopropyl-2-fluoro-6-[2-methoxy-4- (trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2- carboxamide, N-(3-carbamoyl-4- fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide, 5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3- (trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide, N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6- (4-fluorophenoxy)-3-(trifluoromethyl)benzamide, or 4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;(40) a combined NaV1.7 and NaV 1.8 blocker, such as DSP-2230, Lohocla201 or BL-1021;(41) a 5-HT3 antagonist, such as ondansetron; (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof; (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 stimulant, such as senrebotase; (47) an angiotensin II antagonist, such as EMA-401; (48) acetaminophen (including without limitation intravenous acetaminophen (e.g., Ofirmev®)); (49) bupivacaine (including without limitation bupivacaine liposome injectable suspension (e.g., Exparel®) bupivacaine ER (Posimir), bupivacaine collagen (Xaracoll) and transdennal bupivacaine (Eladur®)); and (50) bupivacaine and meloxicam combination (e.g., HTX-011).

[0299] In one embodiment, the additional appropriate therapeutic agents are selected from V- 116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine / amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 or ARC-4558.

[0446] In another embodiment, the 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- lH-pyrazole-5-carboxamide; or 3-((4-(4-( trifluoromethoxy )phenyl)- lH-imidazol-2-yl)methyl)oxetan-3-amine. In another embodiment, the additional therapeutic agent is selected from a GlyT2 / 5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulator such as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, or MDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitor such as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonist such as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such as NEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or a p75NTR-Fc modulator such as LEVI-04. In another embodiment, the additional therapeutic agent is oliceridine or ropivacaine (TLC590). In another embodiment, the additional therapeutic agent is a NaV1.7 blocker such as ST-2427, ST-2578 and thosedisclosed in WO2010 / 129864, WO2015 / 157559, WO2017 / 059385, WO2018 / 183781, WO2018 / 183782, W02020 / 072835, and / or WO2022 / 036297 the entire contents of each application hereby incorporated by reference. In another embodiment, the additional therapeutic agent is ASP18071, CC-8464, ANP-230, ANP-231, NOC-lOO, NTX-1175, ASN008, NW3509, AM-6120, AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (UnafraTM), brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88, LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739, KLS- 2031 , MEDI 7352, or XT- 150. Tn another embodiment, the additional therapeutic agent is Olinvyk, Zynrelef, Seglentis, Neumentum, Nevakar, HTX-034, CPL-01, ACP-044, HRS- 4800, Tarlige, BAY2395840, LY3526318, Eliapixant, TRV045, RTA901, NRD1355-E1, MT-8554, LY3556050, AP-325, tetrodotoxin, Otenaproxesul, CFTX-1554, Funapide, iN1011-N17, JMKX000623 / ODM-111, ETX-801, OLP-1002, ANP-230 / DSP-2230, iN1011-N17, DSP-3905 or ACD440. In another embodiment, the additional therapeutic agent is a sodium channel inhibitor (also known as a sodium channel blocker).

[0300] As used herein, the term “local anesthetic” means a drug which provides local numbness or pain relief. In some or any embodiments, local anesthetic includes aminoacylanilide compounds (in some or any embodiments, lidocaine, prilocaine, bupivacaine, ropivacaine, and mepivacaine) and related local anesthetic compounds having various substituents on the ring system or amine nitrogen; aminoalkyl benzoate compounds (in some or any embodiments, procaine, chloroprocaine, propoxycaine, hexylcaine, tetracaine, cyclomethycaine, benoxinate, butacaine, and proparacaine) and related local anesthetic compounds; cocaine; amino carbonate compounds (in some or any embodiments, diperodon); N-phenylamidine compounds (in some or any embodiments, phenacaine); N-aminoalkyl amide compounds (in some or any embodiments, dibucaine); aminoketone compounds (in some or any embodiments, fahcaine and dyclonine); and amino ether compounds (in some or any embodiments, pramoxine and dimethisoquien).

[0301] In one embodiment, the therapeutic compositions and treatments disclosed herein may precede, be co-current with and / or follow another treatment or agent by intervals ranging from minutes to weeks. In embodiments where agents are applied separately to a cell, tissue or organism, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic agents would still be able to exert an advantageously combined effect on the cell, tissue or organism. For example, in such instances, it is contemplated that one may contact the cell, tissue or organism with two, three, four or more agents or treatments substantially simultaneously(i.e., within less than about a minute). In other aspects, one or more therapeutic agents or treatments may be administered or provided within 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more, and any range derivable therein, prior to and / or after administering another therapeutic agent or treatment.

[0302] The amount of additional therapeutic agent present in the compounds, salts, prodrugs, and compositions of this disclosure, or administered in combination with the compounds, salts, prodrugs, and compositions of the disclosure, may be more, less, or no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. In some embodiments, the combination is synergistic. In some embodiments, the combination is additive. As used herein, the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and / or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[0303] The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10% to 1000% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent. The compounds, prodrugs, and salts of this disclosure or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the disclosure, in another embodiment, includes a composition for coating an implantable device comprising a compound, prodrug, or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another embodiment, the disclosure includes an implantable device coated with a composition comprising a compound, prodrug, or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0304] Another embodiment of the disclosure relates to inhibiting K+ channel activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of the disclosure, prodrug, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, faeces, semen, tears, or other body fluids or extracts thereof. Inhibition of K+ channel activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of potassium channels in biological and pathological phenomena; and the comparative evaluation of new potassium channel inhibitors.

[0305] RADIOLABELED ANALOGS OF THE COMPOUNDS OF THE DISCLOSURE

[0306] In another embodiment, the disclosure relates to radiolabeled analogs of the compounds of the disclosure. As used herein, the term “radiolabeled analogs of the compounds of the disclosure” refers to compounds that are identical to the compounds ofthe disclosure, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the disclosure. As used herein, the term “radioisotope’' refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36C1, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980). The radiolabeled analogs may be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and / or carbon-14 (14C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. In another embodiment, the disclosure relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure. In another embodiment, the disclosure relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure. In another embodiment, the disclosure relates to methods of inhibiting voltage-gated potassium channels and methods of treating or lessening the severity of various diseases and disorders, including pain, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure. In another embodiment, the disclosure relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0307] In another embodiment, the disclosure relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure. In another embodiment, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, may be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0308] Also provided herein are isotopically enriched compounds. Isotopic enrichment (in some or any embodiments, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD’*), and toxicity profiles, has been demonstrated previously with some classes of drugs. Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrees the production of deleterious metabolites in specific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination therapy is intentional or not. Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C — H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C — H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. High DKIE values may be due in part to a phenomenon known as tunnelling, which is a consequence of the uncertainty principle. Tunnelling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon. Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life=12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitutionof tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S, or 36S for sulphur, 15N for nitrogen, and 170 or 180 for oxygen, may lead to a similar kinetic isotope effect.

[0309] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. In some or any embodiments, such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C — H) bond to either a carbon-oxygen (C — O) or carboncarbon (C — C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.

[0310] KITS

[0311] Certain aspects of the disclosure also encompass kits for performing the methods of the disclosure, such as treatment of K+-channel-associated conditions (e.g., pain). Embodiments relate to kits comprising the therapeutic pharmaceutical compositions of the disclosure. The kits may be useful in the treatment methods of the disclosure.

[0312] Kits may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a composition which includes a probe that is useful for prognostic or non-prognostic applications, such as described above. The label on the container may indicate that the composition is used for a specific therapeutic or non-therapeutic application, and may also indicate directions for either in vivo or in vitro use, such as those described above. The kit may comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0313] In some embodiments, when the components of the kit are provided in one and / or more liquid solutions, the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly useful. In some cases, the container means may itself be asyringe, pipette, and / or other such like apparatus, or may be a substrate with multiple compartments for a desired reaction.

[0314] Some components of the kit may be provided as dried powder(s). When reagents and / or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means. The kits may also comprise a second container means for containing a sterile acceptable buffer and / or other diluent.EXAMPLESSUMMARY

[0315] FIG. 1 illustrates the formulas of 7 of the compounds tested, which are examples of the compounds 1 to IV. Compounds V to XI were tested at different levels: results on voltage recordings are presented in FIG.s 2A-D, FIG.s 3A-D, FIG.s 4A-D, FIG.s 5A-D, FIG.s 6A-D, FIG.s 7A-D, FIG.s 8A-D, FIG.s 9A-D, FIG.s 10A-D, FIG.s 11 A-D and FIG.s 12A-D, whereas results on ionic currents are presented in FIGs 13 A-B, FIG. 14, FIG. 15, FIG. 16, FIG. 17, FIG. 18, FIG. 19 and FIG.s 20A-G; finally, the results of in vivo efficacy, are presented in FIG.s 21A-B, FIG. 22, FIG. 23, FIG. 24, FIG. 25, FIG. 26, FIG. 27 and FIG. 28. The experimental details and conclusions are described below.

[0316] The oxazolidone-derived compounds of the disclosure result from a medicinal chemistry effort in which focus was given to the compound-mediated effects on excitability patterns found in small diameter dorsal root ganglia neurons (sdDRGns). SdRGns have a key role in ‘pain-sensing’, and, in particular, sdDRGns derived from rat pain models, such as the chronic constriction injury of the sciatic nerve (CCI). The sdDRGns obtained from the ipsilateral leg (injured leg) from the latter show hyperexcitability, consistent with a ‘pain condition’. The paradigm here is that a marked decrease of such hyperexcitability caused by a given compound identifies it as a candidate for an analgesic. Excitability was studied with current clamp studies from sdDRGns. The effect in excitability was further investigated by recordings of the underlying voltage activated K+ currents, and the effect of the compounds on those were characterized.Finally, potential hits were tested using rat animal models for chronic and acute pain, revealing analgesic effects with important potential for human application.

[0317] The results of the oxazolidone-derived compounds on action potential firing were consistent with a drug-evoked marked decrease neuronal excitability. The decrease, and in cases total abolishment of action-potential firing was observed in both, spontaneous firing and evoked firing. Interestingly, such drug evoked decrease or disappearance of actionpotentials were consistently preceded by a transient increase in firing rate which, in turn, appear to cause nerve firing failure.

[0318] The K+currents affected by the identified compounds, recorded from sdDRGns (and sdTGns) under whole-cell voltage-clamp techniques, were object of intensive research. The use of rat pain models was fundamental to perform previous target validation, i.e., to determine the K+current component differentially expressed in pain conditions (the slow decaying current component, Islow). At the end, it was concluded that the K+current component affected with pain condition is the one principally modulated (diminished) by the compound(s) of interest. The nature of the recorded modulatory effect on the currents was studied by monitoring several biophysical parameters, such as voltage dependencies of activation and inactivation and kinetics. Results were also confirmed in small diameter trigeminal ganglion neurons (sdTGns) that showed identical pharmacological effects in very similar K+current profiles.

[0319] Both acute and chronic pain involves the complex alteration of the processing and conduction of electrical signals from peripheral nerves to the central nervous system (CNS). The electrical excitability and activity levels of a normal condition, or those related to chronic pain, are primarily a result of the inflow or outflow of charged metal ions such as sodium (Na+), potassium (K+) or calcium (Ca2+) through membrane ion channels (Nav, Kv or Cav, respectively), causing the generation, propagation and transmission of electric signals throughout the cell and from cell to cell. In chronic pain, the neuronal network underlying pain signalling is altered, with abnormal ionic currents brought by altered expression and biophysics of the underlying channels, resulting in excessive and sustained neuronal excitability and activity. Therefore, an effective analgesic acting at the peripheric nervous system level, may need to be able to suppress the hyperexcitability of the pain signalling network, restoring the physiologic expression and / or biophysical profiles of the functioning channels, and, in turn, restoring the network activity to resting levels.

[0320] Small-diameter DRG neurons sdDRGns (c-fibers), also called pain-sensing neurons, are located outside of the spinal cord that carry the nociceptive input to the CNS(i.e, leading to ‘pain’). Usually, in normal conditions, these neurons have little spontaneous firing activity (e.g Ly et al., 2018), a situation that changes during pain episodes and, indeed with chronic pain. The present underlying therapeutics strategy is to target key ion channels localized in such neurons in the DRG ganglia and those in trigeminal ganglia (TG), to “switch-off’ such ‘pain-induced’ hyperexcitability. Consequently, the transmission of the “pain signal” to the CNS is interrupted or diminished, preventing, this way, all the sensitization processes upwards and, ultimately, brain perception of pain.

[0321] Several ion channels have been identified as key effectors in pain propagation. The ionic currents produced by some of those ions are particularly experessed in these painsensing neurons. Therefore, specifically modulating their activity would block pain without affecting other body functions. It is disclosed herein that Oxazolidone-derived compounds are modulators of slow voltage- activated K+currents recorded from the small diameter (sdDRGnssdDRGns also sdTGns, thought to correspond with c-fibers), modulation of which that underlies a marked inhibition on hyperexcitability on c-fibres, and, consequently, resulting into analgesia.

[0322] EXEMPLARY METHODS FOR SYNTHESIS OF EXEMPLARY COMPOUNDS

[0323] Synthesis of compound V

[0324] Synthesis of precursor to compound V: (S,E)-3-benzylidene-5- ethyldihydrofuran-2(3H)-one

[0325] At -78°C and under inert atmosphere, 2.5 M n-BuLi (960 pl, 2.40 mmol) was added gradually to a solution of ethyl ethenyl ether 48%wt (500 pl, 2.40 mmol) and anhydrous tetrahydrofuran (4.4 ml). After 15 minutes, (S)-(-)-l,2-epoxybutane (103 pl, 1.20 mmol) was added and the reaction mixture was stirred for 5 min. Then boron trifluoride etherate ca. 48% BF3 (304 pl, 2.40 mmol) was added dropwise. The reaction mixture was then stirred for 2 hours at -78°C. Next, benzaldehyde (244 pl, 2.40 mmol) was added followed by dropwise addition of boron trifluoride etherate ca. 48% BF3 (304 pl, 2.40 mmol). The reaction mixture was stirred for 1 hour at -78°C whereafter it was allowed to warm to room temperature. Methanol (486 pl, 12.0 mmol) was added dropwise and the reaction mixture was stirred at room temperature of 16 hours. The mixture was partitioned between sat. aq. NaHCOi and diethyl ether (10 mL). The organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude material was purified by silica column chromatography to afford (S,E)-3-benzylidene-5- ethyldihydrofuran-2(3H)-one (170 mg, 35%). [M+H]+= 203. ’H NMR (400 MHz, CDCI3)5 7.59 - 7.23 (m, 7H), 4.62 - 4.52 (m, 1H), 3.34 (ddd, J = 17.5, 7.9, 2.8 Hz, 1H), 2.84 (ddd, J = 17.5, 5.6, 3.0 Hz, 1H), 1.88 - 1.66 (m, 2H), 1.55 (d, J = 1.3 Hz, 1H), 1.05 (t, J = 7.4 Hz, 3H).

[0326] Synthesis of compound V: (S,Z)-3-benzylidene-5-ethyldihydrofuran-2(3H)- one

[0327] A mixture of (S,E)-3-benzylidene-5-ethyldihydrofuran-2(3H)-one (110 mg, 0.544 mmol), copper(II) acetate (4.94 mg, 0.027 mmol) and S-(-) BINAP (16.93 mg, 0.027 mmol) in anhydrous tetrahydrofuran (1 .8 mL) was stirred for 2 hours at room temperature with blue led light. The mixture was concentrated under and purified by silica column chromatography to afford (S,Z)-3-benzylidene-5- ethyldihydrofuran- 2(3H)-one (32.1 mg, 29 % yield). [M+H]+= 203. H NMR (400 MHz, CDCh) 5 7.86 - 7.79 (m, 2H), 7.42 - 7.30 (m, 3H), 6.96 (t, J = 2.5 Hz, 1H), 4.49 (p, J = 6.7 Hz, 1H), 3.18 (ddd, J = 16.4, 7.3, 2.2 Hz, 1H), 2.78 (ddd, J = 16.3, 6.7, 2.7 Hz, 1H), 1.89 - 1.63 (m, 2H), 1.03 (t, 7 = 7.4 Hz, 3H).

[0328] Synthesis of compounds VI, VII, X and XII

[0329] Synthesis of precursor for compound VI and VII : 5-ethyloxazolidin-2-one

[0330] A suspension of l-amino-butan-2-ol (25 g, 0.28 mol), ethyl carbonate (35 g, 0.29 mol) and potassium carbonate (7.8 g, 56 mmol) was heated to 150 °C for 3 hours. The mixture was cooled to room temperature and stirred for 16 hours. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the combined organics were washed with brine, dried and concentrated a colorless oil. The crude product was purified with silica column chromatography to afford 5-ethyloxazolidin-2-one (21.6 g, 64 %) as a colorless solid, m / z = 115. *H NMR (400 MHz, CDC13) 6 6.04 (s, 1H), 4.58 (dtd, J = 8.3, 7.0, 5.8 Hz, 1H), 3.67 (td, J = 8.4, 0.8 Hz, 1H), 3.25 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 1.91 - 1.56 (m, 2H), 1.01 (t, 7 = 7.5 Hz, 3H).

[0331] Synthesis of compound VI: 3-benzyl-5-ethyloxazolidin-2-one

[0332] To a solution of 5-ethyloxazolidin-2-one (10.0 g, 86.9 mmol) and sodium hydride (7.64 g, 60% Wt, 191 mmol) in DMF (250 mL) was added benzyl bromide (19.3 g, 13.4 mL, 113 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was carefully with water and then the solvents were removed in vacuo. Ethyl acetate and water were added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed several times with brine / water (1: 1) and lastly with brine, dried with sodium sulfate, filtered and concentratedin vacuo. The crude was directly purified with silica column yielding 3-benzyl-5- ethyloxazolidin-2-one (14.3 g, 76 %). [M+H]+=206. *H NMR (400 MHz, CDCh) 5 7.43 - 7.04 (m, 5H), 4.51 - 4.27 (m, 3H), 3.46 (t, J = 8.5 Hz, 1H), 3.02 (dd, J = 8.6, 7.0 Hz, 1H), 1.83 - 1.42 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0333] Synthesis of compound VII: 5-ethyl-3-[(pyridin-3-yl)methyl]-l,3-oxazolidin- 2-one

[0334] To a solution of 5-ethyloxazolidin-2-one (7.50 g, 65.1 mmol) and 3- (bromomethyl)pyridine hydrogen bromide (24.7 g, 97.7 mmol) in DMF (300 mL) was added sodium hydride (10.4 g, 60% Wt, 261 mmol) and the mixture was stirred for 16 hours. The mixture was quenched with water and ethyl acetate was added. Tthe layers were separated and the water layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica column chromatography yielding 5- ethyl-3-(pyridin-3-ylmethyl)oxazolidin-2- one (13.4 g, 70%). [M+H]+=207.]H NMR (400 MHz, DMSO) 5 8.57 - 8.47 (m, 2H), 7.70 (dt, J = 7.8, 2.0 Hz, 1H), 7.41 (dd, J= 7.9,4.8 Hz, 1H), 4.52 - 4.31 (m, 3H), 3.54 (t, J = 8.5 Hz, 1H), 3.31 (s, 2H), 3.08 (dd, J = 8.7,6.8 Hz, 1H), 1.69 - 1.52 (m, 2H), 0.87 (q, J = 6.6 Hz, 3H).

[0335] Synthesis of compound X: 3-(2-(benzyloxy)ethyl)-5-ethyloxazoIidin-2-one

[0336] To a solution of 5-ethyloxazolidin-2-one (50 mg, 0.43 mmol) and benzyl-2- bromoethylether (0. 12 g, 0.56 mmol) in DMF (2.0 mL) was added sodium hydride (35 mg, 60% wt, 0.87 mmol) and the mixture was stirred for 16 hours. The reaction was quenched by the slow addition of water and this was filtered through a 0.45 uG filter. The crude product was purified using preparative HPLC to afford 3-(2-(benzyloxy)ethyl)-5- ethyloxazolidin-2-one (0.11 g, 79%) as a colorless oil. [M+H]+= 250.2. 1H (400 MHz, CDC13) 5 7.40 - 7.27 (m, 5H), 4.57 - 4.47 (m, 2H), 4.47 - 4.35 (m, 1H), 3.76 - 3.60 (m, 3H), 3.54 - 3.39 (m, 2H), 3.29 (dd, J = 8.7, 7.0 Hz, 1H), 1.82 - 1.61 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0337] Synthesis of compound XII: 5-ethyl-3-((6-methylpyridin-2- yl)methyl)oxazolidin-2-one

[0338] To an ice-cold solution of 5-ethyloxazolidin-2-one (1.00 g, 8.69 mmol) and 2- (bromomethyl)-6-methylpyridine (2.42 g, 13.0 mmol) in DMF (40 mL) was added sodium hydride (1.39 g, 60% Wt, 34.7 mmol) portionwise and the mixture was stirred for 16 hours. The mixture was quenched with water and then ethylacetate and water were added and the layers were separated. The aqueous layer was extracted once more with ethylacetate. Theorganic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude material was purified by silica column chromatography and then by preparative HPLC to afford 5-ethyl-3-((6-methylpyridin-2- yl)methyl)oxazolidin-2-one (1.16g, 58%). [M+H]+=221. 1H NMR (400 MHz, CDC13) 5 7.58 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 4.57 - 4.41 (m, 3H), 3.64 (t, J = 8.6 Hz, 1H), 3.22 (dd, J = 8.6, 7.0 Hz, 1H), 2.54 (s, 3H), 1.85 - 1.60 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0339] Synthesis of compounds VTIT and XI

[0340] Synthesis of precursor for 5-((benzyIoxy)methyl)oxazolidin-2-one, precursor for compounds VIII and XI: l-amino-3-(benzyloxy)propan-2-oI, A solution of 2- ((benzyloxy)methyl)oxirane (50 g, 0.30 mol) in ammonium hydroxide (880 g 25.1 mol) was stirred at 25 °C for 16 hours. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica column chromatography yielding l-amino-3 -(benzyloxy )propan-2-ol (55 g, 65%) as a white solid. |M+H|+=182. H NMR (400 MHz, CDCh) 5 7.40 - 7.23 (m, 5H), 4.56 (s, 2H), 3.77 (tt, J = 6.7, 4.1 Hz, 1H), 3.56 - 3.40 (m, 2H), 2.83 (dd, 7 = 12.9, 4.1 Hz, 1H), 2.73 (dd, 7= 12.9, 7.1 Hz, 1H).

[0341] Synthesis of precursor for compound VIII and XI: 5- ((benzyloxy)methyl)oxazolidin-2-one

[0342] A suspension of l-amino-3-(benzyloxy)propan-2-ol (37.89 g, 209.1 mmol), ethyl carbonate (25.93 g, 219.5 mmol) and potassium carbonate (5.779 g, 41.81 mmol) was heated to 150 °C for 3 hours. The mixture was cooled to room temperature and stirred for 16 hours. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the combined organics were washed with brine, dried and concentrated. The crude product was purified with silica column chromatography to afford 5-((benzyloxy)methyl)oxazolidin-2-one (21.9 g, 48 %) as a colorless solid. [M+H]+=208.:H NMR (400 MHz, CDCh) 5 7.41 - 7.23 (m, 5H), 6.11 (s, 1H), 4.76 (ddt, 7 = 9.2, 6.5, 4.8 Hz, 1H), 4.59 (s, 2H), 3.72 - 3.53 (m, 3H), 3.52 - 3.38 (m, 1H).

[0343] Synthesis of compound VIII: 5-[(benzyloxy)methyl]-3-[(pyridin-4-yl)methyI]- l,3-oxazolidin-2-one

[0344] To a cooled (with ice) solution of 5-((benzyloxy)methyl)oxazolidin-2-one (21.9 g, 106 mmol) and 4-(bromomethyl)pyridine hydrogen bromide (40.1 g, 159 mmol) in DMF(850 mL) was added sodium hydride (16.9 g, 60% Wt, 423 mmol) and the mixture was stirred for 3 hours. The mixture was carefully with water and then the solvents were removed in vacuo. Ethyl acetate and water were added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed several times with brine / water (1:1) and lastly with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified with silica column yielding 5-((benzyloxy)methyl)-3-(pyridin-4-ylmethyl)oxazolidin-2-one (22 g, 66 %). [M+H]+=299.!H NMR (400 MHz, CDC13) 5 8.53 - 8.43 (m, 2H), 7.42 - 7.24 (m, 5H), 7.21 - 7.12 (m, 2H), 4.75 - 4.50 (m, 4H), 4.31 (d, J = 16.0 Hz, 1H), 3.75 - 3.36 (m, 4H).

[0345] Synthesis of compound XI: 3-(2-(benzyloxy)ethyI)-5-((benzyloxy)methyl)oxazolidin-2-one

[0346] To a solution of 5-((benzyloxy)methyl)oxazolidin-2-one (70 mg, 0.34 mmol) and benzyl-2-bromoethylether (87 mg, 0.41 mmol) in DMF (2.0 mL) was added sodium hydride (27 mg, 60% Wt, 0.68 mmol). The suspension was stirred for 3 days and then quenched by the slow addition of water and this was filtered through a 0.45 uG filter. The crude was purified using preparative HPLC to afford 3-(2-(benzyloxy)ethyl)-5- ((benzyloxy)methyl)oxazolidin-2-one (0.12 g, 62%) as a colorless oil. [M+H]+= 342, *H NMR (400 MHz, CDC13) 8 7.39 - 7.24 (m, 10H), 4.69 - 4.42 (m, 5H), 3.72 (t, J = 8.9 Hz, 1H), 3.68 - 3.38 (m, 7H).

[0347] Synthesis of compound IX: 5-((3-(furan-3-yl)propoxy)methyl)-3-(3-(furan-3- yl)propyl)oxazolidin-2-one

[0348] To a solution of 5-(hydroxymethyl)oxazolidin-2-one (40 mg, 0.34 mmol) and 3- (furan-3-yl)propyl 4-methylbenzenesulfonate (287 mg, 1.02 mmol) in DMF (2.0 mL) was added NaH (68.3 mg, 60% Wt, 1.71 mmol). The suspension was stirred for 1 day. The reaction was quenched by the slow addition of water and this was filtered through a 0.45 uG filter. The crude was purified using preparative HPLC to afford 5-((3-(furan-3- yl)propoxy)methyl)-3-(3-(furan-3-yl)propyl)oxazolidin-2-one (40.4 mg, 36%). [M+H]+= 334. 1H NMR (400 MHz, CDC13) 57.38 - 7.31 (m, 2H), 7.25 - 7.22 (m, 1H), 7.22 - 7.17 (m, 1H), 6.30 - 6.21 (m, 2H), 4.64 - 4.55 (m, 1H), 3.62 - 3.54 (m, 3H), 3.52 (t, J = 6.3 Hz, 2H), 3.40 (dd, J = 8.5, 6.2 Hz, 1H), 3.37 - 3.24 (m, 2H), 2.52 - 2.43 (m, 4H),1.87 - 1.76 (m, 4H).

[0349] Synthesis of compound XIII

[0350] Synthesis of precursor for (3-benzyl-2-oxooxazolidin-5-yl)methyl 4- methylbenzenesulfonate, precursor for compound XIII: 3-benzyl-5- (hydroxymethyl)oxazolidin-2-one

[0351] At room temperature, benzylamine (5.00 g, 46.7 mmol) was added to a solution of (chloromethyl)-oxirane (22.0 g, 0.239 mol), potassium carbonate (32 g, 0.23 mol), and triethylamine (24 g, 0.23 mol) in methanol (235.0 mL). The mixture was stirred for 16 hours at reflux. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica column chromatography to afford 3-benzyl-5- (hydroxymethyl)oxazolidin-2-one (1.82 g, 18%). [M+H]+=208.

[0352] Synthesis of precursor for compound XIII: (3-benzyl-2-oxooxazolidin-5- yl)methyl 4-methyIbenzenesuIfonate

[0353] To a solution of 3-benzyl-5-(hydroxymethyl)oxazolidin-2-one (1.84 g, 8.88 mmol) in dichlorometane (15 mL) at 0 °C were added triethylamine (1.80 g, 17.8 mmol) and p- toluenesulfonyl chloride (2.03 g, 10.7 mmol) in dichloromethane (12 mL). The reaction was stirred at 0 °C for 1 hour and at room temperature for 16 hours. The mixture was diluted with dichloro methane (25 mL) was washed with IM HC1 (25 mL). The organic layer was washed with sodium bicarbonate, dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified with flash chromatography to afford (3- benzyl-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (2.77 g, 82%). [M+H]+=262.

[0354] Synthesis of compound XIII; 3-benzyl-5-((4,4-difhioropiperidin-l- yl)methyl)oxazolidin-2-one

[0355] A mixture of (3-benzyl-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (1.07 g, 2.96 mmol), 4,4-difluoro-piperidine (716 mg, 5.91 mmol) and triethylamine (1.20 g, 11.8 mmol) in anhydrous tetrahydrofuran (5.0 mL) was heated in a microwave at 120 °C for 2 hours. The reaction was concentrated under reduced pressure. The crude material was purified by flash column chromatography and then by preparative HPLC to afford 3- benzyl-5-((4,4-difluoropiperidin-l-yl)methyl)oxazolidin-2-one (244 mg, 25%). [M+H]+=311. 1H NMR (400 MHz, CDC13) 5 7.40 - 7.26 (m, 5H), 4.60 (ddt, J = 8.6, 7.0, 5.0 Hz, 1H), 4.50 - 4.35 (m, 2H), 3.46 (t, J = 8.6 Hz, 1H), 3.17 (dd, J = 8.6, 7.0 Hz, 1H),2.70 - 2.55 (m, 6H), 2.00 - 1.83 (m, 4H).

[0356] Synthesis of compound XIV and XV

[0357] Synthesis of precursor for compound XIV and XV: 5-(hydroxymethyl)-3-((2- methylpyridin-4-yl)methyl)oxazolidin-2-one

[0358] 4-(Aminomethyl)-2-methylpyridine (1.00 g, 8.19 mmol) was added to a solution of (chloromethyl) -oxirane (3.80 g, 41.3 mmol), potassium carbonate (5.7 g, 41 mmol), and triethylamine (4.1 g, 41 mmol) in methanol (47.0 mL). The reaction was stirred at reflux for 16 hours. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude material was purified by purified by preparative HPLC to afford 5-(hydroxymethyl)-3-((2- methylpyridin-4-yl)methyl)oxazolidin-2-one (68 mg, 4%). [M+f I ]+=223.

[0359] Synthesis of compound XIV: 5-(((4-fhiorobenzyl)oxy)methyi)-3-((2- methylpyridin-4-yl)methyl)oxazolidin-2-one

[0360] At 0°C under a N2 atmosphere, sodium hydride (32.4 mg, 60% Wt, 0.810 mmol) was added to a solution of 5-(hydroxymethyl)-3-((2-methylpyridin-4- yl)methyl)oxazolidin- 2-one (120 mg, 0.540 mmol) and l-(bromomethyl)-4-fhiorobenzene (122 mg, 0.648 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 16 hours. The crude was purified with preparative HPLC to afford 5-(((4- fluorobenzyl)oxy)methyl)-3-((2-methylpyridin-4-yl)methyl)oxazolidin-2-one (71.6 mg, 36%). [M+H]+=331. 1H NMR (400 MHz, CDC13) 6 8.39 (d, J = 5.1 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.08 - 6.94 (m, 4H), 4.72 - 4.63 (m, 1H), 4.60 - 4.49 (m, 2H), 4.46 (d, J = 15.7 Hz, 1H), 4.32 (d, J = 15.8 Hz, 1H), 3.72 - 3.55 (m, 2H), 3.49 (t, J = 8.7 Hz, 1H), 3.41 - 3.31 (m, 1H), 2.51 (s, 3H).

[0361] Synthesis of compound XV; 5-((cyclopropyhnethoxy)methyl)-3-((2- methylpyridin-4-yl)methyl)oxazolidin-2-one

[0362] At 0°C under a N2 atmosphere, sodium hydride (18.0 mg, 60% Wt, 0.450 mmol) was added to a solution of 5-(hydroxymethyl)-3-((2-methylpyridin-4- yl)methyl)oxazolidin-2-one (68 mg, 0.306 mmol) and (bromomethyl)cyclopropane (50.0 mg, 0.373 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 16 hours. The crude was purified with preparative HPLC to afford 5- ((cyclopropylmethoxy)methyl)-3-((2-methylpyridin-4-yl)methyl)oxazolidin-2-one (23.0 mg, 26%). [M+H]+ =277. 1H NMR (400 MHz, CDC13) 5 8.47 (d, J = 5.1 Hz, 1H), 7.13 - 6.97 (m, 2H), 4.71 - 4.62 (m, 1H), 4.47 (d, J = 15.8 Hz, 1H), 4.35 (d, J = 15.7 Hz, 1H), 3.68 - 3.60 (m, 2H), 3.50 (t, J = 8.7 Hz, 1H), 3.43 - 3.30 (m, 3H), 2.56 (s, 3H), 1.09 - 0.97 (m, 1H), 0.62 - 0.45 (m, 2H), 0.25 - 0.14 (m, 2H).EXAMPLE 1IN VIVO AND EX VIVO PAIN MODELS

[0363] IN VIVO PAIN MODELS

[0364] NEUROPATHIC PAIN MODEL: CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE - CCI PAIN MODEL

[0365] Ethics and animal monitorization : All the procedures involving animal subjects (Rattus novergicus Wistar Han) were carried out at the rodent house of NOVA Medical School (NMS) of Universidade Nova de Lisboa (Portugal), in accordance with the institution’ s Ethics Committee and Directive 86 / 609 / EEC (14 / 2015 / CEFCM), and with the European and Portuguese guidelines for the protection of animals used for scientific purposes (European Union Directive 2010 / 63 / EU, transposed to Portuguese Legislation by the Decrete DL 113 / 2013). Female Wistar Han rats, 70 days old, weighing 200-250g, were accommodated in 12 h Light / dark cycle cage, with room temperature of 21 ± 3° C and an adequate quantity of food and water.

[0366] CCI model induction; surgical preparation: Animals were anaesthetised by intraperitoneal (i.p.) administration of a combined solution of 0.3 mg / kg Medetomidine and 50 mg / kg Ketamine prior to surgical exposure of the right sciatic nerve at mid-thigh level. Under anaesthesia, the sciatic nerve was exposed by a small incision through the skin at the lateral thigh. The sciatic nerve of the right (ipsilateral) leg was accessed by the exposure of the mid-tight muscles by a blunt dissection with an iris scissor at the fascial planes, using retractors for a better access of the nerve. Four chromic gut loose ligations were tied at the proximal half of the nerve, 1mm apart. Suture of skin was done with soft silk. All the animals were allowed to recover after i.p. administration of atipamezol, one per cage. During the 4 weeks of development of the model, two littermates were housed per cage.

[0367] “Pain Assessment” with Behavioral testing - sensitivity to mechanical stimuli: Behavioural testing was performed in a lowly lit room, during the day portion of the circadian cycle only (6am-6pm), and by the same operator throughout the experiment. Rats were acclimatized to the room, the experimenter, and the testing procedures for a week before the model is induced. Animals were placed in a transparent acrylic cage (‘behavioral cage’) with a thin grid floor which allowed full access to the paws. Behavioral accommodation was permitted for 15-20 minutes until cage exploration and groomingactivities ceased. Calibrated von Frey monofilaments (vFF) (Bio-VF-M, BiosebR) were used to measure withdrawal thresholds by applying increasing pressure stimulus placed onto the medial plantar surface of the paw. Each filament, with an increasing bending force (from 0.6 to a maximum of 26g), was tested up to 5 times on each paw with at least 5 seconds interval between stimuli. The threshold is taken as the first filament that elicited 3 pain responses (i.e., paw withdrawal, shaking or licking the paw). The withdrawal threshold is determined as the weakest force that elicited a positive response more than 50% of the trials. Mechanical sensitivity is a direct measurement of primary hyperalgesia in the case of CCI rat models, enabling to measure and compare the paw sensitivity between both injured (ipsilateral) and not injured (contralateral) hindpaws. The measurements obtained in the last three days of habituation were used to establish a baseline level of responsiveness, before pain induction. Measurements were also performed on the 3rd, 7th, 14th, 21st and 28th day after the CCI surgery to evaluate and validate the establishment of the respective pain model.

[0368] In Vivo analgesic efficacy testing; time-course of the mechanical threshold measurement: To accesses efficacy in Chronic conditions, the analgesic efficacy of compounds was assessed from day 21 onwards. For acute pain, responses were studied on the third day after surgery. All compounds were dissolved in cyclodextrin solution (vehicle) and injected intravenously (i.v., at 6mg / kg) or orally administered (at 60 mg / Kg). Following administration, the mechanical sensitivity was monitored for at least 90 min, in 15-minute intervals, for i.v. applications, and for at least 150 min, in 30-minute intervals, for oral administrations.

[0369] Readout - Maximum Possible Effect (%):_Responses of sensitivity to mechanical stimulus were accessed either directly, using the threshold response of each vF filament (in grams), or in a normalised manner, using the Maximum Possible Effect (%): MPE% is commonly used in studies of behavioural pharmacology, and is calculated with the following equation, towards a better understanding of the analgesic efficacy of the compound when applied:(reaction pressure after treatment— control reaction pressure) x 100

[0370] % MPE = (cutoff pressure- control reaction pressure)

[0371] In other words, MPE is a parameter that relates the experimental / compound analgesic effect (over the injured leg; numerator) with the theorical maximum analgesic effect (taken at the non-injured leg; denominator).

[0372] INFLAMATORY PAIN MODEL: COMPLETE FREUND’S ADJUVANT (CFA) KNEE INJECTION

[0373] All the procedures described for the CCI model were the same with exception of the surgical insult. For this inflammatory pain model, CFA was used as it induces monoarthritis (adapted from Bennet & Xie, 1988 A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Anaesthetised rats were injected in the knee with CFA: injection of lOOpL of CFA medially between patella and femur-tibia junction of the rats. The right knee joint (ipsilateral) was gently rubbed at least 50 times in a circular manner. The model was maintained for 3 weeks (Bennet & Xie, 1988). Compounds were tested with iv injections on day 3 and on day 7, after model injection. “Pain Assessment” with Behavioral testing of the sensitivity to mechanical stimuli was accessed as described for the CCI model.

[0374] POST OPERATIVE PAIN MODEL: POP

[0375] For the POP model, all the procedures were like those described for the CCI model, with the exception of the surgical procedure. The POP model was induced as described elsewhere (Brennan, T. J. et al 1996 Characterization of a rat model of incisional pain. Pain, 64, 493-501). Rats were anesthetized with a mixture of medetomidine (SEDA START® 500 pl / kg, i.p.) and ketamine (Ketamidor® 75mg / kg, i.p.). After antiseptic preparation of the right hind paw with ethanol 70%, a 5 mm longitudinal incision was made with a no. 11 blade through the skin and fascia of the plantar foot. The incision was started 2 mm from the proximal edge of the heel and extended toward the toes. The underlying muscle was elevated with a curved forceps, also incised longitudinally. The skin was apposed with a single knot suture of Monosyn®, a sterile synthetic absorbable monofdament, on a 4 / 0 needle, and the wound was cleaned with 10% povidone- iodine solution. The anaesthesia was reversed with atipamezole (SEDA STOP® 50 pL / kg, i.p.). The animals were tested 36 h after surgery, upon iv Administration of the compounds. “Pain Assessment” with Behavioral testing of the sensitivity to mechanical stimuli was accessed as described for the CCI model.

[0376] OROFACIAL PAIN MODEL: ION-CCI

[0377] ION (infraorbital nerve ) -CCI model induction- Surgical preparation : Female Wistar rats were anaesthetised with the similar procedure described above, for the CCIIl lmodel. A small incision was made parallel to the nasal bone starting at the caudal end of the third row of whiskers towards the ipsilateral orbit. The muscle was bluntly separated to expose the distal portion of the infraorbital nerve (ION), outside of the orbital cavity. Using chromic catgut ligature (4-0), a knot was loosely tied around the nerve trunk lightly compressing the nerve but without cutting off the circulation through the superficial vasculature. The skin was closed using a silk-based thread.Pain Acessement” with Behavioral testing - sensitivity to mechanical stimuli: To measure the mechanical withdrawal threshold in the TON-CCI model, animals were gently restrained with a towel, allowing movements of the head and front paws, and von Frey filaments of increasing force were applied within the infraorbital nerve territory, on the hairy skin surrounding the mystacial vibrissae, at a 90° angle until bent. Each filament was tested 5 times on each side, injured and non-injured, with at least 5 seconds interval between stimuli making sure that the same site was not repeatedly stimulated. Response scoring was as follows: positive responses include withdrawal reaction during which the rat turned the head away when stimulated, sometimes accompanied with a single face swipe which was scored as 1; escape / attack response was scored as 2 and was defined as active avoidance of further contact with the stimulus object and / or making biting and grabbing actions towards it; the maximal score of 3 was used for asymmetric face-grooming responses. When the animal turned the head to the stimulating object and explored it, sniffing or licking it, the response was considered as simple detection and was scored with 0. The withdrawal threshold was determined as the lower force that elicited more than 50% of positive response and the maximal cut-off was established as 15g.

[0378] OSTEOARTHRITES PAIN MODEL: MIA

[0379] To establish this model, monosodium iodoacetate (MIA) was administered intraarticularly (i.a.) into the left knee joint at a dose of 1 mg in 50 pL sterile saline under brief isoflurane anesthesia. This dosing regimen was selected to mimic the progressive cartilage degradation and joint pathology characteristic of osteoarthritis in humans. MIA inhibits glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, leading to cell death, matrix breakdown, and joint inflammation, thereby producing a reproducible model of chronic joint pain. Repeated behavioral assessments revealed a gradual development of joint dysfunction and hypersensitivity to mechanical stimuli, typically emerging within 3-5 days post-injection and persisting for several weeks. Test compounds were administered systemically or intraarticularly at day 7 or 14 post-MIA injection, at the established phase of osteoarthriticsymptomatology, to evaluate their therapeutic efficacy in reversing or attenuating chronic pain-related behaviors. Pain Assessment with behavioral testing of the sensitivity to mechanical stimuli was accessed as described for the CCI model, for both hind paws, with special attention to the affected (ipsilateral) limb.

[0380] CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY PAIN MODEL: CIPN

[0381] To establish this model, paclitaxel (PTX) was administered intravenously (i.v.; slow intravenous infusion into the tail vein) at a dose of 10 mg / kg once weekly for a duration of 4 to 6 weeks. This dosing regimen was selected to approximate the cumulative neurotoxic burden associated with clinical chemotherapy protocols. Repeated PTX administration results in a gradual onset of peripheral nerve dysfunction, thereby enabling the assessment of both early-stage and persistent neuropathic alterations. Test compounds were administered intravenously at week 6, at the established phase of neuropathic symptomatology, to evaluate their therapeutic efficacy in reversing or attenuating CIPN-associated symptoms. “Pain Assessment” with Behavioral testing of the sensitivity to mechanical stimuli was accessed as described for the CCI model, for both paws.

[0382] GASTROINTESTINAL INFLAMATORY BOWEL DISEASE PAIN MODEL: IBD

[0383] For the IBD pain model, colitis was induced using 2,4,6-trinitrobenzene sulfonic acid (TNBS): Female Wistar rats (200-300 g) were food-deprived for 16 hours prior to induction. Under anaesthesia with medetomidine and ketamine, animals were placed in a supine position. A 25 mg / mL TNBS solution (in 50% ethanol / 50% H2O) was administered at a dose of 50 mg / kg via rectal instillation. Following slow injection, the cannula was flushed with air to ensure full delivery and removed while maintaining positive air pressure to prevent reflux. Animals remained in a head-down position for 10 minutes to promote distribution of the compound. Anaesthesia was reversed with atipamezole, and animals were returned to their cages. “Pain Acessement” with Behavioral testing - sensitivity to mechanical stimuli: Analgesic efficacy was assessed three days post-induction by intravenous administration of test compounds at 6 mg / kg. Mechanical hypersensitivity was evaluated using calibrated von Frey filaments applied to the abdominal area. The withdrawal response thresholds obtained after compound administration were compared to the baseline sensitivity levels recorded pre-treatment and to the ones recorded pre-TNBS induction.

[0384] EX VIVO PAIN MODEL FOR ELECTROPHSIOLOGICAL STUDIES.

[0385] Dorsal root ganglia harvesting and neurons dissociation: Rats were overdosed with sodium pentobarbital (100 mg / kg i.p.) and sacrificed by decapitation. Dorsal root ganglia (DRG) harvesting was performed as follows. Harvested ganglia were immediately transferred and dissected in four equal pieces in cold Krebs dissociation solution consisting of (in mM): NaCl 120, KC1 5, PIPES 20 (NaOH), CaC12 1, MgC12 1, glucose 25, saturated with oxygen, pH 7.4. Next, all ganglia were incubated for 45 minutes at 32°C in collagenase 3 mg • mL-1 (type IA, Sigma C9891) prepared in Krebs dissociation solution. For cell isolation, enzymatic treatment was used with trypsin (2.5 mg / niL-1 ) for 40 minutes, and pieces of DRG ganglia were mechanically dissociated with fire-polished Pasteur pipettes at 20 minutes and 40 minutes of digestion. The cell suspension was then centrifuged for 5 minutes at 2000 rpm and the resulting pellet was resuspended in 2 mL of Krebs dissociation solution. Cells were used up to 6h after the end of the digestion. For the sdTRns and the trigeminal ganglia, same procedures were applied.

[0386] Electrophysiology recordings: For the electrophysiological recordings from the ex vivo neurons, whole-cell current-clamp and voltage-clamp recordings were performed on neurons isolated from rat sdDRG (and sTGs). Recordings were performed from the soma that often contained the proximal fraction of axon, at room temperature (20-24°C). The composition of the bath solution was as follows (in mM): NaCl 135; KC1 5.4; CaC12 2; MgC12 2; HEPES 10 (NaOH); D(+)-glucose 25 (pH 7.4; 300-31 OmOsm). Patch pipettes (2-3.8 MQ), pulled from borosilicate glass, were filled with pipette solution containing (in mM): KF 140; MgC12 1; Nal / 2-HEPES 10 (KOH); EGTA 10; CaC12 1; Na2ATP 2; Na- GTP 0.4 (pH 7.2-7.3; 290- 300m0sm). Neuronal excitability was studied via recordings of membrane potential under current-clamp (whole-cell). Voltage signals were recorded with a HEKA electrometer (EPC10) (filtered at 2kHz and sampled at 10kHz). Only cells with a membrane potential more negative than -50 mV were used, with the membrane potential maintained at -60 mV by injection of biased current. Action potentials were recorded in three different ways: (l)’Spontaneous activity’, which was recorded after switching off the holding constant injection current; (2) evoked action potentials following a ramp current protocol (with a slope of 1 pA / 1 ms to InA); (3) action potentials evoked by depolarizing current injections with incremental amplitude (0 to 500 pA, in 50 pA increments, 1000 ms duration, every 60 s), in which action potentials were counted considering an amplitude threshold of lOmV - Number of action potentials were plottedagainst current injection (before and during treatment of drugs). For voltage clamp, currents, recorded with an Axopatch 200B electrometer (Axon Instruments) and a pCLAMP 6.0 software (Axon Instruments), were filtered at 2kHz and sampled at 10kHz using a DigiData 1200 interface (Axon Instruments). Holding potential was -70mV. Series resistance (Rs) was compensated to about 85%. Electrode and cell membrane capacitances were compensated, and membrane surface area was estimated from the reading of the cell capacitance compensation dial, assuming a specific membrane capacitance of 1 pF / cm2. Holding current and series resistance were monitored throughout all experiments. Patch pipettes were positioned over the soma of cells with cell body size about 15-25 pm, visually selected with an eyepiece reticule. After attaining whole cell configuration, cells were lifted from the bottom of the chamber, brought near the surface and remained under continuous bath perfusion. Control and sample solutions were continuously perfused at a rate of 1-2 mL / min. Samples were dissolved in ethanol, resulting in bath concentrations of ethanol of -0.1%, which was also included in sample-free control solutions. This concentration of ethanol had no discernible effect on currents or spike firing.

[0387] Hepatotoxicity: Human primary hepatocytes were isolated using established protocols and cultured under physiologically relevant conditions (37°C, 5% CO2). Compounds were tested at varying concentrations, including a vehicle control, for a predetermined exposure period, reflecting potential clinical scenarios. At the end of the exposure period, the MTT assay was conducted to assess cell viability. Cytotoxicity assessment was performed by quantification of the lactate dehydrogenase (LDH) activity.

[0388] Carditoxicity was evaluated following the Comprehensive In Vitro Proarrhythmia Assay (CiPA), (Thomas Colatsky, Bernard Fermini, Gary Gintant, Jennifer B. Pierson, Philip Sager, Yuko Sekino, David G. Strauss, Norman Stockbridge, The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress, Journal of Pharmacological and Toxicological Methods, Volume 81, 2016, Pages 15-20, ISSN 1056- 8719) namely by performing the in vitro voltage-clamp assays on ion channels hERG (human Ether-a-go-go-Related Gene), Navi.5 (Sodium Voltage-Gated Channel Alpha Subunit 5), and Cavl.2 (Voltage-Gated Calcium Channel Subunit Alphal C) to assess the compound's effects on cardiac repolarization and depolarization. These assays were designed to assess the compound's effects on cardiac repolarization (hERG) and depolarization (Navi.5 and Cavl.2), crucial aspects of cardiac performance. Assays were performed using automated patch clamp techniques in cells selectively expressing each of the ion channels.

[0389] Genotoxicity: The Ames test is a bacterial assay designed to assess the mutagenic potential of chemical compounds. The method involves the use of specific strains of Salmonella bacteria that carry mutations in genes related to histidine synthesis, providing a means of screening for mutagenicity. Agar plates with minimal medium lacking histidine are prepared, creating a growth environment that necessitates histidine production for bacterial survival. The compounds were applied to the agar plates hosting the bacterial strains. Plates were incubated to allow the bacteria to grow and replicate in the presence of the test substance. Mutagenic compounds induce reverse mutations, leading to the formation of revertant colonies capable of synthesizing histidine. The number of revertant colonies is observed and compared to control plates without the test substance. A positive result suggests the potential for mutagenicity, prompting further investigation and safety assessments.

[0390] The Irwin Test was used to evaluate the qualitative effects of the compounds on behavior and physiological function. This test provides a broad estimate of the duration of action of the compound on the different end-points. Because these measures involve subjective assessment of different aspects of animal behavior, to ensure reproducibility, the test is performed in a highly standardized manner by experienced observers. Behavioral modifications, physiological and neurotoxicity symptoms, rectal temperature, and pupil diameter were recorded. Specific items recorded as part of the Irwin test include death, convulsions, tremor, Straub tail, sedation, excitation, jumping, abnormal gait, motor incoordination, altered muscle tone, loss of grasping, akinesia, catalepsy, loss of traction, loss of balance, fore-paw treading, writhing, piloerection, stereotypic behaviors, headtwitches, scratching, altered respiration, aggression, altered fear, altered reactivity to touch, ptosis, exophthalmia, loss of the righting reflex, loss of corneal reflex, defecation / diarrhoea, salivation, lacrimation, rectal temperature, and pupil diameter.EXAMPLE 2PROPOSED MODE OF ACTION

[0391] A mode of action of oxazolidone-derived compounds as analgesic is disclosed herein for the first time. It involves reduction of neuronal excitability of sdDRGns and in sdTGns. Such reduction in neuronal excitability is, at least in part, due to an effect on voltage activated K+current: a reduction in K+currents rather than their potentiation.

[0392] The inhibitory effect of oxazolidone-derived compounds in excitability ofsdDRGns (and sdTGns) is noticeable (see FIG.s 2A-D, FIG.s 3A-D, FIG.s 4A-D, FIG.s 5A-D, FIG.s 6A-D, FIG.s 7A-D, FIG.s 8A-D, FIG.s 9A-D, FIG.s 10A-D, FIG.s 11A-D, FIG.s 12A-D). Action potential firing spontaneously is abolished in most cases or clearly reduced. Interestingly, the drug-induced inhibition of the action potentials is preceded by a transitory apparent increase in frequency firing, followed by firing failure. This was observed in both spontaneous- and induced-action potential firing. Moreover, all the oxazolidone-derived compounds induced a shift in the action-potential induction curves, suggesting that there is a primary facilitation of action-potential due to the drug-treatments (requires less current injection) that, in turn, is responsible for nerve-firing failure. Indeed, at a given current injection pulse, spike inactivation trough out the current injection is always observed as a consequence of the treatments of all oxazolidone-derived compounds.

[0393] As referred, the drug-induced reduction of the voltage activated K+currents may, at least in part, underly the reduction in excitability. For such reason, it is important to characterise first the potassium currents present in the sdDRGns and in sdTGNs. The voltage activated whole-cell K+currents recorded from sdDRGns upon a depolarizing step (say, to +40mV lasting 1 second) showed a fast activation followed by two phases of inactivation (see FIG. 13 A). The current decay at depolarised potentials is thus better fit by a sum of two exponential functions: a relatively fast component (here termed Ifast - associated to what is known as A-current), showing a time course (Tfast) of tens of milliseconds, followed by a much slower inactivating current(here termed IsiOw), showing a time course (TSIOW) of hundreds of milliseconds (see FIG. 13 A). Different proportion for Ifast and Flow are found from cell to cell and even some cells show only one component, Isiow- The currents found in sdDRGns are very similar to those described for sdTGns.

[0394] All oxazolidone-derived compounds inhibited the slowly inactivacting K+currents from sdDRGns and from sdTGNs in a dose dependent manner. In concentrations up to ~30|rM , oxazolidone-derived compounds specifically reduced Isiow(see FIG. 13B, FIG. 14, FIG. 15, FIG. 16, FIG 17, FIG. 18, FIG. 19), current component of which is over expressed in sdDRGn neurons (and in sdTGns) obtained from ‘injured nerves’ from chronic pain rat models (CCI and Orofacial). In all the typical examples presented (FIG. 13B and from FIG 14. to FIG.19), one may note that the peak current is not altered significantly by treatment of all oxazolidone-derived compounds, whereas the slower component is indeed reduced. The drug sensitive current components (trace subtraction at the bottom of each figure) shows a current decay that is better fit by a single exponentialof few hundred of milliseconds (150 to 1100 ms, in the examples given). This further suggests that, at moderate concentrations, the effect of oxazolidone-derived compounds is specific on Isiow. Here, Islow may not only include slowly inactivacting current but also non-inactivating currents. In contrast, Ifast, was unaffected by oxazolidone-derived compounds at concentrations up to ~50pM.

[0395] Oxazolidone-derived compounds inhibition of slow K+currents involve a pharmacological process of ‘channel-state dependent blockage’ . Also, it involves a change in the voltage dependence of steady state of inactivation (and not of activation). In fact, all compounds tested induce shifts to more hyperpolarised potentials the I-V curves related to the voltage dependence of inactivation (see FIG.s 20A-G). Thus, the compounds inhibit slow voltage-activated currents recorded from sdDRGns by promoting K+channel inactivation, which is impaired in chronic pain conditions. More precisely, the compounds shift the voltage sensitivity of the steady-state inactivation to less depolarised values (or more hyperpolarised), facilitating inactivation. The drug- inhibitory effect on Islow in sdDRGns, as well as the described effect on the voltage-dependence of inactivaction, were very similar to those observed in sdTGns.

[0396] How the effect of oxazolidone-derived compounds on Kv currents results in the analgesic effect may be still a matter of debate. One would expect that an increase of Kv currents, rather than an inhibition, would calm down neuroexcitability of the hyperexcitable C fibers. In the present case, one must stress that slowly inactivating- potassium currents are exacerbated in chronic pain conditions (sdDRGns obtained from CCI, and sdTGns from ION-CCI rat model), showing abnormal depolarised inactivation profiles, i.e. channels inactivating less. In order to sustain repetitive firing for long periods, the typical situation under chronic pain, the increase of the “excitatory force” brought by the consensual increase in Na+currents, has to be sustained by a counter-balancing increase in K+currents that would accommodate repetitive -long-term firing patterns. The effect of the compounds disclosed herein is such that it reverts such patterns to control profiles, decreasing the slowly-inactivating Kv-mediated current. This drug-evoked effect of the slow K+currents would not allow the required accommodation of the increase of sodium conductance (Nav), typical in pain situations. As a result, the exacerbated sodium currents would inactivate in the presence of the oxazolidone-derived compounds (also due to a depolarization evoked by the decrease of Kv currents), switching off spike firing principally in the affected nerves. This means that, during pain, namely, in chronic pain,Kv blockers, and not only the Kv potentiators or openers, should be considered as potential analgesics.

[0397] How a reduction of K+currents resulted in a marked decrease of neuronal excitability may be explained in different ways or, most likely, by a combination of phenomena. Importantly, as mentioned above, the drug-induced decrease of K+currents may have resulted in a slow depolarization of the affected neurons in a way that membrane potential is kept at a depolarized level, so the usual threshold potential may pass without an action potential having been fired. It would thus result in an accommodation-like process as depolarization would close inactivation gates of the Na+channels, remaining closed, preventing the upstroke of action potential to occur (not enough Na+channels ‘activatable’).EXAMPLE 3EFFICACY RESULTS

[0398] For efficacy studies, nociception was assessed in all animals from all pain models, in particular from the Neuropathic pain model CCI, by regular behavioural monitoring, by quantifying the sensitivity to mechanical stimuli with Von Frey filaments, and consequently reflecting hyperalgesia when hypersensitive. In the CCI model, a marked increase of sensitivity to mechanical stimuli was observed in the ipsilateral (injured) limb whereas, on the contralateral (non-injured) leg, the sensitivity remains unaltered. Such effects are noticeable right after the surgery and are sustained throughout a month (see example experiment in FIG. 21 A). This is relevant because to test for efficacy in Chronic conditions, the analgesic efficacy of compounds have to be assessed from day 21 onwards (hence considered as chronic, in rats). For acute pain, responses were studied on the third day after surgery.

[0399] The following results concern intravenous (i.v.) injections of purified compounds (>95 % - compound of formulas V, VI, VII, VIII, IX and XI, examples of templateformulas I-IV) (80 pg / mL of blood; 6 mg / Kg).

[0400] Naive Wistar controls: There was never any change in sensitivity scores following i.v. injections of any oxazolidone-derived compounds, for both paws.

[0401] With CCI rats, following i.v. administrations, for all the examples of oxazolidone- derived compounds, there was a noticeable decrease of sensitivity to mechanical stimuli in the ipsilateral (injured) paw, for both acute (3 days after induction of the model) andchronic (22 or 28 days) situations. Typical experiments are presented in FIG.s 21A-B to FIG. 26. The compound-induced decrease of hypersensitivity was robust in chronic pain. The duration of the pain mitigation lasted for 1.5 to 2 hours. Importantly, there were no significant changes in the behavioural scores of the contralateral (uninjured) paw for all the animals tested, in response to all oxazolidone-derived compounds.

[0402] Oral administration (p.o.) of compounds through stomach gavage (endogastric), with ~10 times the quantity administered by i.v. injection (60 mg / kg), was tested in CCI rats (21 or 28 days after surgery). In all animals tested, there was similar mitigation of pain, i.e. a decrease in the sensitivity values. FIG. 27, FIG. 28 and FIG. 29 represent three examples of p.o. administration of three oxazolidone-derived compounds. Such effects lasted for about 2-4 hours.

[0403] In POP (Post-surgery pain) rats, there was a noticeable decrease of sensitivity to mechanical stimuli in the ipsilateral paw after drug p.o. administration (60 mg / kg). FIG. 30, FIG. 31 and FIG. 32 represent three examples of p.o. administration of three oxazolidone-derived compounds. The duration of the analgesic response lasted for > 2 hours and, as with the CCI rats, and was confined to the ipsilateral-injured paw.

[0404] In CFA (inflammatory pain) rats, there was a noticeable decrease of sensitivity to mechanical stimuli in the ipsilateral paw after drug i.v. injection for both situations: 3 days and 7 days after the CFA injection. FIG. 33 and FIG. 34 represent two examples of i.v injections of two oxazolidone-derived compounds (80 pg / mL of blood; 6 mg / Kg). The duration of the pain mitigation lasted for 1.5 to 2 hours and, as with the CCI rats, was confined to the ipsilateral-injured paw.

[0405] In MIA (osteoarthritic pain) rats, there was a noticeable decrease of sensitivity to mechanical stimuli in the ipsilateral paw after drug i.v. injection for both situations: 7 and 14 days after the MIA injection. FIG. 35 and FIG. 36 represent two examples of i.v injections of two oxazolidone-derived compounds (80 pg / mL of blood; 6 mg / Kg). The duration of the pain mitigation lasted for 1.5 to 2 hours and, as with the CCI rats, was confined to the ipsilateral-injured paw.

[0406] In CIPN rats (model for chemotherapy -induced peripheral neuropathic pain), drug i.v. administration consistently resulted in a marked reduction of mechanical sensitivity, assessed in both hind paws six weeks after model induction. FIG. 37 represents an example of an i.v .injection of an oxazolidone-derived compound (80 pg / mL of blood; 6 mg / Kg).

[0407] In ION-CCI rats (model for orofacial pain), drug i.v. administration consistently resulted in a marked reduction of mechanical sensitivity, assessed at the whisker pad region 23-28 days after surgery (chronic). FIG. 38 represents an example of i.v. injection of an oxazolidone-derived compound (80 ug / mL of blood; 6 mg / Kg). The duration of the pain mitigation lasted for about 2 hours and was confined to the injured whisker pad (injured face-side only).

[0408] In IBD rats (model of pain associate to inflammatory bowel disease), drug i.v.. administration consistently resulted in a marked reduction of mechanical sensitivity, assessed in the abdominal area, 3 days after model induction. FIG. 39 represents an example of an i.v. injection of a oxazolidone-derived compound (80 pg / mL of blood; 6 mg / Kg).

[0409] In summary, oxazolidone-derived compounds have shown to be effective for short- term / acute and long-term / chronic neuropathic pain, short-term / acute and long- term / chronic inflammatory pain, chronic orofacial pain. Efficacy has been demonstrated for intravenous and oral administration.

[0410] The above results described in the FIGS (2 to 39) are examples. Other results concerning other compounds are summarised in Tabel I.

[0411] Table I. Summary table of ex vivo and in vivo results derived from the application of compounds depicted in FIG. 1. ‘Current reduction’ concerns effect on the Slow current component (whole-cell voltage-clamp recordings); ‘Reduction in excitability' is characterized by changes in nerve firing as depicted from the examples given; in vivo results relate to effects on mechanical sensitivity (Von Frey Filaments) higher than 20% MPE on at least one of the following Pain Models: CCI, POP, CFA, MIA, CIPN, TG, IB...

Claims

We Claim:Claim 1. A compound of formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein; n- represents a carbon-carbon single bond or a carbon-carbon double bond;X is selected from C, CH, or N;Q is selected from O, NH or N-CH3R1, R2, R3are independently selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;D is selected from C, CH;One of A and E is H and the other is selected from H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine -(CH2)n-R5, wherein Rsis selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine.Claim 2. The compound of formula I according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is C;Q is O;R1is H or CH3;R2is H or CH3;R3is H, CH3alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CHi)n-R4wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is C or CH;E is H; andA is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH3)n-R5; wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;Claim 3. The compound of formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, whereinX is N;Q is O;R1is H or CH3;R2is H or CH3;R3is H or alkyl [excluding only when for -(CH)n-CH3n=l, 2, 4, 5, 6 or 9 and A is benzene], aryl (except benzene when A is -(CH)n-CH3with n=l, 2, 4, 5, 6 or benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for-(CH3)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H; andA is alkyl [excluding only for when -(CH)n-CH3 n=l, 2, 4, 5, 6 or 9 or when R3is benzene], aryl [excluding benzene when R1and R2are both H and R3is methyl or (CH)n-CH3 with n= 2, 4, 6 or R3is also benzene], furan, imidazole, isoxazole, anisole [excluding when R3is also anisole], pyridine, pyrimidine, piperidine or -(CFEjn-Rh wherein R5is selected from aryl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(CFbh-CEh], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;Claim 4. The compound of formula I according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, whereinX is N;Q is N-CH3;R1is H or CH3;R2is H or CH3;R3is H, CH3 (except for when R1and R2are H and A is benzene or anisole; or for when A is - CH2-R5and R5is benzene), alkyl | except for when -(CH2)n-CH3 with n=2, 4, 6 and A is benzene; or for when -(CH2)4-CH3 and A is anisole], aryl (except benzene when A is benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or - (CH2)n-R4wherein R4is selected from aryl [except when for-(CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H; andA is aryl [except for benzene when R1and R2are both H and R3is methyl or (CH)n-CH3 with n= 2, 4, 6], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, alkyl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(Cfth-CH?], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidineClaim 5. The compound of formula I according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is N;Q is NH;R1is H or CH3;R2is H or CH3;R3is H, CH3(except for when R1and R2are H and A is benzene or anisole; or for when A is - CH2-RSand R5is benzene), alkyl [except for when -(CH2)n-CH3with n=2, 4, 6 and A is benzene; or for when -(CH2)4-CH3and A is anisole], aryl (except benzene when A is benzene or anisole or -CH2-R5and R5is benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for- (CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H; andA is aryl [except for benzene when R1and R2are both H and R3is methyl or (CH)n-CH3with n= 2, 4, 6], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, alkyl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(CH2)2-CH3; or when for -CH2-R5with and R3is alkyl -(CH2)2-CH3or R3is is benzene and R is NH], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine;Claim 6. The compound of formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is N;Q is O;R1is H or CH3;R2is H or CH3;R3is H or alkyl [excluding only when for -(CH)n-CH3n=l, 2, 4, 5, 6 or 9 and A is benzene], aryl (except benzene when A is -(CH)n-CH3with n=l, 2, 4, 5, 6 or benzene), furan, imidazole, isoxazole, anisole (except when A is benzene), pyridine, pyrimidine, piperidine or -(CH2)n-R4wherein R4is selected from aryl [except when for-(CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H;andA is alkyl [excluding only for when -(CH)n-CH3n=l, 2, 4, 5, 6 or 9 or when R3is benzene], aryl [excluding benzene when R1and R2are both H and R3is methyl or (CH)n-CH3with n= 2, 4, 6 or R3is also benzene], furan, imidazole, isoxazole, anisole [excluding when R3is also anisole], pyridine, pyrimidine, piperidine;Claim 7. The compound of formula II according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is N;Q is O;R1is H or CH3;R2is H or CH3;R3is - (CH2)n-R4wherein R4is selected from aryl [except when for-(CH2)-R4R4is bezene and A is benzene], furan, imidazole, isoxazole, anisole pyridine, pyrimidine, piperidine;D is CH;E is H; andA is -(CH2)n-R5; wherein R5is selected from aryl [except benzene when for -CH2-R5, R1and R2are both H and R3is methyl -or -(CH2)2-CH3], furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;Claim 8. The compound of formula 111 according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein X is N;Q is O;R1is H or CH3;R2is H or CH3;R3is H, alkyl, aryl, furan, imidazole, isoxazole, anisole, pyridine or pyrimidine, piperidine or - (CH3)n-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine.D is CH;E is H; andA is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-R5; wherein R5is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;Claim 9. The compound of formula IV according to Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, whereinX is N;R2is H or CH3;R3is H, alkyl or aryl, furan, imidazole, isoxazole, anisole, pyridine or pyrimidine, piperidine or - (CHiln-R4; wherein R4is selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine or piperidine.D is CH;E is H; andA is alkyl, aryl [excluding benzene and when R1is also benzene], aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine or -(CH2)n-Rs; wherein Rsis selected from aryl, furan, imidazole, isoxazole, anisole, pyridine, pyrimidine, piperidine;Claim 10: The compound of Claim 1 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound is selected from the compounds of formula V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XIV, XXV, XXVI, XXVII, XVIII, XIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XL, XLI, XLII, XLIII, XLIV, XLV, XL VI, XLVII, XL VIII as follows:Claim 11: The compound of Claim 10, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound is selected from the compounds of formula VI, XII and XV as follows:Claim 12. A compound of formula I, II, III or IV, according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof,, for use in the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.Claim 13. The compound for use of Claim 12, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof , wherein the pain is chronic pain including, but not limited to, at least one of the following: neuropathic pain, nociceptive pain psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, postoperative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short- term / acute or long-term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, and pain associated with osteoarthritis.Claim 14. A compound of formula I, II, III or IV, according to any one of Claims 1 to 11, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for use as an antiepileptic or antiseizure agent in a subject in need thereof.Claim 15. The compound for use according to any one of Claims 12 to 14, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the subject is a warm-blooded vertebrate, preferably a mammal, more preferably a human.Claim 16. The compound for use according to any one of Claims 12 to 15, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound or a pharmaceutically acceptable salt or prodrug thereof, is used in a therapeutic dose ranging from 3 to 6 mg / kg body weight as the peak blood concentration, if by intravenous administration, or from 1 to 300 mg / Kg of body weight, preferably a dose ranging from 30 to 100 mg / Kg body weight by any route of administration, preferably by oral administration.Claim 17. The compound for use according to any one of Claims 12 to 15, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, wherein the compound or a pharmaceutically acceptable salt or prodrug thereof, is used in a therapeutic dose ranging from 0. 1 to 20 mg / Kg of body weight, preferably a dose ranging from 3 to 6 mg / Kg body weight by any route of administration, preferably by intravenous administration.Claim 18. A pharmaceutical composition comprising at least one compound according to formula I, II, III or IV, according to any one of claims 1 to 11, and / or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, and a pharmacologically acceptable diluent or carrier.Claim 19. A method of method of treating, preventing, or lessening the severity of pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I, II, III or IV according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof.Claim 20. The method according to Claim 19, wherein the pain is a chronic pain including, but not limited to, at least one of the following: neuropathic pain, nociceptive pain psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short-term / acute or long term / chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, bladder pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, and pain associated with osteoarthritis.Claim 21. A method of treatment of epilepsy or seizures in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of formula I, II, III and or IV according to any one of claims 1 to 1 1 , and / or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, to the subject.Claim 22. The method according to Claims 19 to 21, wherein the therapeutically effective dose ranges from 10 to 300 mg / kg of body weight, preferably from 30 to 60 mg / kg body weight as the peak blood concentration, by any route of administration, preferably by oral administration.Claim 23. The method according to Claims 19 to 21, wherein the therapeutically effective dose ranges from 0.1 to 20 mg / kg of body weight, preferably from 3 to 6 mg / kg body weight as the peak blood concentration, by any route of administration, preferably by intravenous administration.Claim 24. The compound according to Claims 1 through 23, and a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof,, wherein the compound, pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof,or a prodrug thereof, is isolated or synthetically produced.Claim 25. Use of a compound of formula I, II, III or IV, according to any one of Claims 1 to 11, or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.Claim 26. A compound of formula I, II, III or IV, according to any one of Claims 1 to 11 , or a pharmaceutically acceptable salt or solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer, or polymorphic crystal structure thereof, or a prodrug thereof, for use in the treatment, prevention or reduction of severity of pain in a subject in need thereof, preferably, chronic pain.