Compounds as GABA receptor modulators

Abstract

Provided herein are compounds that modulate GABAAR and methods of treating chronic or acute pain, or methods of aestheticizing a subject, using compounds of the disclosure. Further disclosed are compounds that can act as stimulants through their GABAAR modulating activity.

Description

COMPOUNDS AS GABA RECEPTOR MODULATORSSTATEMENT OF GOVERNMENT SUPPORT[1] This invention was made with government support under R01 AA022583 and NS5 R35 NS097306 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD[2] The present disclosure relates generally to GABAAR modulators, including methods of using the same to treat acute or chronic pain, as analgesics, and as stimulants.BACKGROUND[3] y-Aminobutyric acid type A receptors (GABAAR), the major inhibitory neurotransmitter receptors responsible for fast inhibition in the basal ganglia, belong to the superfamily of ligand-gated ion channels. GABAAR form as pentameric assemblies of subunits, with a central chloride anion permeable pore. On binding of two GABA molecules to the extracellular receptor domain, a conformational change is induced in the oligomer and chloride anion, in most adult neurons, moves into the cell leading to an inhibitory hyperpolarization.[4] Many drugs bind at sites on the GABAA receptor distinct from the GABA-binding site; these drugs change the shape of the receptor oligomer so that the efficacy of GABA at opening the channel is either activated (positive allosteric agonists, e.g., benzodiazepines and related sedative-hypnotics) or decreased (negative allosteric agonists, e.g., the p-carboline, DMCM). At clinically relevant concentrations, general anesthetics modulate the activity of various ion channels, including the intravenous anesthetics propofol and etomidate.[5] Thus, a need exists for modulators of GABAAR and their use as treatments for acute or chronic pain, analgesics, sedative-hypnotics, and stimulants.SUMMARY[6] Provided herein are compounds having a structure of Formula (I(I) or a pharmaceutically acceptable salt thereof, wherein: L1is Co-2alkylene; Ring B is phenyl or naphthyl; n is 0 to 2; each RBis independently selected from Ci-3alkoxy, Ci-salkyl, halogen, Ci-shaloalkoxy and Ci-shaloalkyl; RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0, and the ring is substituted with 0, 1 or 2 RA; or RN1and RN2are selected from H, Ci-salkyl, Co-salkylene-phenyl, and Co-salkylene-naphthyl, and the phenyl or naphthyl is substituted with 0-2 RA, with the proviso that only one of RN1and RN2can be H; and each RAis independently Ci-salkyl, halogen, or Ci-shaloalkyl; with the proviso when ring B is paramethoxyphenyl and RN1and RN2together with the nitrogen to which they are each attached form a piperidine ring, then 2 RAare not each methyl.[7] Further provided herein are compounds, or pharmaceutically acceptable salt thereof, wherein the compound is B1-B7, C1-C10, D1-D7, or E1-E8.[8] Further provided are methods of modulating y-aminobutyric acid type A receptor (GABAAR) comprising contacting GABAA with a compound selected from A1-A3, B1-B7, and C1-C10 in an amount effective to modulate GABAAR. In some embodiments, the method comprises contacting GABAAR with a compound that activates GABAAR. In some embodiments, the compound that activates GABAAR is A1, A2, A3, B1, B2, B3, B4, B5, B6, or B7. In some embodiments, the method comprises contacting GABAAR with a compound that inhibits GABAAR. In some embodiments, the compound that inhibits GABAAR is C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10.[9] Also provided are methods of using one or more of the compounds disclosed herein, or a pharmaceutical composition thereof. The methods of use include use as an analgesic, treatment for acute or chronic pain, as a sedative-hypnotic, and / or as a stimulant. In some embodiments, a compound selected from A1-A3 and B1-B7 is used as an analgesic. In some embodiments, a compound selected from B1-B7 is used as an analgesic. In some embodiments, compound B1 is used as an analgesic. In some embodiments, a compound selected from A1-A3 and B1-B7 is used as a treatment for acute or chronic pain. In some embodiments, a compound selected from A1-A3 and B1-B7 is used as a sedative-hypnotic. In some embodiments, a compound selected from B1-B7 is used as a sedative-hypnotic. In some embodiments, a compound selected from B1-B7 is used as a treatment for acute or chronic pain. In some embodiments, compound B1 is used as a treatment for acute or chronic pain. In some embodiments, a compound selected from C1-C10 is used as a stimulant.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1. Structures of 28 compounds from chemical library (Chembridge).

[0011] Figure 2. Behavior assay results for 28 compounds from chemical library (Chembridge).

[0012] Figure 3. ED50 LORR results for various compounds in adult zebrafish.

[0013] Figure 4. ED50 LORR results for various compounds in mice.

[0014] Figure 5. Behavior assay results for compounds B1-B7, 01-010, and D1-D7.DETAILED DESCRIPTION

[0015] In studies in knock-in mouse lines with propofol- and etomidate-insensitive p subunits, it has been found that propofol and etomidate exert nearly all of their anesthetic actions entirely through GABAAR. An investigation into other compounds that act through GABAAR, or phenocopy known GABAergic ligands, is provided herein.

[0016] Provided herein are compounds that have a structure of Formula (I):pharmaceutically acceptable saltthereof. Also provided herein are compounds that act on GABAA receptors. The compounds described herein can be used as an analgesic, treatment for acute or chronic pain, as a sedative-hypnotic, and / or as a stimulant.Chemical Definitions

[0017] As used herein, the term "alkyl” refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms. The term Cnmeans the alkyl group has “n” carbon atoms. For example, Cealkyl refers to an alkyl group that has 6 carbon atoms. Cualkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (i.e., 1 to 7 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 3-6, 2, 3, 4, 5, 6, and 7 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2- methylpropyl), and t-butyl (1,1 -dimethylethyl). Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0018] As used herein, the term "alkylene" refers to a bivalent saturated aliphatic radical. The term Cnmeans the alkylene group has "n" carbon atoms, e.g., a Chalkylene is CH2. For example, Ci-ealkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for "alkyl" groups.

[0019] As used herein, the term "alkoxy” or “alkoxyl” refers to a O-alkyl” group.

[0020] As used herein, the term "halogen" is defined as fluoro, chloro, bromo, and iodo. Accordingly, a “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. In some cases, the haloalkyl group is a perhaloalkyl, i.e., all hydrogen atoms of the alkyl group have been substituted with a halogen. Some non-limiting examples of haloalkyl groups include CF3, CHF2, CH2F, CCI3, CI3, and CH2CF3 Similarly, a "haloalkoxy” refers to an alkoxy group that is substituted with one or more halogen atoms, e.g., OCF3.

[0021] As used herein, the term "5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0” refers to a ring system having a ring of any size as long as the total number of ring atoms are 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) with 0-1 ring heteroatoms and can be aromatic (aryl or heteroaryl), fully saturated, or partially saturated, and are substituted as described herein.

[0022] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as a single stereoisomer, or as a mixture of stereoisomers. Stereochemistry of the compounds shown herein indicate a relative stereochemistry, not absolute, unless discussed otherwise. As indicated herein,a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.Compounds of the Disclosure

[0023] Disclosed herein are compounds having a structure of Formula (I):wherein:L1is Co-2alkylene;Ring B is phenyl or naphthyl; n is 0 to 2; each RBis independently selected from Ci-3alkoxy, Ci-salkyl, halogen, Ci-shaloalkoxy and Ci-shaloalkyl;RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0, and the ring is substituted with 0, 1 or 2 RA; orRN1and RN2are selected from H, Ci-salkyl, Co-salkylene-phenyl, and Co-salkylene-naphthyl, and the phenyl or naphthyl is substituted with 0-2 RA, with the proviso that only one of RN1and RN2can be H; and each RA, when present, is independently Ci-salkyl, halogen, or Ci-shaloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso when ring B is paramethoxyphenyl and RN1and RN2together with the nitrogen to which they are each attached form a piperidine ring, then 2 RAare not each methyl.

[0024] In compounds of Formula (I), L1can be Co-2alkylene. In various cases, L1is CH2. In various cases, L1is Coalkylene (i.e., a bond).

[0026] In compounds of Formula (I), Ring B can be phenyl or naphthyl. In various cases, Ring B is phenyl. In various cases, Ring B is naphthyl.

[0027] In compounds of Formula (I), n can range from 0 to 2. In various cases, n is 0. In various cases, n is 1 . In various cases, n is 2.(231 In various cases, n is 1 and Ring B has a structure ofIn various cases, n is 2 and Ring B has a structure

[0029] In compounds of Formula (I), each RBis independently Ci-salkoxy, Ci-salkyl, halogen, Ci-shaloalkoxy, or Ci-shaloalkyl. In various cases, at least one RBis Ci^alkoxy or Ci-shaloalkyl . In various cases, at least one RBis Ci-salkyl or Ci-shaloalkyl. In various cases, at least one RBis Ci^alkoxy or Ci-salkyl.

[0030] In compounds of Formula (I), each of RN1and RN2are H, Ci-salkyl, Co salkylene-phenyl, or Co-3alkylene- naphthyl, and the phenyl or naphthyl is substituted with 0-2 RA, with the proviso that only one of RN1and RN2can be H. In various cases, each of RN1and RN2are H or Ci-salkyl. In various cases, one of RN1and RN2is H and the other is Co-3alky lene-phenyl or Co salkylene-naphthyl. In various cases, RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom selected from N and 0, and the ring is substituted with 0, 1 or 2 RA. In various cases, RN1and RN2together with the

[0031] In compounds of Formula (I), each RA, when present, can independently be Ci-salkyl, halogen, or Ci- shaloalkyl. In various cases, one RAis present. In various cases, RAis absent. In various cases, two RAare present. In various cases, at least one RAis Ci-salkyl, halogen, or Ci-shaloalkyl. In various cases, each RAis Ci- salkyl, halogen, or Ci-shaloalkyl.

[0032] Further provided herein are modulators of GABAAR, having a structure as shown in Table A, or a pharmaceutically acceptable salt thereof.Table A

[0033] In various cases, the compound is B1-B7, C1-C10, D1-D7, or E1-E8. In various cases, the compound ispharmaceutically acceptable salt thereof.

[0034] In various cases, the compound activates GABAAR, e.g., as for A1, A2, A3, B1, B2, B3, B4, B5, B6, or B7. In other cases, the compound inhibits GABAA , e.g., as for C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10.

[0035] Compounds disclosed herein not from a chemical library can be prepared as described in the examples below, e.g., for compounds B1-B7, C1-C10, D1-D7, and E1-E8.Pharmaceutically Acceptable Salts

[0036] The compounds of the present disclosure can be provided as pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0037] 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0038] Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.

[0039] Examples of pharmaceutically acceptable, non-toxic 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 pharmaceuticallyacceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0040] Where the compound described herein contains a carboxyl group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. In practice, use of the base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N+(Ci-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0041] Basic addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. The sodium and potassium salts are usually preferred. 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. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

[0042] Other acids and bases, although not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0043] It should be understood that a compound disclosed herein can be present as a mixture / combination of different pharmaceutically acceptable salts. Also contemplated are mixtures / combinations of compounds in free form and pharmaceutically acceptable salts.Methods of Use of GABAAR Modulators

[0044] Provided herein are methods of using a compound of the disclosure as an analgesic, a treatment for acute or chronic pain, a sedative-hypnotic, or as a stimulant. It is contemplated that GABAAR activator compounds, compositions, and methods are useful in the treatment of acute or chronic pain, as analgesics, or as sedative-hypnotics. It is contemplated that GABAAR inhibitor compounds, compositions, and methods are useful as stimulants. In some cases, a GABAAR activator compound (e.g., a compound selected from A1-A3 and B1- B7) can be used as an analgesic, a sedative-hypnotic or for acute or chronic pain by administering to a subject in need thereof a therapeutically effective amount of the GABAAR activator compound or a composition thereof, as disclosed herein.

[0045] Acute or chronic pain includes, but is not limited to, AIDS / HI V-related pain, ankylosing spondylitis, arachnoiditis, back pain, breakthrough pain, burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome pain, cauda equina syndrome, central pain syndrome, Charcot-Marie-Tooth disease, chronic functional abdominal pain, chronic pancreatitis pain, complex regional pain syndrome, corneal neuropathic pain, degenerative disc disease, Dercum's disease, dermatomyositis, diabetic peripheral neuropathy, Ehlers-Danlos syndrome, endometriosis, erythromelalgia, failed back surgery syndrome, fibromyalgia, intercostal neuraligia, interstitial cystitis, irritable bowel syndrome, juvenile dermatositis, leg pain, loin pain-haematuria syndrome, meralgia paresthetica, migraine, multiple sclerosis pain, musculoskeletal pain, myofascial pain, myositis, neuropathic pain, occipital neuralgia, osteoarthritis pain, Paget's disease, pelvic pain, peripheral neuropathy, phantom limb pain, pinched nerve, polymyalgia rhuematica, polymyositis, post-herniorraphy pain syndrome, post-mastectomy pain syndrome, post-stroke pain, post-thorocotomy pain syndrome, post-traumatic neuropathy, postherpetic neuralgia, post-polio syndrome, primary lateral sclerosis, psoriatic arthritis, pudendal neuralgia, Raynaud's disease, restless leg syndrome, rheumatoid arthritis, sacroiliac joint dysfunction, sarcoidosis, sciatica, postherpetic neuralgia, sickle cell pain, Sjogren's syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinal cord injury, spinal stenosis, syringomyelia, Tarlov cysts, thoracic outlet syndrome (TOS), temporomandibular joint disorder, transverse myelitis, trigeminal neuralgia, ulcerative Colitis, vascular pain, vulvodynia, and whiplash pain.

[0046] In some cases, a GABAAR inhibitor compound (e.g., a compound selected from C1-C10) can be used as a stimulant by administering to a subject in need thereof a therapeutically effective amount of the GABAAR inhibitor compound or a composition thereof, as disclosed herein. It is contemplated that GABAAR inhibitor compounds, compositions, and methods are useful in the reversal of anesthesia or sedation, or as analeptics.Pharmaceutical Compositions and Administration

[0047] Also provided herein are pharmaceutical formulations that include an effective amount of compounds of the disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term "formulation” is used interchangeable with "composition.”

[0048] An "effective amount" includes a "therapeutically effective amount" and a "prophylactically effective amount." The term "therapeutically effective amount" refers to an amount effective in treating and / or ameliorating a disease or condition in a subject. The term "prophylactically effective amount" refers to an amount effective in preventing and / or substantially lessening the chances of a disease or condition in a subject. As used herein, the terms "patient” and "subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans). The terms "patient” and "subject” include males and females.

[0049] As used herein, the term "excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

[0050] The compounds of the disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered all at once, as for example, by a bolus injection, multiple times, e.g. by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.

[0051] The compounds disclosed herein and other pharmaceutically active compounds, if desired, can be administered to a subject or patient by any suitable route, e.g. orally, topically, rectally, parenterally, (for example, subcutaneous injections, intravenous, intramuscular, intrasternal, and intrathecal injection or infusion techniques), or as a buccal, inhalation, or nasal spray. The administration can be to provide a systemic effect (e.g. eneteral or parenteral). All methods that can be used by those skilled in the art to administer a pharmaceutically active agent are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0052] Suitable oral compositions or formulations in accordance with the disclosure include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs. Compositions or formulations suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

[0053] 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 compounds, 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, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, 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 can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0054] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound 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.

[0055] 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 can 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 can 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 can 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 polethylene glycols and the like.

[0056] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound 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. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can 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 can be used include polymeric substances and waxes.

[0057] The pharmaceutical compositions and formulations described herein may also be administered topically or transdermally , especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract, e.g., can be effected in a rectal suppository formulation or in a suitable enema formulation. Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0058] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment, cream, lotion, or gel, containing the active component suspended or dissolved in one or more carriers, and any needed preservatives or buffers as may be required. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary I alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0059] Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present 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 can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0060] 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 can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0061] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0062] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquidsuspension 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 the compound in biodegradable polymers such as poly lactide-polyglycol ide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0063] Compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein 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.

[0064] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic 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 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. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0065] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0066] The compounds for use in the methods of the disclosure can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desiredtherapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

[0067] The compounds of the disclosure can be administered to a subject or patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that will be used can potentially depend on a number of factors, including the requirements of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular subject or patient is within the ordinary skill in the art.

[0068] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of "administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique {e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the "administering” of compositions includes both methods practiced on the human body and also the foregoing activities.

[0069] It is to be understood that while the disclosure is read in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.Embodiments1 . A compound having a structure of Formula (I):wherein:L1is Co-2alkylene;Ring B is phenyl or naphthyl; n is 0 to 2; each RBis independently selected from Cvsalkoxy, Ci-salkyl, halogen, Ci-shaloalkoxy and Ci-shaloalkyl;RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and O, and the ring is substituted with 0, 1 or 2 RA; orRN1and RN2are selected from H, Ci-salkyl, Co-salkylene-phenyl, and Co-salkylene-naphthyl, and the phenyl or naphthyl is substituted with 0-2 RA, with the proviso that only one of RN1and RN2can be H; and each RAis independently Ci-salkyl, halogen, or Ci-shaloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso when ring B is paramethoxyphenyl and RN1and RN2together with the nitrogen to which they are each attached form a piperidine ring, then 2 RAare not each methyl.The compound of embodiment 1 , whereinhas a structure ofThe compound of embodiment 1 , whereinhas a structure of4. The compound of any one of embodiments 1-3, wherein L1isCH2.5. The compound of any one of embodiments 1-3, wherein L1is Coalkylene (i.e., a bond).6. The compound of any one of embodiments 1-5, wherein Ring B is phenyl.7. The compound of embodiment 6, wherein n is 1 .The compound of embodiment 7, wherein Ring B has a structure ofThe compound of embodiment 6, wherein n is 2.The compound of embodiment 9, wherein Ring B has a structure11 . The compound of any one of embodiments 1-10, wherein at least one RBis Cvsalkoxy or Ci. shaloalkyl.12. The compound of any one of embodiments 1-11, wherein each of RN1and RN2is selected from H and Ci-salkyl.13. The compound of embodiment 12, wherein one of RN1and RN2is H and the other is Co- salkylene-phenyl or Co-salkylene-naphthyl.14. The compound of any one of embodiments 1-10, wherein RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0, and the ring is substituted with 0, 1 or 2 RA.15. The compound of embodiment 13, wherein RN1and RN2together with the nitrogen to which16. The compound of any one of embodiments 1 to 15, wherein one RAis present.17. The compound of any one of embodiments 1 to 16, wherein each RAis Ci-salkyl, halogen, or Ci-3haloalkyl.18. A compound, or pharmaceutically acceptable salt thereof, wherein the compound is B1-B7, C1-C10, D1-D7, or E1-E8.19. The compound of embodiment 18, wherein the compound is B1 or pharmaceutically acceptable salt thereof.20. A pharmaceutical composition comprising the compound of any one of embodiments 1-19 and a pharmaceutically acceptable excipient.21 . A method of modulating y-aminobutyric acid type A receptor (GABAAR) comprising contacting GABAA with a compound in an amount effective to modulate GABAAR, wherein the compound is a compound of any one of embodiments 1-19 or compound A1-A3.22. The method of embodiment 21 , wherein the compound activates GABAAR.23. The method of embodiment 22, wherein the compound is A1 , A2, A3, B1 , B2, B3, B4, B5, B6, or B7.24. The method of embodiment 21 , wherein the compound inhibits GABAAR.25. The method of embodiment 24, wherein the compound is C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10.26. Use of the compound of any one of embodiments 1-19 and A1-A3, or a pharmaceutically acceptable salt thereof, as an analgesic.27. The use of embodiment 26, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.28. The use of embodiment 27, wherein the compound is B1 , or a pharmaceutically acceptable salt thereof.29. Use of the compound of any one of embodiments 1 -19 and A1 -A3, or a pharmaceutically acceptable salt thereof, for treating acute or chronic pain.30. The use of embodiment 29, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.31 . The use of embodiment 30, wherein the compound is B1 , or a pharmaceutically acceptable salt thereof.32. Use of a compound selected from C1-C10, or a pharmaceutically acceptable salt thereof, as a stimulant.33. Use of the compound of any one of embodiments 1 -19 and A1 -A3, or a pharmaceutically acceptable salt thereof, as a sedative-hypnotic.34. The use of embodiment 33, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.35. The use of embodiment 34, wherein the compound is B1, or a pharmaceutically acceptable salt thereof.EXAMPLES

[0070] The following examples are provided for illustration and are not intended to limit the scope of the disclosure in any way.Experimental ProceduresExperimental Methods

[0071] All reagents and dry solvents were purchased from Sigma-Aldrich or Spectrum Chemicals and used without further purification. Column chromatography was performed using Silica Gel 60 A (40-63 .m). Analytical thin-layer chromatography (TLC) was performed using Silica Gel 60 A F254 precoated plates at 0.25mm thickness. NMR spectra were generated using a Varian 400 MHz using either CDCI3 or d6-DMSO as an acquisition solvent. Chemical shifts are reported in ppm (5) with the solvent reference relative to tetramethyl silane (TMS, 5 0.0) employed as the internal standard (CDCI3, 3 7.26 ppm; d6-DMSO, 5 2.50 ppm).Compound Synthesis

[0072] Compounds B1-B7, C1-C10, D1-D7, and E1-E8 were synthesized following the below general scheme.

[0073] Step 1. Ethyl nitroacetate (1, 3.0 mmol, 1.0 eq), 1,4-diazabicyclo[2.2.2]octane (DABCO), and the appropriate terminal alkyne (2-R, 1.2 mmol, 0.4 eq) were added to a 2-5mL microwave vial equipped with a magnetic stir bar. Ethanol-free chloroform stabilized by amylenes (4 mL, 0.75 M) was added to the microwave vial and the vial was sealed. The vial was heated at 140 °C for 1 h at Normal absorption level. Solvent was removed under reduced pressure. The resulting crude material was dissolved in diethyl ether and washed withwater. The organic layer was separated and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to provide the desired product, 3 which was used without further purification.

[0074] Step 2. The isoxazole ethyl ester (3, 2.0 mmol, 1 .0 eq) was dissolved in dry methanol (5 mL, 0.4 M) and potassium hydroxide (KOH) was added to the flask. A nitrogen balloon was used to flush the reaction flask and the flask was kept under inert atmosphere while the reaction was heated at 35°C for 1 h. The reaction was quenched with water and washed with Et20. The aqueous layer was separated, acidified with 6 M hydrochloric acid (HOI) dropwise until the reaction mixture reached a pH of approximately 3, and filtered to provide the desired product, 3-R, which was used without further purification.

[0075] Step 3. The isoxazole acid (3-R, 2.0 mmol, 1 .0 eq) was added to a round bottom flask under inert atmosphere. Thionyl chloride (SOCI2, 22.0mmol, 11.0 eq) was added dropwise and the reaction was refluxed at 85 °C for 2 h. The remaining SOCI2 was removed under reduced pressure to provide the desired product, 4-R which was used without further purification.

[0076] Step 4. The isoxazole acid chloride (4-R, 2.0 mmol, 1 .0 eq) was charged with dry tetrahydrofuran (5.1 mL, 0.39 M) and a magnetic stir bar under inert conditions. Triethylamine (TEA, 5.4 mmol, 2.7 eq) was added dropwise and briefly stirred. The desired amine (1.8 mmol, 0.9 eq) was added to an equal amount of THF (5.1 mL, 0.19 M) in a second flame dried flask. The solution was added dropwise to the reaction mixture containing the acid chloride, TEA, and THF. The reaction stirred for 16 h at room temperature under inert atmosphere. The solution was concentrated under reduced pressure and purified by column chromatography, with a mobile phase of 10-15% ethyl acetate in hexanes, to provide the product.

[0077] Table 1 . Terminal alkynes used in the synthesis of compounds of the disclosure.

[0078] Compound B1.1H NMR (400 MHz, CDCI3) 5 7.67, 7.66, 7.64, 7.21, 7.20, 6.93, 6.92, 6.90, 6.57, 6.55, 4.12, 4.09, 3.79, 3.79, 3.60, 3.35, 3.20, 3.16, 3.13, 2.88, 2.85, 2.82, 2.11, 1.73, 1.69, 1.66, 1.64, 1.60, 1.56, 1.49, 1.43, 1.27, 1.26, 1.24, 1.23, 1.21;13C NMR (101 MHz, CDCI3) 5 170.16, 16.37, 160.07, 159.96, 159.51, 127.57, 119.69, 114.50, 99.93, 98.75, 77.40, 77.08, 76.76, 55.44, 50.06, 44.94, 42.39, 37.72, 30.89, 29.89, 26.44, 25.56, 18.85, 17.26, 15.68.

[0079] Compound B1-R.1H NMR (400 MHz, CDCI3) 5 7.79-7.69 (d, 2 H), 7.05-6.95 (d, 2 H), 6.67-6.60 (s, 1 H), 5.13-4.16 (m, 2 H), 3.90-3.86 (s, 3 H), 3.34-2.85 (dt, 1 H), 1.86-1.46 (m, 6H), 1.38-1.29 (dddd, 3 H); LCMS (m / z) [M+H]+ calcd, 300.15; found, 301.14.

[0080] Compound B1-S.1H NMR (400 MHz, CDCI3) 5 7.80-7.68 (d, 2 H), 7.06-6.94 (d, 2 H), 6.67-6.61 (s, 1 H), 5.12-4.16 (m, 2 H), 3.90-3.86 (s, 3 H), 3.32-2.87 (dt, 1 H), 1.85-1.47 (m, 6H), 1.39-1.28 (dddd, 3 H); LCMS (m / z) [M+H]+ calcd., 300.15; found, 301.27.

[0081] Compound B2.1H NMR (400 MHz, CDCI3) 5 7.77, 7.76, 7.75, 7.74, 7.73, 7.02, 7.00, 6.99, 6.98, 6.71 , 6.70, 6.70, 3.89, 3.88, 3.87, 3.68, 3.67, 3.65, 3.60, 3.59, 3.57, 3.55, 1.31 , 1.30, 1.29, 1.28, 1.27, 1.26, 1.25;13C NMR (101 MHz, CDCI3) 5 170.02, 161.36, 160.59, 159.65, 127.55, 119.70, 114.51 , 99.19, 77.38, 77.07, 76.75, 55.44, 43.41 , 40.82, 14.70, 12.75.

[0082] Compound B3.1H NMR (400 MHz, CDCI3) 5 8.01 , 7.99, 7.77, 7.75, 7.74, 7.29, 7.28, 7.02, 7.00, 6.99, 6.82, 6.82, 6.81 , 6.80, 5.20, 5.19, 5.18, 4.72, 4.50, 4.49, 4.48, 4.47;13C NMR (101 MHz, CDCI3) 5 171.72, 161.56, 160.18, 156.91 , 134.00, 130.63, 127.59, 119.43, 114.55, 114.12, 98.55, 77.40, 77.08, 76.76, 63.27, 62.80, 62.17, 55.45, 14.18, 13.95.4.46, 4.46, 4.44, 4.36, 4.36, 3.89, 3.88, 3.87, 3.87, 1.82, 1.48, 1.48, 1.46, 1.46,1.45, 1.44, 1.43, 1.42, 1.40.

[0083] Compound B4.1H NMR (400 MHz, CDCI3) 5 6.11 , 6.10, 4.94, 4.92, 4.91 , 4.52, 4.48, 4.44, 4.04, 4.01 , 3.15, 3.12, 3.09, 2.85, 2.82, 2.79, 2.75, 2.72, 2.69, 2.01 , 1.98, 1.76, 1.73, 1.67, 1.65, 1.62, 1.59, 1.54, 1.52, 1.48,1.46, 1.44, 1.40, 1.37, 1.35, 1.33, 1.30, 1.23, 1.21 , 1.20, 1.18, 1.15;13C NMR (101 MHz, CDCI3) 5 178.01 ,160.35, 160.24, 158.67, 158.57, 99.89, 99.72, 77.45, 77.14, 76.82, 49.90, 44.78, 42.27, 36.22, 34.21 , 31.01 , 30.84, 30.30, 26.37, 25.70, 2559, 25.52, 18.81, 18.41 , 17.17, 15.61.

[0084] Compound B5.1H NMR (400 MHz, CDCI3 ) 5 7.78, 7.76, 7.66, 7.43, 7.42, 7.40, 7.34, 7.29, 6.80, 6.78, 5.05, 5.04, 5.02, 5.01 , 4.62, 4.58, 4.35, 4.18, 4.14, 4.01 , 4.00, 3.74, 3.28, 3.24, 3.21 , 2.96, 2.93, 2.89, 1.80, 1.77, 1.74, 1.71 , 1.68, 1.64, 1.61 , 1.58, 1.56, 1.53, 1.51 , 1.35, 1.33, 1.31 , 1.30, 1.28, 1.24;13C NMR (101 MHz, CDCI3 ) 5 170.27, 168.60, 160.19, 159.64, 159.54, 156.76, 135.16, 130.85, 130.53, 130.46, 129.32, 128.41 , 128.08, 125.93, 124.04, 101.25, 101.06, 100.75, 77.45, 77.13, 76.81 , 52.99, 50.11 , 45.03, 42.39, 37.28, 30.88, 29.86, 29.42, 26.40, 26.17, 25.53, 18.80, 18.43.

[0085] Compound B6.1H NMR (400 MHz, CDCI3) 5 8.24, 7.97, 7.83, 7.01 , 7.00, 5.05, 5.04, 5.02, 4.63, 4.60,4.35, 4.19, 4.16, 4.01 , 3.32, 3.28, 3.25, 2.99, 2.96, 2.93, 1.84, 1.80, 1.77, 1.74, 1.71 , 1.66, 1.61 , 1.59, 1.57, 1.56, 1.55, 1.53, 1.52, 1.36, 1.35, 1.32, 1.30, 1.26, 0.87;13C NMR (101 MHz, CDCI3) 5 166.75, 159.94, 159.83, 159.01 , 158.92, 133.34, 133.01 , 132.67, 132.33, 128.75, 125.91 , 125.86, 124.17, 123.89, 123.86, 123.82, 123.78, 123.75, 123.45, 102.80, 102.63, 77.37, 77.06, 76.74, 50.21, 45.18, 42.43, 37.38, 30.89, 29.84, 26.39, 25.51 , 18.76.

[0086] Compound B7.1H NMR (400 MHz, CDCI3 ) 5 8.20, 8.19, 8.16, 8.13, 7.79, 7.77, 7.73, 7.71 , 7.70, 7.46,7.35, 7.27, 7.26, 7.24, 7.19, 7.18, 7.13, 7.11 , 7.09, 7.05, 6.77, 6.76, 6.73, 6.71 , 4.98, 4.96, 4.95, 4.56, 4.53, 4.13,4.10, 3.93, 3.85, 3.84, 3.21 , 3.17, 3.14, 2.89, 2.85, 2.82, 1.72, 1.68, 1.66, 1.63, 1.60, 1.49, 1.47, 1.44, 1.28, 1.26,1.24, 1.22, 1.21 , 1.17, 1.16, 1.08;13C NMR (101 MHz, CDCI3) 5 170.45, 169.83, 159.52, 158.98, 135.54, 130.25,128.93, 128.87, 128.43, 127.71 , 125.86, 125.63, 124.60, 124.39, 123.42, 122.60, 122.00, 119.95, 105.87, 100.58, 99.97, 99.77, 77.44, 77.13, 76.81 , 55.42, 50.11 , 44.97, 42.43, 37.25, 30.90, 29.90, 26.45, 25.57, 18.85, 17.27, 15.70.

[0087] Compound C1.1H NMR (400 MHz, CDCI3) 5 7.79, 7.78, 7.77, 7.76, 7.75, 7.04, 7.03, 7.02, 7.01 , 7.00,6.84, 6.83, 6.82, 4.03, 4.03, 4.02, 4.01 , 3.91 , 3.90, 3.89, 3.88, 0.91 , 0.89, 0.86;13C NMR (101 MHz, CDCI3) 5171.84, 161.61 , 160.64, 156.63, 127.63, 119.39, 114.58, 98.55, 77.36, 77.04, 76.73, 55.48, 52.89.

[0088] Compound C2.1H NMR (400 MHz, CDCI3) 5 8.34, 7.94, 7.68, 7.66, 7.64, 7.57, 7.46, 7.29, 7.28, 7.27,7.24, 7.23, 7.22, 6.94, 6.93, 6.92, 6.90, 6.85, 6.83, 6.81 , 6.79, 6.74, 4.76, 4.59, 4.58, 4.56, 4.51 , 3.81 , 3.79, 3.79, 3.73, 3.72, 3.70;13C NMR (101 MHz, CDCI3) 5 171.69, 161.53, 159.03, 137.39, 128.84, 128.80, 127.92, 127.79,127.61 , 119.58, 114.57, 97.85, 77.39, 77.07, 76.75, 55.49, 43.54, 29.73.

[0089] Compound C3.1H NMR (400 MHz, CDCI3) 5 11.93, 9.10, 8.03, 8.01 , 7.99, 7.93, 7.92, 7.90, 7.82, 7.80, 7.78, 7.76, 7.67, 7.61 , 7.59, 7.57, 7.56, 7.54, 7.52, 7.05, 7.04, 7.02, 7.01 , 6.99, 6.84, 6.64, 6.49, 3.90, 3.89;13C NMR (101 MHz, CDCI3) 5 172.21 , 161.65, 159.46, 157.45, 134.11 , 131.34, 128.83, 127.68, 126.75, 126.64, 126.25, 126.21 , 125.75, 120.48, 120.39, 119.47, 114.63, 97.89, 77.40, 77.08, 76.76, 55.50, 8.65.

[0090] Compound C4.1H NMR (400 MHz, CDCI3) 5 7.97, 7.95, 7.69, 7.68, 7.68, 7.66, 7.65, 6.94, 6.94, 6.93, 6.92, 6.90, 6.64, 6.63, 3.81 , 3.80, 3.79, 3.78, 3.27, 3.26, 3.25, 3.25, 3.09, 3.09, 3.08, 3.07, 2.07, 0.82, 0.80, 0.77;13C NMR (101 MHz, CDCI3 ) 5 170.18, 161.40, 161.16, 159.43, 132.19, 127.59, 119.63, 114.52, 113.67, 99.30, 77.39, 77.07, 76.75, 55.45, 38.84, 36.03, 29.72.

[0091] Compound C5.1H NMR (400 MHz, CDCI3 ) 5 7.68, 7.67, 7.66, 7.65, 7.64, 6.93, 6.91 , 6.89, 6.59, 6.58, 4.72, 4.69, 4.41 , 4.37, 3.79, 3.78, 3.03, 3.00, 2.96, 2.69, 2.65, 2.62, 1.75, 1.72, 1.68, 1.65, 1.29, 1.26, 1.25, 1.23,1.22, 1.20, 1.19, 1.17, 0.84, 0.83, 0.82, 0.81 ;13C NMR (101 MHz, CDCI3) 5 170.20, 161.38, 159.55, 159.31, 127.56, 119.65, 114.50, 99.06, 77.43, 77.11 , 76.79, 55.43, 47.77, 43.24, 42.68, 32.35, 30.11 , 28.99, 19.68.

[0092] Compound C6.1H NMR (400 MHz, CDCI3) 5 7.67, 7.65, 7.63, 7.45, 6.92, 6.91 , 6.89, 6.58, 6.57, 6.56,4.22, 3.79, 3.78, 3.77, 3.68, 3.67, 3.66, 3.65, 1.99, 1.97, 1.96, 1.62, 1.57, 1.23, 1.18, 1.17;13C NMR (101 MHz, CDCI3 ) 5 170.20, 16.38, 159.69, 159.29, 127.56, 119.66, 114.50, 99.01 , 77.41 , 77.09, 76.78, 55.43, 48.23, 43.60, 26.63, 24.54.

[0093] Compound C7.1H NMR (400 MHz, CDCI3 CDCI3) 5 7.67, 7.66, 7.64, 7.21 , 7.20, 6.93, 6.92, 6.90, 6.62,6.61 , 3.87, 3.85, 3.80, 3.79, 3.77, 2.62, 2.46, 2.45, 2.43, 2.42, 2.28, 2.27, 1.18;13C NMR (101 MHz, CDCI3 ) 5 173.38, 161.45, 159.63, 159.05, 127.99, 119.54, 114.54, 99.31 , 77.36, 77.06, 76.75, 55.44, 55.37, 54.58, 46.88,45.93, 42.42.

[0094] Compound C8.1H NMR (400 MHz, CDCI3 ) 5 7.66, 7.65, 7.63, 7.53, 7.52, 7.50, 7.27, 7.25, 7.19, 7.18,7.15, 7.13, 7.11 , 7.09, 7.08, 7.06, 7.02, 7.00, 6.98, 6.96, 6.94, 6.93, 6.91 , 6.90, 6.88, 6.84, 6.82, 6.72, 6.71 , 6.70,6.49, 6.48, 6.48, 5.50, 5.49, 5.48, 4.42, 4.18, 4.17, 4.15, 4.14, 4.12, 4.09, 4.08, 4.06, 4.04, 4.02, 3.89, 3.87, 3.86, 3.84, 3.82, 3.78, 3.77, 3.74, 3.73, 3.73, 3.58, 2.38, 2.36, 2.34, 2.32, 2.31 , 2.29, 2.00, 1.99, 1.97, 1.95, 1.93, 1.91 , 1.90, 1.87;13C NMR (101 MHz, CDCI3) 5 130.69, 130.56, 129.35, 129.22, 128.67, 128.58, 128.49, 127.56, 127.46, 126.77, 126.73, 124.06, 124.02, 123.91 , 123.88, 119.66, 119.59, 115.76, 115.63, 115.54, 115.42, 114.53, 114.39, 99.65, 99.03, 77.42, 77.10, 46.78, 57.52, 57.49, 56.95, 56.92, 55.44, 55.40, 49.77, 47.89, 34.36, 32.55, 24.52, 21.40, 21.07, 14.22.

[0095] Compound C9.1H NMR (400 MHz, CDCI3) 5 7.34, 7.33, 7.31 , 7.28, 7.26, 6.16, 4.99, 4.97, 4.57, 4.54,4.50, 4.09, 4.06, 3.85, 3.21 , 3.17, 3.14, 2.91 , 2.87, 2.84, 1.77, 1.73, 1.70, 1.67, 1.64, 1.59, 1.58, 1.53, 1.48, 1.45, 1.29, 1.27, 1.25, 1.23, 1.11 ;13C NMR (101 MHz, CDCI3 ) 5 172.41, 159.99, 159.90, 159.01, 158.91 , 134.40, 128.91 , 128.87, 127.30, 102.78, 102.60, 77.54, 77.22, 76.90, 49.94, 44.84, 42.29, 37.14, 33.10, 30.85, 29.83, 26.36, 25.52, 18.82, 18.80.

[0096] Compound C10.1H NMR (400 MHz, CDCI3 ) 5 7.72, 7.70, 7.68, 7.21 , 7.10, 7.08, 7.06, 6.64, 4.97, 4.95,4.93, 4.54, 4.51 , 4.10, 4.07, 3.19, 3.16, 3.13, 2.88, 2.84, 2.81 , 1.72, 1.68, 1.66, 1.63, 1.59, 1.55, 1.53, 1.50, 1.48, 1.45, 1.42, 1.34, 1.26, 1.24, 1.22, 1.20, 1.17;13C NMR (101 MHz, CDCI3) 5 169.14, 165.17, 162.66, 159.71, 159.62, 159.53, 128.09, 128.00, 123.27, 123.23, 116.45, 116.22, 100.18, 100.00, 77.47, 77.15, 76.83, 50.07, 44.98, 37.23, 30.87, 30.30, 29.85, 26.40, 25.53, 18.80.

[0097] Compound D1.1H NMR (400 MHz, CDCI3 ) 5 7.76, 7.76, 7.75, 7.74, 7.73, 7.02, 7.02, 7.01 , 7.00, 6.98, 6.68, 6.67, 6.66, 6.65, 4.72, 4.69, 4.42, 4.38, 3.89, 3.88, 3.87, 3.87, 3.69, 3.18, 3.17, 3.14, 3.11 , 2.85, 2.84, 2.81 , 2.78, 1.81 , 1.78, 1.74, 1.71 , 1.68, 1.31 , 1.27, 1.24, 1.21 , 1.01 , 1.00, 0.99, 0.98, 0.98;13C NMR (101 MHz, CDCI3) 5 170.21 , 161.38, 159.69, 159.31 , 127.57, 119.66, 114.51 , 99.03, 77.40, 77.76, 55.44, 47.51 , 42.98, 34.85, 33.77, 31.12, 21.66.

[0098] Compound D2.1H NMR (400 MHz, CDCI3) 5 7.76, 7.75, 7.74, 7.72, 7.28, 7.01 , 7.01 , 6.99, 6.97, 6.83, 6.82, 6.81 , 6.81 , 3.93, 3.91 , 3.90, 3.88, 3.87, 3.86, 3.85, 3.71 , 3.69, 3.68, 3.66, 2.27, 2.03, 2.01 , 1.99, 1.98, 1.96,1.94, 1.93, 1.27, 1.25, 1.23, 1.23;13C NMR (101 MHz, CDCI3) 50170.03, 161.33, 160.41 , 127.52, 119.71 , 114.49, 99.39, 77.42, 77.10, 76.78, 55.43, 48.74, 46.97, 26.30, 23.95

[0099] Compound D3.1H NMR (400 MHz, CDCI3) 5 6.13, 6.12, 5.13, 5.10, 4.96, 4.94, 4.93, 4.91 , 4.71 , 4.52, 4.49, 4.45, 4.44, 4.12, 4.04, 4.01 , 3.89, 3.16, 3.13, 3.09, 3.06, 3.04, 3.02, 3.01 , 2.99, 2.86, 2.82, 2.79, 1.72, 1.68, 1.65, 1.62, 1.59, 1.54, 1.52, 1.48, 1.47, 1.44, 1.42, 1.40, 1.28, 1.26, 1.25, 1.22, 1.20, 1.18;13C NMR (101 MHz, CDCI3) 5 178.93, 160.31 , 160.21 , 158.74, 158.65, 99.92, 99.78, 77.41 , 77.09, 76.78, 49.94, 44.81 , 42.29, 21.93, 37.13, 30.85, 27.15, 26.38, 36.17, 25.54, 25.08, 20.77, 18.82, 1842, 17.19, 16.87, 15.63.

[0100] Compound D4.1H NMR (400 MHz, CDCI3) 5 6.18, 6.17, 4.97, 4.95, 4.55, 4.52, 4.47, 4.45, 4.06, 4.03, 3.19, 3.16, 3.12, 2.89, 2.85, 2.82, 2.74, 2.72, 2.71 , 2.69, 1.75, 1.73, 1.71 , 1.69, 1.68, 1.65, 1.62, 1.27, 1.26, 1.24, 1.22, 0.99, 0.98, 0.96, 0.94;13C NMR (101 MHz, CDCI3 ) 5 173.79, 160.23, 160.11 , 158.84, 158.73, 101.52, 101.33, 77.49, 77.17, 76.86, 50.68, 49.88, 44.75, 44.56, 43.43, 42.66, 42.23, 28.48, 26.63, 26.33, 25.93, 25.49, 24.47, 20.79, 18.78, 17.12, 15.57, 13.63, 13.49.

[0101] Compound D5.1H NMR (400 MHz, CDCI3) 5 6.12, 4.94, 4.92, 4.52, 4.49, 4.45, 4.05, 4.01 , 3.16, 3.14, 3.13, 3.09, 2.86, 2.82, 2.79, 1.86, 1.71 , 1.69, 1.67, 1.65, 1.62, 1.59, 1.54, 1.52, 1.49, 1.47, 1.44, 1.40, 1.23, 1.22, 1.20, 1.18;13C NMR (101 MHz, CDCI3) 5 172.72, 160.32, 160.21 , 158.74, 158.64, 100.25, 100.09, 77.44, 77.12, 76.80, 49.91 , 44.78, 42.27, 37.36, 37.10, 31.82, 30.84, 29.84, 26.37, 25.53, 25.24, 18.82.

[0102] Compound D6.1H NMR (400 MHz, CDCI3) 5 7.29, 7.28, 7.28, 6.22, 6.20, 5.04, 5.02, 4.89, 4.62, 4.58,4.42, 4.31 , 4.26, 4.23, 4.17, 3.25, 3.22, 3.18, 2.95, 2.92, 2.88, 2.55, 2.54, 2.53, 2.51 , 2.43, 2.13, 2.11 , 1.57, 1.53, 1.52, 1.50, 1.43, 1.39, 1.38, 1.34, 1.32, 1.30, 1.29, 1.28, 1.25, 1.24, 1.23;13C NMR (101 MHz, CDCI3) 5 181.48, 99.39, 99.27, 77.36, 77.04, 77.73, 49.95, 44.84, 42.31 , 37.39, 37.18, 32.85, 31.86, 26.35, 25.57, 25.27, 18.86.

[0103] Compound D7.1H NMR (400 MHz, CDCI3 ) 5 6.14, 6.13, 5.04, 5.02, 5.00, 4.99, 4.90, 4.60, 4.56, 4.50,4.42, 4.10, 4.07, 3.23, 3.20, 3.17, 2.93, 2.90, 2.87, 2.11 , 2.09, 2.07, 2.06, 1.91 , 1.80, 1.76, 1.32, 1.31 , 1.29, 1.27, 1.24, 1.13, 1.11 , 1.09, 1.03, 1.01 , 0.87;13C NMR (101 MHz, CDCI3 ) 5 175.16, 160.22, 158.93, 99.45, 99.35,77.37, 77.05, 76.73, 49.94, 44.81 , 42.30, 37.12, 30.85, 29.85, 26.40, 25.53, 18.83, 8.63, 8.0.

[0104] Compound E1.1H NMR (400 MHz, CDCI3) 5 7.85 - 7.65 (m, 2H), 7.06 - 6.89 (m, 2H), 6.65 (d, J = 11 .9 Hz, 1 H), 4.65 (dp, J = 54.1 , 6.8 Hz, 1 H), 3.87 (s, 3H), 3.53 (dq, J = 45.6, 7.1 Hz, 2H), 1.28 (dt, J = 20.9, 6.8 Hz, 9H);13C NMR (100 MHz, CDCI3) 5 170.10, 161.36, 160.78, 159.78, 127.55, 127.53, 119.70, 114.49, 99.05,98.76.55.42, 49.97, 47.12, 39.41 , 36.19, 21.46, 20.35, 16.92, 14.56.

[0105] Compound E2.1H NMR (400 MHz, CDCI3) Rotamer 5 7.82 - 7.65 (m, 2H), 7.09 - 6.87 (m, 2H), 6.79 (d, J = 4.9 Hz, 1 H), 4.41 (pd, J = 6.4, 3.6 Hz, 1 H), 4.01 - 3.89 (m, 1 H), 3.86 (d, J = 0.8 Hz, 3H), 3.77 - 3.64 (m, 1 H), 2.18 - 1.85 (m, 3H), 1.79 - 1.58 (m, 1 H), 1.34 (d, J = 6.4 Hz, 2H), 1.22 (d, J = 6.4 Hz, 1 H);13C NMR (100 MHz, CDCI3) 5 169.94, 161.31 , 160.74, 158.72, 127.51 , 119.76, 114.49, 99.47, 99.42, 55.42, 54.45, 54.28, 48.86, 46.43, 33.10, 31.83, 24.34, 21.44, 21.29, 19.28.

[0106] Compound E3.1H NMR (400 MHz, CDCI3) 5 8.51 (s, 1 H), 7.86 - 7.60 (m, 2H), 7.31 (d, J = 21.5 Hz, 2H), 7.10 - 6.96 (m, 2H), 6.93 (s, 1 H), 6.88 - 6.79 (m, 1 H), 3.89 (s, 3H), 2.36 (s, 6H);13C NMR (100 MHz, CDCI3) 5 171.98, 161.59, 159.49, 156.74, 138.91, 136.87, 127.64, 126.73, 119.50, 117.82, 114.56, 97.84, 55.45, 21.41.

[0107] Compound E4.1H NMR (400 MHz, CDCI3) Rotamer 5 7.81 - 7.66 (m, 2H), 7.04 - 6.91 (m, 2H), 6.71 (d, J = 11.7 Hz, 1 H), 5.41 (ddd, J = 18.6, 15.2, 9.0 Hz, 1 H), 4.76 - 4.44 (m, 1 H), 3.86 (s, 3H), 3.48 - 2.93 (m, 1 H), 2.25 - 2.01 (m, 1 H), 2.00 - 1.69 (m, 4H), 1.64 (s, 1 H);13C NMR (100 MHz, CDCI3) 5 170.62, 170.57, 161.53, 159.08, 158.68, 127.61 , 127.59, 119.40, 119.35, 114.54, 99.66, 99.16, 55.41 , 53.73, 49.29, 48.99, 44.30, 39.50, 25.14, 24.19, 23.35, 22.75, 19.40, 19.33.

[0108] Compound E6.1H NMR (400 MHz, CDCI3) 5 9.27 (s, 1 H), 8.23 (d, J = 3.0 Hz, 1 H), 7.85 - 7.64 (m, 2H), 7.14 - 6.98 (m, 2H), 6.93 (s, 1 H), 6.87 (d, J = 8.9 Hz, 1 H), 6.67 (dd, J = 8.9, 3.0 Hz, 1 H), 3.91 (d, J = 10.2 Hz, 6H), 3.85 (s, 3H);13C NMR (100 MHz, CDCI3) 5 171.95, 156.71 , 153.82, 142.63, 127.63, 127.51 , 114.59, 110.92,109.37, 106.33, 97.74, 56.35, 55.84, 55.47.

[0109] Compound E7.1H NMR (400 MHz, CDCI3) Rotamer 5 7.86 - 7.68 (m, 2H), 7.04 - 6.96 (m, 2H), 6.93 (s, 1 H), 4.75 (d, J = 168.4 Hz, 1 H), 4.44 - 3.89 (m, 1 H), 3.86 (s, 3H), 3.10 (d, J = 124.3 Hz, 1 H), 1.93 - 1.47 (m, 6H), 1.36 (d, J = 18.9 Hz, 3H);13C NMR (100 MHz, CDCI3) 5 165.21 , 161.91 , 161.28, 157.47, 128.30, 120.69, 114.45, 55.37, 18.81.

[0110] Compound E7-R.1H NMR (400 MHz, CDCI3) 5 7.86 - 7.65 (m, 2H), 7.08 - 6.98 (m, 2H), 6.94 (s, 1 H), 4.76 (d, J = 168.2 Hz, 1 H), 4.43 - 3.93 (m, 1 H), 3.87 (s, 3H), 3.11 (d, J = 123.8 Hz, 1 H), 1.85 - 1.51 (m, 6H), 1.35 (s, 3H);13C NMR (100 MHz, CDCI3) 5 165.22, 161.92, 161.29, 157.48, 128.32, 120.70, 114.45, 55.38, 18.82.

[0111] Compound E7-S.1H NMR (400 MHz, CDCI3) 5 7.86 - 7.65 (m, 2H), 7.04 - 6.97 (m, 2H), 6.94 (s, 1 H), 4.76 (d, J = 167.9 Hz, 1 H), 4.21 (d, J = 128.3 Hz, 1 H), 3.87 (s, 3H), 3.11 (d, J = 124.1 Hz, 1 H), 1.74 (m, 6H), 1.35 (s, 3H);13C NMR (100 MHz, CDCI3) 5 165.23, 161.93, 161.29, 157.47, 128.32, 120.71 , 114.46, 55.39, 18.82.

[0112] Compound E8-R.1H NMR (400 MHz, CDCI3) 5 7.78-7.72 (d, 2 H), 7.05-6.98 (d, 2 H), 6.74-6.70 (s, 1 H), 4.83-3.52 (m, 7 H), 3.91-3.85 (s, 3 H), 1.52-1.39 (d, 3 H); LCMS (m / z) [M+H]+calcd., 302.13; found, 303.11

[0113] Compound E8-S.1H NMR (400 MHz, CDCI3) 5 7.79-7.71 (d, 2 H), 7.05-6.98 (d, 2 H), 6.74-6.70 (s, 1 H), 4.82-3.52 (m, 7 H), 3.90-3.87 (s, 3 H), 1.51-1.41 (d, 3 H); LCMS (m / z) [M+H]+calcd., 302.13; found, 303.19.Zebrafish Behavioral Profiling Apparatus

[0114] The zebrafish behavioral profiling apparatus as disclosed in McCarroll, M.N., Gendelev, L, Kinser, R. et al. Nat Commun 10, 4078 (2019) , was used to assess the compounds of the disclosure, but with improvements made to the hardware build of the behavioral profiling apparatus used. The hardware was improved by adding a laser cut groove into the stage that the 96-well plate rests inside to improve the signal to noise ratio in behavioral assays and installing rubber padding around the solenoid to isolate the stimulus and optimize the acoustic startle response.Behavioral AssaysInitial Behavioral Assays

[0115] Two assays were used: I) 30 second "soft tap” assay where the stimulus is a soft solenoid tap delivered to the stage that the 96-well plate of fish was located; and II) a 30 second assay of 3 each 5-second-long high intensity violet light flashes were presented at different intervals. These two assays provided a total of 1500 data points per condition to be compared to etomidate as a control.Secondary Behavioral Assays

[0116] Loss of righting reflex (LORR) is a behavioral phenotype indicative of anesthesia across multiple animal species. An observation was made while performing LORR experiments on adult zebrafish: while etomidate would cause LORR in both larval and adult zebrafish, compounds that produced LORR in larval zebrafish but not in mice also did not produce LORR in the adult zebrafish. Based on this observation, an assay was developedusing a single adult zebrafish 6-12 months of age in each well of a 6-well plate. Each well of the 6-well plate was filled with 8ml of egg water and 10 M etomidate or 50 piM of compound. This assay was used to identify which compounds from the larval screen would cause LORR in the adult fish (like etomidate).Analysis of Behavioral Assays

[0117] Analysis of the behavioral assay data was performed with a version of phenoscore, using a Pearson correlation metric from the scikit python package, and an improved, extended behavioral profile of etomidate as a comparator of anesthetic like molecules, as well as an acoustic startle metric. Data from the initial behavioral assays were analyzed with python and Jupyter to identify molecules that exhibit a behavioral profile like that of etomidate profile from a 12,000-compound library (Chembridge).

[0118] Twenty-eight compounds from the 12,000 compound library were further investigated using the secondary behavioral assay, as described above, and the structures of these 28 compounds are shown in Figure 1 . The results of the 28 compounds used in the LORR assay, and the control experiments of solvent and of etomidate, are shown in Figure 2.Solubility Screening

[0119] Although the compounds are quite soluble in DMSO, a more pharmacologically friendly solvent system was desired. It was determined that a 50% ethanol and 50% Kolliphor formulation would dissolve compound A1, after brief sonication and mixing. This formulation can be made in high concentration and subsequently diluted into a working concentration in sterile saline solution and stay in solution long enough to perform an IP injection into mice.

[0120] Using etomidate as a positive control, both etomidate and A1 were dissolved in the same 1 :1 ethanol / Koll iphor formulation as vehicle at a higher starting concentration, and then diluting into sterile saline at a working concentration and LORR was determined for both etomidate and A1 in the mouse.

[0121] Since ethanol has sedating behavioral effects on mouse models, a new formulation of 1 :4EtO H / Kal II phor was used to prevent any off-target effects of the vehicle. Next, solubility tests were performed to determine the highest starting concentration of the new isoxazoles that could get into the formulation without crashing out. Finally, to determine the ED50, the Dixon test was used. The ED50 in adult zebrafish (Figure 3) was performed initially, then the ED50 in mice (Figure 4) was calculated. From these calculations, a correlation between the ED50 from the fish and the ED50 in the mouse was determined. Specifically, the ED50 of the mouse was a multiplication factor of the ED50 in fish.

[0122] Compounds B1-B7, C1-C10, and D1-D7 were analyzed using the behavioral assays described above, and the data are shown in Figure 5. Compounds E1-E4 and E6-E8 were also analyzed using the behavioral assays described above, and the data are tabulated in Table 2, along with the data for racemic and (S) and (R)- B1.

[0123] Table 2. Behavioral assay results.

Claims

What is claimed is:

1. A compound having a structure of Formula (I):wherein:L1is Co-2alkylene;Ring B is phenyl or naphthyl; n is 0 to 2; each RBis independently selected from Cvsalkoxy, Ci-salkyl, halogen, Ci-shaloalkoxy and Ci-shaloalkyl;RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0, and the ring is substituted with 0, 1 or 2 RA; orRN1and RN2are selected from H, Ci-salkyl, Co-salkylene-phenyl, and Co-salkylene-naphthyl, and the phenyl or naphthyl is substituted with 0-2 RA, with the proviso that only one of RN1and RN2can be H; and each RAis independently Ci-salkyl, halogen, or Ci-shaloalkyl; or a pharmaceutically acceptable salt thereof; with the proviso when ring B is paramethoxyphenyl and RN1and RN2together with the nitrogen to which they are each attached form a piperidine ring, then 2 RAare not each methyl.The compound of claim 1 , wherein4. The compound of any one of claims 1-3, wherein L1IsCF5. The compound of any one of claims 1-3, wherein L1is Coalkylene (i.e., a bond).

6. The compound of any one of claims 1-5, wherein Ring B is phenyl.The compound of claim 6, wherein n is 1 .The compound of claim 7, wherein Ring B has a structure ofThe compound of claim 6, wherein n is 2.

10. The compound of claim 9, wherein Ring B has a structure11. The compound of any one of claims 1-10, wherein at least one RBis Cvsalkoxy or Ci-shaloalkyl.

12. The compound of any one of claims 1-11, wherein each of RN1and RN2is selected from H and Ci-3alkyl.

13. The compound of claim 12, wherein one of RN1and RN2is H and the other is Co-3alkylene- phenyl or Co-salkylene-naphthyl.

14. The compound of any one of claims 1-10, wherein RN1and RN2together with the nitrogen to which they are each attached form a 5-10 membered ring comprising 0 or 1 additional ring heteroatom independently selected from N and 0, and the ring is substituted with 0, 1 or 2 RA.

15. The compound of claim 13, wherein RN1and RN2together with the nitrogen to which they are each attached form a ring having a structure16. The compound of any one of claims 1 to 15, wherein one RAis present.

17. The compound of any one of claims 1 to 16, wherein each RAis Ci-salkyl, halogen, or Ci. shaloalkyl.

18. A compound, or pharmaceutically acceptable salt thereof, wherein the compound is B1-B7, C1-C10, D1-D7, or E1-E8.

19. The compound of claim 18, wherein the compound is B1 or pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of any one of claims 1-19 and a pharmaceutically acceptable excipient.21 . A method of modulating y-aminobutyric acid type A receptor (GABAAR) comprising contacting GABAA with a compound in an amount effective to modulate GABAAR, wherein the compound is a compound of any one of claims 1-19 or compound A1-A3.

22. The method of claim 21 , wherein the compound activates GABAAR.

23. The method of claim 22, wherein the compound is A1 , A2, A3, B1 , B2, B3, B4, B5, B6, or B7.

24. The method of claim 21 , wherein the compound inhibits GABAAR.

25. The method of claim 24, wherein the compound is C1, C2, C3, C4, C5, C6, C7, C8, C9, orC10.

26. Use of the compound of any one of claims 1-19 and A1-A3, or a pharmaceutically acceptable salt thereof, as an analgesic.

27. The use of claim 26, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.

28. The use of claim 27, wherein the compound is B1 , or a pharmaceutically acceptable salt thereof.

29. Use of the compound of any one of claims 1-19 and A1-A3, or a pharmaceutically acceptable salt thereof, for treating acute or chronic pain.

30. The use of claim 29, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.31 . The use of claim 30, wherein the compound is B1 , or a pharmaceutically acceptable salt thereof.

32. Use of a compound selected from C1-C10, or a pharmaceutically acceptable salt thereof, as a stimulant.

33. Use of the compound of any one of claims 1-19 and A1-A3, or a pharmaceutically acceptable salt thereof, as a sedative-hypnotic.

34. The use of claim 33, wherein the compound is selected from B1-B7, or a pharmaceutically acceptable salt thereof.

35. The use of claim 34, wherein the compound is B1 , or a pharmaceutically acceptable salt thereof.

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