Polyheterocyclic uncharged bisoxime antidotes for organophosphate poisoning and methods for making and using them

Abstract

In alternative embodiments, provided are polyheterocyclic uncharged bisoxime antidotes, including polyheterocyclic uncharged bisoximes, and methods for treating, preventing or ameliorating excessive acetylcholine stimulation in the brain comprising administering to an individual in need thereof a polyheterocyclic uncharged bisoxime antidote as provided herein. In alternative embodiments, provided are methods for treating, preventing or ameliorating excessive acetylcholine stimulation in the brain; or, treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE) comprising administering to an individual in need thereof a polyheterocyclic uncharged bisoxime antidote as provided herein.

Description

[0001] PATENT 0321.153519PCT / SD2024-022

[0002] POLYHETEROCYCLIC UNCHARGED BISOXIME ANTIDOTES FOR ORGANOPHOSPHATE POISONING AND METHODS FOR MAKING AND USING THEM

[0003] RELATED APPLICATIONS

[0004] This Patent Convention Treaty (PCT) International Application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. (USSN) 63 / 684,490, August 19, 2024. The aforementioned application is expressly incorporated herein by reference in its entirety and for all purposes. All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes.

[0005] STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under 1 R21 NS120884- 01 Al and 1 R21 NS120839-01 Al awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.

[0007] TECHNICAL FIELD

[0008] This invention generally relates to antidote chemistry for treatment of organophosphate intoxication. In alternative embodiments, provided are polyheterocyclic uncharged bisoxime antidotes.

[0009] BACKGROUND

[0010] Catalytic activity of hAChE is essential in diaphragm of the peripheral nervous system and in the brain (the central nervous system; CNS). Currently approved antidotes (pralidoxime, obidoxime, asoxime) are all charged pyridinium derivatives that can not reach CNS in order to reactivate brain hAChE. They are effective only in the peripheral nervous system.

[0011] Polyheterocyclic uncharged bisoximes are uncharged molecules that have potential to spontaneously diffuse into CNS and reactivate OP inhibited brain hAChE, in addition to be effective reactivators of the peripheral system hAChE in the diaphragm. Maintaining normal diaphragm function and preventing brain seizures are both related to reactivation of organophosphate (OP) inhibited hAChE and are essential for saving life in OP intoxication. PATENT

[0012] 0321.153519PCT / SD2024-022

[0013] Standard, currently approved pyridinium-based cationic antidotes (pralidoxime, obidoxime, asoxime) are not capable of crossing BBB and reactivating brain AChE. They cannot provide full and fast recovery from the OP intoxication.

[0014] SUMMARY

[0015] In alternative embodiments, provided are compounds having one of the following structures or compositions having one or more compounds of the following structures, or equivalents thereof, or an isomer, optical isomer or a stereoisomer thereof, a racemate or racemic mixture thereof, an enantiomer, an individual diastereomer or a diastereomeric mixture thereof, or an analog thereof, or a crystalline product or crystalline intermediate thereof, or a pharmaceutically acceptable salt thereof, or prodrug thereof, or a bioisostere thereof; or a composition comprising an isolated, substantially isolated or purified compound consisting essentially of, or consisting of:

[0016] (a) the compound having the formula:

[0017] X = N,CH; Y = N,CH; R1 = 0, CH2NH, CH2CH2NH, CH2CH2CH2NH; R2 = 0, CH2NH; CH2CH2NH, CH2CH2CH2NH; R3 = alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, acyl, sulfonyl, lactam, sultam, cyano, hydroxy, halogen. and optionally when fused rings comprise:

[0018] (1) if X=N, Y=N, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l compound TAL 993,

[0019] (2) if X=N, Y=CH, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l-> compound TAL 1025,

[0020] (3) if X=N, Y=CH, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=0, compound TAL 1093, or

[0021] () spirocyclic ring comprises: if X=N, Y=N, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l^ compound TAL 847; or

[0022] (b) a compound having the formula; PATENT

[0023] 0321.153519PCT / SD2024-022

[0024] (also called Tai 847),

[0025] (also called Tai 1025), or

[0026] (4)

[0027] (also called Tai 1093).

[0028] In alternative embodiments, provided are formulations or pharmaceutical compositions comprising a compound or composition as provided herein, wherein optionally the formulation further comprises a pharmaceutically acceptable excipient, PATENT 0321.153519PCT / SD2024-022 and optionally the pharmaceutically acceptable excipient comprises a sterile saline, a sterile buffer and / or a sterile water. In alternative embodiments, the formulation or the pharmaceutical composition is formulated for enteral or parenteral administration. In alternative embodiments, the formulation or pharmaceutical composition is formulated for administration orally, parenterally, by inhalation spray or mist, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or the formulation is a solid, liquid, aerosol, mist, powder or emulsion formulation. In alternative embodiments, the formulation or pharmaceutical composition is formulated as or in or on: a liquid, a powder, an emulsion, a lyophilized powder, a spray, a cream, a lotion, a controlled release formulation, a tablet, a pill, a capsule, a gel, a geltab, a patch, an implants, an applicator stick, a solutions, a suspension, an ointment, a paste, a jelly, a paint, a powder, a mists an aerosol, an elixirs, a syrup, a liposome, a nanoliposome, a nanoparticle or a particle.

[0029] In alternative embodiments, provided are products of manufacture comprising: a compound as provided herein, or a formulation or pharmaceutical composition as provided herein, or a product of manufacture comprising and fabricated or manufactured to deliver to an individual in need thereof: a compound as provided herein, or a formulation or pharmaceutical composition as provided herein. In alternative embodiments, the product of manufacture is fabricated or manufactured as a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising: a compound as provided herein, or a formulation or pharmaceutical composition as provided herein; or, fabricated to deliver to an individual in need thereof a compound as provided herein, or a formulation or pharmaceutical composition as provided herein. In alternative embodiments, the product of manufacture is fabricated or manufactured as a nebulizer or an inhaler comprising: a compound as provided herein, or a formulation or pharmaceutical composition as provided herein; or, fabricated to deliver to an individual in need thereof a compound as provided herein, or a formulation or pharmaceutical composition as provided herein. PATENT 0321.153519PCT / SD2024-022

[0030] In alternative embodiments, provided are methods for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE), comprising: administering to a patient or an individual in need thereof, a compound as provided herein, or a formulation or a pharmaceutical composition as provided herein, or a product of manufacture as provided herein, wherein optionally the compound or formulation is administered enterally or parenterally, wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or administering the compound as provided herein, or a formulation or a pharmaceutical composition as provided herein, using a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi -chambered pump, a syringe, a cartridge or a pen or a jet injector.

[0031] In alternative embodiments of methods as provided herein:

[0032] - the organophosphate (OP) toxicity, poisoning or toxic exposure is caused by exposure of the patient or individual to an alkyl methylphosphonate or related nerve agent, or an alkylphosphorate insecticide, and optionally the organophosphate (OP) is or is a component of a toxin, an herbicide, an insecticide, or a nerve gas or nerve agent, and optionally the organophosphate (OP) is or comprises a parathion, a malathion, a methyl parathion, a chlorpyrifos, a diazinon, a dichlorvos, a phosmet, a fenitrothion, a tetrachlorvinphos, an azamethiphos or an azinphos methyl, or the nerve agent is a soman (O-Pinacolyl methylphosphonofluoridate), a tabun (Ethyl N,N Dimethyl-phosphoramido-cyanidate) or a sarin ((A5)-propan-2-yl methylphosphonofluoridate); and / or,

[0033] - the acetylcholinesterase (AChE) is in the central nerve system (CNS), or the acetylcholinesterase (AChE) is a human acetylcholinesterase (hAChE).

[0034] In alternative embodiments, provided are methods for treating, preventing or PATENT 0321.153519PCT / SD2024-022 ameliorating excessive acetylcholine stimulation in the brain, comprising: administering to a patient or an individual in need thereof, a compound as provided herein, or a formulation or a pharmaceutical composition as provided herein, or a product of manufacture as provided herein, wherein optionally the compound or formulation is administered enterally or parenterally, wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray or mist, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or administering to a patient or an individual in need thereof as set forth a compound as provided herein, or the formulation or a pharmaceutical composition as provided herein, or the product of manufacture as provided herein.

[0035] In alternative embodiments of methods as provided herein, the excessive acetylcholine stimulation in the brain, the CNS or the PNS is caused by a drug, a drug overdose, or a poisoning or a toxic exposure to a drug, and optionally the drug, drug overdose or poisoning causing the excessive acetylcholine stimulation is caused at least in part by a carbamate (wherein optionally the carbamate is or comprises physostigmine or eserine (for example, ANTILIRIUM™), neostigmine (for example, BLOXIVERZ™, PROSTIGMIN™, or VAGOSTIGMIN™), pyridostigmine (for example, MESTINON™), carbaryl, carbaril or 1 -naphthyl methylcarbamate, for example, SEVIN™)); or, an organophosphate agent such as a pesticide or poison (wherein optionally the organophosphate agent is or comprises diisopropyl- fluorophosphate (DFP) or isoflurophate, and / or echothiophate (for example, PHOSPHOLINE IODIDE™ or PHOSPHOLINE™).

[0036] In alternative embodiments, provided are compounds, or a formulation or pharmaceutical composition, or a product of manufacture, for use in: treating, preventing or ameliorating excessive acetylcholine stimulation in the brain; or, treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE), wherein the compounds, or the formulation or pharmaceutical composition, or the product of manufacture thereof are those as provided herein.

[0037] In alternative embodiments, provided are uses of compounds, or a formulation PATENT 0321.153519PCT / SD2024-022 or pharmaceutical composition, or a product of manufacture, for: treating, preventing or ameliorating excessive acetylcholine stimulation in the brain; or, treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE), wherein the compounds, or the formulation or pharmaceutical composition, or the product of manufacture thereof are those as provided herein. The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0038] All publications, patents, patent applications cited herein are hereby expressly incorporated by reference in their entireties for all purposes.

[0039] DESCRIPTION OF DRAWINGS

[0040] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0041] The drawings set forth herein are illustrative of exemplary embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims.

[0042] FIG. 1, FIG. 2, FIG. 3 and FIG. 4 schematically illustrate exemplary synthetic schemes to synthesize compounds as provided herein, as described in detail in Example 1, below.

[0043] FIG. 5 schematically illustrates in vitro reactivation of POX-hAChE by exemplary polyheterocyclic uncharged bisoxime antidotes as provided herein, and their reactivation rate constants compared to the monoheterocyclic bis-oxime LG-703, monoheterocyclic monoxime RS194B and cationic pyridinium -based aldoximes 2PAM and MMB4 are given in the Table 1, as described in detail in Example 2, below.

[0044] FIG. 6 illustrates Table 1, which shows kinetic constants for reactivation of OP-hAChE conjugates, in vitro, by polyheterocyclic bis-oximes (shaded yellow) compared to the monoheterocyclic bis-oxime LG-703, monoheterocyclic monoxime RS194B and cationic pyridinium -based aldoximes 2PAM and MMB4, as described in detail in Example 2, below. PATENT 0321.153519PCT / SD2024-022

[0045] FIG. 7 illustrates Table 2 which shows data from the therapy of OP exposed mice with the exemplary polyheterocyclic uncharged TAL-1025 bis-oxime as provided herein, as described in detail in Example 4, below.

[0046] Like reference symbols in the various drawings indicate like elements.

[0047] DETAILED DESCRIPTION

[0048] In alternative embodiments, provided are polyheterocyclic uncharged bisoxime antidotes. In alternative embodiments, provided is a new class of polyheterocyclic uncharged bisoximes that we designed and synthesized, which can quickly recover activity of organophosphate (OP) inhibited (nerve agent or pesticide OP) human acetylcholinesterase (AChE), in minutes upon poisoning, much more efficiently than existing antidotes in the current use. hAChE is the target enzyme in OP intoxication and its inhibition can be lethal.

[0049] Polyheterocyclic bisoximes are several-fold more effective reactivators of OP inhibited hAChE in vitro than any previously disclosed centrally active antidotes, such as RS194B (described in the PCT / US2014 / 016639) or LG703 (described in the PCT / US2020 / 034051). Consequentially, the recovery is faster and occurs at a lower reactivator dose.

[0050] The novel polyheterocyclic bisoximes as provided herein are uniquely better than approved antidotes under 1) because they have potential for faster and more complete reactivation of OP inhibited hAChE in both peripheral and central nervous system, while standard antidotes cannot access central nervous system.

[0051] Our novel polyheterocyclic bisoximes are uniquely better than monoheterocyclic monoximes and bisoximes listed under 2) and 3) because in vitro they have been demonstrated to act several-fold faster resulting in potential to provide life-saving recovery of hAChE activity in both peripheral and central nervous systems, at a fraction of time and at lower dose, than what monoheterocyclic momoximes and bisoximes can do.

[0052] Because of their inability to cross biological membranes currently approved antidotes have to be administered intramuscularly or intravenously only to organophosphate (OP) intoxicated patients. In contrast, polyheterocyclic bisoximes as provided herein are uncharged and have capacity to diffuse spontaneously across biological membranes and have potential for oral administration. PATENT 0321.153519PCT / SD2024-022

[0053] In alternative embodiments, polyheterocyclic uncharged bisoxime antidotes as provided herein are formulated as tablets, pills, geltabs, capsules, powders and the like. Storage and distribution of antidotes in a solid state (as tablets, pills, geltabs, capsules, powders and the like) simplifies tremendously ability to protect large population of OP- exposed individuals from poisoning due to improved compound stability in a solid state, facile distribution of a pill and simple and quick administration of exposed patients.

[0054] In alternative embodiments, polyheterocyclic bisoxime antidotes as provided herein are uncharged and will cross biological membranes including blood-brain- barrier (BBB) unlike standard pyridinium-based antidotes.

[0055] In alternative embodiments, polyheterocyclic bisoxime antidotes as provided herein are formulated to be given to OP -intoxicated patients either by inhalation, sublingually, intramuscularly, intravenously or as an oral pill.

[0056] Polyheterocyclic bisoximes are uncharged and will cross biological membranes including blood-brain-barrier (BBB) unlike standard pyridinium-based antidotes. They are uncharged but have either three or four ionizable groups. In solution, such as human blood, ionization equilibrium will be established where compound will be either uncharged, have one or two protonated centers or have both one or two protonated centers with two anionic centers. Three forms should be dominant: uncharged, singly protonated and zwitterionic singly protonated with one anionic center. The uncharged form will first cross the BBB, then it will re-equilibrate to form protonated form that will bind to the inhibited molecular target (OP-hAChE). This binding was demonstrated to be better than the monoheterocyclic monoxime or bisoxime binding. In the next step reactive oxime group of the polyheterocyclic bisoxime will attack P atom of OP-hAChE conjugate in significantly more efficient and rapid manner than what was observed for monoheterocyclic monoximes or bisoximes. As a result recovery of catalytic activity of OP inhibited hAChE will be faster and more complete, at a lower antidote dose, compared to all prior art antidotes.

[0057] Because of their inability to cross biological membranes currently approved antidotes have to be administered intramuscularly or intravenously only to organophosphate (OP) intoxicated patients. In contrast, polyheterocyclic bisoximes as provided herein are uncharged and have capacity to diffuse spontaneously across biological membranes and have potential for oral administration. PATENT

[0058] 0321.153519PCT / SD2024-022

[0059] In alternative embodiments, the term “alkyl” refers to a saturated chain containing only carbon atoms, which may be linear or branched. Alkyl groups may be further substituted at any atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Alkyl groups may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, O or S, it may form a double bond to the chain as in a ketone or an oxime. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Alkyl groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkyl groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkyl group size is defined, for example, as C1-6, which refers to the number of atoms in the group. Some non-limitative examples of linear alkyl groups include methyl, ethyl, propyl, butyl, pentyl or hexyl. Some non- limitative examples of branched alkyl groups include isopropyl, isobutyl, ec-butyl, tert-butyl or tert-amyl.

[0060] In alternative embodiments, the term “alkenyl” refers to a fully or partially unsaturated chain containing only carbon atoms, which may be linear or branched, containing at least one carbon-carbon double bond. Alkenyl groups may be further substituted at any atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Alkenyl groups may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the PATENT

[0061] 0321.153519PCT / SD2024-022 heteroatom is N, O or S, it may form a double bond to the chain as in a ketone or an oxime.. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Alkenyl groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the chain or a =CF2 group at the terminus of the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkenyl groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkenyl group size is defined, for example, as C1-6, which refers to the number of atoms in the group. Some non- limitative examples of linear alkenyl groups include vinyl, allyl, allenyl or 2-propenyl. Some non-limitative examples of branched alkyl groups include isopropenyl or methallyl.

[0062] In alternative embodiments, the term “alkynyl” refers to a fully or partially unsaturated chain containing only carbon atoms, which may be linear or branched, containing at least one carbon-carbon triple bond. Alkynyl groups may be further substituted at any atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Alkynyl groups may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, O or S, it may form a double bond to the chain as in a ketone or an oxime. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Alkynyl groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkynyl groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkynyl group size is defined, for example, as C1-6, which refers to the number of atoms in the group. Some non-limitative examples of linear alkynyl groups include ethynyl or propargyl. PATENT

[0063] 0321.153519PCT / SD2024-022

[0064] In alternative embodiments, the term “alkyloxy” refers to a saturated chain containing carbon and oxygen atoms, which may be linear or branched, where the connection to a compound as provided herein is through a carbon-carbon bond. Alkyloxy groups may be further substituted at any oxygen atom independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups, as defined herein, to form an ether. Alkyloxy groups may be further substituted at any oxygen atom independently with an additional acyl or sulfonyl group to form an ester, carbonate, carbamate, sulfonate or sulfamate. Alkyloxy groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a - CF2- group in the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkyloxy groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkyloxy group size is defined, for example, as C1-6, which refers to the number of atoms in the group, and wherein one or more C is replaced independently by O. Some non-limitative examples of alkyloxy groups include methoxymethyl, methoxyethyl, isopropoxymethyl, or hydroxymethyl.

[0065] In alternative embodiments, the term “alkylamino” refers to a saturated chain containing carbon and nitrogen atoms, which may be linear or branched, where the connection to a compound as provided herein is through a carbon-carbon bond. Alkylamino groups may be further substituted at any nitrogen atom independently with one or more additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl groups. Alkylamino groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkylamino groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkylamino groups may contain a nitrogen atom that is part of a ring system, such as a lactam or sultam, as defined herein. Alkylamino group size is defined, for example, as C1-6, which refers to the number of atoms in the group, and wherein one or more C is replaced independently by N. Some non-limitative examples of alkylamino groups include methylmethanamino and aminomethyl. PATENT

[0066] 0321.153519PCT / SD2024-022

[0067] In alternative embodiments, the term “alkylthio” refers to a saturated chain containing carbon and sulfur atoms, which may be linear or branched, where the connection to a compound as provided herein is through a carbon-carbon bond. Alkylthio groups may be further substituted at any sulfur atom independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups, as defined herein, to form a thioether. Alkylthio groups may be further substituted at any sulfur atom independently with an additional acyl group to form a thioester. Alkylthio groups may be oxidized at any sulfur atom independently with one or more O atoms, as a sulfoxide or sulfone. Alkylthio groups may be further substituted at any sulfur atom in the SO2 oxidation state with an additional nitrogen to form a sulfonamide, which may be substituted twice independently at N with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. Alkylthio groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the chain, or tri substituted as in, for example, a -CF3 group at the terminus of the chain. Alkylthio groups may be fused through a single disubstituted atom in the chain to a ring to form a cycloalkyl or heterocycloalkyl structure. Alkylthio group size is defined, for example, as C1-6, which refers to the number of atoms in the group, and wherein one or more C is replaced independently by S. Some non-limitative examples of alkylthio groups include methylthiomethyl and thiomethyl.

[0068] In alternative embodiments, the term “cycloalkyl” refers to a saturated or partially unsaturated ring system containing only carbon atoms in the backbone of the ring. When the cycloalkyl ring is partially unsaturated, it may contain one or more double bonds but is not aromatic. Cycloalkyl rings may be further substituted at any atom independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Cycloalkyl rings may be substituted at any atom independently with exocyclic heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. PATENT

[0069] 0321.153519PCT / SD2024-022

[0070] When the heteroatom is N, O or S, it may form a double bond to the ring as in a ketone or an oxime.. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Cycloalkyl rings may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a -CF2- group in the ring backbone. Cycloalkyl rings may be monocyclic, wherein all of the atoms of the cycloalkyl ring are contained in a single ring, or may be part of a polycyclic ring system containing multiple rings. Cycloalkyl rings may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein, to form a bicyclic ring system. Cycloalkyl rings may be fused through a single disubstituted atom to an additional ring to form a spirocyclic cycloalkyl or heterocycloalkyl structure. Cycloalkyl rings may also contain a bridging structure, which may be 1-2 carbon atoms. Cycloalkyl groups may optionally include multiple ring fusions, spirocyclic fusions or bridged structures, or a combination of these, as part of a larger ring system containing multiple rings. In alternative embodiments, a cycloalkyl ring size is a C3-10, which refers to the number of atoms in the backbone of the ring. Some non-limitative examples of cycloalkyl rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, cyclooctadiene, spiro[3.3]heptane, spiro[4.4]nonane, norbornane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, indane, tetralone.

[0071] In alternative embodiments, the term “heterocycloalkyl” refers to a saturated or partially unsaturated ring system having one or more heteroatoms chosen from N, O or S in the backbone of the ring, where the connection to a compound as provided herein is through a carbon-carbon bond or a carbon-nitrogen bond. When the heterocycloalkyl ring is partially unsaturated, it may contain one or more double bonds but is not aromatic. Heterocycloalkyl rings may be further substituted at any C or N atom independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Heterocycloalkyl rings containing one or more S atom in the ring backbone may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Heterocycloalkyl rings may be lactams or sultams, as defined herein. Heterocycloalkyl rings may be substituted at any atom independently with exocyclic PATENT

[0072] 0321.153519PCT / SD2024-022 heteroatoms chosen from N, O or S, which may be further substituted independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, O or S, it may form a double bond to the ring as in a ketone or an oxime.. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Heterocycloalkyl rings may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a CF2 group in the ring backbone. Heterocycloalkyl rings may be monocyclic, wherein all of the atoms of the heterocycloalkyl ring are contained in a single ring, or may be part of a polycyclic ring system containing multiple rings (Polyheterocyclic rings). Heterocycloalkyl rings may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein, to form a bicyclic polyheterocyclic ring system. Heterocycloalkyl rings may be fused through a single atom to an additional ring to form a spirocyclic bicyclic polyheterocyclic structure. Heterocycloalkyl rings may also contain a bridging structure, which may be 1-2 atoms, to form a bicyclic polyheterocyclic ring system. Heterocycloalkyl groups may optionally include multiple ring fusions, spirocyclic fusions or bridged structures, or a combination of these, as part of a larger polyheterocyclic ring system containing multiple rings. Heterocycloalkyl ring size is defined, for example, as C4-10, which refers to the number of atoms in the ring, and wherein one or more C is replaced independently by a heteroatom. Some non-limitative examples of C4 heterocycloalkyl rings are oxetane, azetidine or P-lactam. Some non-limitative examples of C5 heterocycloalkyl rings are tetrahydrofuran, pyrrolidine, or sulfolane. Some non-limitative examples of Ce heterocycloalkyl rings are tetrahydropyran, piperidine, piperazine, tetrahydrothiopyran or 1,1-dioxo-tetrahydrothiopyran. Some non-limitative examples of C7 heterocycloalkyl rings are hexamethyleneimine, diazepane or oxazepine. Some non-limitative examples of Cs heterocycloalkyl rings are oxocane or heptamethyleneimine.

[0073] In alternative embodiments, the term “phenyl” refers to a benzene ring, which may be substituted independently at any position with additional hydrogen, alkyl, PATENT

[0074] 0321.153519PCT / SD2024-022 alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cyano, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Phenyl groups may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Phenyl groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or I. Phenyl groups may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein. Phenyl groups may optionally include multiple ring fusions, optionally further substituted with spirocyclic fusions or bridged structures, or a combination of these, as part of a larger ring system containing multiple rings. Some non-limitative examples of phenyl groups include benzene, naphthalene, indane or tetrahydronaphthal ene .

[0075] In alternative embodiments, the term “heteroaryl” refers to an aromatic ring system having one or more heteroatoms chosen from N, O or S in the backbone of the ring, where the connection to a compound as provided herein is through a carboncarbon or carbon-nitrogen bond. Heteroaryl rings may be further substituted at any C or N atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cyano, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Heteroaryl groups may be substituted at any carbon atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is O, it may form a double bond to the ring as in a ketone, which may be a tautomer of an OH group. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Heteroaryl groups may be substituted at any atom independently with halogens chosen from F, Cl, Br or PATENT 0321.153519PCT / SD2024-022

[0076] I. Heteroaryl rings may be monocyclic, wherein all of the atoms of the heteroaryl ring are contained in a single ring, or may be part of a bicyclic ring system containing two rings. Heteroaryl groups may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein. Heteroaryl groups may optionally include multiple ring fusions, optionally further substituted with spirocyclic fusions or bridged structures, or a combination of these, as part of a larger ring system containing multiple rings. Some non-limitative examples of heteroaryl groups include pyrrole, imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,2,4-oxadiazole, 1,2,5- oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2, 3 -triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, indole, indazole, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzisoxazole or benzisothi azole.

[0077] In alternative embodiments, the term “acyl” refers to a carbon-oxygen double bond as in a carbonyl. Acyl groups may be further substituted at the carbon atom with alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Acyl groups may be substituted at the carbon atom with heteroatoms chosen from N, O or S, as in, for example, an amide, carbamate, urea, ester, carbonate, thioester, or thiocarbamate, where the heteroatom may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. Some non- limitative examples of acyl groups include acetyl, benzoyl, or acetamido.

[0078] In alternative embodiments, the term “sulfonyl” refers to a sulfur atom substituted with two sulfur-oxygen double bonds, as in SO2. Sulfonyl groups may be further substituted at the sulfur atom with alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Sulfonyl groups may be substituted at the sulfur atom with heteroatoms chosen from N or O, as in, for example, a sulfonamide or sulfonate, where the heteroatom may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or PATENT

[0079] 0321.153519PCT / SD2024-022 heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. Some non-limitative examples of sulfonyl groups include methanesulfonyl, p-toluenesulfonyl, or sulfonamido.

[0080] In alternative embodiments, the term “lactam” refers to a saturated or partially unsaturated ring having at least one N atom in the backbone of the ring, and where at least one carbon in the backbone of the ring is substituted with a double bond to an exocyclic O atom, as in a carbonyl, and where an N atom of the ring is bonded to a carbonyl carbon in the ring as in an amide. Lactam rings may contain one or more additional heteroatoms chosen from N, O or S in the backbone of the ring. When the lactam ring is partially unsaturated, it may contain one or more double bonds but is not aromatic. Lactam rings may be further substituted at any C or N atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Lactam rings containing one or more S atom in the ring backbone may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Lactam rings may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is O, it may form a double bond to the ring as in a ketone. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Lactam rings may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a CF2 group in the ring backbone. Lactam rings may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein. Lactam rings may be monocyclic, wherein all of the atoms of the cycloalkyl ring are contained in a single ring, or may be part of a bicyclic ring system containing two rings. Lactam rings may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as PATENT

[0081] 0321.153519PCT / SD2024-022 defined herein. Lactam rings may be fused through a single atom to an additional ring to form a spirocyclic structure. Lactam rings may also contain a bridging structure, which may be 1-2 atoms. Lactam ring size is defined, for example, as C4-10, which refers to the number of atoms in the ring, and wherein one or more C is replaced independently by a heteroatom. Some non-limitative examples of lactams include 2- azetidinone, 2-pyrrolidinone and 3-morpholinone.

[0082] In alternative embodiments, the term “sultam” refers to a saturated or partially unsaturated ring having at least one N atom and at least one S atom in the backbone of the ring, and where at least one S atom in the backbone of the ring is substituted with double bonds to two exocyclic O atom, as in a sulfonyl group, and where an N atom of the ring is bonded to a sulfonyl sulfur in the ring as in a sulfonamide. Sultam rings may contain one or more additional heteroatoms chosen from N, O or S in the backbone of the ring. When the sultam ring is partially unsaturated, it may contain one or more double bonds but is not aromatic. Sultam rings may be further substituted at any C or N atom independently with additional alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups as defined herein. Sultam rings containing one or more additional S atoms in the ring backbone may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Sultam rings may be substituted at any atom independently with heteroatoms chosen from N, O or S, which may be further substituted independently with additional hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N, it may be substituted twice independently with hydrogen, alkyl, alkyloxy, alkylamino, alkylthio, acyl, sulfonyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl groups. When the heteroatom is N or O, it may form a double bond to the ring as in a ketone or an oxime. When the heteroatom is S, it may be oxidized at S with one or more O atoms, as a sulfoxide or sulfone. Sultam rings may be substituted at any atom independently with halogens chosen from F, Cl, Br or I, and may be disubstituted as in, for example, a CF2 group in the ring backbone. Sultam rings may be monocyclic, wherein all of the atoms of the cycloalkyl ring are contained in a single ring, or may be part of a bicyclic ring system containing two rings. Sultam rings may be fused through two adjacent atoms to an additional ring, which may be substituted cycloalkyl, heterocycloalkyl, phenyl or heteroaryl as defined herein. Sultam rings may be fused through a single PATENT 0321.153519PCT / SD2024-022 atom to an additional ring to form a spirocyclic structure. Sultam rings may also contain a bridging structure, which may be 1-2 atoms. Sultam ring size is defined, for example, as C4-10, which refers to the number of atoms in the ring, and wherein two or more C are replaced independently by a heteroatom. Some non-limitative examples of sultams include 1,3-propanesultam or 1,2-thiazinane 1,1 -di oxide.

[0083] In alternative embodiments, the term “cyano” refers to a carbon-nitrogen triple bond, where the connection to a compound as provided herein is through a carboncarbon bond.

[0084] In alternative embodiments, the term “halogen” refers to the atoms fluorine, chlorine, bromine or iodine. In alternative embodiments, the term “hydroxy” refers to an oxygen atom substituted with a hydrogen atom, as in an alcohol or a phenol. A hydroxy group attached to an atom adjacent to another heteroatom may exist as the keto tautomer.

[0085] Bioisosteres of Compounds

[0086] In alternative embodiments, provided are bioisosteres of compounds as provided herein. In alternative embodiments, bioisosteres as provided herein are compounds as provided herein comprising one or more substituent and / or group replacements with a substituent and / or group having substantially similar physical or chemical properties which produce substantially similar biological properties to a compound as provided herein, or stereoisomer, racemate or isomer thereof. In one embodiment, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structures.

[0087] For example, in one embodiment, bioisosteres as provided herein are made by replacing one or more hydrogen atom(s) with one or more fluorine atom(s), for example, at a site of metabolic oxidation; this may prevent metabolism (catabolism) from taking place. Because the fluorine atom is only slightly larger than the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the molecule may have a longer half-life or be less toxic, and the like. PATENT

[0088] 0321.153519PCT / SD2024-022

[0089] Products of manufacture and Kits

[0090] Also provided are products of manufacture and kits for practicing the methods as provided herein. In alternative embodiments, provided are products of manufacture and kits comprising all the components needed to practice a method as provided herein.

[0091] Provided are kits comprising compositions and / or instructions for practicing methods as provided herein. In alternative embodiments, provided are kits comprising: a composition used to practice a method as provided herein, optionally comprising instructions for use thereof.

[0092] In alternative embodiments, provided are pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion device, infusion pens, needles, reservoirs, ampoules, vials, syringes, cartridges, disposable pen or jet injectors, prefilled pens or syringes or cartridges, cartridge or disposable pen or jet injectors, two chambered or multi-chambered pumps, syringes, cartridges or pens or jet injectors comprising a composition or a formulation as provided herein. In alternative embodiments, the injector is an autoinjector, for example, a SMARTJECT® autoinjector (Janssen Research and Development LLC); or a MOLLY®, or DAI®, or DALRNS® autoinjector (SHL Group, Deerfield Beach, FL). In alternative embodiments, the injector is a hypodermic or a piston syringe.

[0093] Hand-Held or Portable Devices

[0094] In alternative embodiments, provided are products of manufacture fabricated or manufactured as a portable, for example, hand-held (or worn around the neck), medical device, for example, an inhaler, a nebulizer (for example, an asthma-type nebulizer), comprising, or for administering, a composition or a formulation as provided herein, where in alternative embodiments the product of manufacture administers an inhalation product (for example, powder, mist, any liquid spray) comprising a composition or a formulation as provided herein.

[0095] As discussed above, in alternative embodiments, the portable or hand-held medical device comprises a cassette, packette, interchangeable disk (for example, for holding a powder) or reservoir (optionally a refillable reservoir) in or on the product of manufacture, or a removable cassette or packette, interchangeable disk (for example, for holding a powder) that can be inserted into a slot or port on the product of manufacture, or a separate reservoir or container operatively linked or joined to the PATENT

[0096] 0321.153519PCT / SD2024-022 product of manufacture, that comprises a composition or a formulation as provided herein for inhalation delivery to a user.

[0097] In alternative embodiments, a product of manufacture, for example, a medical device, as provided herein for inhalation delivery of a composition or a formulation as provided herein to a user is fabricated as a meter-dose inhaler (MDI) (either open or closed mouth MDI), which can comprise a pressurized canister of the drug or medication in a plastic case with a mouthpiece, and a holding chamber having a plastic tube with a mouthpiece, a valve to control mist delivery and a soft sealed end to hold the MDI; the holding chamber can assist delivery of the drug or medication to the nose and / or lungs, for example, as an AEROCHAMBER™ device. In alternative embodiments, the inhaler or nebulizer is breath activated, for example, as an REDIHALER™ device.

[0098] In alternative embodiments, a product of manufacture, for example, a medical device, as provided herein for inhalation delivery of a composition or a formulation as provided herein to a user is fabricated a dry powder inhaler (such as a dry powder disk inhaler, for example, as a DISKUS™ device), optionally having a dose counter window so user can see how many doses are left), for example, where the powder is dose dispensed by (using) a disposable, refillable or replaceable cassette, packette or disk; and the dry powder dispensing can be breath activated, for example, as an AEROLIZER™, FLEXHALER™, PRESS AIR™, DISKUS™, HANDIHALER™, TWISTHALER™, ELLIPTA™, NEOHALER™, RESPICLICK™, ROTAHALER™ or TUBUHALER™ device.

[0099] In alternative embodiments, provided is a product of manufacture, for example, a medical device, for inhalation delivery of a composition or a formulation as provided herein to a user is fabricated a nebulizer or soft mist inhaler, which can comprise a nebulizer delivery system comprising a nebulizer (for example, a small plastic bowl with a screw-top lid) and a source for compressed air to generate a mist comprising the drug or medication, which also can be dose dispensed using a disposable, refillable or replaceable cassette, packette or disk.

[0100] Formulations and pharmaceutical compositions

[0101] In alternative embodiments, provided are compounds and compositions, including formulations and pharmaceutical compositions, for use in in vivo, in vitro or ex vivo methods for catalyzing the hydrolysis of organophosphate (OP)-inhibited PATENT 0321.153519PCT / SD2024-022 human acetylcholinesterase (hAChE) in the central nerve system (CNS); or, for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE); or, for treating, preventing or ameliorating excessive acetylcholine stimulation in the CNS, or the brain.

[0102] In alternative embodiments, the pharmaceutical compositions as provided herein can be administered parenterally, topically, orally or by local administration, such as by aerosol, mist or transdermally. In alternative embodiments, pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, capsules, suspensions, taken orally, suppositories and salves, lotions and the like. Pharmaceutical formulations as provided herein may comprise one or more diluents, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, lyophilized powders, sprays, creams, lotions, controlled release formulations, tablets, pills, gels, geltabs, on patches, in implants, etc. The pharmaceutical compounds can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, mists and aerosols. Oral carriers can be elixirs, syrups, capsules, tablets, pills, geltabs and the like.

[0103] In alternative embodiment, compositions as provided herein are delivered orally, for example, as pharmaceutical formulations for oral administration, and can be formulated using pharmaceutically acceptable carriers well known in the art in appropriate and suitable dosages. Such carriers enable the pharmaceuticals to be formulated in unit dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Pharmaceutical preparations for oral use can be formulated as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein fillers include, for example, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl- cellulose, or sodium carboxy -methylcellulose; and gums including arabic and tragacanth; and proteins, for example, gelatin and collagen. Disintegrating or PATENT

[0104] 0321.153519PCT / SD2024-022 solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0105] In alternative embodiments, liquid carriers are used to manufacture or formulate compounds as provided herein, or a composition used to practice the methods as provided herein, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient (for example, a composition as provided herein) can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can comprise other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.

[0106] In alternative embodiments, solid carriers are used to manufacture or formulate compounds as provided herein, or a composition used to practice the methods as provided herein, including solid carriers comprising substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (for example, povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound PATENT

[0107] 0321.153519PCT / SD2024-022 moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0108] In alternative embodiments, concentrations of therapeutically active compound in a formulation can be from between about 0.1% to about 100% by weight.

[0109] In alternative embodiments, therapeutic formulations are prepared by any method well known in the art, for example, as described by Brunton et al., eds., Goodman and Gilman's: The Pharmacological Bases of Therapeutics , 12th ed., McGraw-Hill, 2011; Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000; Avis et al., eds., Pharmaceutical Dosage Forms: Parenteral Medications, published by Marcel Dekker, Inc., N.Y., 1993; Lieberman et al., eds., Pharmaceutical Dosage Forms: Tablets, published by Marcel Dekker, Inc., N.Y., 1990; and Lieberman et al., eds., Pharmaceutical Dosage Forms: Disperse Systems, published by Marcel Dekker, Inc., N.Y., 1990.

[0110] In alternative embodiments, therapeutic formulations are delivered by any effective means appropriated for a particular treatment. For example, depending on the specific antitumor agent to be administered, the suitable means include oral, rectal, vaginal, nasal, pulmonary administration, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) infusion into the bloodstream. For parenteral administration, compounds as provided herein may be formulated in a variety of ways. Aqueous solutions of the modulators can be encapsulated in polymeric beads, liposomes, nanoparticles or other injectable depot formulations known to those of skill in the art. In alternative embodiments, compounds as provided herein are administered encapsulated in liposomes (see below). In alternative embodiments, depending upon solubility, compositions are present both in an aqueous layer and in a lipidic layer, for example, a liposomic suspension. In alternative embodiments, a hydrophobic layer comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surfactants such a diacetylphosphate, stearylamine, or phosphatidic acid, and / or other materials of a hydrophobic nature. PATENT

[0111] 0321.153519PCT / SD2024-022

[0112] The pharmaceutical compositions can be formulated in any way and can be administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general medical condition of each patient, the resulting preferred method of administration and the like. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co., Easton PA (“Remington’s”). For example, in alternative embodiments, these compositions as provided herein are formulated in a buffer, in a saline solution, in a powder, an emulsion, in a vesicle, in a liposome, in a nanoparticle, in a nanolipoparticle and the like. In alternative embodiments, the compositions can be formulated in any way and can be applied in a variety of concentrations and forms depending on the desired in vivo, in vitro or ex vivo conditions, a desired in vivo, in vitro or ex vivo method of administration and the like. Details on techniques for in vivo, in vitro or ex vivo formulations and administrations are well described in the scientific and patent literature. Formulations and / or carriers can be in forms such as tablets, pills, powders, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for in vivo, in vitro or ex vivo applications.

[0113] Compounds (for example, formulations) as provided herein can comprise a solution of compositions (for example, apratoxin F and apratoxin G compounds, and / or apratoxin F and apratoxin G stereoisomers, derivatives and analogs) disposed in or dissolved in a pharmaceutically acceptable carrier, for example, acceptable vehicles and solvents that can be employed include water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can be employed as a solvent or suspending medium. For this purpose any fixed oil can be employed including synthetic mono- or diglycerides, or fatty acids such as oleic acid. In one embodiment, solutions and formulations are sterile and can be manufactured to be generally free of undesirable matter. In one embodiment, these solutions and formulations are sterilized by conventional, well known sterilization techniques.

[0114] The solutions and formulations can comprise auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and can be selected primarily based on PATENT 0321.153519PCT / SD2024-022 fluid volumes, viscosities and the like, in accordance with the particular mode of in vivo, in vitro or ex vivo administration selected and the desired results.

[0115] The compositions and formulations as provided herein can be delivered by the use of liposomes. In alternative embodiments, by using liposomes, particularly where the liposome surface carries ligands specific for target cells or organs, or are otherwise preferentially directed to a specific tissue or organ type, one can focus the delivery of the active agent into a target cells in an in vivo, in vitro or ex vivo application.

[0116] The compositions and formulations as provided herein can be directly administered, for example, under sterile conditions, to an individual (for example, a patient) to be treated. The modulators can be administered alone or as the active ingredient of a pharmaceutical composition. Compositions and formulations as provided herein can be combined with or used in association with other therapeutic agents. For example, an individual may be treated concurrently with conventional therapeutic agents.

[0117] Nanoparticles, Nanolipoparticles and Liposomes

[0118] Also provided are nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds and compositions used to practice the methods as provided herein, for example, methods for catalyzing the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS); or, for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE); or, for treating, preventing or ameliorating excessive acetylcholine stimulation in the CNS, or the brain.

[0119] Also provided are multilayered liposomes comprising compounds, for example, as described in Park, et al., U.S. Pat. Pub. No. 20070082042. The multilayered liposomes can be prepared using a mixture of oil-phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition as provided herein.

[0120] Liposomes can be made using any method, for example, as described in Park, et al., U.S. Pat. Pub. No. 20070042031, including method of producing a liposome by PATENT 0321.153519PCT / SD2024-022 encapsulating an active agent as provided herein, the method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution with the organic lipid solution in a first mixing region to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution.

[0121] In one embodiment, liposome compositions comprise a substituted ammonium and / or polyanions, for example, for targeting delivery of a compound as provided herein to a desired cell type or organ, for example, brain, as described for example, in U.S. Pat. Pub. No. 20070110798.

[0122] Also provided are nanoparticles comprising compounds as provided herein in the form of active agent-containing nanoparticles (for example, a secondary nanoparticle), as described, for example, in U.S. Pat. Pub. No. 20070077286. In one embodiment, provided are nanoparticles comprising a fat-soluble active agent as provided herein or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt.

[0123] In one embodiment, solid lipid suspensions can be used to formulate and to deliver compositions as provided herein to mammalian cells in vivo, in vitro or ex vivo, as described, for example, in U.S. Pat. Pub. No. 20050136121.

[0124] Delivery vehicles

[0125] In alternative embodiments, any delivery vehicle can be used to practice the methods or used, for example, to deliver compositions as provided herein to mammalian cells in vivo, in vitro or ex vivo. For example, delivery vehicles comprising polycations, cationic polymers and / or cationic peptides, such as polyethyleneimine derivatives, can be used for example as described, for example, in U.S. Pat. Pub. No. 20060083737.

[0126] In one embodiment, a dried polypeptide-surfactant complex is used to formulate a composition as provided herein, for example as described, for example, in U.S. Pat. Pub. No. 20040151766.

[0127] In one embodiment, a composition can be applied to cells using vehicles with cell membrane-permeant peptide conjugates, for example, as described in U.S. Patent Nos. 7,306,783; 6,589,503. In one aspect, the composition to be delivered is PATENT 0321.153519PCT / SD2024-022 conjugated to a cell membrane-permeant peptide. In one embodiment, the composition to be delivered and / or the delivery vehicle are conjugated to a transportmediating peptide, for example, as described in U.S. Patent No. 5,846,743, describing transport-mediating peptides that are highly basic and bind to poly-phosphoinositides.

[0128] In one embodiment, electro-permeabilization is used as a primary or adjunctive means to deliver the composition to a cell, for example, using any electroporation system as described for example in U.S. Patent Nos. 7,109,034; 6,261,815; 5,874,268.

[0129] Dosaging

[0130] The pharmaceutical compositions and formulations as provided herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, compositions are administered to a subject already exposed to a toxin, or exposed to any agent or chemical causing or resulting in excessive acetylcholine stimulation in the brain, for example, exposure to a drug, a drug overdose, or a poisoning or a toxic exposure to a drug, and optionally the drug overdose causing the excessive acetylcholine stimulation is caused at least in part by: physostigmine, neostigmine, pyridostigmine, diisopropylfluorophosphate, or echothiophate an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of the agent and / or its complications (a “therapeutically effective amount”).

[0131] The amount of pharmaceutical composition adequate to accomplish this is defined as a "therapeutically effective dose." The dosage schedule and amounts effective for this use, i.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient’s physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration.

[0132] The dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents’ rate of absorption, bioavailability, metabolism, clearance, and the like (see, for example, Hidalgo- Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51 :337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84: 1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24: 103-108; the latest Remington’s, supra). The state of the PATENT 0321.153519PCT / SD2024-022 art allows the clinician to determine the dosage regimen for each individual patient, active agent and disease or condition treated. Guidelines provided for similar compositions used as pharmaceuticals can be used as guidance to determine the dosage regiment, i.e., dose schedule and dosage levels, administered practicing the methods as provided herein are correct and appropriate.

[0133] Any of the above aspects and embodiments can be combined with any other aspect or embodiment as disclosed here in the Summary, Figures and / or Detailed Description sections.

[0134] As used in this specification and the claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0135] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”.

[0136] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About (use of the term “about”) can be understood as within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12% 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

[0137] Unless specifically stated or obvious from context, as used herein, the terms “substantially all”, “substantially most of’, “substantially all of’ or “majority of’ encompass at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%, or more of a referenced amount of a composition.

[0138] The entirety of each patent, patent application, publication and document referenced herein hereby is incorporated by reference. Citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Incorporation by reference of these documents, standing alone, should not be construed as an assertion or admission that any portion of the contents of any document is considered to be essential material for satisfying any national or regional statutory disclosure requirement for patent applications. Notwithstanding, the right is reserved for relying upon any of such PATENT 0321.153519PCT / SD2024-022 documents, where appropriate, for providing material deemed essential to the claimed subject matter by an examining authority or court.

[0139] Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of, and "consisting of' may be replaced with either of the other two terms. Thus, the terms and expressions which have been employed are used as terms of description and not of limitation, equivalents of the features shown and described, or portions thereof, are not excluded, and it is recognized that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

[0140] The invention will be further described with reference to the examples described herein; however, it is to be understood that the invention is not limited to such examples.

[0141] EXAMPLES

[0142] Example 1 : Exemplary compositions

[0143] This example described making and using exemplary compositions as provided herin.

[0144] A set of three polyheterocyclic uncharged bisoxime antidotes selected for synthesis and further in vitro functional evaluation based on computational in silico docking study of six selected candidates from the set of 51 initially proposed heterocyclic compounds. Structures of the three antidotes were a new structural class, described herein as "polyheterocyclic uncharged bisoxime antidotes".

[0145] In alternative embodiments, provided are synthetic schemes to synthesize compounds as provided herein, wherein the synthetic schemes are set forth in FIG. 1, FIG. 2, FIG. 3 and FIG. 4. PATENT 0321.153519PCT / SD2024-022

[0146] For the synthetic schemes are set forth in FIG. 1, FIG. 2, FIG. 3 and FIG. 4, reagents and reaction conditions comprise: (a) BrCH2CN, ACN, 60°C, 4h; (b) LiALH4, THF, 60°C, 4h; (c) ethyl (E)-2-(hydroxyimino)acetate, EtOH, 90°C, 72h; (d) diethyl (cyanomethyl)phosphonate, NaH, THF, 0 to 20°C, 4h; (e) i. H2, Pd / C, MeOH, rt, 6h; ii. HC1, MeOH, rt, 3h.

[0147] Synthetic Schemes for Making Exemplary Compounds

[0148] General procedure A (Alkylation reaction) To a solution of amine or amine hydrochloride (1 equiv (equivalents)) in ACN (0.2 M) was added successively bromoacetonitrile (1.1 equiv or 2.2 equiv) and potassium carbonate (2.5 equiv or 4.5 equiv) and the mixture was heated to 60 °C for 4 hrs. The reaction mixture was then concentrated under reduced pressure and the solid residue redissolved in water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic fractions were washed with brine 2X, dried and concentrated under reduced pressure. Purification over flash chromatography (Hexanes / EtOAc or DCM / MeOH) provided the desired compounds as clear oils.

[0149] General procedure B (LiAHB reduction) To a solution of Lithium aluminium hydride (4 equiv) in dry THF (0.1 M) was added a solution of the dicyano derivative (1 equiv) in dry THF (0.1 M) at r.t. and the mixture was heated to 90 °C for 4 hrs. The reaction was quenched at r.t. with water (2 equiv) and a 10% NaOH solution (6 equiv). The white solid was filtered off, rinced with THF and the filtrate was concentrated under reduced pressure. The crude was purified over silica (DCM / MeOH : 90 / 10-75 / 25 to DCM / Me0H / NH40H 70 / 20 / 10) to furnish the bis-primary amines as yellow oils.

[0150] General procedure C (Acylation reaction) To a solution of the desired bis-primary amine (1 equiv) in absolute EtOH (0.1 M) was added a solution of ethyl (E)-2- (hydroxyimino)acetate (2.5 equiv) and the mixture was heated to 90 °C for 72 hrs. It was then concentrated under reduced pressure. Purification over silica (DCM / MeOH : 90 / 10 to 70 / 30) furnished the desired bis oxime as a white solid after trituration in cold MeOH.

[0151] General procedure D (Horner-Emmons-Wadsworth reaction) To a solution of diethyl cyanomethylphosphonate (1.3 equiv) in dry THF (0.1 M) was added sodium hydride (60% in oil, 1.2 equiv) portionwise. The mixture was stirred at r.t. for 15 min before the desired ketone (1 equiv) was added and the reaction stirred at r.t. for 3 hrs. The reaction was then quenched with water. The aqueous layer was extracted with EtOAc PATENT 0321.153519PCT / SD2024-022 twice and the combined organic fractions were washed with brine, dried and concentrated under reduced pressure. Purification over silica (Hexanes / EtOAc : 98 / 2 to 85 / 15) provided the desired unsaturated cyano derivative as a colorless oil.

[0152] General procedure E (Hydrogenation andBoc deprotection) To a solution of the desired unsaturated cyano derivative (1 equiv) in MeOH (0.1 M) under N2 was added palladium on carbon (10% Wt, 0.1 equiv) and the solution was backfilled three times with hydrogen. The mixture was stirred at r.t. for 6 hrs before it was put back under N2, then filtered over Celite and rinced with MeOH. The filtrate was then concentrated to furnish the desired saturated cyano derivatives a pale-yellow oil which were dissolved in MeOH (0.1 M) before addition of a 4M HC1 solution in 1,4- dioxane (15 equiv). The mixture was stirred at r.t. for 3 hrs before it was concentrated under reduced pressure and precipitated out of DCM / Hexanes to furnish the desired amine hydrochloride as a light brown solid was used in the next step without further purification.

[0153] 2,2'-(2,6-diazaspiro [3.4] octane-2, 6-diyl)diacetonitrile 6 Following general procedure A using 5 (0.235 g, 1.350 mmol), bromoacetonitrile (0.226 mL, 0.389 g, 3.240 mmol) and potassium carbonate (0.840 g, 6.081 mmol). Purification on silica (DCM / MeOH : 99 / 1) furnished 6 (0.110 g, 0.578 mmol, 43%) as a light yellow oil. 'H NMR (600 MHz, CDCh) 5 3.62 (s, 2H), 3.43 (s, 2H), 3.37 (d, J= 7.2 Hz, 2H), 3.30 (d, J= 7.1 Hz, 2H), 2.85 (s, 2H), 2.68 (t, J= 7.1 Hz, 2H), 2.06 (t, J= 7.1 Hz, 2H) ppm.13C NMR (150 MHz, CDCh) 5 114.96, 114.85, 64.35, 62.73, 51.54, 44.17, 41.88, 40.87, 36.41 ppm. LCMS : [M + H]+, 191.

[0154] 2,2'-(2,6-diazaspiro[3.4]octane-2,6-diyl)6 / s(ethan-l-amine) 7 Following general procedure B using 6 (0.100 g, 0.526 mmol) and a LiAlH4 solution in THF (0.604 mL, 4 M, 0.092 g, 2.418 mmol). Purification on silica furnished 7 (0.052 g, 0.262 mmol, 50%) as a light yellow oil. 'H NMR (600 MHz, MeOD) 5 3.29 (d, J= 7.5 Hz, 2H), 3.21 (d, J= 7.5 Hz, 2H), 2.84 - 2.69 (m, 4H), 2.62 (t, J= 6.7 Hz, 2H), 2.60 - 2.52 (m, 6H), 2.04 (t, J= 7.2 Hz, 2H) ppm. LCMS : [M + H]+, 199.

[0155] (2 / / .27 / )-.\..\'-((2.6-diazaspiro|3.4|octane-2.6-diyl) / n’v(ethane-2.1-diyl)) / u’v(2- (hydroxyimino)acetamide) 1 Following general procedure C using 7 (0.050 g, 0.252 mmol) and ethyl (£)-2-(hydroxyimino)acetate (0.074 g, 0.630 mmol). Purification on silica furnished 1 (0.018 g, 0.053 mmol, 21%) as a white solid after trituration in cold MeOH. ‘HNMR (600 MHz, DMSO) 5 8.11 - 7.85 (m, 2H), 7.43 (s, 1H), 7.42 (s, PATENT

[0156] 0321.153519PCT / SD2024-022

[0157] 1H), 3.22 (q, J = 6.4 Hz, 2H), 3.13 - 2.88 (m, 6H), 2.45 - 2.39 (m, 8H), 1.89 - 1.80 (m, 2H) ppm. HRMS (ES+) calcd for C14H24N6O4 [M + H]+, 341.1932; found 341.1933.

[0158] 2.2'-(tetraliydropyrrolo|3.4-c|pyrrole-2.5( l / / .3 / / )-diyl)diacetonitrile 9 Following general procedure A using 8 (0.500 g, 4.46 mmol), bromoacetonitrile (683 uL, 1.180 g, 9.81 mmol) and potassium carbonate (1.540 g, 11.100 mmol). Purification on silica (Hexanes / EtOAc : 70 / 30 to 0 / 100) furnished 9 (0.765 g, 4.020 mmol, 90%) as a light yellow oil. 'H NMR (600 MHz, CDCh) 5 3.66 (s, 4H), 2.88 - 2.64 (m, 6H), 2.54 (dd, J= 8.9, 2.7 Hz, 4H) ppm.13C NMR (150 MHz, CDCh) 5 114.69, 58.29, 42.22, 41.52 ppm. LCMS : [M + H]+, 191.

[0159] 2,2'-(tetrahydropyrrolo[3,4-c]pyrrole-2,5( l / / .3 / / )-diyl) / nv(ethan-l -amine) 10

[0160] Following general procedure B using 9 (0.750 g, 3.942 mmol) and a LiAlH4 solution in THF (3.940 mL, 4 M, 0.598 g, 15.770 mmol). Purification on silica furnished 10 (0.382 g, 1.926 mmol, 49%) as a light yellow oil. 'H NMR (600 MHz, MeOD) 5 2.76 (t, J= 6.8 Hz, 4H), 2.75 - 2.70 (m, 2H), 2.70 - 2.63 (m, 4H), 2.53 (t, J= 6.8 Hz, 4H), 2.42 (dd, J= 9.4, 3.6 Hz, 4H) ppm.13C NMR (150 MHz, MeOD) 5 60.86, 58.46, 42.85, 40.73 ppm. LCMS : [M + H]+, 199.

[0161] (2 / / .27 / )-\.\'-((tetraliydropyrrolo|3.4-c|pyrrole-2.5( l / / .3 / / )-diyl) / u’v(ethane-2.1- diyl)) / s(2-(hydroxyimino)acetamide) 2 Following general procedure C using 10 (0.250 g, 1.261 mmol) and ethyl (E)-2-(hydroxyimino)acetate (0.369 g, 3.152 mmol). Purification on silica furnished 2 (0.085 g, 0.250 mmol, 20%) as a white solid after trituration in cold MeOH. ‘HNMR (600 MHz, MeOD) 5 7.45 (s, 2H), 3.45 (t, J= 6.5 Hz, 4H), 2.92 - 2.47 (m, 14H) ppm.13C NMR (150 MHz, MeOD) 5 165.30, 144.00, 60.77, 55.11, 42.38, 38.55 ppm. LCMS : [M - H]+, 339. terf-butyl 5-(cyanomethylene)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate 12 Following general procedure D using 11 (1.000 g, 4.539 mmol), NaH (60%, 0.213 g, 5.326 mmol) and diethyl cyanomethylphosphonate (0.934 mL, 1.022 g, 5.770 mmol). Purification on silica furnished 12 (1.054 g, 4.224 mmol, 96%) as a colorless oil.XH NMR (600 MHz, CDCh) 5 5.41 - 5.15 (m, 1H), 3.56 (s, 2H), 3.26 - 2.96 (m, 2H), 2.93 - 2.67 (m, 4H), 2.62 - 2.47 (m, 1H), 2.46 - 2.33 (m, 1H), 1.45 (s, 9H) ppm.13C NMR (150 MHz, CDCh) 5 171.74, 154.61, 116.89, 92.83, 79.68, 38.47, 37.69, 28.62 ppm. LCMS : [M + H]+, 249. PATENT

[0162] 0321.153519PCT / SD2024-022

[0163] 2-(octahydrocyclopenta[c]pyrrol-5-yl)acetonitrile hydrochloride 13 Following general procedure E using 12 (1.044 g, 4.204 mmol), Pd / C (10% wt., 0.447 g, 0.420 mmol), then HC1 in 1,4-dioxane (4 M, 15.730 mL, 2.294 g, 62.91 mmol) furnished 13 (0.780 g, 4.178 mmol, 99%) as a light brown solid after precipitation. LCMS : [M + H]+, 149.

[0164] 2,2'-(hexahydrocyclopenta[c]pyrrole-2,5(lH)-diyl)diacetonitrile 14 Following general procedure A using 13 (0.674 g, 3.610 mmol), bromoacetonitrile (0.277 mL, 0.476 g, 3.972 mmol) and potassium carbonate (1.247 g, 9.026 mmol). Purification on silica (HexanesZEtOAc : 70 / 30 to 0 / 100) furnished 14 (0.352 g, 1.860 mmol, 52%) as a light yellow oil. 'H NMR (600 MHz, CDCh) 5 3.61 (s, 2H), 2.87 - 2.71 (m, 4H), 2.50 - 2.38 (m, 1H), 2.41 - 2.36 (m, 2H), 2.36 (d, J= 6.6 Hz, 2H), 1.74 (dd, J= 12.8, 6.0 Hz, 2H), 1.60 - 1.52 (m, 2H) ppm.13C NMR (150 MHz, CDCh) 5 118.94, 114.65, 60.17, 42.07, 41.65, 38.92, 35.77, 21.60 ppm. LCMS : [M + H]+, 190.

[0165] 2,2'-(hexahydrocyclopenta[c]pyrrole-2,5(lET)-diyl)6 / s(ethan-l-amine) 15

[0166] Following general procedure B using 14 (0.150 g, 0.793 mmol) and a LiAlH4 solution in THF (0.793 mL, 4 M, 0.120 g, 3.117 mmol). Purification on silica furnished 15 (0.105 g, 0.532 mmol, 67%) as a light yellow oil. 'H NMR (600 MHz, MeOD) 5 2.74 (t, J= 6.9 Hz, 2H), 2.67 - 2.60 (m, 2H), 2.59 - 2.42 (m, 6H), 2.37 (dd, J= 9.0, 6.5 Hz, 2H), 2.05 (dt, J= 13.4, 6.7 Hz, 2H), 1.86 - 1.73 (m, 1H), 1.53 (q, J= 7.3 Hz, 2H), 0.99 (q, J= 11.4 Hz, 2H) ppm. LCMS : [M + H]+, 198.

[0167] (2£',2'£)-A^V-((hexahydrocyclopenta[c]pyrrole-2,5(lEr)-diyl)6 / s(ethane-2,l- diyl))6 / s(2-(hydroxyimino)acetamide) 3 Following general procedure C using 15 (0.098 g, 0.497 mmol) and ethyl (£)-2-(hydroxyimino)acetate (0.145 g, 1.240 mmol). Purification on silica furnished 3 (0.038 g, 0.112 mmol, 23%) as a white solid after trituration in cold MeOH. *HNMR (600 MHz, MeOD) 5 7.43 (s, 2H), 3.45 (s, 2H), 3.28 (t, J= 7.5 Hz, 2H), 2.82 - 2.64 (m, 4H), 2.67 - 2.52 (m, 4H), 2.14 - 2.03 (m, 2H), 1.89 - 1.73 (m, 1H), 1.61 (q, J= 7.5 Hz, 2H), 1.09 - 0.96 (m, 2H) ppm. LCMS : [M - H]+, 338. terf-butyl 4-(cyanomethylene)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0168] 17 Following general procedure D using 16 (0.600 g, 2.663 mmol), NaH (60%, 0.128 g, 3.196 mmol) and diethyl cyanomethylphosphonate (0.561 mL, 0.613 g, 3.462 mmol). Purification on silica furnished 17 as a mixture of Z and E isomers (0.454 g, 1.828 mmol, 69%) as a colorless oil. 'H NMR (600 MHz, CDCh) 5 5.29 (s, 0.5H), PATENT

[0169] 0321.153519PCT / SD2024-022

[0170] 5.25 (s, 0.5H), 3.88 (bs, 0.4H), 3.66 (bs, 0.5H), 3.59 - 3.41 (m, 1.6H), 3.35 - 3.04 (m, 2.4H), 2.88 - 2.77 (m, 2H), 2.76 - 2.62 (m, 1H), 2.57 - 2.48 (m, 0.5H), 2.04 - 1.92 (m, 1H), 1.77 - 1.61 (m, 1H), 1.44 (s, 4H), 1.44 (s, 5H) ppm.13C NMR (150 MHz, CDCh) 5 174.13, 154.31, 116.84, 93.06, 92.68, 79.83, 60.51, 50.84, 50.53, 50.32, 50.21, 34.22, 32.89, 30.05, 28.58 (d, J= 2.9 Hz), 21.17, 14.31 ppm. LCMS : [M + H]+, 249.

[0171] 2-(octahydrocyclopenta[c]pyrrol-4-yl)acetonitrile hydrochloride 18 Following general procedure E using 17 (0.400 g, 1.611 mmol), Pd / C (10% wt., 0.171 g, 0.161 mmol), then HC1 in 1,4-dioxane (4 M, 5.992 mL, 0.874 g, 23.970 mmol) furnished 18 (0.298 g, 1.610 mmol, 99%) as a light brown solid after precipitation. LCMS : [M + H]+, 149.

[0172] 2,2'-(hexahydrocyclopenta[c]pyrrole-2,4(lH)-diyl)diacetonitrile 19 Following general procedure A using 18 (0.258 g, 1.382 mmol), bromoacetonitrile (0.106 mL, 0.182 g, 1.520 mmol) and potassium carbonate (0.401 g, 2.902 mmol). Purification on silica (HexanesZEtOAc : 70 / 30 to 0 / 100) furnished 19 (0.151 g, 0.798 mmol, 58%) as a light yellow oil. LCMS : [M + H]+, 190.

[0173] 2,2'-(hexahydrocyclopenta[c]pyrrole-2,4(lET)-diyl)6is(ethan-l-amine) 20

[0174] Following general procedure B using 19 (0.227 g, 1.199 mmol) and a LiAlH4 solution in THF (1.199 mL, 4 M, 0.182 g, 4.798 mmol). Purification on silica furnished 20 (0.092 g, 0.466 mmol, 39%) as a light yellow oil. 'H NMR (600 MHz, CDCh) 5 3.71 (s, 1.5H), 3.65 (s, 0.5H), 2.90 - 2.78 (m, 1H), 2.76 - 2.53 (m, 5H), 2.42 (d, J= 6.8 Hz, 3H), 2.37 (d, J = 6.5 Hz, 0.5H), 2.25 - 2.17 (m, 2H), 2.11 - 2.06 (m, 1H), 1.80 - 1.72 (m, 1H), 1.60 - 1.54 (m, 1H), 1.28 - 1.19 (m, 2H) ppm. LCMS : [M + H]+, 198.

[0175] (2E,2'E)-A^V-((hexahydrocyclopenta[c]pyrrole-2,4(lET)-diyl)6 / s(ethane-2,l- diyl))6 / s(2-(hydroxyimino)acetamide) 4 Following general procedure C using 20 (0.085 g, 0.431 mmol) and ethyl (E)-2-(hydroxyimino)acetate (0.126 g, 1.080 mmol). Purification on silica furnished 4 (0.042 g, 0.124 mmol, 29%) as a white solid after trituration in cold MeOH. 'H NMR (599 MHz, MeOD) 5 7.42 (s, 2H), 3.42 (t, J = 6.5 Hz, 2H), 3.27 (t, J = 7.3 Hz, 2H), 2.74 - 2.51 (m, 4H), 2.42 (bs, 1H), 2.13 - 1.97 (m, 2H), 1.83 - 1.73 (m, 1H), 1.72 - 1.50 (m, 3H), 1.49 - 1.23 (m, 3H), 1.07 - 0.97 (m, 1H), 0.95 (t, J = 7.5 Hz, 1H), 0.94 - 0.87 (m, 1H) ppm. LCMS : [M - H]+, 338. PATENT

[0176] 0321.153519PCT / SD2024-022

[0177] Example 2: In vitro reactivation efficacy of two exemplary polyheterocyclic bisoximes

[0178] Exemplary polyheterocyclic uncharged bisoxime antidotes were tested as reactivators of paraoxon inhibited human acetylcholinesterase (hAChE) in vitro, with positive results. The in vitro reactivation efficacy of two most efficient tested polyheterocyclic antidote (out of four synthesized) was shown to approach in vitro efficacy of MMB4, one of most effective aldoxime antidotes of all aldoximes. MMB4 is ineffective in the CNS due to its cationic charge, our polyheterocyclic aldoximes are not charged and are expected to cross BBB and function effectively in the CNS.

[0179] In vitro experimental data efficacy with functional data for reactivation rates analyzed with deconstructed kinetic constants for four polyheterocyclic bisoxime compounds in reactivation of four OP inhibited hAChE forms: paraoxon-hAChE, VX-hAChE, sarin-hAChE and cyclosarin-hAChE.

[0180] In vitro reactivation of POX-hAChE by exemplary polyheterocyclic uncharged bisoxime antidotes as provided herein is illustrated in FIG. 5, and their reactivation rate constants compared to the monoheterocyclic bis-oxime LG-703, monoheterocyclic monoxime RS194B and cationic pyridinium -based aldoximes 2PAM and MMB4 are given in the Table 1, as illustrated in FIG. 6.

[0181] Table 1 (FIG. 6) shows kinetic constants for reactivation of OP-hAChE conjugates, in vitro, by polyheterocyclic bis-oximes compared to the monoheterocyclic bis-oxime LG-703, monoheterocyclic monoxime RS194B and cationic pyridinium-based aldoximes 2PAM and MMB4. Listed are: maximal reactivation rate constant k2 (min-1), Michaelis-Menten type constant Kox(mM), and the overall second order reactivation rate constant kr(Mimin'1).

[0182] Example 3 : Maximal tolerated doses of polyheterocyclic bis-oximes in mice

[0183] Tolerability of the two exemplary polyheterocyclic bis-oximes, TAL-1025 and TAL-1093, was determined in female CD-I mice, upon i.v., i.m. and p.o. bis-oxime administration to mice. The bis-oximes were aseptically dissolved in the 100 mM citrate buffer pH 5 and sterile filtered prior to administration to mice.

[0184] A single i.m. administration of exemplary TAL 1025 or TAL 1093 (20, 40, 80 and 160 mg / kg) to 2 female CD-I mice per group was well tolerated with no mortality / morbidity or clinical signs indicative of significant toxicity. While a maximum tolerated dose (MTD) could not be established after a single intramuscular PATENT 0321.153519PCT / SD2024-022

[0185] (i.m.) dose of each test article, the MTD for exemplary TAL 1025 was greater than (>) 20 mg / kg after intravenous (i.v.) administration and > 160 mg / kg after a single i.m. dose. The MTD for exemplary TAL 1093 was between 80 mg / kg and 160 mg / kg (i.m.) and between 10 mg / kg and 20 mg / kg (i.v.).

[0186] Thus, both of the exemplary bis-oximes were tolerated in CD-I mice several- fold better than the standard of care antidote 2PAM (LD50 for mice intramuscular (i.m.) 106 mg / kg) and comparable to the monoheterocyclic monoxime RS194B (LD50 for mice i.m. 500 mg / kg).

[0187] Example 4: In vivo therapeutic efficacy of exemplary polyheterocyclic bis-oxime in OP-exposed mice

[0188] The antidotal effect of the exemplary polyheterocyclic bisoxime TAL- 1025 was tested, by intramuscular (i.m.) administration of the bis-oxime and atropine (10 mg / kg) 1 min after an OP compound (given subcutaneously (s.c.)) to male CD-I mice. The OP dose was escalated by geometric progression from 1 x LD50 up to the dose at which the mortality matches the data shown in Thomson and Weil tables for calculating LD50. The bis-oxime antidote dose was selected to be 20 mg / kg, well below their respective MTD and what was significantly lower compared to the common monoheterocyclic monoxime RS194B dose (125 mg / kg) and slightly lower than the approved 2PAM antidote dose (26.4 mg / kg, as previously described: Radic et al., JBC 2012). The antidotal efficacy against OP poisoning given in the Table 2 (FIG. 7) is expressed as protective index (PI= LD50+oxime / LD50). Symptoms of poisoning were carefully monitored up to 24 h after exposure to OP, and compared between given antidotal post-treatments. Survival within 24 h after OP exposure also allowed us to determine the highest dose of OP compound at which all animals survived 24 h with oxime therapy (MDP).

[0189] Table 2 (FIG. 7) shows data from the therapy of OP exposed mice with the exemplary polyheterocyclic uncharged TAL- 1025 bis-oxime as provided herein. The results are presented as protective index, PI (95% confident limits are given in parentheses) and maximal dose of OP that all mice survived, MDP. Mice were treated i.m. with 1 / 4 of oxime’s LD50 + 10 mg / kg atropine, 1 minute after OP application given s.c.. Literature values for monoheterocyclic monoxime RS194B and pyridinium-based cationic monoxime 2PAM are given for comparison. PATENT 0321.153519PCT / SD2024-022

[0190] In vivo determined therapeutic efficacy of a representative polyheterocyclic bis-oxime antidote described as a PI, proved comparable or better than that of the approved antidote 2PAM (Table 2), considering a lower dose and unique property of TAL-1025 to act antidotaly in the CNS, unlike 2PAM. The efficacy of polyheterocyclic TAL-1025 in the paraoxon-exposed mice proved several -fold better than the one of the previously published centrally active antidote RS194B (Table 2), and at a much lower dose.

[0191] Example 5: Pharmacokinetic analysis and bioavailability of polyheterocyclic bisoximes in CD-I mice

[0192] The plasma pharmacokinetics of TAL-1025 and TAL-1093 in female CD-I mice was determined following a single i.m., intravenous (i.v.), or oral (p.o.) dose administration. The bis-oximes were aseptically dissolved in the 100 mM citrate buffer pH 5 and sterile filtered prior to administration to mice.

[0193] The plasma concentration data was analyzed using PHOENIX® WINNONLIN® (version 8.5) software to perform noncompartmental pharmacokinetic analysis with the sparse sampling feature. The doses administered were input into the program as mg / kg, and as a result, no additional corrections for individual body weights of the animals were necessary. The following plasma PK parameters were determined: maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the plasma concentration-time curve to the last timepoint (AUClast) and extrapolated to infinity (AUCinf), terminal phase elimination half-life (t 1 / 2), and mean residence time to the last time point (MRTlast) and extrapolated to infinity (MRTinf). For the iv groups only, theoretical concentration at time 0 (CO), volume of distribution at steady state (Vss), and clearance (Cl) were calculated. For the im and po groups only, bioavailability (F) was calculated by comparing AUCinf values corrected for the administered dose.

[0194] The results of the pharmacokinetic analysis following a single 20 mg / mg i.v., 160 mg / kg i.m., or 160 mg / kg p.o. dose administration of the exemplary TAL-1025 or TAL-1093 to female CD-I mice are as follows. When the exemplary TAL-1025 was administered to mice, the CO was 11,400 ng / ml for the i.v. group, while the Cmax for the i.m. group (74,400 ± 6,930 ng / ml) was observed at the first blood collection timepoint of 0.083 hr, and the Cmax for the p.o. group (8,840 ± 2,610 ng / ml) was observed at a Tmax of 1 hr. Plasma exposure values based on AUC.inf were 4,040, PATENT 0321.153519PCT / SD2024-022

[0195] 34,200, and 15,700 hrng / ml for the i.v., i.m., and p.o. groups, respectively. The the exemplary MRTinf was 0.886, 0.754, and 2.58 hr, and tl / 2 was 1.20, 1.18, and 3.05 hr for the i.v., i.m., and p.o. groups, respectively. Cl and Vss for the i.v. group were 4,950 ml / hr / kg and 4.39 1 / kg, respectively. Bioavailability of TAL 1025 was 106% for the i.m. group and 49% for the p.o. group. When the exemplary TAL 1093 was administered to mice, the Co was 17,600 ng / ml for the i.v. group, while the Cmax for the i.m. group (84,100 ± 21,900 ng / ml) was observed at the first blood collection time point of 0.083 hr, and the Cmax for the p.o. group (685 ± 135 ng / ml) was observed at a Tmax of 1 hr. Plasma exposure based on AUCinf was 2,890, 26,200, and 1,460 hr.ng / ml for the i.v., i.m., and p.o. groups, respectively. The MRTinf was 0.729, 0.528, and 2.19 hr, and tl / 2 was 2.62, 1.04, and 3.47 hr for the i.v., i.m., and p.o. groups, respectively. Cl and Vss for the i.v. group were 6,930 ml / hr / kg and 5.05 1 / kg, respectively. Bioavailability of TAL 1093 was 113% for the i.m. group and 6.3% for the p.o. group.

[0196] In conclusion the plasma exposure based on the AUCinf was higher for TAL - 1025 by all routes of administration. Both exemplary bis-oximes exhibited very good plasma exposure. Bioavailability for both test articles was outstanding at approximately 100% after im administration. The oral bioavailability was also outstanding for TAL-1025 at 49%, and much greater than for TAL -1093 (at 6.3%).

[0197] Both exemplary polyheterocyclic bis-oximes exhibited much higher bioavailability than the standard of care, cationic pyridinium-based antidote 2PAM, and comparable or better bioavailability compared to the uncharged monoheterocyclic monoxime RS194B (as previously described: Radic et al., JBC 2012).

[0198] A number of embodiments of the invention have been described. Nevertheless, it can be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

PATENT0321.153519PCT / SD2024-022WHAT IS CLAIMED IS:

1. A compound having one of the following structures or compositions having one or more compounds of the following structures, or equivalents thereof, or an isomer, optical isomer or a stereoisomer thereof, a racemate or racemic mixture thereof, an enantiomer, an individual diastereomer or a diastereomeric mixture thereof, or an analog thereof, or a crystalline product or crystalline intermediate thereof, or a pharmaceutically acceptable salt thereof, or prodrug thereof, or a bioisostere thereof; or a composition comprising an isolated, substantially isolated or purified compound consisting essentially of, or consisting of:(a) the compound having the formula:X = N,CH; Y = N,CH; R1 = 0, CH2NH, CH2CH2NH, CH2CH2CH2NH; R2 = 0, CH2NH; CH2CH2NH, CH2CH2CH2NH; R3 = alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, acyl, sulfonyl, lactam, sultam, cyano, hydroxy, halogen. and optionally when fused rings comprise:(1) if X=N, Y=N, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l - compound TAL 993,(2) if X=N, Y=CH, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l-> compound TAL 1025,(3) if X=N, Y=CH, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=0,compound TAL 1093, or() spirocyclic ring comprises: if X=N, Y=N, R1=CH2CH2NH, R2= CH2CH2NH, R3=H, n=l, m=l, o=l^ compound TAL 847; or(b) a compound having the formula;(1)PATENT0321.153519PCT / SD2024-022(also called Tai 847),(also called Tai 1025), or(4)(also called Tai 1093).

2. A formulation or pharmaceutical composition comprising a compound or composition as set forth in claim 1, wherein optionally the formulation further comprises a pharmaceutically acceptable excipient, and optionally thePATENT 0321.153519PCT / SD2024-022 pharmaceutically acceptable excipient comprises a sterile saline, a sterile buffer and / or a sterile water.

3. The formulation or pharmaceutical composition of claim 3, wherein formulation or the pharmaceutical composition is formulated for enteral or parenteral administration.

4. The formulation or pharmaceutical composition of claim 2 or claim 3, wherein the formulation or pharmaceutical composition is formulated for administration orally, parenterally, by inhalation spray or mist, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or the formulation is a solid, liquid, aerosol, mist, powder or emulsion formulation.

5. The formulation or pharmaceutical composition of any of claims 2 to 4, formulated as or in or on: a liquid, a powder, an emulsion, a lyophilized powder, a spray, a cream, a lotion, a controlled release formulation, a tablet, a pill, a capsule, a gel, a geltab, a patch, an implants, an applicator stick, a solutions, a suspension, an ointment, a paste, a jelly, a paint, a powder, a mists an aerosol, an elixirs, a syrup, a liposome, a nanoliposome, a nanoparticle or a particle.

6. A product of manufacture comprising: a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5, or a product of manufacture comprising and fabricated or manufactured to deliver to an individual in need thereof: a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5.

7. The product of manufacture of claim 6, fabricated or manufactured as a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising: a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5; or, fabricated to deliver to an individual in need thereof a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5.PATENT0321.153519PCT / SD2024-0228. The product of manufacture of claim 6, fabricated or manufactured as a nebulizer or an inhaler comprising: a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5; or, fabricated to deliver to an individual in need thereof a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5.

9. A method for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE), comprising: administering to a patient or an individual in need thereof, a compound as set forth in claim 1, or a formulation or a pharmaceutical composition of any of claims 2 to 5, or a product of manufacture of any of claims 6 to 8, wherein optionally the compound or formulation is administered enterally or parenterally, wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or administering the compound as set forth in claim 1, or a formulation or a pharmaceutical composition of any of claims 2 to 5, using a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi -chambered pump, a syringe, a cartridge or a pen or a jet injector, optionally as set forth in claim 6.

10. The method of claim 9, wherein the organophosphate (OP) toxicity, poisoning or toxic exposure is caused by exposure of the patient or individual to an alkyl methylphosphonate or related nerve agent, or an alkylphosphorate insecticide, and optionally the organophosphate (OP) is or is a component of a toxin, an herbicide, an insecticide, or a nerve gas or nerve agent, and optionally the organophosphate (OP) is or comprises a parathion, a malathion, a methyl parathion, a chlorpyrifos, a diazinon, a dichlorvos, a phosmet, aPATENT 0321.153519PCT / SD2024-022 fenitrothion, a tetrachlorvinphos, an azamethiphos or an azinphos methyl, or the nerve agent is a soman (O-Pinacolyl methylphosphonofluoridate), a tabun (Ethyl N,N Dimethyl-phosphoramido-cyanidate) or a sarin ((A5)-propan-2-yl methylphosphonofluoridate).

11. The method of claim 9 or claim 10, wherein the acetylcholinesterase (AChE) is in the central nerve system (CNS), or the acetylcholinesterase (AChE) is a human acetylcholinesterase (hAChE).

12. A method for treating, preventing or ameliorating excessive acetylcholine stimulation in the brain, comprising: administering to a patient or an individual in need thereof, a compound as set forth in claim 1, or a formulation or a pharmaceutical composition of any of claims 2 to 5, or a product of manufacture of any of claims 6 to 8, wherein optionally the compound or formulation is administered enterally or parenterally, wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray or mist, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or administering to a patient or an individual in need thereof as set forth a compound as set forth in claim 1, or the formulation or a pharmaceutical composition of any of claims 2 to 5, or the product of manufacture of any of claims 6 to 8.

13. The method of claim 12, wherein the excessive acetylcholine stimulation in the brain, the CNS or the PNS is caused by a drug, a drug overdose, or a poisoning or a toxic exposure to a drug, and optionally the drug, drug overdose or poisoning causing the excessive acetylcholine stimulation is caused at least in part by a carbamate (wherein optionally the carbamate is or comprises physostigmine or eserine (for example, ANTILIRIUM™), neostigmine (for example, BLOXIVERZ™, PROSTIGMIN™, or VAGOSTIGMIN™), pyridostigmine (for example, MESTINON™), carbaryl, carbaril or 1 -naphthyl methylcarbamate, for example, SEVIN™)); or, an organophosphate agent such as a pesticide or poison (whereinPATENT0321.153519PCT / SD2024-022 optionally the organophosphate agent is or comprises diisopropyl-fluorophosphate (DFP) or isoflurophate, and / or echothiophate (for example, PHOSPHOLINE IODIDE™ or PHOSPHOLINE™).

14. A compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5, or a product of manufacture as set forth in any of claims 6 to 8, for use in: treating, preventing or ameliorating excessive acetylcholine stimulation in the brain; or, treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE).

15. Use of a compound as set forth in claim 1, or a formulation or pharmaceutical composition of any of claims 2 to 5, or a product of manufacture as set forth in any of claims 6 to 8, for: treating, preventing or ameliorating excessive acetylcholine stimulation in the brain; or, treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate inhibition of an acetylcholinesterase (AChE).

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