Organic compound (OXIME) to combat chemical warfare agents

Abstract

Described herein are compounds that reactivate acetylcholinesterase and associated methods of treating organophosphate poisoning.

Description

[0001]Attorney Docket No.:PLW-00125ORGANIC COMPOUND (OXIME) TO COMBAT CHEMICALWARFARE AGENTSCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of priority to U.S. Provisional Application Nos.63 / 607,254, filed December 7, 2023, and 63 / 629,963, filed May 6, 2023, and U.S. Non-Provisional Application No. 18 / 144,191, filed May 6, 2023, the contents of each of which arehereby incorporated by reference in their entirety.BACKGROUNDOrganophosphate poisoning is a serious medical condition resulting from exposure toorganophosphate compounds, which are commonly found in insecticides, herbicides, andchemical nerve agents such as VX and sarin. These compounds inhibit the enzymeacetylcholinesterase (AChE), causing an accumulation of acetylcholine in synapses andneuromuscular junctions. This overstimulation of cholinergic receptors leads to a range ofsymptoms and can be fatal if left untreated.The symptoms of organophosphate poisoning can be classified into three categories:muscarinic, nicotinic, and central nervous system (CNS) effects. Muscarinic effects includeincreased salivation, lacrimation, urination, defecation, gastrointestinal motility, andbronchoconstriction. Nicotinic effects involve muscle twitching, weakness, and eventuallyparalysis. CNS effects manifest as seizures, confusion, ataxia, respiratory depression, andcoma. In severe cases, respiratory failure and death may occur.Organophosphate poisoning nerve agents (i.e., Sarin, Soman, or Tabun) are the mostdangerous agents known, triggering seizure activity in the brain and leading to irreversibleseizure-related brain damage.Organophosphate poisoning induces rapid death through different mechanisms,including respiratory and cardiovascular significant dysfunctions. Organophosphatepoisoning nerve agents primarily act by inhibiting the enzyme acetylcholinesterase (AChE),causing an acute cholinergic crisis. Accordingly, medical countermeasures (MCMs) aim tominimize the cholinergic crisis upon deactivating AChE at the neuro synaptic andneuromuscular junctions or to remove the neurotoxic agent by some scavenging process.Alluding to the above, organophosphates are chemicals that can cause poisoning byinhibiting an enzyme called acetylcholinesterase (AChE) in the nervous system. This leads-1 -FH12004864.1 Attorney Docket No.:PLW-00125to an accumulation of acetylcholine, a neurotransmitter, and overstimulation of the nervoussystem, leading to symptoms such as muscle twitching, convulsions, and respiratory failure.Despite the efforts to develop new oxime-based therapeutics, the standard of care stillrelies upon a procedure dating from 1960 consisting of a combination of anti-cholinergicdrugs (e.g. atropine), pralidoxime (2-PAM), obidoxime and benzodiazepines (e.g. diazepam).New and improved treatments for organophosphate poisoning are needed.SUMMARY OF THE INVENTIONIn certain aspects, provided herein are compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof: Formula (I)wherein each R1 is independently selected from nitro and cyano;m is an integer from 0 to 5;R3 is selected from H and alkyl;X is selected from H, alkyl, heterocyclyl, aryl, cycloalkyl, and heteroaryl; orR3 and X, together with the carbon atom that separates them, complete a 4-6 memberedheterocyclyl or cycloalkyl.In certain aspects, provided herein, are compounds of Formula (III), or apharmaceutically acceptable salt thereof: Formula (III)wherein X is a bond or SO2; andR1 and R2 are each independently selected from H, alkyl, aryl, heteroaryl, and cycloalkyl; orR1 and R2, together with the atoms that separate them, complete a 4-8 memberedheterocycloalkyl.-2 -FH12004864.1 Attorney Docket No.:PLW-00125 In certain aspects, provided herein are compounds of Formula (V), or apharmaceutically acceptable salt thereof: Formula (V)wherein R1 is H or alkyl; andR2 is selected from aryl, heteroaryl, heterocyclyl, and cycloalkyl; orR1combines with R2to complete a 4-6 membered ring.In certain aspects, provided herein, are compounds of Formula (VII) andpharmaceutically acceptable salts thereof: Formula (VII)wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;R2 is selected from aryl, alkyl, heterocyclyl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; andn is 0-6.In some embodiments, n is 0.In certain aspects, provided herein, are compounds of Formula (IX), or pharmaceuticallyacceptable salts thereof: Formula (IX)wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;each R2 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano, alkenyl,and alkynyl;n is 0-4; andm is 0-5.-3 -FH12004864.1 Attorney Docket No.:PLW-00125 BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 shows in silico results for (NE)-N-[1-(benzenesulfonyl)quinoline-2-ylidene]hydroxylamine binding to AChE inhibited with SARIN.Figure 2 shows in silico results for (E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanimine binding to AChE inhibited with VX / Novichok.Figure 3 shows in silico results for (E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanimine binding to AChE inhibited with SARIN.Figure 4 shows in silico results (E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanimine binding to AChE inhibited with VX / Novichok.Figure 5 shows a retrosynthetic process of (NE)-N-[1-(benzenesulfonyl)quinoline-2-ylidene]hydroxylamine.Figure 6 shows a retrosynthetic process of (E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanimine.DETAILED DESCRIPTION OF THE INVENTIONBy the way of background and alluding to the above, organophosphates are chemicalsthat can cause poisoning by inhibiting an enzyme called acetylcholinesterase (AChE) in thenervous system. This leads to an accumulation of acetylcholine, a neurotransmitter, andoverstimulation of the nervous system, leading to symptoms such as muscle twitching,convulsions, and respiratory failure.Oximes work as an antidote for organophosphate poisoning by reactivating theinhibited acetylcholinesterase, thereby reducing the accumulation of acetylcholine andrestoring normal nervous system function.When an organophosphate molecule binds to acetylcholinesterase, it inactivates theenzyme and stops it from breaking down acetylcholine. Oximes are drugs that can help toreverse this inactivation by acting as a “bridge” between the acetylcholinesterase and theorganophosphate molecule.The oxime attaches itself to both the acetylcholinesterase and the organophosphatemolecule, helping to break the bond between them. This allows the acetylcholinesterase toregain its normal function, so it can once again break down acetylcholine. This helps toreduce the amount of acetylcholine in the nervous system and relieve the symptoms oforganophosphate poisoning.-4 -FH12004864.1 Attorney Docket No.:PLW-00125 In essence, the oxime acts as an “intermediary” that helps to restore normalacetylcholinesterase function, thereby reducing the toxic effects of the organophosphatemolecule.In certain embodiments, the compounds of the invention are used to combatchemicals causing poisoning of a nervous system of a human by inhibiting an enzyme in thenervous system leading to an accumulation of acetylcholine, a neurotransmitter, andoverstimulation of the nervous system, leading to symptoms such as muscle twitching,convulsions, and respiratory failure.In certain embodiments, the compounds of the invention are used in multi-level andmulti-modal data (i.e. data ranging from the chemical level, pathways, and systems levels)through state-of-the-art AI-based solutions and provides a valuable opportunity to furtherunderstand the molecular mechanisms of CWA exposure in general, as well as patientphenotyping, assessment of patient trajectories as well as the clinical response tointerventions at the onset of CWA exposure.In certain embodiments, the compounds of the invention provide a fast, available andcost-effective platform for treatment design.In certain embodiments, the compounds of the invention are used to treat exposure tonervous agents (organophosphores), has and have been tested in-silica for efficacy and safety.In certain embodiments, the present invention provides the innovative organiccompounds (oxime) that will empower caregivers in the use of novel management tools andcombination therapies enabling the adoption of more effective management and personalizedcare by taking a systems-level approach to fine-tuning treatment and vital support.-5 -FH12004864.1 Attorney Docket No.:PLW-00125 Tables 1a-1b show the affinity of (E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanamine (1) and (NE)-N-[1-(benzenesulfonyl)quinoline-2-ylidene]hydroxylamine (2) against different AChE inhibited with different organophosphates.(E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanamine (1) present the best reactivationresults for most agents tested with good binding affinities for AChE and best median dosage.The differences for VX and A-234 are negligible since they are in linear scale (kcal / mol).Table 1a Table 1b In certain aspects, provided herein, are compounds of Formula (I), or apharmaceutically acceptable salt thereof: Formula (I)wherein each R1 is independently selected from nitro and cyano;m is an integer from 0 to 5;-6 -FH12004864.1 Attorney Docket No.:PLW-00125R3 is selected from H and alkyl;X is selected from H, alkyl, heterocyclyl, aryl, cycloalkyl, and heteroaryl; orR3 and X, together with the carbon atom that separates them, complete a 4-6 memberedheterocyclyl or cycloalkyl.In certain embodiments, m is 1 or 2.In some embodiments, R3 is alkyl. In some embodiments, R3 and X, together with the carbonatom that separates them, complete a 5-6 membered heterocyclic ring. In some embodiments,m is 2. In some embodiments, each instance of R1 is nitro.In certain embodiments, the compounds have the structure of Formula (IA): Formula (IA).In certain embodiments, the compounds have the structure of Formula (II): Formula (II)wherein each R2 is selected from alkyl, amino, carbamate, nitro, hydroxyl, alkoxy (e.g.,aralkyloxy), and halo;wherein R3 is aralkyl;X is selected from alkyl, heterocyclyl, aryl, polycyclyl, cycloalkyl, and heteroaryl; andp is an integer from 0-5.In some embodiments, R1 is nitro.In certain embodiments, the compounds have the structure of Formula (IIA): Formula (IIA).In some embodiments, R1 is cyano.In certain embodiments, the compounds have the structure of Formula (IIB): Formula (IIB).In some embodiments, X is phenyl. In some embodiments, X is heteroaryl. In someembodiments, X is selected from thiophenyl, thiazolyl, furanyl, and pyridinyl. In someembodiments, p is an integer from 0-2. In some embodiments, R2 is selected from methyl,-7 -FH12004864.1 Attorney Docket No.:PLW-00125carbamate, halo, nitro, alkoxy, and alkoxy. In some embodiments, R2 is carbamate. In someembodiments, R2 is halo. In some embodiments, R2 is F.In certain embodiments, provided herein are compounds of Formula (I) havingstructures selected from:, Molecular Weight: 240.24,Molecular W ht: 236.27, A27,Molecular Weight: 358.35, Molecular Weight: 373.37,A42, -8 -FH12004864.1 Attorney Docket No.:PLW-00125 Molecular Weight: 344.39 Molecular Weight: 302.29A45,A18, , , Molecular Weight: 248.26,A17, , , -9 -FH12004864.1 Attorney Docket No.:PLW-00125 Molecular Weight: 286.33Molecular Weight: 262.22 A16,A24, A33, Molecular Weight: 321.33 , Molecular Weight: 364.38 Molecular Weight: 266.34A30,A31, and .In certain aspects, provided herein, are compounds of Formula (III), or apharmaceutically acceptable salt thereof: Formula (III)wherein X is a bond or SO2; andR1 and R2 are each independently selected from H, alkyl, aryl, heteroaryl, and cycloalkyl; orR1 and R2, together with the atoms that separate them, complete a 4-8 memberedheterocycloalkyl.-10 -FH12004864.1 Attorney Docket No.:PLW-00125 When X is a bond, Nh and R1 are directly bonded to one another. In someembodiments, X is SO2. In some embodiments, R1 is alkyl. In some embodiments, R1 isbutyl. In some embodiments, wherein R1 combines with R2 to form a 6-8 memberedheterocycloalkyl. In some embodiments, the 6-8 membered heterocycloalkyl is substitutedwith an aryl.In certain embodiments, the compounds have the structure of Formula (IV) Formula (IV)wherein R1 is selected from aryl, heteroaryl, and cycloalkyl.In some embodiments, R1 is aryl. In some embodiments, R1 is phenyl. In someembodiments, R1 is cycloalkyl. In some embodiments, R1 is cyclopropyl. In someembodiments, R1 is substituted one or more substituents selected from halo, nitro, alkyl, andhaloalkyl. In some embodiments, R2 is alkyl. In some embodiments, R2 is methyl. In someembodiments, R2 is aryl.In certain embodiments, wherein each R3 is independently selected from nitro, cyano, halo, haloalkyl, and alkyl; andm is an integer from 0-5. In some embodiments, R3 is nitro. In some embodiments, R3 iscyano. In some embodiments, R3 is halo. In some embodiments, R3 is bromo. In someembodiments, R3 is alkyl.In certain embodiments, provided herein, are compounds of Formula (IV) havingstructures selected from: , , -11 -FH12004864.1 Attorney Docket No.:PLW-00125 , , , , and .In certain aspects, provided herein, are compounds of Formula (V), or apharmaceutically acceptable salt thereof:R1R2NOHFormula (V)wherein R1 is H or alkyl; andR2 is selected from aryl, heteroaryl, heterocyclyl, and cycloalkyl; orR1 combines with R2 to complete a 4-6 membered ring.In some embodiments, R1 is alkyl. In some embodiments, R1 is methyl. In someembodiments, the 4-6 membered ring is a 5-6 membered ring. In some embodiments, the 4-6-12 -FH12004864.1 Attorney Docket No.:PLW-00125membered ring is a heterocycle. In some embodiments, the 4-6 membered ring is substitutedwith an alkyl ester.In certain embodiments, the compounds have the structure of Formula (VI): Formula (VI)wherein R2 is selected from, heterocyclyl, aryl, cycloalkyl, and heteroaryl.In some embodiments, R2 is a 5 or 6-membered heterocyclyl or heteroaryl. In someembodiments, R2 is a 5 or 6-membered cycloalkyl or aryl. In some embodiments, R2 is aryl.In some embodiments, R2 is phenyl. In some embodiments, R2 is heteroaryl. In someembodiments, R2is . In some embodiments, R2is cycloalkyl. In someembodiments, R2 is polycyclic, e.g. bicyclic. In some embodiments, R2 is . Insome embodiments, R2 is substituted with alkyl, alkoxy, arylsulfone, nitro, carbamate,OR3CF3or heteroaryl, wherein R3 is aryl.In certain embodiments, provided herein, are compounds of Formula (V) havingstructures selected from: , -13 -FH12004864.1 Attorney Docket No.:PLW-00125 , , MoleculBar7Weight: 237.26,Molecular W ht: 281.23, Molecular W ight: 228.25,Molecular ight: 198.23, Molecular Weight: 209.28B99.In certain aspects, provided herein, are compounds of Formula (VII), or apharmaceutically acceptable salts thereof:-14 -FH12004864.1 Attorney Docket No.:PLW-00125 Formula (VII)wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;R2 is selected from aryl, alkyl, heterocyclyl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; andn is 0-6.In some embodiments, n is 0.In certain embodiments, the compounds have the structure of Formula (VIII): Formula (VIII)wherein each R3 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl.m is 0-5.In certain embodiments, the compound have the structure: .In certain aspects, provided herein, are compounds of Formula (IX), orpharmaceutically acceptable salts thereof:-15 -FH12004864.1 Attorney Docket No.:PLW-00125 Formula (IX)wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;each R2 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano, alkenyl,and alkynyl;n is 0-4; andm is 0-5.In some embodiments, each R1 is independently alkyl or cycloalkyl. In someembodiments, each R1 is independently selected from methyl and cyclopropyl. In someembodiments, n is 2.In certain embodiments, the compounds have the structure of Formula (X): Formula (X).wherein each R3 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, halo,alkoxy, nitro, cyano, alkenyl, and alkynyl; ortwo R3 taken together to form a ring; andp is 1-5.In certain embodiments, the compounds have the structure of Formula (XI): Formula (XI).In some embodiments, each R2 is nitro. In some embodiments, m is 1.In certain embodiments, the compound has the structure:-16 -FH12004864.1 Attorney Docket No.:PLW-00125 .In certain embodiments, provided herein, are pharmaceutical compositionscomprising any of the above compounds and a pharmaceutically acceptable excipient. Incertain embodiments, provided herein are methods of treating a subject who has beenexposed to an organophosphate comprising: administering to the subject any of the abovecompounds. In some embodiments, the organophosphate is a chemical nerve agent. In someembodiments, the chemical nerve agent is selected from sarin, soman, tabun and VX.DefinitionsUnless otherwise defined herein, scientific and technical terms used in this applicationshall have the meanings that are commonly understood by those of ordinary skill in the art.Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissueculture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology,immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry,described herein, are those well known and commonly used in the art.The methods and techniques of the present disclosure are generally performed, unlessotherwise indicated, according to conventional methods well known in the art and as describedin various general and more specific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y.(2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al.,“Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al.,“Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert etal., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).Chemistry terms used herein, unless otherwise defined herein, are used according toconventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).All of the above, and any other publications, patents and published patent applicationsreferred to in this application are specifically incorporated by reference herein. In case ofconflict, the present specification, including its specific definitions, will control.-17 -FH12004864.1 Attorney Docket No.:PLW-00125 The term “agent” is used herein to denote a chemical compound (such as an organic orinorganic compound, a mixture of chemical compounds), a biological macromolecule (such asa nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and humanantibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, acarbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, oranimal (particularly mammalian) cells or tissues. Agents include, for example, agents whosestructure is known, and those whose structure is not known. The ability of such agents toinhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in themethods and compositions of this disclosure.A “patient,” “subject,” or “individual” are used interchangeably and refer to either ahuman or a non-human animal. These terms include mammals, such as humans, primates,livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines,etc.) and rodents (e.g., mice and rats).“Treating” a condition or patient refers to taking steps to obtain beneficial or desiredresults, including clinical results. As used herein, and as well understood in the art, “treatment”is an approach for obtaining beneficial or desired results, including clinical results. Beneficialor desired clinical results can include, but are not limited to, alleviation or amelioration of oneor more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. notworsening) state of disease, preventing spread of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment.The term “preventing” is art-recognized, and when used in relation to a condition, suchas a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heartfailure or any other medical condition, is well understood in the art, and includes administrationof a composition which reduces the frequency of, or delays the onset of, symptoms of a medicalcondition in a subject relative to a subject which does not receive the composition. Thus,prevention of cancer includes, for example, reducing the number of detectable cancerousgrowths in a population of patients receiving a prophylactic treatment relative to an untreatedcontrol population, and / or delaying the appearance of detectable cancerous growths in a treatedpopulation versus an untreated control population, e.g., by a statistically and / or clinicallysignificant amount.“Administering” or “administration of” a substance, a compound or an agent to asubject can be carried out using one of a variety of methods known to those skilled in the art.-18 -FH12004864.1 Attorney Docket No.:PLW-00125For example, a compound or an agent can be administered, intravenously, arterially,intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually,orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, andtransdermally (by absorption, e.g., through a skin duct). A compound or agent can alsoappropriately be introduced by rechargeable or biodegradable polymeric devices or otherdevices, e.g., patches and pumps, or formulations, which provide for the extended, slow orcontrolled release of the compound or agent. Administering can also be performed, forexample, once, a plurality of times, and / or over one or more extended periods.Appropriate methods of administering a substance, a compound or an agent to a subjectwill also depend, for example, on the age and / or the physical condition of the subject and thechemical and biological properties of the compound or agent (e.g., solubility, digestibility,bioavailability, stability and toxicity). In some embodiments, a compound or an agent isadministered orally, e.g., to a subject by ingestion. In some embodiments, the orallyadministered compound or agent is in an extended release or slow release formulation, oradministered using a device for such slow or extended release.As used herein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic agents such that the second agent isadministered while the previously administered therapeutic agent is still effective in the body(e.g., the two agents are simultaneously effective in the patient, which may include synergisticeffects of the two agents). For example, the different therapeutic compounds can beadministered either in the same formulation or in separate formulations, either concomitantlyor sequentially. Thus, an individual who receives such treatment can benefit from a combinedeffect of different therapeutic agents.A “therapeutically effective amount” or a “therapeutically effective dose” of a drug oragent is an amount of a drug or an agent that, when administered to a subject will have theintended therapeutic effect. The full therapeutic effect does not necessarily occur byadministration of one dose, and may occur only after administration of a series of doses. Thus,a therapeutically effective amount may be administered in one or more administrations. Theprecise effective amount needed for a subject will depend upon, for example, the subject’s size,health and age, and the nature and extent of the condition being treated, such as cancer or MDS.The skilled worker can readily determine the effective amount for a given situation by routineexperimentation.As used herein, the terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may occur or may not occur, and that the description includes-19 -FH12004864.1 Attorney Docket No.:PLW-00125instances where the event or circumstance occurs as well as instances in which it does not. Forexample, “optionally substituted alkyl” refers to the alkyl may be substituted as well as wherethe alkyl is not substituted.It is understood that substituents and substitution patterns on the compounds of thepresent disclosure can be selected by one of ordinary skilled person in the art to resultchemically stable compounds which can be readily synthesized by techniques known in the art,as well as those methods set forth below, from readily available starting materials. If asubstituent is itself substituted with more than one group, it is understood that these multiplegroups may be on the same carbon or on different carbons, so long as a stable structure results.As used herein, the term “optionally substituted” refers to the replacement of one to sixhydrogen radicals in a given structure with the radical of a specified substituent including, butnot limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl,cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refersto the replacement of one to four hydrogen radicals in a given structure with the substituentsmentioned above. More preferably, one to three hydrogen radicals are replaced by thesubstituents as mentioned above. It is understood that the substituent can be further substituted.The term “acyl” is art-recognized and refers to a group represented by the generalformula hydrocarbylC(O)-, preferably alkylC(O)-.The term “acylamino” is art-recognized and refers to an amino group substituted withan acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.The term “acyloxy” is art-recognized and refers to a group represented by the generalformula hydrocarbylC(O)O-, preferably alkylC(O)O-.The term “alkoxy” refers to an alkyl group having an oxygen attached thereto.Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group andmay be represented by the general formula alkyl-O-alkyl.The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkylgroups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substitutedcycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer. The term“lower alkyl” refers to the alkyl group with 1-6 carbon atoms. Examples of “alkyl” include, butare not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2--20 -FH12004864.1 Attorney Docket No.:PLW-00125pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl,1-octyl, 2-octyl, 3-octyl or 4-octyl and the like.Moreover, the term “alkyl” as used throughout the specification, examples, and claimsis intended to include both unsubstituted and substituted alkyl groups, the latter of which refersto alkyl moieties having substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as,acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from xto y carbons in the chain. C0alkyl indicates a hydrogen where the group is in a terminalposition, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbonatoms in the chain.The term “alkylamino”, as used herein, refers to an amino group substituted with atleast one alkyl group.The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkylgroup and may be represented by the general formula alkylS-.The term “amide”, as used herein, refers to a groupO R9N R10 ,wherein R9 and R10 each independently represent a hydrogen or hydrocarbyl group, orR9 and R10 taken together with the N atom to which they are attached complete a heterocyclehaving from 4 to 8 atoms in the ring structure.The terms “amine” and “amino” are art-recognized and refer to both unsubstituted andsubstituted amines and salts thereof, e.g., a moiety that can be represented by ,wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbylgroup, or R9 and R10 taken together with the N atom to which they are attached complete aheterocycle having from 4 to 8 atoms in the ring structure.The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with anamino group.-21 -FH12004864.1 Attorney Docket No.:PLW-00125 The term “aralkyl”, as used herein, refers to an alkyl group substituted with an arylgroup.The term “aryl” as used herein include substituted or unsubstituted single-ring aromaticgroups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-memberedring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ringsystems having two or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can becycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Arylgroups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.The term “carbamate” is art-recognized and refers to a groupOOR10or10NORO N R9 R9,wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group.The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with acarbocycle group.The term “cycloalkyl”, as used herein refers to a monocyclic or polycyclic non-aromaticring, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with anaromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbonatom). Representative cycloalkyls include, but are not limited to, cycloalkyls having from threeto ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or fromthree to five carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, themonocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Polycyclic ringsinclude, for example, adamantyl, norbornyl, decalinyl, and 3,4-dihydronaphthalen-1(2H)-one.Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionallysubstituted. The terms “cycloalkyl” also include polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoining rings wherein at leastone of the rings is cycloalkyl, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls.The term “carbocycle” includes 5-7 membered monocyclic and 8-12 memberedbicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturatedand aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more-22 -FH12004864.1 Attorney Docket No.:PLW-00125atoms are shared between the two rings. The term “fused carbocycle” refers to a bicycliccarbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ringof a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In anexemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated orunsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination ofsaturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane,bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin,naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or morepositions capable of bearing a hydrogen atom.The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with acarbocycle group.The term “carbonate” is art-recognized and refers to a group -OCO2-.The term “carboxy”, as used herein, refers to a group represented by theformula -CO2H.The term “ester”, as used herein, refers to a group -C(O)OR9 wherein R9 represents ahydrocarbyl group.The term “ether”, as used herein, refers to a hydrocarbyl group linked through anoxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl groupmay be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples ofethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle.Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.The terms “halo” and “halogen” as used herein means halogen and includes chloro,fluoro, bromo, and iodo.The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl groupsubstituted with a hetaryl group.The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromaticsingle ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-memberedrings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms,more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also includepolycyclic ring systems having two or more cyclic rings in which two or more carbons are-23 -FH12004864.1 Attorney Docket No.:PLW-00125common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., theother cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / orheterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.The term “heteroatom” as used herein means an atom of any element other than carbonor hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted witha heterocycle group.The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted orunsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, morepreferably 3- to 7-membered rings, whose ring structures include at least one heteroatom,preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoining rings wherein at leastone of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, forexample, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.The term “hydrocarbyl”, as used herein, refers to a group that is bonded through acarbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms.Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered tobe hydrocarbyl for the purposes of this application, but substituents such as acetyl (which hasa =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, notcarbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle,heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with ahydroxy group.The term “lower” when used in conjunction with a chemical moiety, such as, acyl,acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten orfewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers toan alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certainembodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein arerespectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or loweralkoxy, whether they appear alone or in combination with other substituents, such as in the-24 -FH12004864.1 Attorney Docket No.:PLW-00125recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the arylgroup are not counted when counting the carbon atoms in the alkyl substituent).The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g.,cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in whichtwo or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Eachof the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, eachring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.The term “sulfate” is art-recognized and refers to the group –OSO3H, or apharmaceutically acceptable salt thereof.The term “sulfonamide” is art-recognized and refers to the group represented by thegeneral formulae ,wherein R9 and R10 independently represents hydrogen or hydrocarbyl.The term “sulfoxide” is art-recognized and refers to the group–S(O)-.The term “sulfonate” is art-recognized and refers to the group SO3H, or apharmaceutically acceptable salt thereof.The term “sulfone” is art-recognized and refers to the group –S(O)2-.The term “substituted” refers to moieties having substituents replacing a hydrogen onone or more carbons of the backbone. It will be understood that “substitution” or “substitutedwith” includes the implicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that the substitution results in a stablecompound, e.g., which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organic compounds. In a broad aspect,the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclicand heterocyclic, aromatic and non-aromatic substituents of organic compounds. Thepermissible substituents can be one or more and the same or different for appropriate organiccompounds. For purposes of this disclosure, the heteroatoms such as nitrogen may havehydrogen substituents and / or any permissible substituents of organic compounds describedherein which satisfy the valences of the heteroatoms. Substituents can include any substituentsdescribed herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a-25 -FH12004864.1 Attorney Docket No.:PLW-00125thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino,an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate,a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromaticor heteroaromatic moiety. It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, if appropriate.The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiolgroup.The term “thioester”, as used herein, refers to a group -C(O)SR9 or –SC(O)R9wherein R9 represents a hydrocarbyl.The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen isreplaced with a sulfur.The term “urea” is art-recognized and may be represented by the general formula ,wherein R9 and R10 independently represent hydrogen or a hydrocarbyl.The term “modulate” as used herein includes the inhibition or suppression of a functionor activity (such as cell proliferation) as well as the enhancement of a function or activity.The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments,the term includes compositions, excipients, adjuvants, polymers and other materials and / ordosage forms which are, within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with a reasonable benefit / risk ratio.“Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid additionsalt or a basic addition salt which is suitable for or compatible with the treatment of patients.The term “pharmaceutically acceptable acid addition salt” as used herein means anynon-toxic organic or inorganic salt of any base compounds represented by Formula I.Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic,sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitablesalts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic,cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic andmethanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may-26 -FH12004864.1 Attorney Docket No.:PLW-00125exist in either a hydrated, solvated or substantially anhydrous form. In general, the acidaddition salts of compounds of Formula I are more soluble in water and various hydrophilicorganic solvents, and generally demonstrate higher melting points in comparison to their freebase forms. The selection of the appropriate salt will be known to one skilled in the art. Othernon-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolationof compounds of Formula I for laboratory use, or for subsequent conversion to apharmaceutically acceptable acid addition salt.The term “pharmaceutically acceptable basic addition salt” as used herein means anynon-toxic organic or inorganic base addition salt of any acid compounds represented byFormula I or any of their intermediates. Illustrative inorganic bases which form suitable saltsinclude lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrativeorganic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic aminessuch as methylamine, trimethylamine and picoline or ammonia. The selection of theappropriate salt will be known to a person skilled in the art.Many of the compounds useful in the methods and compositions of this disclosure haveat least one stereogenic center in their structure. This stereogenic center may be present in a Ror a S configuration, said R and S notation is used in correspondence with the rules describedin Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric formssuch as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs ormixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.Furthermore, certain compounds which contain alkenyl groups may exist as Z(zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixtureand separate individual isomers.Some of the compounds may also exist in tautomeric forms. Such forms, although notexplicitly indicated in the formulae described herein, are intended to be included within thescope of the present disclosure.“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host after administration to form thecompound of the present disclosure (e.g., compounds of formula I). Typical examples ofprodrugs include compounds that have biologically labile or cleavable (protecting) groups ona functional moiety of the active compound. Prodrugs include compounds that can be oxidized,reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to producethe active compound. Examples of prodrugs using ester or phosphoramidate as biologically-27 -FH12004864.1 Attorney Docket No.:PLW-00125labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of thisdisclosure are metabolized to produce a compound of Formula I. The present disclosureincludes within its scope, prodrugs of the compounds described herein. Conventionalprocedures for the selection and preparation of suitable prodrugs are described, for example, in“Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter,diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinalor therapeutic use.The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art toquantify the aqueous solubility of a compound. The aqueous solubility of a compoundsignificantly affects its absorption and distribution characteristics. A low solubility often goesalong with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubilitymeasured in mol / liter.EXAMPLESExample 1: Validating the Efficacy of Oxime CompoundsThe first step for validating the efficacy of E)-N-(2,4-dinitrophenoxy)-1-(4-fluorophenyl)methanimine and (NE)-N-[1-(benzenesulfonyl)quinolin-2-ylidene]hydroxylamine as antidotes for different OPs is to assess their chemical propertiesfollowing the protocol below:1. Determine the melting point of the oxime:^Take a small amount of the synthesized oxime (around 1-2 mg) and place it in acapillary tube.^Heat the capillary tube using a melting point apparatus or a Bunsen burner andobserve the temperature at which the oxime melts. This can give you an indication ofthe purity of the oxime and whether it has undergone any decomposition or reaction.2. Determine the solubility of the oxime in different solvents:^Prepare a range of solvents of varying polarities such as water, ethanol, methanol,DMSO, and chloroform.^Take a small amount of the synthesized oxime (around 5-10 mg) and add it to eachsolvent in separate test tubes or vials.-28 -FH12004864.1 Attorney Docket No.:PLW-00125 ^ Shake the test tubes or vials vigorously to dissolve the oxime in the solvents. ^Observe the solution in each test tube or vial and note whether the oxime dissolvescompletely or partially or forms a suspension or precipitate.^Repeat the solubility test at different temperatures (e.g. room temperature, 50°C,80°C) to assess the effect of temperature on the solubility of the oxime.3. Determine the pH-dependent solubility of the oxime:^Prepare a series of buffer solutions of different pH values (e.g. pH 2, 4, 6, 8, 10) usingappropriate buffer systems such as acetate buffer, phosphate buffer, or Tris buffer.^Take a small amount of the synthesized oxime (around 5-10 mg) and add it to eachbuffer solution in separate test tubes or vials.^ Shake the test tubes or vials vigorously to dissolve the oxime in the buffer solutions. ^Observe the solution in each test tube or vial and note whether the oxime dissolvescompletely or partially or forms a suspension or precipitate.^Repeat the solubility test at different temperatures (e.g. room temperature, 50°C,80°C) to assess the effect of temperature on the pH-dependent solubility of the oxime.4. Determine the stability of the oxime in different solvents:^Take a small amount of the synthesized oxime (around 5-10 mg) and add it to eachsolvent in separate test tubes or vials.^Store the test tubes or vials at different temperatures (e.g. room temperature, 4°C, -20°C) for different time periods (e.g. 24 hours, 48 hours, 7 days).^Observe the solution in each test tube or vial and note whether the oxime remainsstable or undergoes any degradation or precipitation.5. Analyze the data:^ Record the results of the solubility and stability tests in a spreadsheet. ^Calculate the solubility parameters such as the solubility product (Ksp) or thesolubility index (SI) for each solvent and pH condition.^Compare the solubility parameters and stability data with literature values for similaroxime compounds to assess the quality and suitability of the synthesized oxime.Example 2: Efficacy StudyThe efficacy of the new oxime against different OPs can be assessed through the followingprotocol:-29 -FH12004864.1 Attorney Docket No.:PLW-001251. Generate IPSC-derived neurons: We can use commercially available IPSC lines orgenerate them from patient-derived cells through one of Prepaire’s partners such asNCARDIA.2. Induce organophosphate poisoning:^Plate IPSC-derived neurons in multi-well plates or culture dishes at an appropriatedensity.^Prepare a stock solution of the organophosphate agent (e.g. VX or Sarin gas) atdifferent concentrations in a suitable solvent (e.g. DMSO, ethanol).^Dilute the stock solution of the organophosphate agent in the culture medium to thedesired final concentration.^Add the diluted organophosphate solution to the culture medium to induceorganophosphate poisoning in the IPSC-derived neurons. Incubate for the desiredduration (e.g. 5 minutes, 1, 4, 8, and 24 hours).3. Test the antidote molecule:^Prepare a stock solution of the antitoxine molecule at a known concentration in asuitable solvent (e.g. DMSO, ethanol or water as per the chemical protocol above).^Dilute the stock solution of the antitoxine molecule in the culture medium to thedesired final concentration (as per the chemical protocol above).^Add the diluted antidote solution to the culture medium at different time points (e.g.before organophosphate exposure, during organophosphate exposure, afterorganophosphate exposure).^Incubate the IPSC-derived neurons with the antidote solution for the desired duration(e.g. 5 minutes, 1, 4, 8, and 24 hours).^To measure the efficacy of the antidote, we can use different assays such as: o Cellviability assays (e.g. MTT assay, LDH release assay)^Mitochondrial function assays (e.g. mitochondrial membrane potential assay). Thisassay is particularly relevant for our purpose.^ Oxidative stress assays (e.g. ROS detection assay or glutathione assay) ^Gene expression analysis (e.g. qPCR)4. Compare with existing antidotes:^Prepare a stock solution of the existing antidotes (2-PAM and Obidoxime) at knownconcentrations in suitable solvents (DMSO, ethanol, or water).-30 -FH12004864.1 Attorney Docket No.:PLW-00125 ^Dilute the stock solutions of the existing antidotes in the culture medium to thedesired final concentrations.^Add the diluted solutions of the existing antidotes to the IPSC-derived neurons atdifferent time points (e.g. 5 minutes, 1, 4, 8, and 24 hours).^Incubate the IPSC-derived neurons with the existing antidotes for the desired duration(e.g. 5 minutes, 1, 4, 8, and 24 hours).^Use the same assays as in step 3 to measure the efficacy of the existing antidotes.5. Statistical analysis: ^Analyze the data using ANOVA, t-tests, or, if necessary, Mann-Whitney U test.^Compare the results between the different treatments (e.g. antitoxine molecule, 2-PAM, Obidoxime, and control) and determine the statistical significance of thedifferences.^Repeat the experiments multiple at least 5 times to ensure reproducibility andreliability of the results.INCORPORATION BY REFERENCEAll publications and patents mentioned herein are hereby incorporated by reference intheir entirety as if each individual publication or patent was specifically and individuallyindicated to be incorporated by reference. In case of conflict, the present application, includingany definitions herein, will control.EQUIVALENTSWhile specific embodiments of the subject invention have been discussed, the abovespecification is illustrative and not restrictive. Many variations of the invention will becomeapparent to those skilled in the art upon review of this specification and the claims below.The full scope of the invention should be determined by reference to the claims, along withtheir full scope of equivalents, and the specification, along with such variations.-31 -FH12004864.1

Claims

Attorney Docket No.:PLW-00125 CLAIMSWe claim:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I)wherein each R1 is independently selected from nitro and cyano;m is an integer from 0 to 5;R3 is selected from H and alkyl;X is selected from H, alkyl, heterocyclyl, aryl, cycloalkyl, and heteroaryl; orR3 and X, together with the carbon atom that separates them, complete a 4-6 memberedheterocyclyl or cycloalkyl.

2. The compound of claim 1, wherein m is 1 or 2.

3. The compound of claim 1 or 2, wherein R3 is alkyl.

4. The compound of any one of claims 1-3, wherein R3 and X, together with the carbonatom that separates them, complete a 5-6 membered heterocyclic ring.

5. The compound of any one of claims 1-4, wherein m is 2.

6. The compound of any one of claims 1-5, wherein each instance of R1 is nitro.

7. The compound of claim 5 or 6, having the structure of Formula (IA):Formula (IA).- 32 -FH12004864.1Attorney Docket No.:PLW-00125 8. The compound of claim 1, having the structure of Formula (II):Formula (II)wherein each R2 is selected from alkyl, amino, carbamate, nitro, hydroxyl, alkoxy (e.g.,aralkyloxy), and halo;wherein R3 is aralkyl;X is selected from alkyl, heterocyclyl, aryl, polycyclyl, cycloalkyl, and heteroaryl; andp is an integer from 0-5.

9. The compound of claim 8, wherein R1 is nitro.

10. The compound of claim 8 or 9, having the structure of Formula (IIA):Formula (IIA).

11. The compound of any one of claims 1-8, wherein R1 is cyano.

12. The compound of claim 11, having the structure of Formula (IIB):

13. The compound of any one of claims 1-12, wherein X is phenyl.

14. The compound of any one of claims 1-12, wherein X is heteroaryl.

15. The compound of claim 14, wherein X is selected from thiophenyl, thiazolyl, furanyl,and pyridinyl.

16. The compound of any one of claims 8-15, wherein p is an integer from 0-2.

17. The compound of any one of claims 8-16, wherein R2 is selected from methyl,carbamate, halo, nitro, alkoxy, and alkoxy.-33 -FH12004864.1Attorney Docket No.:PLW-0012518. The compound of any one of claims 8-17, wherein R2 is carbamate.

19. The compound of any one of claims 6-17, wherein R2 is halo.

20. The compound of claim 19, wherein R2 is F.

21. A compound of Formula (I) having a structure selected from:,Molecular Weight: 240.24,Molecular W ht: 236.27,, -34 -FH12004864.1Attorney Docket No.:PLW-00125Molecular Weight: 373.37,A42,Molecular Weight: 344.39 Molecular Weight: 302.29A45,A18,Molecular Weight: 248.26,A17, -35 -FH12004864.1Attorney Docket No.:PLW-00125ecuA3, Molecular Weight: 321.33 ,Molecular Weight: 364.38 Molecular Weight: 266.34A30,A31, and.

22. A compound of Formula (III), or a pharmaceutically acceptable salt thereof:-36 -FH12004864.1Attorney Docket No.:PLW-00125Formula (III)wherein X is a bond or SO2; andR1 and R2 are each independently selected from H, alkyl, aryl, heteroaryl, and cycloalkyl; orR1 and R2, together with the atoms that separate them, complete a 4-8 memberedheterocycloalkyl.

23. The compound of claim 22, wherein X is SO2.

24. The compound of claim 22 or 23, wherein R1 is alkyl.

25. The compound of any one of claims 22-24, wherein R1 is butyl.

26. The compound of any one of claims 22-25, wherein R1 combines with R2 to form a 6-8 membered heterocycloalkyl.

27. The compound of claim 26, wherein the 6-8 membered heterocycloalkyl is substitutedwith an aryl.

28. The compound of claim 22, having the structure of Formula (IV)wherein R1 is selected from aryl, heteroaryl, and cycloalkyl.

29. The compound of claim 28, wherein R1 is aryl.

30. The compound of claim 28 or 29, wherein R1 is phenyl.

31. The compound of claim 28, wherein R1 is cycloalkyl.-37 -FH12004864.1Attorney Docket No.:PLW-0012532. The compound of claim 31, wherein R1 is cyclopropyl.

33. The compound of any one of claims 28-32, wherein R1 is substituted one or moresubstituents selected from halo, nitro, alkyl, and haloalkyl.

34. The compound of any one of claims 22-25 and 28-33, wherein R2 is alkyl.

35. The compound of claim 34, wherein R2 is methyl.

36. The compound of any one of claims 22-25 and 28-33, wherein R2 is aryl.

37. The compound of claim 36, wherein R2 iswherein each R3 is independently selected from nitro, cyano, halo, haloalkyl, and alkyl; andm is an integer from 0-5.

38. The compound of claim 37, wherein R3 is nitro.

39. The compound of claim 37, wherein R3 is cyano.

40. The compound of claim 37, wherein R3 is halo.

41. The compound of claim 40, wherein R3 is bromo.

42. The compound of claim 37, wherein R3 is alkyl.

43. A compound of Formula (IV) having a structure selected from:-38 -FH12004864.1Attorney Docket No.:PLW-00125, ,, ,, ,, , and.

44. A compound of Formula (V), or a pharmaceutically acceptable salt thereof:-39 -FH12004864.1Attorney Docket No.:PLW-00125Formula (V)wherein R1 is H or alkyl; andR2 is selected from aryl, heteroaryl, heterocyclyl, and cycloalkyl; orR1 combines with R2 to complete a 4-6 membered ring.

45. The compound of claim 44, wherein R1 is alkyl.

46. The compound of claim 44 or 45, wherein R1 is methyl.

47. The compound of any one of claims 44-46, wherein the 4-6 membered ring is a 5-6membered ring.

48. The compound of any one of claims 44-47, wherein the 4-6 membered ring is aheterocycle.

49. The compound of any one of claims 44-48, wherein the 4-6 membered ring issubstituted with an alkyl ester.

50. The compound of claim 44, having the structure of Formula (VI):Formula (VI)wherein R2 is selected from, heterocyclyl, aryl, cycloalkyl, and heteroaryl.

51. The compound of claim 50, wherein R2 is a 5 or 6-membered heterocyclyl orheteroaryl.

52. The compound of claim 50, wherein R2 is a 5 or 6-membered cycloalkyl or aryl.

53. The compound of claim 50, wherein R2 is aryl.

54. The compound of claim 53, wherein R2 is phenyl.-40 -FH12004864.1Attorney Docket No.:PLW-00125 55. The compound of claim 50 or 51, wherein R2is heteroaryl.

56. The compound of claim 55, wherein R2is57. The compound of claim 50 or 52, wherein R2 is cycloalkyl.

58. The compound of claim 50, wherein R2 is polycyclic, e.g. bicyclic.

59. The compound of claim 58, wherein R2 is.

60. The compound of any one of claims 50-59, wherein R2 is substituted with alkyl,alkoxy, arylsulfone, nitro, carbamate, OR3CF3or heteroaryl, wherein R3 is aryl.

61. A compound of Formula (V) having a structure selected from:, ,, ,, -41 -FH12004864.1Attorney Docket No.:PLW-00125MoleculBar7Weight: 237.26,Molecular W ht: 281.23,Molecular W ight: 228.25,Molecular ight: 198.23, andMolecular Weight: 209.28B99.

62. A compound of Formula (VII), or pharmaceutically acceptable salt thereof:Formula (VII)wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;R2 is selected from aryl, alkyl, heterocyclyl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; andn is 0-6.-42 -FH12004864.1Attorney Docket No.:PLW-0012563. The compound of claim 62, wherein n is 0.

64. The compound of claim 62 or 63, having the structure of Formula (VIII):Formula (VIII)wherein each R3 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl.mis 0-5.

65. The compound of any one of claims 62-64, having the structure:wherein each R1 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano,alkenyl, and alkynyl;each R2 is independently selected from alkyl, cycloalkyl, halo, alkoxy, nitro, cyano, alkenyl,and alkynyl;-43 -FH12004864.1Attorney Docket No.:PLW-00125n is 0-4; andm is 0-5.

67. The compound of claim 66, wherein each R1 is independently alkyl or cycloalkyl.

68. The compound of claim 66 or 67, wherein each R1 is independently selected frommethyl and cyclopropyl.

69. The compound of any one of claims 66-68, wherein n is 2.

70. The compound of any one of claims 66-69, having the structure of Formula (X):Formula (X).wherein each R3 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, halo,alkoxy, nitro, cyano, alkenyl, and alkynyl; ortwo R3 taken together to form a ring; andp is 1-5.

71. The compound of any one of claims 66-70, having the structure of Formula (XI):Formula (XI).

72. The compound of any one of claims 66-71, wherein each R2 is nitro.

73. The compound of any one of claims 66-72, wherein m is 1.

74. The compound of any one of claims 66-73, having the structure:-44 -FH12004864.1Attorney Docket No.:PLW-00125<sup>.

75. A pharmaceutical composition comprising a compound of any one of claims 1-74 anda pharmaceutically acceptable excipient.

76. A method of treating a subject who has been exposed to an organophosphatecomprising: administering to the subject a compound of any one of claims 1-74.

77. The method of claim 76, wherein the organophosphate is a chemical nerve agent.

78. The method of claim 77, wherein the chemical nerve agent is selected from sarin,soman, tabun and VX.-45 -FH12004864.1