WO2021252709A1

WO2021252709A1 - Compounds, compositions, and methods for treating, ameliorating, and/or preventing sigma receptor related diseases and/or disorders

Info

Publication number: WO2021252709A1
Application number: PCT/US2021/036719
Authority: WO
Inventors: William J. Welsh; Youyi Peng
Original assignee: Rutgers, The State University Of New Jersey
Priority date: 2020-06-10
Filing date: 2021-06-10
Publication date: 2021-12-16

Abstract

The disclosure relates in one aspect to methods of treating, ameliorating, and/or preventing certain S1R and/or S2R-related diseases and/or disorders, such as for example certain viral infections in a subject, comprising administering to the subject at least one of a compound of the present disclosure and a composition comprising such compounds. In another aspect, the disclosure relates to methods of treating, ameliorating, and/or preventing sigma receptor related diseases and/or disorders in a subject, comprising administering to the subject at least one of a compound of the present disclosure and a composition comprising such compounds. In certain embodiments, the subject is a mammal. In yet other embodiments, the mammal is human.

Description

TITLE

Compounds, Compositions, and Methods for Treating, Ameliorating, and/or Preventing Sigma Receptor Related Diseases and/or Disorders

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/037,396, filed June 10, 2020, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

The sigma receptors were initially identified as an opioid receptor subtype and later as a phencyclidine binding receptor. Now it is widely recognized that sigma receptors comprise a unique family distinct from opioid and phencyclidine receptors, and are classified into two subtypes: sigma 1 receptor (SIR) and sigma 2 receptor (S2R).

The SIR is a protein of 223 amino acids, present in a diverse array of species, including humans, and has a molecular weight of 25.3 kDa. It is highly expressed in both central and peripheral nervous systems, and has been identified as a ligand-gated molecular chaperone protein within the endoplasmic reticulum (ER) and plasma membranes. On the other hand, the S2R was initially identified as progesterone receptor membrane component 1 (PGRMC1), but was later reported as the translation of gene TMEM97. Although the molecular identify of the S2R remains ambiguous, there is overwhelming evidence demonstrating the S2R plays important roles in different types of cancer, neurological diseases, inflammatory and autoimmune diseases.

Recent work has implicated the SIR signaling pathway in a number of pathological diseases and/or disorders ( e.g ., pain). Antagonists selective for SIR have been shown to elicit beneficial effects in neuropathic pain, enhance opioid analgesia, and/or mitigate drug abuse (e.g., alcohol, cocaine, and methamphetamine). Furthermore, the SIR pathway has been implicated in exacerbation of HIV- 1 pathobiology. SIR modulation has the potential to inhibit and/or ameliorate transmission, replication, and/or progression of viral infections (e.g, HIV infection to AIDS and/or SARS-CoV-2 to COVID-19).

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a recently isolated virus known as severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 is now an ongoing global pandemic, having infected about 168.5 million people and caused the death of more than 3.5 million people worldwide. Common symptoms of COVID-19 include fever, cough, fatigue, shortness of breath, and loss of smell and taste. Most COVID-19 infections result in mild symptoms and resolve on their own, but some cases progress to acute respiratory distress syndrome (ARDS), which is associated with dangerously low blood oxygen levels. Further COVID-19 complications include pneumonia, multi-organ failure, septic shock, heart failure, arrhythmias, heart inflammation, and blood clots.

Thus, there is a need in the art to develop novel compounds that bind to the sigma receptors (SIR and/or S2R). Such compounds can be used to treat certain diseases and/or disorders that are associated with SIR and/or S2R. The present invention addresses this unmet need.

BRIEF SUMMARY OF THE DISCLOSURE

The present disclosure relates, in part, to methods of treating, ameliorating, and/or preventing certain SIR and/or S2R-related diseases and/or disorders in a subject, the method comprising administering to the subject at least one of a compound of the present disclosure and/or a composition comprising such a compound.

In certain embodiments, the sigma receptor related disease and/or disorder is pain. In certain embodiments, the sigma receptor related disease and/or disorder is a viral infection.

In certain embodiments, the compound of the present disclosure is a SIR modulator.

In certain embodiments, the compound of the present disclosure is dyclonine, or a salt, solvate, or isotopically labeled derivative thereof.

In certain embodiments, the compound of the present disclosure is a compound of formula (I):

or a salt, solvate, isotopically labeled derivative, enantiomer, diastereomer, or tautomer thereof, wherein the substituents in formula (I) are defined elsewhere herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of illustrative embodiments of the disclosure will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosure, exemplary embodiments are shown in the drawings. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

FIG. 1 illustrates % inhibition of SARS-CoV-2 infection by illustrative compounds 8, 27, and 47 of the present disclosure.

FIG. 2 illustrates reduction of viral titer by approximately 2 logarithmic units (i.e., 100-fold) in monkey VeroE6 cells infected by SARS-CoV-2 (MOI = 0.1) with administration of compounds of the present invention at 5 mM.

FIG. 3 illustrates that Dyclonine exhibits analgesic activity in a Paclitaxel-induced thermal hyperalgesia model in rats.

FIG. 4 illustrates that Dyclonine exhibits analgesic activity in a Paclitaxel-induced mechanical allodynia model in rats.

FIG. 5 illustrates that Dyclonine exhibits analgesic activity in a streptozotocin (STZ)- induced mechanical allodynia model in diabetic rats.

FIG. 6 illustrates that Dyclonine exhibits analgesic activity in a STZ-induced thermal hyperalgesia model in diabetic rats.

FIG. 7 illustrates that Dyclonine potentiates morphine’s analgesia in a mouse model of acute pain (tail flick test, n=8, i.p.).

FIG. 8 illustrates that compound 68 exhibits analgesic activity by attenuating the mechanical allodynia in spinal nerve ligation (SNL) Chung model in rats.

FIG. 9 illustrates that compound 68 exhibits analgesic activity by attenuating the thermal hyperalgesia in spinal nerve ligation (SNL) Chung model in rats.

DETAILED DESCRIPTION OF THE DISCLOSURE

Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g, 1%, 2%, 3%, and 4%) and the sub-ranges (e.g, 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise.

Definitions

In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

In the methods described herein, the acts can be carried out in any order without departing from the principles of the disclosure, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing act X and a claimed act of doing act Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

In one aspect, the terms "co-administered" and "co-administration" as relating to a subject refer to administering to the subject a compound of the disclosure or salt thereof along with a compound that may also treat any disease or disorder contemplated herein and/or with a compound that is useful in treating other medical conditions but which in themselves may cause or facilitate any disease or disorder contemplated herein. In certain embodiments, the co-administered compounds are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

As used herein, a "disease" is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate.

As used herein, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject's state of health.

As used herein, the term "Ki" or "Ki" refers to the binding constant, which is a particular case of the equilibrium constant, that is associated with the binding and unbinding reaction of the sigma receptor (SR) and either the SIR and S2R ligand (L) molecules, which is formalized as: R + L ^ RL.

As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the disclosure, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.

The term "prevent," "preventing," or "prevention," as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. Disease, condition, and disorder are used interchangeably herein.

By the term "specifically bind" or "specifically binds," as used herein, is meant that a first molecule preferentially binds to a second molecule ( e.g ., a particular receptor or enzyme), but does not necessarily bind only to that second molecule.

As used herein, a "subject" may be a human or non-human mammal or a bird. Nonhuman mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human.

The term "treat," "treating," or "treatment," as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. As used herein, the term "alkyl," by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, /f/V-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. In certain embodiments, the alkyl is (Ci-Ce)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, «-pentyl, «-hexyl and cyclopropylmethyl.

As used herein, the term "alkylene" by itself or as part of another substituent means, unless otherwise stated, a straight or branched hydrocarbon group having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups, wherein the group has two open valencies. Examples include methylene, 1,2-ethylene, 1,1 -ethylene, 1,1 -propylene, 1,2-propylene and

1.3 -propylene.

As used herein, the term "cycloalkyl," by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A non-limiting example is (C3-C6)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "alkenyl," employed alone or in combination with other terms, means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl,

1.4-pentadienyl, and the higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

As used herein, the term "alkynyl," employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms. Nonlimiting examples include ethynyl and propynyl, and the higher homologs and isomers. The term "propargylic" refers to a group exemplified by -CH2-CºCH. The term "homopropargylic" refers to a group exemplified by -CH2CH2-CºCH. The term "substituted propargylic" refers to a group exemplified by -CR.2-CºCR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen. The term "substituted homopropargylic" refers to a group exemplified by -CR2CR2-CºCR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen.

As used herein, the term "substituted alkyl," "substituted cycloalkyl," "substituted alkenyl" or "substituted alkynyl" means alkyl, cycloalkyl, alkenyl or alkynyl, as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 haloalkyl, and -OH.

As used herein, the term "alkoxy" employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. A non-limiting example is (Ci-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

As used herein, the term "halo" or "halogen" alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom; in certain embodiments, fluorine, chlorine, or bromine; in certain embodiments, fluorine or chlorine.

As used herein, the term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2- CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH₂CH₂-S(=0)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-S-S- CH3.

As used herein, the term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include - CH=CH-0-CH₃, -CH=CH-CH₂-0H, -CH₂-CH=N-0CH3, -CH=CH-N(CH₃)-CH₃, and -CH ₂- CH=CH-CH₂-SH.

As used herein, the term "aromatic" refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized p (pi) electrons, where n is an integer.

As used herein, the term "aryl," employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. A non-limiting example is naphthyl; another non-limiting example is phenyl.

As used herein, the term "aryl-(Ci-C₃)alkyl" means a functional group wherein a one to three carbon alkylene chain is attached to an aryl group, e.g., -CEhCEh-phenyl or -CH₂- phenyl (benzyl). A non-limiting example is aryl-CEh- and aryl-CH(CH₃)-. The term "substituted aryl-(Ci-C₃)alkyl" means an aryl-(Ci-C₃)alkyl functional group in which the aryl group is substituted. A non-limiting example is substituted aryl(CH₂)-. Similarly, the term "heteroaryl-(Ci-C₃)alkyl" means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g. , -CEhCEh-pyridyl. A non-limiting example is heteroaryl-(CH₂)-. The term "substituted heteroaryl-(Ci-C₃)alkyl" means a heteroaryl-(Ci- C₃)alkyl functional group in which the heteroaryl group is substituted. A non-limiting example is substituted heteroaryl-(CH₂)-.

As used herein, the term "heterocycle" or "heterocyclyl" or "heterocyclic" by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is a heteroaryl. Nonlimiting examples of heterocyclyl include pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, alkyl piperidinyl, cyclohexamino, and azepanyl.

As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include benzothiophene, benzofuran, and indole

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

In certain embodiments, each occurrence of the heteroaryl is independently selected from the group consisting of quinolinyl, imidazo[l,2-a]pyridyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, indolyl (such as, but not limited to, 2-, 3-, 4-, 5-, 6- and 7-indolyl), oxadiazolyl (including 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-oxadiazole), and triazolyl (such as 1,2,3-triazolyl and 1,2,4-triazolyl).

The aforementioned listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

For aryl, aryl-(Ci-C3)alkyl and heterocyclic groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet other embodiments, the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of C1-C6 alkyl, -OH, C1-C6 alkoxy, halo, amino, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being non-limiting.

Throughout this disclosure, various aspects of the disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Description

The disclosure relates in one aspect to compounds, and compositions comprising such compounds, that can be used to treat, ameliorate, and/or prevent a viral infection in a subject. In certain embodiments, the viral infection comprises infection by at least one virus. In certain embodiments, the viral infection comprises infection by essentially one virus. In certain embodiments, the viral infection comprises infection by a virus. In certain embodiments, the subject is a mammal. In other embodiments, the mammal is human.

In certain embodiments, the virus is Hepatitis C virus (HCV).

In other embodiments, the virus is Human Immunodeficiency virus (HIV). In other embodiments, the HIV is HIV-1 and/or HIV-2.

In certain embodiments, the virus is a Coronavirus. In other embodiments, the Coronavirus is an Alphacoronavirus, such as but not limited to Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, and/or Scotophilus bat coronavirus 512. In other embodiments, the Coronavirus is a Betacoronavirus, such as but not limited to Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2), and/or Tylonycteris bat coronavirus HKU4. In yet other embodiments, the Coronavirus is a Gammacoronavirus, such as but not limited to Avian coronavirus and/or Beluga whale coronavirus SW 1. In yet other embodiments, the Coronavirus is a Deltacoronavirus, such as but not limited to Bulbul coronavirus HKU11 and/or Porcine coronavirus HKU15. In yet other embodiments, the Coronavirus is at least one of MERS-CoV, SARS-CoV, and/or SARS-CoV-2.

The disclosures of PCT Patent Application No. PCT/US2019/066048, filed December 12, 2019, and U.S. Provisional Patent Application No. 62/778,498, filed December 12, 2018, are included herein in their entireties by reference.

As described elsewhere herein, the sigma receptors were initially identified in 1976 as an opioid receptor subtype and later as a phencyclidine binding receptor. Now the sigma receptors are now widely recognized as a unique family distinct from opioid and phencyclidine receptors, and are classified into two subtypes: sigma 1 receptor (SIR) and sigma 2 receptor (S2R).

The SIR has been cloned encoding a protein of 223 amino acids in diverse species including human, and has a molecular weight of 25.3 kDa. It is highly expressed in both central and peripheral nervous systems, and has been identified as a ligand-gated molecular chaperone protein within the endoplasmic reticulum (ER) and plasma membranes. On the other hand, the S2R was initially identified as progesterone receptor membrane component 1 (PGRMC1), but later was reported as the translation of gene TMEM97. Although the molecular identity of the S2R is still ambiguous, there is overwhelming evidence demonstrating the S2R plays important roles in different types of cancer, neurological diseases, inflammatory and autoimmune diseases.

In one aspect, a recently published article (Gordon, etal. , 2020, Nature 583:459-468) suggested that regulators of the SIR and S2R could show antiviral activity against coronaviruses, such as but not limited to MERS-CoV, SARS-CoV, and/or SARS-CoV-2.

The evidence showed that at least the viral proteins Nsp6 and Orf9c interact with Sigma receptors that are implicated in lipid remodeling and ER stress response. Consistently, it is proposed that SIR and S2R modulators may disturb the virus lifecycle through mechanisms including cell stress response.

In another aspect, Hepatitis C virus (HCV) genome replication occurs in a membranous cellular compartment derived from the ER. SIR has been identified as a cellular factor that mediates the early steps of HCV RNA replication (Friesland, el al ., 2013,

J. Virol. 87(11):6377-6390). Among the many functions of SIR is regulation of calcium signaling at the mitochondrion-associated ER membranes (MAMs) and lipid storage and trafficking. Downregulation of SIR expression leads to a proportional decrease in susceptibility to HCV infection, as shown by reduced HCV RNA accumulation and intra- and extracellular infectivity in single-cycle infection experiments. The evidence shows that initial steps of HCV infection are regulated by SIR, and thus a SIR modulator can be used to ameliorate and/or inhibit HCV infection.

In yet another aspect, activation of the sigma- 1 signaling pathway has been implicated in exacerbating HIV-1 pathobiology, specifically by increasing virus transmission and replication and accelerating clinical progression to AIDS (Prasad, etal. , 2019, Scientific Reports 9:958). As evidenced by the tool drug methamphetamine, engagement of the SIR signaling pathway alters the expression of HIV-1 co-receptors, enhances HIV-1 replication, activates T-cells, and impairs intrinsic resistance mechanisms of immune cells. Thus a SIR modulator can be used to inhibit and/or ameliorate HIV transmission and/or replication and prevent or deaccelerate progression of HIV infection to AIDS.

The present disclosure provides herein certain SIR ligands and S2R modulators with unique antiviral activity against certain viruses, such as HCV, HIV, and/or Coronaviruses, including but not limited to SARS-CoV-2 (COVID-19), SARS-CoV, and/or MERS-CoV. As such, the SIR and S2R modulators of the disclosure offer strong therapeutic value for the prevention, treatment, and/or cure of diseases and related conditions associated with certain viral infections.

In certain embodiments, the compounds contemplated herein include dyclonine, which is a Sigma Receptor modulator, and its salts, solvates, and/or isotopically labeled derivatives.

In certain embodiments, the compounds contemplated herein include any of the compounds in Table 1 (Peng, etal. , 2019, J. Chem. Inf. Model. 59:486-497; which is incorporated herein in its entirety by reference), or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof.

The compounds of the disclosure can be used to treat, prevent, and/or ameliorate a viral infection in a subject. In certain embodiments, the viral infection comprises infection by at least one virus. In certain embodiments, the viral infection comprises infection by essentially one virus. In certain embodiments, the viral infection comprises infection by a virus. In certain embodiments, the virus is HCV. In other embodiments, the virus is HIV. In yet other embodiments, the virus is a Coronavirus. In yet other embodiments, the Coronavirus is at least one of MERS-CoV, SARS-CoV, SARS-CoV-2. In yet other embodiments, the subject is a mammal. In yet other embodiments, the mammal is human.

The compounds of the disclosure can be used to treat, prevent, and/or ameliorate pain in a subject. In certain embodiments, the pain comprises chronic pain. In certain embodiments, the pain comprises acute pain. In other embodiments, the pain comprises neuropathic pain. In yet other embodiments, the pain comprises nociceptive pain. In yet other embodiments, the pain comprises hyperalgesia. In yet other embodiments, the pain comprises allodynia.

In certain embodiments, the compounds of the disclosure diminish pain without producing respiratory depression, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing constipation, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing nausea, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing significant (or any at all) tolerance, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing significant (or any at all) tachyphylaxis, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing emesis, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing withdrawal adverse effects, which is a side effect characteristic of morphine and other well- known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing dependence, which is a side effect characteristic of morphine and other well-known and widely used opioids and narcotics. In certain embodiments, the compounds of the disclosure diminish pain without producing one or more of the following phenomena: nausea, emesis, constipation, respiratory depression, tolerance, tachyphylaxis, dependence and/or addiction.

In certain embodiments, the compounds and compositions of the disclosure promote neuroprotection in a subject. In certain embodiments, the compounds and compositions of the disclosure inhibit, treat, and/or prevent neurological and neurodegenerative diseases, such as but not limited to Alzheimer's disease-type dementia, motor neuron disease, and/or amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the disclosure improve learning and/or memory in a subject.

In certain embodiments, the compounds and compositions of the disclosure inhibit, treat, and/or prevent cancer and related proliferative diseases.

In certain embodiments, the compounds and compositions of the disclosure inhibit, treat, and/or prevent substance abuse disorders in a subject. In certain embodiments, the compounds and compositions of the disclosure inhibit, treat, and/or prevent depressive disorders in a subject. In certain embodiments, the compounds and compositions of the disclosure inhibit, treat, and/or prevent ocular disorder and/or glaucoma in a subject.

The disclosure provides compounds that bind to at least one sigma receptor selected from the group consisting of SIR and S2R. In certain embodiments, the compounds of the disclosure bind to SIR selectively over S2R. In certain embodiments, the compounds of the disclosure bind to SIR and S2R with equal, or nearly equal, affinity. In certain embodiments, the compounds of the disclosure bind to S2R selectively over SIR.

In certain non-limiting embodiments, the binding selectivity of the compound of the disclosure for S2R over SIR is equal to, or about, 1.

In certain non-limiting embodiments, the binding selectivity of the compound of the disclosure for SIR over S2R is greater than 1. In other non-limiting embodiments, the binding selectivity of the compound of the disclosure for SIR over S2R is equal to or greater than about 1.1, about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1,000, about 2,000, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000, about 20,000, about 30,000, about 40,000, and/or about 50,000.

In certain non-limiting embodiments, the binding selectivity of the compound of the disclosure for S2R over SIR is greater than 1. In other non-limiting embodiments, the binding selectivity of the compound of the disclosure for S2R over SIR is equal to or greater than about 1.1, about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 26, about 28, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1,000, about 2,000, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000, about 20,000, about 30,000, about 40,000, and/or about 50,000.

Compounds and Compositions

The disclosure includes dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof:

In certain embodiments, the compound is dyclonine, or a salt or solvate thereof:

In certain embodiments, the dyclonine is deuterated. In certain embodiments, the compound

salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is

The disclosure includes any of the compounds recited in Table 1 and/or Table 2, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof.

The disclosure includes a compound of formula (I), or a salt, solvate, isotopically labeled derivative (such as, for example, deuterated at one or more positions), enantiomer, diastereomer, and/or tautomer thereof:

wherein:

A¹, A², and A³ are such that one applies: (a) A¹ =N, A² = NR³, and A³ = C; (b) A¹ = NR³, A² = N, and A³ = C; (c) A¹ =N, A² = CR³, and A³ = N;

R¹ is selected from the group consisting of H, Ci-Cx alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C10 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, Ci- C8 alkyl, Ci-Cs haloalkyl, and C3-C8 cycloalkyl;

R² is selected from the group consisting of H, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C10 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, Ci- C8 alkyl, Ci-Cs haloalkyl, and C3-C8 cycloalkyl; or R¹ and R² combine with the N atom to which they are bound to form 3- to 8-membered heterocyclyl, wherein each heterocyclyl is independently optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cx haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C₆ alkyl, wherein two substituents bound to the same atom of the heterocyclyl can combine to form C2-C7 alkylene (thus yielding a spiro bicyclic heterocyclyl) which is optionally substituted with at least one substituent selected from the group consisting of F, Cl,

Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl, and wherein two substituents bound to distinct atoms of the heterocyclyl can combine to form C1-C7 alkylene (thus yielding a fused or bridged bicyclic heterocyclyl) which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl;

Y is -(0¾)h-, wherein n is 0, 1, 2, 3, 4, 5, or 6, and wherein each CFb group in Y is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, F, Cl, Br, and I;

X is selected from the group consisting of -CH2-, -0-, -NH-, -N(CI-C6 alkyl)-, and -S-, wherein if n is 0, then X is -CH2-, and wherein each CFh group in X is independently optionally substituted with at least one selected from the group consisting of C1-C₆ alkyl, C1-C₆ haloalkyl, F, Cl, Br, and I;

R³ is selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 cycloalkyl, wherein each alkyl, alkenyl, alkynyl or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of C1-C4 alkyl, Ci- C4 haloalkyl, F, Cl, Br, and I; each of R^4a-R^4e is independently selected from the group consisting of H, F, Cl, Br, I, Ci- C8 alkyl, Ci-Cs haloalkyl, Ci-Cs haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 cycloalkyl, phenyl, phenoxy, and benzyloxy, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or benzyl is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, F, Cl, Br, and I, or R^4C and R^4d combine with the atoms to which they are bound to form C4-C8 cycloalkyl, phenyl, or heterocyclyl, wherein each cycloalkyl, phenyl, heterocyclyl, or heteroaryl is independently substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl; and wherein the heterocyclyl is selected from the group consisting of pyrrolyl, furanyl and thiophenyl.

In certain embodiments, -NR'R² is an optionally substituted heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, N-(CI-C6 alkyl) piperidinyl, cyclohexyl-amino, and azepanyl.

In certain embodiments, the compound of formula (I) is a compound of formula (la):

In certain embodiments, the compound of formula (I) is a compound of formula (lb):

In certain embodiments, the compound of formula (I) is a compound of formula (Ic):

In certain embodiments, -NR'R² is

In certain embodiments, -NR'R² is

In certain embodiments, -

NR¾² is

In certain embodiments, -NR'R² is

In certain embodiments, -NR'R² is

In certain embodiments, -NR^R² is

. In certain embodiments, -NR R² is

. In certain embodiments, -NR'R² is

. In certain embodiments, -NR'R²

certain embodiments,

certain embodiments, -NR R² is

, certain embodiments,

. In certain embodiments,

In certain embodiments,

In certain embodiments, -NR'R² is

H

. , .

-I-N embodiments,

certain embodiments, NR*R² is ^¾ \ — . In certain

4 embodiments, NR*R² is ⁵

, certain

-i-N embodiments, NR .²lR„²2 is N VZ In certain embodiments, NR²R² is

. In certain embodiments, NR*R² is

. In certain embodiments,

certain embodiments,

In certain embodiments,

certain embodiments,

,

In certain embodiments,

certain embodiments,

, certain embodiments,

certain embodiments,

,

In certain embodiments,

certain embodiments,

, certain embodiments,

certain embodiments,

,

In certain embodiments,

certain embodiments,

R 4a R 4a

, rtain embodiments,

. , is

, certain embodiments,

,

certain embodiments,

certain embodiments,

,

, certain embodiments,

certain embodiments,

, certain embodiments,

certain embodiments,

, In certain embodiments,

certain embodiments,

, In certain embodiments,

certain embodiments,

, certain embodiments,

certain embodiments,

certain embodiments, each occurrence of R is independently H, C1-C₆ alkyl, C1-C₆ haloalkyl, and C3-C8 cycloalkyl. In certain embodiments, each occurrence of R^a, R^b, and R^c is independently H or Cl.

In certain embodiments, R¹ and R² are each -CHa.

In certain embodiments, R³ is methyl. In certain embodiments, R³ is ethyl. In certain embodiments, R³ is isopropyl. In certain embodiments, R³ is cyclopropyl.

In certain embodiments, the compound is l-((5-(4-(tert-butyl)phenyl)-l -methyl- 1H- l,2,4-triazol-3-yl)methyl)piperidine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 4-((5-(4- (tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)morpholine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)-4-methylpiperazine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-((5-(4- (tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)-4-phenylpiperazine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)-4-phenethylpiperazine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-benzyl-4- ((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)piperazine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 4-benzyl-l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4- triazol-3-yl)methyl)piperidine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(tert- butyl)phenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-(5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)- N-(cyclopropylmethyl)-N-methylmethanamine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(4-( 1 -(trifluoromethyl)cyclopropyl)phenyl)- 1H- 1 ,2,4- triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(3,4-dichlorophenyl)-l-methyl-3- (pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-3- (pyrrohdin-l-ylrnethyl)-5-(4-(trifluoromethyl)phenyl)-lH-l, 2,· 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-5-(3-methyl-4-(trifluoromethyl)phenyl)-3- (pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4- isopropylphenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-3-(pyrrolidin-l-ylmethyl)-5-(5, 6,7,8- tetrahydronaphthalen-2-yl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(3-(tert-butyl)phenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-3-(pyrrolidin-l-ylmethyl)-5-(3-(l- (trifluoromethyl)cyclopropyl)phenyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-chlorophenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(3,4-dimethylphenyl)-l-methyl-3-(pyrrolidin-l- ylmethyl)-lH- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 1 -methyl-3 -(pyrrolidin-1- ylmethyl)-5-(p-tolyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4- cyclopropylphenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(2,3-dihydro-lH-inden-5-yl)-l-methyl-3-(pyrrolidin-l- ylmethyl)-lH- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(benzo[b]thiophen-6- yl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(2,3 ',4'-trichloro-[ 1 , 1 '-biphenyl]-4-yl)- 1H- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(2-chlorobenzo[b]thiophen-6- yl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(tert-butyl)phenyl)-3-((3,3-dimethylpyrrolidin-l-yl)methyl)-l-methyl-lH- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4-(tert-butyl)phenyl)-l- methyl-lH-l,2,4-triazol-3-yl)methyl)-2-azaspiro[4.4]nonane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 6-((5-(4-(tert-butyl)phenyl)-l- methyl-lH-l,2,4-triazol-3-yl)methyl)-6-azaspiro[3.4]octane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(tert-butyl)phenyl)-l-ethyl-3-(pynOlidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(tert-butyl)phenyl)-l-isopropyl-3-(pyrrolidin-l- ylmethyl)-lH- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(tert-butyl)phenyl)-l- cyclopropyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 3-(4-(tert-butyl)phenyl)-l-ethyl-5-(pynOlidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 3-(4-(tert-butyl)phenyl)-l-isopropyl-5-(pyrrolidin-l- ylmethyl)-lH- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-(4-(tert-butyl)phenyl)-5- methyl-3-(pynOlidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1 -(4-( 1 -(trifluoromethyl)cyclopropyl)phenyl)- 1H- 1 ,2,4- triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-(3,4-dichlorophenyl)-5-methyl-3- (pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-methyl- 1- (3-methyl-4-(trifluoromethyl)phenyl)-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is , or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-([1,G- biphenyl]-4-yl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-([l,l'-biphenyl]-3-yl)-l-methyl-3-(pyrrolidin-l-ylmethyl)- 1H- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-5-(4-phenoxyphenyl)- 3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-5-(3-phenoxyphenyl)-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(benzyloxy)phenyl)-l -methyl-3 -(pyrrolidin-1 -ylmethyl)- 1H- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(3-(benzyloxy)phenyl)-l- methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-cyclohexylphenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 3-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)-3-azabicyclo[3.1.0]hexane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4- (tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)octahydrocyclopenta[c]pyrrole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is (ls,4s)-7-((5-(4-(tert-butyl)phenyl)-l-methyl-lH- l,2,4-triazol-3-yl)methyl)-7-azabicyclo[2.2.1]heptane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-(benzo[b]thiophen-6-yl)-5-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-methyl-3-(pyrrolidin-l-ylmethyl)-l-(5, 6,7,8- tetrahydronaphthalen-2-yl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-(4-cyclohexylphenyl)-5-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-([l,l'-biphenyl]-4-yl)-5-methyl-3-(pyrrolidin-l-ylmethyl)- 1H- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 3-(4-(tert-butyl)phenyl)-l- methyl-5-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 3-(4-(tert-butyl)phenyl)-l-cyclopropyl-5-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)piperazine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is N-((5-(4-(tert-butyl)phenyl)-l- methyl-lH-l,2,4-triazol-3-yl)methyl)-N-methylcyclopropanamine, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(2,3-dihydrobenzo[b]thiophen-6-yl)-l-methyl-3- (pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(3- chlorophenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-3-(pyrrolidin-l-ylmethyl)-5-(3- (trifluoromethyl)phenyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is l-methyl-3- (pyrrolidin-l-ylmethyl)-5-(m-tolyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-propylphenyl)-l-methyl-3-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof.

In certain embodiments, the compound is 5-(4-(/tv7-butyl )phenyl)-3 -((3,3- dim ethyl pyrrol idin-1 -yl (methyl )-l -ethyl -1 //-l ,2,4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-((5-(4-(/c^j/ /-butyl (phenyl )- l -ethyl - 1 //- 1 ,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 6-((5-(4-(/er/-butyl)phenyl)-l- ethyl - 1 //- 1 , 2, 4-tri azol-3-yl (methyl (-6-azaspiro[3.4]octane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4-(/c77-butyl (phenyl (-1 -ethyl -1//-1 ,2,4-triazol-3-yl)methyl)-2- azaspiro[4.4]nonane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4-(/er/-butyl)phenyl)-l- ethyl-lif-l,2,4-triazol-3-yl)methyl)octahydrocyclopenta[c]pyrrole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(/c77-butyl (phenyl (-3 -((3, 3 -dim ethyl pyrrol idin-1 - yl)methyl)-l -isopropyl- \H- 1,2, 4-triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-((5-(4- (7c77-butyl)phenyl)-l -isopropyl-l//-! ,2,4-triazol-3-yl)methyl)-5-azaspiro[2,4]heptane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 6-((5-(4-(fer/-butyl)phenyl)-l -isopropyl- \H- 1,2,4- triazol-3-yl)methyl)-6-azaspiro[3.4]octane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4- (7c77-butyl)phenyl)- l -isopropyl-l //-l ,2,4-triazol-3-yl)methyl)-2-azaspiro[4,4]nonane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4-(fer/-butyl)phenyl)-l -isopropyl- \H- 1,2,4- triazol-3-yl)methyl)octahydrocyclopenta[c]pyrrole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-(4-(/er/-butyl)phenyl)-l-cyclopropyl-3-((3,3-dimethylpyrrolidin-l-yl)methyl)-lif-l, 2,4- triazole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 5-((5-(4-(/er/-butyl)phenyl)-l- cyclopropyl-l//-l ,2,4-triazol-3-yl)methyl)-5-azaspiro[2,4]heptane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 6-((5-(4-(/er/-butyl)phenyl)-l -cyclopropyl- \H- 1,2, 4-triazol- 3-yl)methyl)-6-azaspiro[3.4]octane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4- (/f/V-butyl )phenyl )- 1 -cyclopropyl- 1 H- 1 ,2,4-triazol-3 -yl)methyl)-2-azaspiro[4.4]nonane, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof. In certain embodiments, the compound is 2-((5-(4-(fer/-butyl)phenyl)-l-cyclopropyl-lif-l,2,4- triazol-3-yl)methyl)octahydrocyclopenta[c]pyrrole, or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof.

In certain embodiments, the compound is MS-377. In certain embodiments, the compound is DuP 734. In certain embodiments, the compound is E-100. In certain embodiments, the compound is E-5482. In certain embodiments, the compound is eperisone. In certain embodiments, the compound is tolperisone. In certain embodiments, the compound is caretapentan. In certain embodiments, the compound is BD-1063. In certain embodiments, the compound is donezepil. In certain embodiments, the compound is fluphenazine. In certain embodiments, the compound is clorgyline. In certain embodiments, the compound is nemonapride. In certain embodiments, the compound is amiodarone. In certain embodiments, the compound is haloperidol. In certain embodiments, the compound is BMS-181100. In certain embodiments, the compound is scopolamine. In certain embodiments, the compound is phenoxybenzamine. In certain embodiments, the compound is trihexylphenodyl. In certain embodiments, the compound is dolasetron. In certain embodiments, the compound is diphenhydramine. In certain embodiments, the compound is SIRA. In certain embodiments, the compound is suloctidil. In certain embodiments, the compound is enclomiphene. In certain embodiments, the compound is clemastine. In certain embodiments, the compound is nadolol. In certain embodiments, the compound is moclobemide. In certain embodiments, the compound is difenidol. In certain embodiments, the compound is propranolol. In certain embodiments, the compound is encainide. In certain embodiments, the compound is dextromethorphan. In certain embodiments, the compound is alizapride. In certain embodiments, the compound is amisulpride. In certain embodiments, the compound is lidocaine. In certain embodiments, the compound is arotinolol. In certain embodiments, the compound is propafenone. In certain embodiments, the compound is metoclopramide. In certain embodiments, the compound is phenyltoloxamine. In certain embodiments, the compound is captodiamine. In certain embodiments, the compound is acebutolol. In certain embodiments, the compound is mepivacaine.

Table 1. Selected SIR Modulators

Synthesis

The present disclosure further provides methods of preparing compounds of the present disclosure. Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.

Compounds of the disclosure can be prepared, in a non-limiting embodiment, using the synthetic route outlined in Scheme I. Benzoic acid (i) can be coupled with hydrazine (ii) using standard coupling reagents, such as but not limited to HATU (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) or EDC (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)/HOBt (Hydroxybenzotriazole) or EDC/PfP-OH (pentafluorophenol), in the presence of a tertiary amine, such as but not limited to trimethylamine or diisopropylethylamine, in a solvent such as but not limited to tetrahydrofuran or dichloromethane, to afford a mixture of acylhydrazines (iii) and (iv), which can be separated using standard separation methods, such as but not limited to recrystallization, precipitation, column separation, and/or extraction. Acylhydrazine (iii) can be coupled with compound (iv) under dehydrating conditions, for example, a mixture of toluene and acetic acid (10: 1) at 100 °C, to afford triazole (vi). Reduction of the ester in (vi) using, for example, a hydride, such as for example lithium aluminum hydride, affords alcohol (vii), which can be derivatized with an appropriate leaving group X to afford (viii). Non-limiting examples of X are Cl, Br, I, tosylate, mesylate, triflate, and the like. Reaction of (viii) with amine HNR'R² affords a compound of Formula (I), wherein -X-Y- is -CEb- (for example, n = 0 and X = -CEb-).

Scheme I.

Non-limiting examples of amines (ix) contemplated within the disclosure follow:

Compounds of the disclosure can be prepared, in a non-limiting embodiment, using the synthetic route outlined in Schemes I-IX. Groups R' and R" are shown for illustrative purposes only and represent groups described elsewhere herein, as it will be appreciated by one skilled in the art.

Scheme II. Non-limiting synthesis of compounds of the disclosure ( e.g ., Compounds 10-25, 39-45, and 57-61)

Scheme III. Non-limiting synthesis of compounds of the disclosure (e.g., Compounds 26-29 and 46-48)

Scheme IV. Non-limiting synthesis of compounds of the disclosure ( e.g ., Compound 30).

Scheme V. Non-limiting synthesis of compounds of the disclosure (e.g., Compound 31) isopropylhydrazine hydrochloride (1.1 eq) L> H2NC(=S)C(=0)Et (2 eq)

Scheme VI. Non-limiting synthesis of compounds of the disclosure (e.g, Compound 32)

Scheme VII. Non-limiting synthesis of compounds of the disclosure ( e.g ., Compounds 33, 34, 53 and 54)

Cu(OAc)2, pyridine, 0₂

Scheme VIII. Non-limiting synthesis of compounds of the disclosure (e.g., Compounds 35- 38 and 49-52)

Scheme IX. Non-limiting synthesis of compounds of the disclosure ( e.g Compounds 62-76) It is appreciated that where typical or exemplary process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, and so forth) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¾ or ¹³C), infrared spectroscopy, spectrophotometry (e.g, UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, etal, Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The compounds of the disclosure may possess one or more stereocenters, and each stereocenter may exist independently in either the ( R ) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms.

It is to be understood that the compounds described herein encompass racemic, optically- active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. All possible stereochemical configurations of a given compound containing chiral center(s) are contemplated. All possible mixtures enriched with a particular enantiomer or diasteromer(s) are contemplated. All pure individual enantiomers or diastereomers are contemplated.

In certain embodiments, the compounds of the disclosure may exist as tautomers. "Tautomerization" is a form of isomerization involving the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible ( e.g ., in solution), a chemical equilibrium of tautomers can be reached. One well known example of tautomerization is between a ketone and its corresponding enol. Heterocycles may form tautomers such as the interconversion of pyrrolidinone and hydroxypyrrole. All tautomers are included within the scope of the compounds presented herein.

Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶C1, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, and ³⁵ S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed disclosure. The compounds of the disclosure may contain any of the substituents, or combinations of substituents, provided herein.

In certain embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

Compounds of the disclosure can in certain embodiments form acids or bases. In certain embodiments, the disclosure contemplates acid addition salts. In other embodiments, the disclosure contemplates base addition salts. In yet other embodiments, the disclosure contemplates pharmaceutically acceptable acid addition salts. In yet other embodiments, the disclosure contemplates pharmaceutically acceptable base addition salts. Pharmaceutically acceptable salts refer to salts of those bases or acids that are not toxic or otherwise biologically undesirable.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, lithium and copper, iron and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (A-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Methods

The disclosure provides methods of treating, ameliorating, and/or preventing a viral infection in a subject. In certain embodiments, the subject is a mammal. In other embodiments, the mammal is human.

In certain embodiments, the virus is Hepatitis C virus (HCV).

The disclosure further provides methods of binding to at least one sigma receptor selected from the group consisting of SIR and S2R in a cell, tissue, and/or subject.

The disclosure further provides methods of modulating activity of at least one sigma receptor selected from the group consisting of SIR and S2R in a cell, tissue, and/or subject.

The disclosure further provides methods of increasing activity of at least one sigma receptor selected from the group consisting of SIR and S2R in a cell, tissue, and/or subject.

The disclosure further provides methods of reducing activity of at least one sigma receptor selected from the group consisting of SIR and S2R in a cell, tissue, and/or subject.

The disclosure further provides methods of modulating (/.£., increasing or decreasing) opioid receptor signaling in a cell, tissue, and/or subject.

The disclosure further provides methods of modulating N-methyl-D-aspartate (NMD A) receptor activity in a cell, tissue, and/or subject.

The disclosure further provides methods of treating, preventing, and/or ameliorating pain in a subject. In certain embodiments, the pain comprises chronic pain. In certain embodiments, the pain comprises acute pain. In other embodiments, the pain comprises neuropathic pain. In yet other embodiments, the pain comprises nociceptive pain. In yet other embodiments, the pain comprises hyperalgesia. In yet other embodiments, the pain comprises allodynia.

In certain embodiments, the methods of the disclosure diminish pain without producing respiratory depression. In certain embodiments, the methods of the disclosure diminish pain without producing constipation. In certain embodiments, the methods of the disclosure diminish pain without producing nauseas. In certain embodiments, the methods of the disclosure diminish pain without producing significant (or any at all) tolerance. In certain embodiments, the methods of the disclosure diminish pain without producing significant (or any at all) tachyphylaxis. In certain embodiments, the methods of the disclosure diminish pain without producing emesis. In certain embodiments, the methods of the disclosure diminish pain without producing withdrawal adverse effects. In certain embodiments, the methods of the disclosure diminish pain without producing dependence. In certain embodiments, the methods of the disclosure diminish pain without producing one or more of the following phenomena: nausea, emesis, constipation, respiratory depression, tolerance, tachyphylaxis, dependence and/or addiction. In certain embodiments, the methods of the disclosure do not cause at least one side effect selected from the group consisting of addiction, respiratory depression, euphoria, and constipation in the subject.

The disclosure further provides methods of promoting neuroprotection in a subject. The disclosure further provides methods of inhibiting, treating, and/or preventing neurological and neurodegenerative diseases, such as but not limited to Alzheimer's disease- type dementia, motomeuron disease, and/or amyotrophic lateral sclerosis (ALS). The disclosure further provides methods of improving learning and/or memory in a subject.

The disclosure further provides methods of inhibiting, treating, and/or preventing cancer and any related proliferative diseases.

The disclosure further provides methods of inhibiting, treating, and/or preventing substance abuse disorders in a subject. The disclosure further provides methods of inhibiting, treating, and/or preventing depressive disorders in a subject. The disclosure further provides methods of inhibiting, treating, and/or preventing ocular disorder and/or glaucoma in a subject.

In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the disclosure. In other embodiments, the method comprises contacting a compound of the disclosure with at least one sigma receptor selected from the group consisting of SIR and S2R in the cell, tissue, and/or subject. In yet other embodiments, the method comprises contacting a compound of the disclosure with SIR in the cell, tissue, and/or subject. In other yet embodiments, the method comprises contacting a compound of the disclosure with S2R in the cell, tissue, and/or subject.

In certain embodiments, the compound of the disclosure is the only therapeutically active agent administered to the subject. In other embodiments, the compound of the disclosure is the only therapeutically active agent administered to the subject in an amount sufficient to produce the desired therapeutic effect.

In certain embodiments, the subject is further administered at least one additional agent that treats, ameliorates, and/or prevents the viral infection. In other embodiments, administration of the compound and at least one additional agent to the subject allows for a lower amount of the at least one additional agent to be administered than if the subject is not administered the compound. In yet other embodiments, administration of the compound and the at least one additional agent to the subject allows for use of an amount of at least one additional agent that does not cause any significant side effect associated with the at least one additional agent use.

Combination Therapies

In one aspect, the compounds of the disclosure are useful within the methods of the disclosure in combination with one or more additional agents useful for treating a disease or disorder contemplated herein. These additional agents may comprise compounds or compositions identified herein, or compounds ( e.g ., commercially available compounds) known to treat, prevent, or reduce the symptoms of a disease or disorder contemplated herein.

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to elsewhere herein may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to elsewhere herein are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations

The disclosure also encompasses pharmaceutical compositions and methods of their use. These pharmaceutical compositions may comprise an active ingredient (which can be one or more compounds of the disclosure, or pharmaceutically acceptable salts thereof) optionally in combination with one or more pharmaceutically acceptable agents. The compositions set forth herein can be used alone or in combination with additional compounds to produce additive, complementary, or synergistic effects.

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated herein. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present disclosure to a patient, such as but not limited to a mammal, such as but not limited to a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated herein. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 0.01 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g ., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease or disorder contemplated herein. In certain embodiments, the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is possible to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.

In certain embodiments, the dose of a compound of the disclosure is from about 1 mg and about 2,500 mg.

In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated herein.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g ., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g. , other analgesic agents.

Routes of administration of any of the compositions of the disclosure include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g, sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compounds of the disclosure may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents ( e.g ., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g, magnesium stearate, talc, or silica); disintegrates (e.g, sodium starch glycolate); or wetting agents (e.g, sodium lauryl sulfate). If desired, the tablets may be coated using suitable methods and coating materials such as OP ADR Y™ film coating systems available from Colorcon, West Point, Pa. (e.g, OP ADR Y™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OP ADR Y™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g, lecithin or acacia); non-aqueous vehicles (e.g, almond oil, oily esters or ethyl alcohol); and preservatives (e.g, methyl or propyl p-hydroxy benzoates or sorbic acid).

Parenteral Administration

For parenteral administration, the compounds of the disclosure may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.

Controlled Release Formulations and Drug Delivery Systems

In certain embodiments, the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release that is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds. As such, the compounds for use the method of the disclosure may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In certain embodiments, the compounds of the disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease or disorder contemplated herein in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

A suitable dose of a compound of the present disclosure may be in the range of from about 0.001 mg to about 5,000 mg per day, such as from about 0.01 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

The compounds for use in the method of the disclosure may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may 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 may be the same or different for each dose.

Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds can lie within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein.

EXPERIMENTAL EXAMPLES

The disclosure is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the disclosure should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present disclosure and practice the claimed methods. The following working examples therefore, specifically point out selected embodiments of the present disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

Materials and Methods

Binding affinity for SIR and S2R - Radiolabeled assays of guinea pig brain

The radiolabeled binding assay of the SIR and S2R were performed using Guinea pig whole brain according to the protocol previously reported (Ganapathy, et al. , 1999, J. Pharmacol. Exp. Ther. 289:251-60). The SIR binding assay was conducted in duplicate on membrane preparations that had been re-suspended in 50 mM Tris-HCl at pH=7.4 using [¾]- pentazocine as the radioligand. Following 1 h incubation at 25 °C, the binding assay was terminated by addition of cold buffer. The mixture was then filtered through Whatman GF/B filters and washed with cold buffer. Radioactivity was identified using the liquid scintillation counter. Non-specific binding for the SIR was measured in the presence of 10 mM unlabeled (+)-Pentazocine.

The S2R binding assay was conducted in duplicate on membrane preparations that had been resuspended in 50 mM Tris-HCl at pH 7.4 using [³H]-DTG as the radioligand. Following 1 h incubation at 25 °C, the binding assay was terminated by addition of cold buffer. The mixture was then filtered through Whatman GF/B filters and washed with cold buffer. Radioactivity was identified using the liquid scintillation counter. Non-specific binding for the S2R was measured in the presence of unlabeled haloperidol.

Receptor binding data were analyzed by nonlinear regression of saturation and competition curves using the GraphPad Prism 7.0 software (GraphPad Software, La Jolla, CA).

Binding affinity for SIR and S2R - Radiolabeled assays of human jurkat cell membranes

The radiolabeled binding assay of the human SIR and S2R were performed using human jurkat cell membranes according to the protocol previously reported (Ganapathy, et al, 1999, J. Pharmacol. Exp. Ther. 289:251-60).

The binding affinity for the human SIR was experimentally determined in human jurkat cell membranes using 15.0 nM [³H] -pentazocine as the radioligand. Membranes were incubated with ligands in 50 mM Tris-HCl at pH 8.0 for 2 hours at 37 °C. The binding process was terminated by addition of cold buffer. Then, the mixture was filtered and washed with cold buffer. Radioactivity was identified using the TopCount NTX liquid scintillation counter (PerkinElmer, Waltham, MA). Non-specific binding for the SIR was measured in the presence of 10 mM unlabeled haloperidol.

The binding affinity for human S2R was performed using Jurkat cell line Clone E6-1 cells with 0.025 pM [³H] DTG as radioligand. The non-specific binding was performed with 10 pM Haloperidol. The cells were incubated in RPMI 1640 Medium with 10% FBS, 100 U/ml penicillin and 100 mg/ml streptomycin. After incubation, the cells were suspended in 5 mM potassium phosphate buffer (pH 7.6). The membrane protein concentration was controlled at 5mg/mL. The collected membrane protein was incubated with ligands in potassium phosphate buffer for 1 hour at room temperature and terminated by adding ice-cold buffer. Then the mixture is filtered with 0.7 pm syringe filter and washed three times. The radioactivity is determined by liquid scintillation spectrometry.

Mechanical allodynia assessment

Mechanical allodynia was assessed by the manual von Frey test and measured prior to injection of inducing agent (/.£., Paclitaxel or STZ) (Day 0) and test article administration (Days 13 or 20) and at 0.5 hours and/or 1.5 hours after dosing of vehicle, test articles, or gabapentin administration on Days 14 or 21. The animals were randomized to each groups based on pre-dose mechanical allodynia values (Days 13 or 20). The animals were given 20 to 30 minutes to acclimatize prior to testing. The paw was touched with a series of 8 manual von Frey monofilaments with logarithmically incremental stiffness [3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1.0 g), 4.31 (2.0 g), 4.56 (4.0 g), 4.74 (6.0 g), 4.93 (8.0 g), and 5.18 (15.0 g)]. The manual von Frey monofilament was applied perpendicularly from underneath the mesh floor to the central plantar surface with sufficient force to cause a slight buckling against the paw, and held for approximately 6-8 seconds. A positive response was noted if the paw is sharply withdrawn; ambulation was considered an ambiguous response, and in such cases, the stimulus was reapplied. Mechanical threshold (50% g threshold) was assessed using the up- and down-method following the procedure described by Chaplan, et al. (J Neurosci Methods 1994, 53:55-63).

Thermal hyperalgesia assessment

The animals were tested prior to study inclusion for thermal hyperalgesia on day 13 and Day 20. Thermal hyperalgesia was measured at 1 and 2 hours, or 15 and 75 minutes, after dosing of vehicle or test article on Day 14 and Day 21 by using the IITC Model-336G (IITC INC. USA) apparatus. Each rat was placed within a plastic box atop a glass floor for 20 to 30 minutes. A light beam under the floor was aimed at the plantar surface of the left hind paw. The time was measured automatically when the paw was withdrawn away from the thermal stimulus. A cut-off latency of 23 sec was imposed. The latency to withdrawal was obtained for each rat and defined as the heat pain threshold.

Mouse caretaking

All aspects of this work including housing, experimentation, and animal disposal were performed in general accordance with the “Guide for the Care and Use of Laboratory Animals: Eighth Edition” (The National Academies Press, Washington, DC, 2011). During the course of the studies described herein, the animals were housed individually under constant temperature, humidity and a 12-hour light-dark cycle. In certain embodiments, the animals were tested prior to study inclusion for mechanical allodynia and thermal hyperalgesia.

Example 1: Binding Affinity to the SIR and S2R

Radiolabeled binding assays were conducted using two different species. Compounds 1-9 were assayed using guinea pig brain membranes for the binding assays. Compounds 10- 76 and dyclonine were assayed using human brain membranes for the binding assays.

Results are summarized in Table 2 and Table 3. Table 2: Binding Affinity to the SIR at 100 nM

Tab e 3: Kj Values for the SIR and S2R of Selected Compounds

The term "Ki" or "Ki" refers to the binding constant, which is a particular case of the equilibrium constant, that is associated with the binding and unbinding reaction of the sigma receptor (SR) and either the SIR and S2R ligand (L) molecules, which is formalized as: R + L ^ RL.

Example 2: Chemical characterization

Selected compounds of the disclosure were prepared using methods illustrated elsewhere herein, and the ¾ NMR data for those compounds is illustrated herein: Compound 1: ¾NMR (400 MHz, CDCb) d 7.63 (d, J= 7.2 Hz, 2H), 7.53 (d, J= 7.7 Hz, 2H), 3.98 (s, 3H), 3.63 (s, 3.73 (m, 2H), 2.62 (b, 4H), 1.67 (b, 4H), 1.37 (b, 2H), 1.27 (s, 9H).

Compound 2: ¹HNMR (400 MHz, CDCb) d 7.63 (d, J= 7.2 Hz, 2H), 7.53 (d, J= 7.1 Hz, 2H), 3.98 (s, 3H), 3.63 (s, 3.73 (b, 2H), 3.72 (b, 2H), 2.67 (b, 4H), 1.37 (s, 9H).

Compound 3: ^lHNMR (400 MHz, CDCb) d 7.62 (d, J= 7.2 Hz, 2H), 7.51 (d, J= 7.1 Hz, 2H), 3.97 (s, 3H), 3.63 (s, 3.73 (s, 2H), 2.58 (b, 8H), 2.34 (s, 3H), 1.37 (s, 9H).

Compound 4: ¹HNMR (400 MHz, CDCb) ¹HNMR (400 MHz, CDCb) d 7.62 (d, J= 7.2 Hz, 2H), 7.51 (d, J= 7.1 Hz, 2H), 7.25 (m, 4H), 3.98 (s, 3H), 3.73 (b, 2H), 3.27 (b, 4H), 2.81 (b, 4H), 1.26 (s, 9H).

Compound 5: ¹HNMR (400 MHz, CDCb) d 7.59 (d, J= 7.2 Hz, 2H), 7.50 (d, J= 7.1 Hz, 2H), 7.29 (m, 2H), 7.20 (s, 3H), 4.13 (s, 3H), 3.93 (b, 2H), 3.12 (b, 2H), 2.66 (B, 1 OH), 1.27 (s, 9H).

Compound 6: ^lHNMR (400 MHz, CDCb) d 7.63 (d, J= 7.2 Hz, 2H), 7.53 (d, J= 7.7 Hz, 2H), 7.32(m, 4H), 7.26(s, 1H), 3.98 (s, 3H), 3.71 (s, 2H), 3.56 (m, 2H), 2.66 (b, 8H),1.37 (s, 9H). Compound 7: ¾NMR (400 MHz, CDCb) d 7.63 (d, J= 7.2 Hz, 2H), 7.60 (d, J= 7.2 Hz, 2H), 7.52 (m, 3H), 7.14(m, 2H), 3.97 (s, 3H), 3.66 (s, 2H),3.05(m, 2H), 2.55 (d, J= 3.5Hz, 2H), 2.34 (m, 2H), 1.68 (m, 2H), 1.59 (b, 1H), 1.39 (m, 2H), 1.27 (s, 9H).

Compound 8: ¹HNMR (400 MHz, CDCb) d 7.61 (d, J= 7.2 Hz, 2H), 7.49 (d, 7= 7.1 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 2H), 2.70 (b, 4H), 1.82 (b, 4H), 1.36 (s, 9H).

Compound 9: ¹HNMR (400 MHz, CDCb) d 7.63 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.82 (b, 2H), 2.49 (b, 5H), 1.37 (s, 9H), 1.04 (b, 1H), 0.55 (b, 2H), 0.19 (b, 2H).

Compound 10: 7.68-7.63 (m, 4H), 4.36 (s, 2H), 4.03 (s, 3H), 3.76 (d, J= 8 Hz, 2H), 3.31 (t, J= 8 Hz, 2H), 2.81 (t, J = 8 Hz, 2H), 1.91 (s, 2H), 1.44 (t, J = 8 Hz, 2H), 1.09 (s, 2H). Compound 11: 7.82 (d, J= 8 Hz, 1H), 7.64 (d, J= 8 Hz, 1H), 7.55-7.52 (m, 1H), 4.35 (s, 2H), 4.04 (s, 3H), 3.79 (t, J = 4 Hz, 2H), 3.28-3.26 (m, 2H), 2.21 (d, J= 4 Hz, 2H), 1.93(s, 2H).

Compound 12: 7.83 (s, 4H), 4.37 (s, 2H), 4.06 (s, 3H), 3.79 (t, J = 8 Hz, 2H), 3.30-3.28 (m, 2H), 2.22 (t, J = 4 Hz, 2H), 1.94 (t, J = 8 Hz, 2H).

Compound 13: 7.79 (d, J= 8 Hz, 1H), 7.64 (s, 1H), 7.58 (t, J = 8 Hz, 1H), 4.36 (s, 2H),

4.04 (s, 3H), 3.30-3.27 (m, 2H), 2.21-2.19 (m, 2H), 2.59 (s, 3H), 2.21-2.19 (m, 2H), 1.95- 1.91 (m, 2H).

Compound 14: 7.63 (d, J= 8 Hz, 2H), 7.42 (d, J= 8 Hz, 2H), 4.42 (s, 2H), 4.05 (s, 3H),

3.77 (s, 2H), 3.35 (s, 2H), 3.04-2.97 (m, 1H), 2.19 (s, 2H), 1.95 (s, 2H), 1.30 (d, J= 8 Hz,

6H).

Compound 15: 7.37 (t, J= 8 Hz, 2H), 7.24 (t ,J= 8 Hz, 1H), 4.37 (s, 2H), 4.01 (s, 3H), 3.75 (t, J = 4 Hz, 2H), 3.34 (d, J= 4 Hz, 2H), 2.85 (s, 4H), 2.18 (d, J= 4 Hz, 2H), 1.92 (s, 2H), 1.85(s, 4H).

Compound 16: 7.66 (s, 1H), 7.59 (d, J= 8 Hz, 1H), 7.55-7.27 (m, 2H), 4.37 (s, 2H), 4.01 (s, 3H), 3.78-3.74 (m, 2H), 3.34 (t, J= 8 Hz, 2H), 2.19 (t, J= 8 Hz, 2H), 1.93 (t, J= 8 Hz, 2H), 1.38 (s, 2H).

Compound 17: 7.76 (s, 1H), 7.64 (t, J= 8 Hz, 2H), 7.54 (t, J= 8 Hz, 1H), 4.36 (s, 2H), 4.02 (s, 3H), 3.76 (s, 2H), 3.31 (t, J= 4 Hz, 2H), 2.20 (d, J= 4 Hz, 2H), 1.93 (s, 2H), 1.46 (t, J = 4 Hz, 2H), 1.1 l(s, 2H).

Compound 18: 7.64 (d, J= 8 Hz, 2H), 7.54 (d, J= 8 Hz, 2H), 4.36 (s, 2H), 4.02 (s, 3H), 3.79-3.75 (m, 2H), 3.31-3.27 (m, 2H), 2.21-2.18 (m, 2H), 1.94-1.90 (m, 2H).

Compound 19: 7.49 (s, 1H), 7.41 (d, J= 9.2 Hz, 1H), 7.32 (d, J= 9.2 Hz, 1H), 4.43 (s, 2H), 4.04 (s, 3H), 3.78-3.82 (m, 2H), 3.33-3.36 (m, 2H), 2.36 (s, 6H), 1.99 (s, 2H), 1.95-1.98 (m, 3H).

Compound 20: 7.57 (d, 7 = 8.4 Hz, 2H), 7.35 (d, 7 = 7.6 Hz, 2H), 4.36 (s, 2H), 4.01 (s, 3H), 3.74-3.76 (m, 2H), 3.31-3.35 (m, 2H), 2.45 (s, 3H), 2.16-2.20 (m, 2H), 1.91 (s, 2H). Compound 21: 7.65 (d, 7 = 8 Hz, 2H), 7.25 (s, 2H) 4.52 (s, 2H), 4.09 (s, 3H), 3.79 (s, 2H), 3.36 (s, 2H), 2.21-2.22 (d, 7 = 8.4 Hz, 2H), 1.98-2.02 (m, 3H), 1.10-1.13 (m, 2H), 0.80-0.81 (m, 2H).

Compound 22: 7.56 (s, 2H), 7.39-7.46 (m, 2H), 4.44 (s, 2H), 4.05 (s, 3H), 3.76-3.78 (d, 7 = 5.2 Hz, 2H) 3.37-3.38 (d, 7= 5.2 Hz, 2H), 2.99-3.02 (m, 4H), 2.12-2.20 (m, 4H), 1.97 (S, 2H). Compound 23: 8.22 (s, 1H), 7.97-7.99 (d, 7 = 8 Hz, 1H), 7.66 (t, 7 = 4 Hz, 1H), 7.44-7.45 (d, 7 = 5.6 Hz, 1H), 4.39 (s, 2H), 4.08 (s, 3H), 3.77 (s, 2H), 3.34 (s, 2H), 2.18-2.21 (d, 7 = 4.8 Hz, 2H), 1.93 (s, 2H).

Compound 24: 7.84 (s, 1H), 7.64-7.65 (d, 7 = 2.4 Hz, 1H), 7.55-7.57 (d, 7 = 8 Hz, 2H), 7.49-7.51 (d, 7 = 8 Hz, 1H), 7.32-7.34 (m, 1H), 4.35-4.37 (d, 7 = 9.2 Hz, 2H), 4.04-4.08 (d, 7 = 16 Hz, 3H), 3.78 (s, 2H), 3.29 (s, 2H), 2.21 (s, 2H), 1.94-1.95 (d, 7 = 5.6 Hz, 2H). Compound 25: (400 MHz, DMSO-ifc): d 10.97 (br s, 1H), 8.47 (s, 1H), 7.98 (d, J = 8.44 Hz, 1H), 7.84 (d, J = 8.31 Hz, 1H), 7.67 (s, 1H), 4.49 (br d, J = 5.01 Hz, 2H), 4.05 (s, 3H), 3.57 (br d, J = 5.01 Hz, 2H), 3.22 (br d, J = 7.21 Hz, 2H), 1.86-2.03 (m, 4H).

Compound 26: (400 MHz, DMSO-ifc): <5 11.36 (br s, 1H), 7.74 (d, 7 = 8.6 Hz, 2H), 7.60 (d, 7 = 8.4 Hz, 2H), 4.37 - 4.52 (m, 2H), 4.00 (s, 3H), 3.65 (qd, 7 = 6.0, 12.0 Hz, 1H), 3.29 - 3.46 (m, 2H), 3.04 (dd, 7= 7.5, 11.2 Hz, 1H), 1.70 - 1.89 (m, 2H), 1.33 (s, 9H), 1.10 (d, 7= 11.9 Hz, 6H).

Compound 27: (400 MHz, DMSO-ifc): <5 11.19 (br s, 1H), 7.74 (d, 7 = 8.4 Hz, 2H), 7.60 (d, 7 = 8.4 Hz, 2H), 4.42 - 4.52 (m, 2H), 4.00 (s, 3H), 3.61 (qd, 7= 6.0, 11.9 Hz, 1H), 3.31 - 3.50 (m, 2H), 3.16 (dd, 7= 7.1, 11.5 Hz, 1H), 1.75 - 1.97 (m, 2H), 1.71 - 1.49 (m, 8H), 1.33 (s, 9H).

Compound 28: (400 MHz, DMSO-7e): <5 11.27 (br s, 1H), 7.74 (d, 7= 8.6 Hz, 2H), 7.60 (d, 7= 8.4 Hz, 2H), 4.45 - 4.53 (m, 1H), 4.53 (br s, 1H), 4.00 (s, 3H), 3.65 - 3.76 (m, 1H), 3.41 - 3.51 (m, 1H), 3.24 - 3.38 (m, 2H), 1.83- 2.03 (m, 2H), 1.33 (s, 9H), 0.55 - 0.72 (m, 4H). Compound 29: (400 MHz, DMSO-7e): <5 11.02 (br s, 1H), 7.74 (d, 7= 8.6 Hz, 2H), 7.60 (d, 7= 8.6 Hz, 2H), 4.43 (br d, 7= 4.2 Hz, 2H), 4.00 (s, 3H), 3.51 - 3.60 (m, 2H), 3.15 - 3.38 (m, 2H), 2.06 - 2.18 (m, 2H), 1.69-2.04 (m, 6H), 1.33 (s, 9H).

Compound 30: (400 MHz, DMSO-7e): d 10.97 (br s, 1 H), 7.56 - 7.70 (m, 4 H), 4.48 (d, J = 5.01 Hz, 2 H), 4.27 (q, J = 7.21 Hz, 2 H), 3.45 - 3.64 (m, 2 H), 3.16 - 3.26 (m, 2 H), 1.81 - 2.05 (m, 4 H), 1.41 (t, J = 7.15 Hz, 3 H), 1.33 (s, 9 H). Compound 31: (400 MHz, DMSO-ifc): d 10.99 - 11.19 (m, 1 H), 7.57 - 7.63 (m, 4 H), 4.70 (quin, J = 6.56 Hz, 1 H), 4.48 (d, J = 5.07 Hz, 2 H), 3.55 (br dd, J = 10.25, 4.96 Hz, 2 H), 3.14 - 3.27 (m, 2 H), 1.83 - 2.03 (m, 4 H), 1.44 (d, J = 6.39 Hz, 6 H), 1.33 (s, 9 H). Compound 32: (400 MHz, DMSO-ifc): <5 11.27 (br s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.60 (d,

J = 8.6 Hz, 2H), 4.42 (d, J = 4.9 Hz, 2H), 3.90 - 3.97 (m, 1H), 3.54 (br dd, J = 5.0, 10.3 Hz, 2H), 3.14 - 3.22 (m, 2H), 1.85 - 2.00 (m, 4H), 1.31 - 1.35 (m, 9H), 1.03 - 1.14 (m, 4H). Compound 33: (400 MHz, DMSO-ifc): d 10.37 - 11.12 (m, 1 H), 7.89 - 7.97 (m, 2 H), 7.47 - 7.54 (m, 2 H), 4.74 (br s, 2 H), 4.29 (q, J = 7.21 Hz, 2 H), 3.65 (br d, J = 3.30 Hz, 2 H), 3.15 - 3.28 (m, 2 H), 1.89 - 2.12 (m, 4 H), 1.43 (t, J = 7.21 Hz, 3 H), 1.31 (s, 9 H).

Compound 34: (400 MHz, DMSO-d6): <5 11.39 - 11.60 (m, 1 H), 7.93 (d, J = 8.31 Hz, 2 H), 7.49 (d, J = 8.44 Hz, 2 H), 4.89 (quin, J = 6.39 Hz, 1 H), 4.75 (br d, J = 3.06 Hz, 2 H), 3.63 (br s, 2 H), 3.27 (br s, 2 H), 2.06 (br s, 2 H), 1.93 (br d, J = 4.65 Hz, 2 H), 1.47 (d, J = 6.48 Hz, 6 H), 1.31 (s, 9 H).

Compound 35: ¹HNMR (400 MHz, CDCb) d 7.17 (d, J= 7.3 Hz, 2H), 7.02 (d, J = 6.9 Hz, 2H), 4.46 (s, 2H), 3.97 (s, 3H), 2.39 (m, 4H), 1.62 (m, 4H), 1.27 (s, 9H).

Compound 36: ¹HNMR (400 MHz, CDCb) d 7.29 (d, J= 7.2 Hz, 2H), 7.21 (d, J = 7.0 Hz, 2H), 4.41 (s, 2H), 2.31 (s, 3H), 2.25 (m, 4H), 1.51 (m, 4H), 0.41 (b, 4H).

Compound 37: ¹HNMR (400 MHz, CDCb) d 7.21 (m, 2H), 7.14 (d, J = 7.0 Hz, 1H), 4.46 (s, 2H), 2.36 (s, 3H), 2.27 (m, 4H), 1.56 (m, 4H).

Compound 38: ¹HNMR (400 MHz, CDCb) d 7.14 (d, J= 7.0 Hz, 1H), 7.19 (m, 2H), 4.41 (s, 2H), 2.32 (s, 3H), 2.27 (m, 4H), 1.56 (m, 4H).

Compound 39: (400 MHz, DMSO-ifc): d 10.98 - 11.08 (m, 1H), 7.88 - 7.94 (m, 4H), 7.77 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.41 - 7.46 (m, 1H), 4.49 (br d, J = 5.1 Hz, 2H), 4.05 (s, 3H), 3.54 - 3.61 (m, 2H), 3.18 - 3.26 (m, 2H), 1.88 - 2.04 (m, 4H).

Compound 40: (400 MHz, DMSO-ifc): <5 11.04 (br s, 1H), 8.04 (s, 1H), 7.88 (d, J = 7.83 Hz, 1H), 7.66-7.82 (m, 4H), 7.51 (t, J = 7.16 Hz, 2H), 7.40-7.46 (m, 1H), 4.42 - 4.58 (m, 2H),

4.06 (s, 3H), 3.51 - 3.62 (m, 2H), 3.16 - 3.27 (m, 2H), 2.00 (br s, 2H), 1.84 - 1.97 (m, 2H). Compound 41: (400 MHz, DMSO-ifc): <5 11.24 (br s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.20 - 7.26 (m, 1H), 7.09 - 7.17 (m, 4H), 4.44 (br d, J = 4.9 Hz, 2H), 3.94 - 4.01 (m, 3H), 3.54 (br d, J = 5.3 Hz, 2H), 3.19 (br dd, J = 6.7, 10.5 Hz, 2H), 1.85 - 2.02 (m, 4H).

Compound 42: (400 MHz, DMSO-ifc): <5 11.11 (br s, 1H), 7.51 - 7.66 (m, 2H), 7.39 - 7.46 (m, 3H), 7.15 - 7.26 (m, 2H), 7.09 (d, J = 7.83 Hz, 2H), 4.41 - 4.48 (m, 2H), 3.99 (s, 3H),

3.52 (br dd, J = 4.89, 10.27 Hz, 2H), 3.11 - 3.23 (m, 2H), 1.82 - 2.02 (m, 4H). Compound 43: (400 MHz, DMSO-ifc): <5 11.36 (br s, 1H), 7.75 (d, J= 8.6 Hz, 2H), 7.46 - 7.50 (m, 2H), 7.40 (t, J= 7.3 Hz, 2H), 7.31 - 7.36 (m, 1H), 7.20 (d, J= 8.6 Hz, 2H), 5.20 (s, 2H), 4.43 (br d, J= 4.2 Hz, 2H), 3.99 - 3.94 (m, 3H), 3.54 (br d, J= 5.1 Hz, 2H), 3.15 - 3.25 (m, 2H), 1.85 - 2.00 (m, 4H).

Compound 44: (400 MHz, DMSO-ifc): <5 11.18 (br s, 1H), 7.32 - 7.53 (m, 8H), 7.24 (d, J = 7.54 Hz, 1H), 5.20 (s, 2H), 4.45 (d, J = 4.77 Hz, 2H), 3.96 (s, 3H), 3.55 (br d, J = 5.14 Hz, 2H), 3.19 (br dd, J = 6.91, 10.58 Hz, 2H), 1.83 - 2.03 (m, 4H).

Compound 45: (400 MHz, DMSO-ifc): <5 11.41 (br s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.41 (d,

J = 8.2 Hz, 2H), 4.43 (br d, J = 4.4 Hz, 2H), 3.94 - 4.01 (m, 3H), 3.54 (br d, J = 5.1 Hz, 2H), 3.15 - 3.24 (m, 2H), 2.54 - 2.62 (m, 1H), 1.85 - 2.01 (m, 4H), 1.80 (br d, J = 7.7 Hz, 4H), 1.70 (br d, J = 12.3 Hz, 1H), 1.32 - 1.49 (m, 4H), 1.19 - 1.29 (m, 1H).

Compound 46: (400 MHz, DMSO-ifc): <5 11.13 (br s, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.59 (d, J= 8.4 Hz, 2H), 4.33 - 4.42 (m, 2H), 3.99 (s, 3H), 3.54 - 3.62 (m, 2H), 3.47 (br d, J= 9.5 Hz, 2H), 1.72 (br s, 2H), 1.33 (s, 9H), 1.04 (br d, J= 4.4 Hz, 1H), 0.58 - 0.68 (m, 1H).

Compound 47: (400 MHz, DMSO-ifc): S 10.92- 11.23 (m, 1H), 7.74 (d, J= 8.2 Hz, 2H), 7.60 (d, J= 8.4 Hz, 2H), 4.47 (br d, J= 4.6 Hz, 1H), 4.39 (br d, J= 3.7 Hz, 1H), 3.99 (s, 3H), 3.77 (br s, 1H), 3.36 - 3.46 (m, 1H), 3.28 (br d, J= 11.2 Hz, 1H), 2.68 - 2.86 (m, 3H), 1.44 - 1.81 (m, 6H), 1.33 (s, 9H).

Compound 48: (400 MHz, DMSO-ifc): S 10.67 (br s, 1H), 7.75 (d, J= 8.2 Hz, 2H), 7.60 (d, J= 8.2 Hz, 2H), 4.33 (br d, J= 4.2 Hz, 2H), 4.26 (br s, 2H), 4.00 (s, 3H), 2.21 (br d, J= 8.8 Hz, 2H), 2.02 (br d, J= 7.8 Hz, 2H), 1.77 (br d, J= 8.4 Hz, 2H), 1.68 (br d, J =7.7 Hz, 2H), 1.33 (s, 9H)

Compound 49: ¹HNMR (400 MHz, CDCb) d 8.03 (s, 1H), 7.82 (m, 1H), 7.35 (m, 3H), 4.45 (s, 2H), 2.37 (s, 3H), 2.23 (m, 4H), 1.55 (m, 4H).

Compound 50: ¹HNMR (400 MHz, CDCb) d 7.09 (m, 2H), 6.89 (d, J= 6.2 Hz, 1H), 4.39 (s, 2H), 2.69 (m, 4H), 2.30 (s, 3H), 2.26 (m, 4H), 1.76 (m, 4H), 1.49 (s, 4H).

Compound 51: ¹HNMR (400 MHz, CDCb) d 7.26 (m, 4H), 4.29 (s, 2H), 2.39 (m, 1H), 2.31 (s, 3H), 2.25 (m, 4H), 1.60 (m, 6H), 1.09 (m, 8H).

Compound 52: ¹HNMR (400 MHz, CDCb) d 7.79 (d, J= 7.6 Hz, 2H), 7.52 (m, 5H), 7.29 (d, J= 7.3 Hz, 2H), 4.46 (s, 2H), 2.34 (s, 3H), 2.25 (m, 4H), 1.51 (m, 4H).

Compound 53: ¹HNMR (400 MHz, CDCb) d 8.49 (d, J= 7.4 Hz, 2H), 7.37 (d, J= 7.2 Hz, 2H), 3.65 (s, 2H), 3.62 (s, 3H), 2.54 (m, 4H), 1.45 (m, 4H), 1.31 (s, 9H).

Compound 54: ¹HNMR (400 MHz, CDCb) d 8.39 (d, J= 7.2 Hz, 2H), 7.31 (d, J= 7.0 Hz, 2H), 3.63 (s, 2H), 2.62 (m, 1H), 2.54 (m, 4H), 1.59 (m, 4H), 1.31 (s, 9H), 0.54 (b, 4H). Compound 62: (400 MHz, DMSO-d₆) d = 11.42 (br s, 1H), 7.71 - 7.56 (m, 4H), 4.46 (br d, 7 = 3.9 Hz, 2H), 4.28 (q, 7 = 7.2 Hz, 2H), 3.65 (qd, 7 = 5.9, 11.9 Hz, 1H), 3.48 - 3.30 (m, 2H), 3.05 (br dd, 7 = 7.3, 11.4 Hz, 1H), 1.86 - 1.68 (m, 2H), 1.41 (t, 7 = 7.2 Hz, 3H), 1.33 (s, 9H), 1.10 (d, 7 = 19.2 Hz, 5H).

Compound 63: (400 MHz, DMSO-d₆) d = 11.21 (br s, 1H), 7.71 - 7.54 (m, 4H), 4.52 (br s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.78 - 3.64 (m, 1H), 3.52 - 3.41 (m, 1H), 3.38 - 3.22 (m, 2H), 2.03 - 1.83 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H), 0.73 - 0.53 (m, 4H).

Compound 64: (400 MHz, DMSO-d₆) d = 10.97 (br s, 1H), 7.68 - 7.59 (m, 4H), 4.45 (d, 7 = 4.8 Hz, 2H), 4.48 - 4.40 (m, 2H), 4.28 (q, 7 = 7.2 Hz, 2H), 3.61 - 3.52 (m, 2H), 3.36 - 3.27 (m, 1H), 3.23 (dd, J = 6.4, 11.8 Hz, 1H), 2.17 - 2.07 (m, 2H), 2.02 - 1.73 (m, 6H), 1.42 (t, 7 = 7.2 Hz, 3H), 1.34 (s, 9H).

Compound 65: (400 MHz, DMSO-d₆) d = 11.15 (br s, 1H), 7.68 - 7.59 (m, 4H), 4.48 (br d, 7 = 4.8 Hz, 2H), 4.28 (q, 7 = 7.2 Hz, 2H), 3.67 - 3.57 (m, 1H), 3.49 - 3.34 (m, 2H), 3.18 (dd, 7 = 7.0, 11.6 Hz, 1H), 1.96 - 1.75 (m, 2H), 1.70 - 1.51 (m, 8H), 1.41 (t, 7 = 7.2 Hz, 3H), 1.34 (s, 9H).

Compound 66: (400 MHz, DMSO-d₆) d = 11.00 - 10.76 (m, 1H), 7.68 - 7.59 (m, 4H), 4.51 - 4.39 (m, 2H), 4.27 (q, 7 = 7.3 Hz, 2H), 3.78 (br s, 1H), 3.48 - 3.23 (m, 1H), 2.93 - 2.63 (m, 4H), 1.81 - 1.62 (m, 2H), 1.62 - 1.47 (m, 4H), 1.41 (t, 7 = 7.2 Hz, 3H), 1.31 - 1.29 (m, 9H). Compound 67: (400 MHz, DMSO-d₆) d = 11.21 (br s, 1H), 7.66 - 7.55 (m, 4H), 4.71 (td, 7 = 6.5, 13.0 Hz, 1H), 4.47 (br d, 7 = 4.5 Hz, 2H), 3.65 (qd, 7 = 5.9, 11.9 Hz, 1H), 3.46 - 3.31 (m, 2H), 3.04 (br dd, 7 = 7.4, 11.4 Hz, 1H), 1.84 - 1.71 (m, 2H), 1.44 (d, 7 = 6.5 Hz, 6H), 1.33 (s, 9H), 1.09 (d, 7 = 18.6 Hz, 6H).

Compound 68: (400 MHz, DMSO-d₆) d = 11.12 (br s, 1H), 7.65 - 7.55 (m, 4H), 4.71 (td, 7 = 6.5, 13.1 Hz, 1H), 4.53 (br d, 7 = 3.3 Hz, 2H), 3.71 (br d, 7 = 4.8 Hz, 1H), 3.53 - 3.42 (m,

1H), 3.40 - 3.22 (m, 2H), 2.06 - 1.82 (m, 2H), 1.44 (d, 7 = 6.5 Hz, 6H), 1.33 (s, 9H), 0.75 - 0.55 (m, 4H).

Compound 69: (400 MHz, DMSO-d₆) d = 11.33 (br s, 1H), 7.67 - 7.52 (m, 4H), 4.71 (spt, 7 = 6.5 Hz, 1H), 4.50 - 4.34 (m, 2H), 3.61 - 3.47 (m, 2H), 3.37 - 3.16 (m, 2H), 2.19 - 2.02 (m, 2H), 2.02 - 1.67 (m, 6H), 1.44 (d, 7 = 6.6 Hz, 6H), 1.33 (s, 9H).

Compound 70: (400 MHz, DMSO-d₆) d = 11.54 (br s, 1H), 7.66 - 7.52 (m, 4H), 4.71 (spt, 7 = 6.5 Hz, 1H), 4.44 (d, 7 = 4.4 Hz, 2H), 3.61 (qd, 7 = 6.0, 11.8 Hz, 1H), 3.49 - 3.31 (m, 2H), 3.18 (dd, 7 = 6.7, 11.6 Hz, 1H), 1.90 - 1.75 (m, 2H), 1.70 - 1.46 (m, 8H), 1.44 (d, 7 = 6.6 Hz, 6H), 1.33 (s, 9H).

Compound 71: (400 MHz, DMSO-d₆) d = 11.01 - 10.67 (m, 1H), 7.67 - 7.53 (m, 4H), 4.70 (br d , J = 6.5 Hz, 1H), 4.52 - 4.44 (m, 2H), 3.78 (br s, 1H), 3.47 - 3.24 (m, 1H), 2.94 - 2.55 (m, 4H), 1.83 - 1.47 (m, 6H), 1.44 (d, J = 6.5 Hz, 6H), 1.33 (s, 9H).

Compound 72: (400 MHz, DMSO-ifc) d = 11.17 (br s, 1H), 7.91 {d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 4.43 (br d, J = 2.4 Hz, 2H), 3.94 (tt, J = 3.7, 7.2 Hz, 1H), 3.64 (qd, J = 6.1, 12.0 Hz, 1H), 3.44 - 3.26 (m, 2H), 3.02 (br dd, J = 7.0, 11.3 Hz, 1H), 1.87 - 1.70 (m, 2H), 1.34 (s, 9H), 1.18 - 1.02 (m, 10H).

Compound 73: (400 MHz, DMSO-ifc) d = 11.20 (br s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 4.48 (br s, 2H), 3.94 (tt, J = 3.7, 7.2 Hz, 1H), 3.70 (br d, J = 4.2 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.37 - 3.22 (m, 2H), 2.04 - 1.83 (m, 2H), 1.33 (s, 9H), 1.17 - 0.99 (m, 4H), 0.74 - 0.51 (m, 4H).

Compound 74: (400 MHz, DMSO-ifc) d = 11.13 (br s, 1H), 7.94 - 7.88 (m, 2H), 7.63 - 7.57 (m, 2H), 4.39 (d, J = 4.9 Hz, 2H), 3.94 (tt, J = 3.7, 7.2 Hz, 1H), 3.59 - 3.48 (m, 2H), 3.34 - 3.16 (m, 2H), 2.15 - 2.05 (m, 2H), 2.01 - 1.71 (m, 6H), 1.33 (s, 9H), 1.16 - 1.01 (m, 4H). Compound 75: (400MHz, DMSO-ifc) d = 11.59 (br s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.40 (d, J = 4.4 Hz, 2H), 3.99 - 3.88 (m, 1H), 3.60 (qd, J = 6.0, 11.9 Hz,

1H), 3.48 - 3.30 (m, 2H), 3.16 (dd, J = 7.1, 11.5 Hz, 1H), 1.92 - 1.77 (m, 2H), 1.73 - 1.47 (m, 8H), 1.33 (s, 9H), 1.18 - 1.02 (m, 4H).

Compound 76: (400 MHz, DMSO-ifc) d = 10.74 - 10.44 (m, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 4.47 (br d, J = 5.1 Hz, 2H), 3.94 (td, J = 3.4, 7.2 Hz, 1H), 3.77 (br s, 1H), 3.45 - 3.25 (m, 1H), 2.74 (br s, 4H), 1.82 - 1.62 (m, 2H), 1.62 - 1.45 (m, 4H), 1.34 (s, 9H), 1.17 - 1.10 (m, 2H), 1.10 - 1.02 (m, 2H).

Example 3: Inhibition and/or reduction of SARS-CoV-2 in infected VeroE6 cells

Compounds of the disclosure were tested for antiviral activity against SARS-CoV-2 using a previously established cell-based assay (Severson, et al ., 2007, J. Biomol. Screen. 12:33-40). Briefly, VeroE6 cells were grown in 12-well plates, and were preincubated with an equal amount of infection media (Minimum Essential Media with Earle’s salts (MEM) + 2% FBS + 1% penicillin-streptomycin) and compound (2X concentration) for 2 h at 37 °C, 5% CO2. Cells were washed and infected with 0.2 mL of SARS-CoV-2 at 0.1 MOI for 1 h.

At 48 h later, the SARS-CoV-2 mediated cytopathic effect (CPE) was assessed by XTT Cell Viability (ThermoFischer) using the manufacturer’s protocol.

A titer reduction assay was conducted to confirm antiviral potency of our compounds at concentrations of 5 mM. Each test compound was assessed in three independent biological replicates. Vero E6 cells were incubated in the infection media and treated with our compounds prior to the infection of SARS-CoV-2 at 0.1 MOI. After 48 h incubation, the supernatants were collected and were quantified for residual virus titers by Tissue Culture Infectious Dose (TCIDso). Briefly, 10-fold dilutions of supernatants (10-1 to 10-8) were made, and 0.1 mL of each dilution was added to 96 well plates seeded with Vero E6 cells. Following 72 h incubation at 37 °C, 5% CO2, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide; Sigma-Aldrich) was added to each well. Plates were read at a wavelength of 570 nm. Wells were scored as positive or negative, and TCID50 was calculated based on the Reed Muench method (Reed, et al , 1938, Am. J. Epidemiol. 27, 493-497). Inhibition (%inhibition) of SARS-CoV-2 infection with administration of dyclonine and each of compounds 8, 27, and 47, was determined (FIG. 1).

Additionally, a 100-fold reduction of viral titer was observed in VeroE6 cells infected by SARS-CoV-2 (MOI = 0.1) with administration of selected SIR antagonists (e.g., compounds 69, 71, 74, and 75) at a concentration of 5 mM (FIG. 2). SIR ligands demonstrated moderate antiviral activity (IC50) in VeroE6 cells infected by SARS-CoV-2 (MOI = 0.1). Furthermore, low cytotoxicity of SIR compounds was observed in VeroE6 cells without SARS-CoV-2 infection (Table 4).

Table 4. Antiviral activity (ICso) of SIR ligands in monkey VeroE6 cells infected by SARS- CoV2 (MOI = 0.6) low cytotoxicity in monkey VeroE6 cells without virus infection.

Example 4: Dyclonine exhibits analgesic activity in Paclitaxel-induced thermal hyperalgesia and mechanical allodynia models in rats

Male Sprague-Dawley rats weighing 240 ± 20 grams were employed. Paclitaxel (brand name TAXOL®, 2 mg/kg) is injected intraperitoneally (i.p.) on days 1, 3, 5 and 7 with a total cumulative dose of 8 mg/kg. The behavioral assessments included mechanical allodynia and thermal hyperalgesia, as described elsewhere herein. Test articles, vehicle and gabapentin were administered intraperitoneally on Days 14 or 21.

Experimental results indicate that dyclonine exhibits analgesic activity in both Paclitaxel-induced thermal hyperalgesia (FIG. 3) and mechanical allodynia (FIG. 4).

Example 5: Dyclonine exhibits analgesic activity in (STZ)-induced thermal hyperalgesia and mechanical allodynia models in diabetic rats

Male Sprague-Dawley rats weighing 225-250 grams were employed. Streptozotocin (STZ, 50 mg/kg) freshly dissolved in 0.9% sterile saline was injected intraperitoneally on day 0. Three days later, diabetes was confirmed by existence of blood glucose >350 mg/dL as measured by glucometer. Animal health was monitored bi-weekly for 14 days, at which point mechanical allodynia and thermal hyperalgesia were measured, as described elsewhere herein, and confirmed. The behavioral assessments include mechanical allodynia and thermal hyperalgesia. Test articles, vehicle and gabapentin were administered intraperitoneally on Days 14 or 21.

Experimental results indicate that dyclonine exhibits analgesic activity in both (STZ)- induced thermal hyperalgesia (FIG. 5) and mechanical allodynia (FIG. 6) in diabetic rats.

Example 6: Dyclonine potentiates morphine’s analgesia in a mouse model of acute pain

Male young CD-I mice (at the age of 7-8 weeks) were used in this study. Tail flick latency was determined using a lamp device (design derived from D’Amour & Smith, 1941,

J. Pharmacol. Exp. Ther. 72(l):74-79). The behavioral endpoint was defined as a flick of the tail out of the path of the light. The intensity of the light was adjusted to provide a baseline response time of approximately 2-4 seconds. The light beam was focused approximately 4 cm from the tip of the tail. A cut off time of 20 seconds was used to prevent tissue damage. Mice received a single intra-peritoneal (IP) injection of either vehicle (saline) or test substance at appropriate doses followed immediately by a single subcutaneous (SC) administration of saline or morphine at the appropriate dose for each group. Thirty minutes after the SC administration, the animals were gently restrained in a manner which allowed access to the tail and positioned beneath a light beam (D’ Amour & Smith, 1941, J Pharmacol Exp Ther 72(l):74-79) with the tail aligned for measurement at approximately 4 cm from tail tip. The lamp device automatically timed each tail flick response once the tail was flicked away from the light beam by a sensor beneath the platform. Mice were observed at the time of testing and each animal was tested only once.

Experimental results indicate that dyclonine potentiates morphine’s analgesia in a mouse model of acute pain, demonstrating a 10-fold enhancement in maximum possible effect with co-administration (FIG. 7).

Example 7: Compound 68 exhibits analgesic activity by attenuating mechanical allodynia and thermal hyperalgesia in spinal nerve ligation (SNL) Chung model in rats

Groups of 6 male Sprague Dawley rats weighing 160-200 grams were used. Prior to surgery and post-operatively, the animals were housed socially under constant temperature, humidity, and a 12-hour light-dark cycle. Following acclimation to the animal colony for 7 days, the rats were tested for mechanical allodynia and thermal hyperalgesia for baseline (pre-dose) values on Day -1. On Day 0, the animals were anesthetized with pentobarbital (50 mg/kg, i.p.). The left paraspinal muscles were separated from the spinous processes (L4-S2) and the L6-S1 facet joint was nipped. The transverse process of L6 was removed to allow for identifying the location of the L5 and L6 spinal nerves. The left L5-L6 spinal nerves were isolated and tightly ligated with 6.0 silk sutures. The rats are allowed to recover for 13 days.

Rats were tested for mechanical allodynia and thermal hyperalgesia following acclimation on Day -1 for baseline (pre-dose) values. Following the recovery period, the rats were tested to verify the mechanical allodynia on Day 13. The rats were pre-selected for experimentation only if the pain threshold after nerve ligation (pre-treatment) is reduced by 10 grams of force relative to the response of the individual paw before nerve ligation (preligation), namely, with clear presence of allodynia. The rats were randomized based on predose mechanical allodynia scores to balanced treatment groups.

The manual von Frey test was repeated again 15 and 75 minutes following administration of the vehicle, compound 68 at two doses, or the positive control, gabapentin 50 mg/kg, IP, on Day 14 post-surgery.

Following a four (4) day wash out “period”, the rats were tested in the thermal hyperalgesia test and randomized to balance treatment groups. On Day 19, the rats were administered vehicle, Compound 68 at two doses, or gabapentin 50 mg/kg, IP. At 15 and 75 minutes post-dose the thermal hyperalgesia is tested again.

Experimental results indicate that compound 68 exhibits analgesic activity by attenuating the mechanical allodynia (FIG. 8) and thermal hyperalgesia (FIG. 9) in spinal nerve ligand (SNL) Chung model in rats.

Enumerated Embodiments

The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance.

Embodiment 1 provides a method of treating, ameliorating, and/or preventing a viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one agent selected from: dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof; a compound selected from the group consisting of MS-377, DuP 734, E-100, E-5482, eperisone, tolperisone, caretapentan, BD-1063, donezepil, fluphenazine, clorgyline, nemonapride, amiodarone, haloperidol, BMS-181100, scopolamine, phenoxybenzamine, trihexylphenodyl, dolasetron, diphenhydramine, SIRA, suloctidil, enclomiphene, clemastine, nadolol, moclobemide, difenidol, propranolol, encainide, dextromethorphan, alizapride, amisulpride, lidocaine, arotinolol, propafenone, metoclopramide, phenyltoloxamine, captodiamine, acebutolol, and mepivacaine; and a compound of formula (I), or a salt, solvate, isotopically labeled derivative, enantiomer, diastereoisomer, or tautomer thereof:

wherein:

A¹, A², and A³ are such that one applies: (a) A¹ = N, A² = NR³, and A³ = C; (b) A¹ = NR³, A² = N, and A³ = C; (c) A¹ =N, A² = CR³, and A³ = N;

R¹ is selected from the group consisting of H, Ci-Cx alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C10 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, and C3-C8 cycloalkyl;

R² is selected from the group consisting of H, Ci-Cx alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C10 cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C8 cycloalkyl; or R¹ and R² combine with the N atom to which they are bound to form 3- to 8- membered heterocyclyl, wherein each heterocyclyl is independently optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl, wherein two substituents bound to the same atom of the heterocyclyl can combine to form C2-C7 alkylene which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl, and wherein two substituents bound to distinct atoms of the heterocyclyl can combine to form C1-C7 alkylene which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl;

Y is -(0¾)h-, wherein n is 0, 1, 2, 3, 4, 5, or 6, and wherein each CFb group in Y is independently optionally substituted with at least one selected from the group consisting of C1-C₆ alkyl, C1-C₆ haloalkyl, F, Cl, Br, and I;

R³ is selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 cycloalkyl, wherein each alkyl, alkenyl, alkynyl or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, F, Cl, Br, and I; and each of R^4a, R^4b, R^4c, R^4d, and R^4e is independently selected from the group consisting of H, F, Cl, Br, I, Ci-Cs alkyl, Ci-Cs haloalkyl, Ci-Cs haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 cycloalkyl, phenyl, phenoxy, and benzyloxy, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or benzyl is independently optionally substituted with at least one selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, F, Cl, Br, and I, or R^4C and R^4d combine with the atoms to which they are bound to form C4-C8 cycloalkyl, phenyl, or heterocyclyl, wherein each cycloalkyl, phenyl, heterocyclyl, or heteroaryl is independently substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci- C8 alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, and C2-C8 alkynyl; and wherein the heterocyclyl is selected from the group consisting of pyrrolyl, furanyl and thiophenyl.

Embodiment 2 provides the method of Embodiment 1, wherein the virus is a Coronavirus.

Embodiment 3 provides the method of Embodiment 2, wherein the Coronavirus is at least one of MERS-CoV, SARS-CoV, and/or SARS-CoV-2.

Embodiment 4 provides the method of any of Embodiments 1-3, wherein the virus is Hepatitis C virus (HCV).

Embodiment 5 provides the method of any of Embodiments 1-4, wherein the virus is Human Immunodeficiency virus (HIV).

Embodiment 6 provides the method of any of Embodiments 1-5, wherein the at least one agent is dyclonine, or a salt, solvate, or isotopically labeled derivative thereof.

Embodiment 7 provides the method of any of Embodiments 1-6, wherein the at least one agent is dyclonine, or a salt or solvate thereof:

Embodiment 8 provides the method of any of Embodiments 1-6, wherein the dyclonine is deuterated.

Embodiment 9 provides the method of any of Embodiments 1-6 and 8, wherein the deuterated dyclonine comprises at least one of:

Embodiment 10 provides the method of any of Embodiments 1-5, wherein the compound of formula (I) is selected from the group consisting of:

Embodiment 11 provides the method of any of Embodiments 1-5 and 10, wherein in the compound of formula (I), -NR'R² is an optionally substituted heterocyclyl selected from the group consisting of pyrrolidinyl, piped dinyl, morpholinyl, thiomorpholinyl, piperazinyl, N- (Ci-Ce alkyl) piperidinyl, cyclohexyl-amino, and azepanyl.

Embodiment 12 provides the method of any of Embodiments 1-5 and 10-11, wherein in the compound of formula (I) -NR'R² is selected from the group consisting of:

Embodiment 13 provides the method of any of Embodiments 1-5 and 10-12, wherein

5 in the compound of formula (

selected from the group consisting of:

wherein each occurrence of R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3- C8 cycloalkyl, and wherein each occurrence of R^a, R^b, and R^c is independently H or Cl.

Embodiment 14 provides the method of any of Embodiments 1-5 and 10-13, wherein in the compound of formula (I) R¹ and R² are each methyl.

Embodiment 15 provides the method of any of Embodiments 1-5 and 10-14, wherein in the compound of formula (I) R³ is methyl, ethyl, isopropyl or cyclopropyl.

Embodiment 16 provides the method of any of Embodiments 1-15, wherein the at least one agent is deuterated.

Embodiment 17 provides the method of any of Embodiments 1-16, wherein the at least one agent is selected from the group consisting of: dyclonine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)piperidine;

4-((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)morpholine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-4- methylpiperazine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-4- phenylpiperazine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-4- phenethylpiperazine; l-benzyl-4-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)piperazine;

4-benzyl-l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)piperidine; 5-(4-(tert-butyl)phenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -(5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)-N-(cyclopropylmethyl)-N- methylmethanamine;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(4-( 1 -(trifluoromethyl)cyclopropyl)phenyl)- 1H- 1,2,4-triazole;

5-(3 ,4-dichlorophenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(4-(trifluoromethyl)phenyl)- 1H- 1 ,2,4-triazole;

1 -methyl-5-(3 -methyl-4-(trifluoromethyl)phenyl)-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4- triazole;

5-(4-isopropylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(5, 6,7, 8-tetrahydronaphthalen-2-yl)-lH-l, 2,4- triazole;

5-(3 -(tert-butyl)phenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(3 -( 1 -(trifluoromethyl)cyclopropyl)phenyl)- 1H- 1,2,4-triazole;

5-(4-chlorophenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

5-(3 ,4-dimethylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(p-tolyl)- 1H- 1 ,2,4-triazole; 5-(4-cyclopropylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(2,3-dihydro-lH-inden-5-yl)-l -methyl-3 -(pyrrolidin- 1 -ylmethyl)- lH-1, 2, 4-tri azole; 5-(benzo[b]thiophen-6-yl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

1 -methyl-3 -(pyrrolidin- l-ylmethyl)-5-(2, 3', 4'-tri chi oro-[l,l'-biphenyl]-4-yl)-lH-l, 2,4- triazole;

5-(2-chlorobenzo[b]thiophen-6-yl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4- triazole;

5 -(4-(tert-butyl)phenyl)-3 -((3 ,3 -dimethylpyrrolidin- 1 -yl)m ethyl)- 1 -methyl- 1 H- 1 ,2,4- triazole;

2-((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-2- azaspiro[4.4]nonane;

5-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane;

6-((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-6- azaspiro[3 ,4]octane;

5-(4-(tert-butyl)phenyl)- 1 -ethyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole; 5-(4-(tert-butyl)phenyl)- 1 -isopropyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(4-(tert-butyl)phenyl)- 1 -cyclopropyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

3 -(4-(tert-butyl)phenyl)- 1 -ethyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

3 -(4-(tert-butyl)phenyl)- 1 -isopropyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -(4-(tert-butyl)phenyl)-5-m ethyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1 -(4-( 1 -(trifluoromethyl)cyclopropyl)phenyl)- 1H- 1,2,4-triazole;

1 -(3 ,4-dichlorophenyl)-5-m ethyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-methyl-l-(3-methyl-4-(trifluoromethyl)phenyl)-3-(pyrrolidin-l-ylmethyl)-lH- 1,2,4- triazole;

5-([ 1 , 1 '-biphenyl]-4-yl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

5-([ 1 , 1 '-biphenyl]-3 -yl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-5-(4-phenoxyphenyl)-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-5-(3 -phenoxyphenyl)-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(4-(benzyloxy)phenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(3-(benzyloxy)phenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- lH-1, 2, 4-tri azole; 5-(4-cyclohexylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

3 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-3 - azabicyclo[3.1.OJhexane;

2-((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole; (ls,4s)-7-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)-7- azabicyclo[2.2.1 Jheptane;

1 -(benzo[b]thiophen-6-yl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole; 5-methyl-3-(pyrrolidin-l -ylmethyl)- 1 -(5,6,7, 8-tetrahydronaphthalen-2-yl)-lH-l, 2,4- triazole;

1 -(4-cyclohexylphenyl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

1 -([ 1 , 1 '-biphenyl]-4-yl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

3 -(4-(tert-butyl)phenyl)- 1 -methyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

3 -(4-(tert-butyl)phenyl)- 1 -cyclopropyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)piperazine; N-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3-yl)methyl)-N- methylcyclopropanamine;

5-(2,3-dihydrobenzo[b]thiophen-6-yl)-l -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1,2, 4- triazole;

5-(3 -chlorophenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(3 -(trifluoromethyl)phenyl)- 1H- 1 ,2,4-triazole;

1-methyl-3-(pyrrolidin-l-ylmethyl)-5-(m-tolyl)-lH-l, 2, 4-triazole; 5-(4-propylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

5 -(4-(/er/-butyl)phenyl)-3 -((3 ,3 -dimethylpyrrolidin- 1 -yl)methyl)- 1 -ethyl- \H- 1 ,2,4- triazole;

5-((5-(4-(/c77-butyl)phenyl)- l -ethyl- 1//- 1 ,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane;

6-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1 H- 1 ,2,4-triazol-3 -yl)methyl)-6- azaspiro[3 ,4]octane;

2-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1 H- 1 ,2,4-triazol-3 -yl)methyl)-2- azaspiro[4.4]nonane;

2-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1 H- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole;

5 -(4-(/er/-butyl)phenyl)-3 -((3 ,3 -dimethylpyrrolidin- 1 -yl)m ethyl)- 1 -i sopropyl- 1 H- 1,2,4-triazole;

5-((5-(4-(/t77-butyl)phenyl)- l -i sopropyl - 1//-1 , 2, 4-tri azol -3-yl (methyl )-5- azaspiro[2.4]heptane;

6-((5-(4-(/t77-butyl)phenyl)- l -i sopropyl - 1//-1 , 2, 4-triazol-3-yl (methyl )-6- azaspiro[3 ,4]octane;

2-((5-(4-(/t77-butyl)phenyl)- l -i sopropyl - 1//-1 , 2, 4-triazol-3-yl (methyl )-2- azaspiro[4.4]nonane;

2-((5-(4-(/t77-butyl)phenyl)- 1 -isopropyl- 1 H- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole;

5-(4-(/t77-butyl)phenyl)- l -cyclopropyl -3 -((3, 3 -dimethylpyrrolidin-! -yl (methyl )-!//- 1,2,4-triazole;

5-((5-(4-(/t77-butyl)phenyl)- l -cyclopropyl- l//-l ,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane;

6-((5-(4-(/t77-butyl)phenyl)- 1 -cyclopropyl- 1 H- 1 ,2,4-triazol-3 -yl)methyl)-6- azaspiro[3 ,4]octane;

2-((5-(4-(/t77-butyl)phenyl)- 1 -cyclopropyl- 1 H- 1 ,2,4-triazol-3 -yl)methyl)-2- azaspiro[4.4]nonane; and

2-((5-(4-(/t77-butyl)phenyl)- 1 -cyclopropyl- 1 H- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole; or a salt, solvate, isotopically labeled, enantiomer, diastereomer, and/or tautomer thereof.

Embodiment 18 provides the method of any of Embodiments 1-17, wherein the at least one agent is formulated as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

Embodiment 19 provides the method of any of Embodiments 1-18, wherein the subject is administered at least one additional therapeutic agent that treats, ameliorates, and/or prevents the viral infection.

Embodiment 20 provides the method of Embodiment 19, wherein the at least one compound and the at least one additional therapeutic agent are co-formulated.

Embodiment 21 provides the method of any of Embodiments 1-18, wherein the at least one agent is the only therapeutically active agent administered to the subject.

Embodiment 22 provides the method of any of Embodiments 1-18, wherein the at least one agent is the only therapeutically active agent administered to the subject in an amount sufficient to treat, ameliorate, and/or prevent the viral infection.

Embodiment 23 provides the method of any of Embodiments 1-22, wherein the at least one agent binds to SIR selectively over S2R.

Embodiment 24 provides the method of any of Embodiments 1-22, wherein the at least one agent binds to S2R selectively over SIR.

Embodiment 25 provides the method of any of Embodiments 1-22, wherein the at least one agent binds to SIR and S2R with equal, or nearly equal, affinity.

Embodiment 26 provides the method of any of Embodiments 1-25, wherein the subject is a mammal.

Embodiment 27 provides the method of Embodiment 26, wherein the mammal is a human.

Embodiment 28 provides a method of increasing or decreasing activity of at least one sigma receptor selected from the group consisting of sigma 1 receptor (SIR) and sigma 2 receptor (S2R), the method comprising contacting the at least one sigma receptor with dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof.

Embodiment 29 provides the method of Embodiment 28, wherein the at least one sigma receptor is in a cell.

Embodiment 30 provides the method of Embodiment 29, wherein the cell is mammalian. Embodiment 31 provides the method of any of Embodiments 29-30, wherein the cell is in a subject.

Embodiment 32 provides provides the method of any of Embodiments 28-31, wherein the contacting promotes antinociception in the subject.

Embodiment 33 provides a method of inhibiting, treating, and/or preventing pain in a subject, the method comprising administering to the subject a therapeutically effective amount of dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof.

Embodiment 34 provides the method of Embodiment 33, wherein the administration promotes antinociception in the subject.

Embodiment 35 provides the method of any of Embodiments 33-34, wherein the pain comprises chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, and/or allodynia.

Embodiment 36 provides the method of any of Embodiments 33-35, wherein the dyclonine is the only therapeutically active agent administered to the subject.

Embodiment 37 provides the method of any of Embodiments 33-36, wherein the dyclonine is the only therapeutically active agent administered to the subject in an amount sufficient to treat or prevent pain.

Embodiment 38 provides the method of any of Embodiments 33-35, wherein the subject is further administered at least one therapeutic agent that treats or prevents pain.

Embodiment 39 provides the method of Embodiment 38, wherein the dyclonine and the at least one additional therapeutic agent are co-administered to the subject.

Embodiment 40 provides the method of any of Embodiments 38-39, wherein the dyclonine and the at least one additional therapeutic agent are co-formulated.

Embodiment 41 provides the method of any of Embodiments 38-40, wherein the at least one therapeutic agent comprises an opioid agent.

Embodiment 42 provides the method of Embodiment 41, wherein administration of the opioid agent and the dyclonine to the subject allows for a lower amount of the opioid agent to be administered than if the subject is not administered the dyclonine.

Embodiment 43 provides the method of any of Embodiments 41-42, wherein administration of the opioid agent and the dyclonine to the subject allows for use of an amount of the opioid agent that does not cause any significant side effect associated with opioid agent use.

Embodiment 44 provides a method of inhibiting, treating, and/or preventing a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof. wherein the disease or disorder is at least one selected from the group consisting of cancer and any other related proliferative diseases, neurological and neurodegenerative diseases, substance abuse disorders, depressive disorders, ocular disorders, and glaucoma.

Embodiment 45 provides the method of any of Embodiments 33-44, wherein the dyclonine is deuterated.

Embodiment 46 provides the method of any of Embodiments 33-45, wherein the deuterated dyclonine comprises at least one of:

Embodiment 47 provides the method of any of Embodiments 33-46, wherein the subject is a mammal.

Embodiment 48 provides the method of Embodiment 47, wherein the mammal is a human.

Embodiment 49 provides a compound selected from the group consisting of:

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While the disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

What is claimed is:

1 A method of treating, ameliorating, and/or preventing a viral infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one agent selected from: dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof; a compound selected from the group consisting of MS-377, DuP 734, E-100, E-5482, eperisone, tolperisone, caretapentan, BD-1063, donezepil, fluphenazine, clorgyline, nemonapride, amiodarone, haloperidol, BMS-181100, scopolamine, phenoxybenzamine, trihexylphenodyl, dolasetron, diphenhydramine, SIRA, suloctidil, enclomiphene, clemastine, nadolol, moclobemide, difenidol, propranolol, encainide, dextromethorphan, alizapride, amisulpride, lidocaine, arotinolol, propafenone, metoclopramide, phenyltoloxamine, captodiamine, acebutolol, and mepivacaine; and a compound of formula (I), or a salt, solvate, isotopically labeled derivative, enantiomer, diastereoisomer, or tautomer thereof:

wherein:

R² is selected from the group consisting of H, Ci-Cx alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C1₀ cycloalkyl, wherein each alkyl, alkenyl, alkynyl, or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of F, Cl, Br, I, C1-C8 alkyl, C1-C8 haloalkyl, and C3-C8 cycloalkyl; or R¹ and R² combine with the N atom to which they are bound to form 3- to 8- membered heterocyclyl, wherein each heterocyclyl is independently optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-Cx alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl, wherein two substituents bound to the same atom of the heterocyclyl can combine to form C2-C7 alkylene which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, C1-C8 alkyl, Ci-Cs haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl, and wherein two substituents bound to distinct atoms of the heterocyclyl can combine to form C1-C7 alkylene which is optionally substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci-C8 alkyl, Ci-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkenyl, phenyl, heteroaryl, and (aryl)-Ci-C6 alkyl;

Y is -(CH2)n-, wherein n is 0, 1, 2, 3, 4, 5, or 6, and wherein each CH₂ group in Y is independently optionally substituted with at least one selected from the group consisting of C1-C₆ alkyl, C1-C₆ haloalkyl, F, Cl, Br, and I;

X is selected from the group consisting of -CH2-, -0-, -NH-, -N(CI-C6 alkyl)-, and -S-, wherein if n is 0, then X is -CH2-, and wherein each CH₂ group in X is independently optionally substituted with at least one selected from the group consisting of C1-C₆ alkyl, C1-C₆ haloalkyl, F, Cl, Br, and I;

R³ is selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C₃-C₆ cycloalkyl, wherein each alkyl, alkenyl, alkynyl or cycloalkyl is independently optionally substituted with at least one selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, F, Cl, Br, and I; and each of R^4a, R^4b, R^4c, R^4d, and R^4e is independently selected from the group consisting of H, F, Cl, Br, I, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈ haloalkoxy, C₂-C₆ alkenyl, C₂-C₈ alkynyl, C₃-C1₀ cycloalkyl, phenyl, phenoxy, and benzyloxy, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or benzyl is independently optionally substituted with at least one selected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl, F, Cl, Br, and I, or R^4c and R^4d combine with the atoms to which they are bound to form C₄-C₈ cycloalkyl, phenyl, or heterocyclyl, wherein each cycloalkyl, phenyl, heterocyclyl, or heteroaryl is independently substituted with at least one substituent selected from the group consisting of F, Cl, Br, I, Ci- C₈ alkyl, C₁-C₈ haloalkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl; and wherein the heterocyclyl is selected from the group consisting of pyrrolyl, furanyl and thiophenyl.

2. The method of claim 1, wherein the virus is a Coronavirus.

3. The method of claim 2, wherein the Coronavirus is at least one of MERS-CoV,

SARS-CoV, and/or SARS-CoV-2.

4. The method of claim 1, wherein the virus is Hepatitis C virus (HCV).

5. The method of claim 1, wherein the virus is Human Immunodeficiency virus (HIV).

6. The method of any of claims 1-5, wherein the at least one agent is dyclonine, or a salt, solvate, or isotopically labeled derivative thereof.

7. The method of any of claims 1-6, wherein the at least one agent is dyclonine, or a salt or solvate thereof:

8 The method of any of claims 1-6, wherein the dyclonine is deuterated.

9. The method of any of claims 1-6 and 8, wherein the deuterated dyclonine comprises at least one of:

10. The method of any of claims 1-5, wherein the compound of formula (I) is selected from the group consisting of:

11. The method of any of claims 1-5 and 10, wherein in the compound of formula (I), - NR'R² is an optionally substituted heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, N-(CI-C₆ alkyl) piperidinyl, cyclohexyl-amino, and azepanyl.

12. The method of any of claims 1-5 and 10-11, wherein in the compound of formula (I) - NR'R² is selected from the group consisting of:

13. The method of any of claims 1-5 and 10-12, wherein in the compound of formula (I)

selected from the group consisting of:

wherein each occurrence of R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3- C₈ cycloalkyl, and wherein each occurrence of R^a, R^b, and R^c is independently H or Cl.

14. The method of any of claims 1-5 and 10-13, wherein in the compound of formula (I) R¹ and R² are each methyl.

15. The method of any of claims 1-5 and 10-14, wherein in the compound of formula (I) R³is methyl, ethyl, isopropyl or cyclopropyl.

16. The method of any of claims 1-15, wherein the at least one agent is deuterated.

17. The method of any of claims 1-16, wherein the at least one agent is selected from the group consisting of: dyclonine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)piperidine; 4-((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)morpholine; 1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-4- methylpiperazine;

1 -((5-(4-(tert-butyl)phenyl)- 1 -methyl- 1H- 1 ,2,4-triazol-3 -yl)methyl)-4- phenethylpiperazine; l-benzyl-4-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)piperazine; -benzyl-l-((5-(4-(tert-butyl)phenyl)-l-methyl-lH-l,2,4-triazol-3- yl)methyl)piperidine;

5-(4-(tert-butyl)phenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)-5-(p-tolyl)- 1H- 1 ,2,4-triazole;

5-(4-cyclopropylphenyl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

5-(2,3-dihydro-lH-inden-5-yl)-l -methyl-3 -(pyrrolidin- 1 -ylmethyl)- lH-1, 2, 4-tri azole;

5-(benzo[b]thiophen-6-yl)- 1 -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole;

5-(4-(tert-butyl)phenyl)- 1 -ethyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(4-(tert-butyl)phenyl)- 1 -isopropyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole; 5-(4-(tert-butyl)phenyl)- 1 -cyclopropyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -(benzo[b]thiophen-6-yl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2, 4-tri azole; 5-methyl-3-(pyrrolidin-l -ylmethyl)-l -(5,6,7, 8-tetrahydronaphthalen-2-yl)-lH-l, 2,4- triazole;

1 -(4-cyclohexylphenyl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

1 -([ 1 , 1 '-biphenyl]-4-yl)-5-methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

3 -(4-(tert-butyl)phenyl)- 1 -methyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

3 -(4-(tert-butyl)phenyl)- 1 -cyclopropyl-5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazole;

5-(2,3-dihydrobenzo[b]thiophen-6-yl)-l -methyl-3 -(pyrrolidin- 1 -ylmethyl)- 1H- 1,2,4- triazole;

5 -(4-(/er/-butyl)phenyl)-3 -((3 ,3 -dimethylpyrrolidin- 1 -yl)methyl)- 1 -ethyl- 1/7- 1 ,2,4- triazole;

5-((5-(4-(/er/-butyl)phenyl)-l -ethyl- 1/7-1, 2, 4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane;

6-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1/7- 1 ,2,4-triazol-3 -yl)methyl)-6- azaspiro[3 ,4]octane;

2-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1/7- 1 ,2,4-triazol-3 -yl)methyl)-2- azaspiro[4.4]nonane;

2-((5-(4-(/er/-butyl)phenyl)- 1 -ethyl- 1/7- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole;

5 -(4-(/er/-butyl)phenyl)-3 -((3 ,3 -dimethylpyrrolidin- 1 -yl)m ethyl)- 1 -i sopropyl- 1/7- 1,2,4-triazole;

5-((5-(4-(/c77-butyl)phenyl)- l -isopropyl - 177-1 , 2, 4-tri azol -3-yl (methyl )-5- azaspiro[2.4]heptane;

6-((5-(4-(/c77-butyl (phenyl )- l -isopropyl - 177-1 , 2, 4-triazol-3-yl (methyl )-6- azaspiro[3 ,4]octane;

2-((5-(4-(/c77-butyl (phenyl (- 1 -isopropyl - 177-1 , 2, 4-triazol-3-yl (methyl )-2- azaspiro[4.4]nonane;

2-((5-(4-(/t77-butyl)phenyl)- 1 -isopropyl- 1/7- 1 ,2,4-triazol-3 - yl)methyl)octahydrocyclopenta[c]pyrrole;

5-(4-(7c77-butyl)phenyl)-l -cyclopropyl-3-((3,3-dimethylpyrrolidin- 1 -yljmethyl )-!//- 1,2,4-triazole;

5-((5-(4-(/t77-butyl)phenyl)-l -cyclopropyl - 1//- 1 ,2,4-triazol-3-yl)methyl)-5- azaspiro[2.4]heptane;

18. The method of any of claims 1-17, wherein the at least one agent is formulated as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

19. The method of any of claims 1-18, wherein the subject is administered at least one additional therapeutic agent that treats, ameliorates, and/or prevents the viral infection.

20. The method of claim 19, wherein the at least one compound and the at least one additional therapeutic agent are co-formulated.

21. The method of any of claims 1-18, wherein the at least one agent is the only therapeutically active agent administered to the subject.

22. The method of any of claims 1-18, wherein the at least one agent is the only therapeutically active agent administered to the subject in an amount sufficient to treat, ameliorate, and/or prevent the viral infection.

23. The method of any of claims 1-22, wherein the at least one agent binds to SIR selectively over S2R.

24. The method of any of claims 1-22, wherein the at least one agent binds to S2R selectively over SIR.

25. The method of any of claims 1-22, wherein the at least one agent binds to SIR and S2R with equal, or nearly equal, affinity.

26. The method of any of claims 1-25, wherein the subject is a mammal.

27. The method of claim 26, wherein the mammal is a human.

28. A method of increasing or decreasing activity of at least one sigma receptor selected from the group consisting of sigma 1 receptor (SIR) and sigma 2 receptor (S2R), the method comprising contacting the at least one sigma receptor with dyclonine (l-(4-butoxyphenyl)-3- (l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof.

29. The method of claim 28, wherein the at least one sigma receptor is in a cell.

30. The method of claim 29, wherein the cell is mammalian.

31. The method of any of claims 29-30, wherein the cell is in a subject.

32. The method of claim 31, wherein the contacting promotes antinociception in the subject.

33. A method of inhibiting, treating, and/or preventing pain in a subject, the method comprising administering to the subject a therapeutically effective amount of dyclonine (l-(4- butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof.

34. The method of claim 33, wherein the administration promotes antinociception in the subject.

35. The method of any of claims 33-34, wherein the pain comprises chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, and/or allodynia.

36. The method of any of claims 33-35, wherein the dyclonine is the only therapeutically active agent administered to the subject.

37. The method of any of claims 33-36, wherein the dyclonine is the only therapeutically active agent administered to the subject in an amount sufficient to treat or prevent pain.

38. The method of any of claims 33-35, wherein the subject is further administered at least one therapeutic agent that treats or prevents pain.

39. The method of claim 38, wherein the dyclonine and the at least one additional therapeutic agent are co-administered to the subject.

40. The method of claim 39, wherein the dyclonine and the at least one additional therapeutic agent are co-formulated.

41. The method of any of claims 38-40, wherein the at least one therapeutic agent comprises an opioid agent.

42. The method of claim 41, wherein administration of the opioid agent and the dyclonine to the subject allows for a lower amount of the opioid agent to be administered than if the subject is not administered the dyclonine.

43. The method of any of claims 41-42, wherein administration of the opioid agent and the dyclonine to the subject allows for use of an amount of the opioid agent that does not cause any significant side effect associated with opioid agent use.

44. A method of inhibiting, treating, and/or preventing a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of dyclonine (l-(4-butoxyphenyl)-3-(l-piperidyl)propan-l-one), or a salt, solvate, or isotopically labeled derivative thereof. wherein the disease or disorder is at least one selected from the group consisting of cancer and any other related proliferative diseases, neurological and neurodegenerative diseases, substance abuse disorders, depressive disorders, ocular disorders, and glaucoma.

45. The method of any of claims 33-44, wherein the dyclonine is deuterated.

46. The method of any of claims 33-45, wherein the deuterated dyclonine comprises at least one of:

47. The method of any of claims 33-46, wherein the subject is a mammal.

48. The method of claim 47, wherein the mammal is a human.

49. A compound selected from the group consisting of:

or a salt and/or solvate thereof.