Haloperidol derivatives, pharmaceutical composition comprising said derivatives, and therapeutic use thereof

Abstract

The present disclosure provides for compounds including derivatives of haloperidol, pharmaceutical compositions including haloperidol derivatives, methods of use of the haloperidol derivatives and their pharmaceutical compositions, and the like. Compounds and pharmaceutical compositions of the present disclosure can be used in combination with one or more therapeutic agents for treating inflammatory arthritis, gout, or other inflammation-related diseases or conditions.

Description

TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) HALOPERIDOL DERIVATIVES, PHARMACEUTICAL COMPOSITION COMPRISING SAID DERIVATIVES, AND THERAPEUTIC USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application entitled “HALOPERIDOL DERIVATIVES, PHARMACEUTICAL COMPOSITION COMPRISING SAID DERIVATIVES, THERAPEUTIC USE THEREOF” and having serial number 63 / 557,778, filed on February 26, 2024, and U.S. Provisional Application entitled “HALOPERIDOL DERIVATIVES, PHARMACEUTICAL COMPOSITION COMPRISING SAID DERIVATIVES, THERAPEUTIC USE THEREOF” and having serial number 63 / 606,708, filed on December 6, 2023, each of which is incorporated herein by reference in its entirety. STATEMENT ON FUNDING PROVIDED BY THE U.S. GOVERNMENT

[0002] This invention was made with Government support under contract R01EY031039 awarded by the National Institutes of Health. The Government has certain rights in the invention. SEQUENCE LISTING

[0003] This application contains a sequence listing filed in electronic form as an .xml file in ST.26 format entitled “222117_2460 Sequence Listing.xml”, created on December 4, 2024 and having a size of 2kb. The content of the sequence listing is incorporated herein in its entirety as if fully set forth herein. BACKGROUND

[0004] Gout is the most common form of inflammatory arthritis and is estimated to affect 2 to 3% of the world’s population, with the incidence of gout having roughly doubled in most of the world within the past three decades. A common feature of gout is the deposition of monosodium urate (MSU) crystals deposition in and around joints. A principal therapy for gout is the reduction of serum urate levels to enable dissolution of deposited crystals. Other first-line therapies include non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids to limit the inflammation and pain that accompany gout flares. Unfortunately, many patients tolerate these therapies poorly or respond inadequately. Although several drugs are approved for the management of gout, most have significant potential side effects.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) Further, to date no medications have been approved for reducing the risk of gout or preventing the disease. Therefore, there is a need to explore alternate therapeutic strategies. SUMMARY

[0005] The present disclosure provides for compounds including derivatives of haloperidol, pharmaceutical compositions including haloperidol derivatives, methods of use of the haloperidol derivatives and their pharmaceutical compositions, and the like.

[0006] The present disclosure provides for a compound having a formula represented by structure II or the pharmaceutically acceptable salt thereof:   R3b1wherein each R1is independently selected from hydrogen, a halogen, or a C1 to C6 alkyl group; R2aand R2bare each independently selected from hydrogen or oxygen, when R2ais oxygen, oxygen has a double bond to the carbon atom and the carbon atom is not bonded to R2bdue to the double bond to carbon; n is an integer from 0 to 8; and R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are each independently selected from hydrogen, halogen, -OH, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group, and wherein the compound is not one of the following: ,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)composition comprising a therapeutically effective amount of a compound to treat a condition (e.g., an inflammatory arthritis, gout, or an inflammation-related disease) in a subject, wherein the compound has a formula represented by structure II or the pharmaceutically acceptable salt thereof:   R3b1R3b2each R1is independently selected from hydrogen, halogen, or a C1 to C6 alkyl group; R2aand R2bare each independently selected from hydrogen or oxygen, when R2ais oxygen, oxygen has a double bond to the carbon atom and the carbon atom is not bonded to R2bdue to the double bond to carbon; n is an integer from 0 to 8; andTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are independently selected from hydrogen, halogen, -OH, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group, and wherein the compound is not one of the following: for treating a condition (e.g., anor an related disease) comprising: administering to a subject in need thereof, a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or the pharmaceutical composition of described above or herein. BRIEF DESCRIPTION OF DRAWINGS

[0009] Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0010] FIG.1 is representative immunofluorescent images showing LPS+ATP induces ASC specks (green circular aggregates) in human THP-1 cells, and Haloperidol (HAL) reduces specks. Cell nuclei stained blue by DAPI. Bar graph of mean and SEM. N = 7 per group. *P=0.007 (LPS+ATP+HAL compared to LPS+ATP+Vehicle), two-tailed Student t test.

[0011] FIG.2 is representative western blot images showing LPS+ATP induces cleavage of pro-caspase-1 (45 kDa) into active caspase-1 (33 kDa) in human THP-1 macrophages, and haloperidol (HAL) reduces caspase-1 activation induced by LPS+ATP. ^-actin loading control shows protein loading per lane. N = 3 per group.

[0012] FIGS.3A and 3B are ELISAs of secreted IL-1β from human THP-1 macrophages (3A) and IL-6 from human synovial fibroblasts (3B), showing LPS+ATP induces secretion of these cytokines, and Haloperidol (HAL) reduces secretion induced by LPS+ATP. N = 3 per group. Data show mean and SEM. *P<0.05 (LPS+ATP+HAL compared to LPS+ATP+Vehicle), two-tailed Student t test.

[0013] FIG.4 is an ELISA of secreted IL-1β from human THP-1 macrophages, showing MSU-induced secretion of IL-1β is reduced by Haloperidol in a dose-dependent manner. Data show mean and SEM. P values (compared to MSU+Vehicle), one-way ANOVA with post-hoc Tukey’s test. NS, not significant.

[0014] FIG.5 shows the amino acid sequence of mouse LAMTOR1 with amino acid residues (SEQ. ID. No.1) identified in mass spectrometry highlighted.

[0015] FIG.6 is representative immunofluorescent images showing LPS + ATP induces peri- nuclear (blue, DAPI) aggregation of NLRP3 (green) and LAMTOR1 (red) in macrophages. Haloperidol (HAL, 1 µM) reduces LAMTOR1–NLRP3 aggregation. Bar graph of mean and SEM. N = 9 per group. *P < 0.0001 compared to LPS + ATP, two-tailed Student t test.

[0016] FIG.7 is in silico binding analysis of haloperidol with the Ragulator complex. The highest ranked docking complex, whose binding energy was calculated as ΔG = –8.1 kcal / mol, is shown.

[0017] FIG.8 is in silico binding analysis of haloperidol with the Ragulator complex. An alternate docked pose, whose binding energy was calculated as ΔG = –7.9 kcal / mol, is shown.

[0018] FIG.9 shows structures of haloperidol derivatives.

[0019] FIG.10 shows families of haloperidol derivatives.

[0020] FIGs.11A-11D illustrate NLRP3 inflammasome activation in monosodium urate (MSU)-induced mouse model of gout.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0021] FIGs.12A-12C illustrates that haloperidol reduces inflammation and ankle swelling in MSU-induced mouse model of gout.

[0022] FIF.13 illustrate that haloperidol reduces neutrophil infiltration in MSU-induced mouse model of gout. DETAILED DESCRIPTION

[0023] This disclosure is not limited to particular embodiments described, and as such may, of course, vary. The terminology used herein serves the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0024] Where a range of values is provided, each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0025] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0026] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to perform the methods and use the compositions and compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C, and pressure is at or near atmospheric. Standard temperature and pressure are defined as 20 °C and 1 atmosphere.

[0027] Before the embodiments of the present disclosure are described in detail, it is to be understood that, unless otherwise indicated, the present disclosure is not limited to particular materials, reagents, reaction materials, manufacturing processes, dimensions, frequency ranges, applications, or the like, as such can vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is notTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) intended to be limiting. It is also possible in the present disclosure that steps can be executed in different sequence, where this is logically possible. It is also possible that the embodiments of the present disclosure can be applied to additional embodiments involving measurements beyond the examples described herein, which are not intended to be limiting. It is furthermore possible that the embodiments of the present disclosure can be combined or integrated with other measurement techniques beyond the examples described herein, which are not intended to be limiting.

[0028] It should be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a support” includes a plurality of supports. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

[0029] Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; “application cited documents”), and each of the PCT and foreign applications or patents corresponding to and / or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference. Further, documents or references cited in this text, in a Reference List before the claims, or in the text itself; and each of these documents or references (“herein cited references”), as well as each document or reference cited in each of the herein-cited references (including any manufacturer’s specifications, instructions, etc.) are hereby expressly incorporated herein by reference.

[0030] Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated. Definitions

[0031] It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0032] It will be understood by those skilled in the art that the moieties substituted can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphorylTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be substituted in the same manner.

[0033] The term "alkyl", either alone or within other terms such as "thioalkyl" and "arylalkyl", as used herein, means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. An alkyl radical for use in the present disclosure generally comprises from about 1 to 20 carbon atoms, particularly from about 1 to 10, 1 to 8 or 1 to 7, more particularly about 1 to 6 carbon atoms, 1 to 2 or 3 to 6. Illustrative alkyl radicals include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, n-actyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n- hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along with branched variations thereof. In certain aspects of the disclosure an alkyl radical is a C1-C6 lower alkyl comprising or selected from the group comprising methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert-pentyl, and n-hexyl. An alkyl radical may be optionally substituted with substituents as defined herein at positions that do not significantly interfere with the preparation of compounds of the disclosure and do not significantly reduce the efficacy of the compounds. In certain aspects of the disclosure, an alkyl radical is substituted with one to five substituents including halo, lower alkoxy, lower aliphatic, a substituted lower aliphatic, hydroxy, cyano, nitro, thio, amino, keto, aldehyde, ester, amide, substituted amino, carboxyl, sulfonyl, sulfuryl, sulfenyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g. CF3), halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, cycloaliphatic, substituted cycloaliphatic, or aryl (e.g., phenylmethyl benzyl)), heteroaryl (e.g., pyridyl), and heterocyclic (e.g., piperidinyl, morpholinyl). Substituents on an alkyl group may themselves be substituted.

[0034] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above and is included within theTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0035] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms or 2 to 8 carbon atoms or 2 to 6 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (R1R2)C=C(R3R4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0036] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0037] As used herein, "alkynyl" or “alkynyl group” refers to straight or branched chain hydrocarbon groups having 2 to 40, 2 to 20, 2 to 10, or 2 to 5 carbon atoms and at least one triple carbon to carbon bond, such as ethynyl. Reference to "alkynyl" or “alkynyl group” includes unsubstituted and substituted forms of the hydrocarbon moiety.

[0038] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon tripleTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) bound. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0039] The terms "alkoxyl" or "alkoxyalkyl" as used herein refer to an alkyl-O- group wherein alkyl is as described herein. The term "alkoxyl" as used herein can refer to C1-20inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, t-butoxyl, and pentoxyl.

[0040] The Ar (e.g., Ar1, Ar2, etc.) group is an aromatic system or group such as an aryl group. “Aryl”, as used herein, refers to C5-C20-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems. In an aspect, “aryl”, can include 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, functional groups that correspond to benzene, phenyl, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics”. The aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF3, -CN; and combinations thereof.

[0041] The term “aryl” also includes polycyclic ring systems (C5-C30) having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocycles. Examples of heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined above for “aryl”.

[0042] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to a, wherein n is typically an integer. to represent five independent substituents, Rn(a), Rn(b), Rn, , . By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0043] The term "carboxyl" as used herein, alone or in combination, refers to -C(O)OR25- or -C(-O)OR25wherein R25is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl, thioalkyl, thioaryl, thioalkoxy, a heteroaryl, or a heterocyclic, which may optionally be substituted. In aspects of the disclosure, the carboxyl groups are inTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) an esterified form and may contain as an esterifying group lower alkyl groups. In particular aspects of the disclosure, -C(O)OR25provides an ester or an amino acid derivative. An esterified form is also particularly referred to herein as a "carboxylic ester". In aspects of the disclosure a "carboxyl" may be substituted, in particular substituted with allyl which is optionally substituted with one or more of amino, amine, halo, alkylamino, aryl, carboxyl, or a heterocyclic. Examples of carboxyl groups are methoxycarbonyl, butoxycarbonyl, tert.alkoxycarbonyl such as tert-butoxycarbonyl, arylmethyoxycarbonyl having one or two aryl radicals including without limitation phenyl optionally substituted by for example lower alkyl, lower alkoxy, hydroxyl, halo, and / or nitro, such as benzyloxycarbonyl, methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl, 2- iodoethoxycarbonyltert.butylcarborlyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy- carbonyl, benzhydroxycarbonyl, di-(4-methoxyphenyl-methoxycarbonyl, 2- bromoethoxycarbonyl, 2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2- triphenylsilylethoxycarbonyl. Additional carboxyl groups in esterified form are silyloxycarbonyl groups including organic silyloxycarbonyl. The silicon substituent in such compounds may be substituted with lower alkyl (e.g. methyl), alkoxy (e.g. methoxy), and / or halo (e.g. chlorine). Examples of silicon substituents include trimethylsilyi and dimethyltertbutylsilyl. In aspects of the disclosure, the carboxyl group may be an alkoxy carbonyl, in particular methoxy carbonyl, ethoxy carbonyl, isopropoxy carbonyl, t- butoxycarbonyl, t-pentyloxycarbonyl, sir heptyloxy carbonyl, especially methoxy carbonyl or ethoxy carbonyl.

[0044] The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such a term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0045] When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition toTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) the compound of the present disclosure is contemplated. Accordingly, the pharmaceutical compositions of the present disclosure include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, but not intended to be limiting, when a compound of the present disclosure is combined with another agent, the weight ratio of the compound of the present disclosure to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present disclosure and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0046] A composition of the disclosure can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Various delivery systems are known and can be used to administer a composition of the disclosure, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like.

[0047] A therapeutic composition of the disclosure may comprise a carrier, such as one or more of a polymer, carbohydrate, peptide or derivative thereof, which may be directly or indirectly covalently attached to the compound. A carrier may be substituted with substituents described herein including without limitation one or more alkyl, amino, nitro, halogen, thiol, thioalkyl, sulfate, sulfonyl, sulfinyl, sulfoxide, hydroxyl groups. In aspects of the disclosure the carrier is an amino acid including alanine, glycine, praline, methionine, serine, threonine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl. A carrier can also include a molecule that targets a compound of the disclosure to a particular tissue or organ.

[0048] Compounds of the disclosure can be prepared using reactions and methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application including the Examples. The reactions are performed in solvent appropriate to the reagents and materials used and suitable for the reactions being affected. ItTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) will be understood by those skilled in the art of organic synthesis that the functionality present on the compounds should be consistent with the proposed reaction steps. This will sometimes require modification of the order of the synthetic steps or selection of one particular process scheme over another in order to obtain a desired compound of the disclosure. It will also be recognized that another major consideration in the development of a synthetic route is the selection of the protecting group used for protection of the reactive functional groups present in the compounds described in this disclosure. An authoritative account describing the many alternatives to the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

[0049] A compound of the disclosure may be formulated into a pharmaceutical composition for administration to a subject by appropriate methods known in the art. Pharmaceutical compositions of the present disclosure or fractions thereof comprise suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21.sup.st Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. By way of example for oral administration in the form of a capsule or tablet, the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like. For oral administration in a liquid form, the chug components may be combined with any oral, non-toxic, pharmaceutically, acceptable inert carrier such as ethanol, glycerol, water, and the like. Suitable binders (e.g., gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes), lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride), disintegrating agents (e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum), flavoring agents, and coloring agents may also be combined in the compositions or components thereof. Compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.

[0050] The terms “administering” and “administration” as used herein refer to introducing a composition of the present disclosure into a subject. As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia.

[0051] The terms "subject", "individual", or "patient" as used herein are used interchangeably and refer to an animal preferably a warm-blooded animal such as a mammal. Mammal includes without limitation any members of the Mammalia. A mammal, as a subject or patient in the present disclosure, can be from the family of Primates, Carnivora, Proboscidea, Perissodactyla, Artiodactyla, Rodentia, and Lagomorpha. In a particular embodiment, the mammal is a human. In other embodiments, animals can be treated; the animals can be vertebrates, including both birds and mammals. In aspects of the disclosure, the terms include domestic animals bred for food or as pets, including equines, bovines, sheep, poultry, fish, porcines, canines, felines, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.

[0052] The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which a probe of the disclosure is administered, and which is approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. When administered to a patient, the probe and pharmaceutically acceptable carriers can be sterile. Water is a useful carrier when the probe is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as glucose, lactose, sucrose, glycerol monostearate, sodium chloride, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The present compositions advantageously may take the form of solutions, emulsion, sustained-release formulations, or any other form suitable for use. Pharmaceutically acceptable carriers may also include a dentifrice.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0053] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Additionally, the term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0054] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition (e.g., an inflammatory arthritis, gout, or an inflammation-related disease) or prevention of a disease or condition or enhance and / or tune the immune system of the subject to the desirable responses for certain diseases or conditions. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms or prevention of a disease or condition and / or tune the immune system of the subject to the desirable responses for certain pathogens but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0055] As used herein, the terms "treating” and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) symptom, or condition (e.g., an inflammatory arthritis, gout, or an inflammation-related disease) thereof, such as infections and consequences thereof and / or tuning the immune system of the subject to the desirable responses for certain diseases or conditions. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of inflammation and / or infections in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease, condition, inflammation and / or infection but has not yet been diagnosed as having it; (b) inhibiting the disease, condition, inflammation and / or infection, i.e., arresting its development; and (c) relieving the disease, condition, inflammation and / or infection i.e., mitigating or ameliorating the disease and / or its symptoms or conditions, (d) and / or tune the immune system of the subject to the desirable responses for certain diseases or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. and / or tuning the immune system of the subject to the desirable responses for certain diseases or conditions. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0056] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect and / or tuning the immune system of the subject to the desirable responses for certain diseases or conditions. Discussion

[0057] The present disclosure provides for compounds including derivatives of haloperidol, pharmaceutical compositions including haloperidol derivatives, methods of use of the haloperidol derivatives and their pharmaceutical compositions, and the like. Compounds and pharmaceutical compositions of the present disclosure can be used in combination with oneTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) or more therapeutic agents for treating inflammatory arthritis, gout, and other inflammation- related diseases or conditions.

[0058] In some aspects, the condition to be treated is gout. Gout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments for gout exist, many patients are poorly responsive and have significant potential side effects. Furthermore, there is no approved preventive drug for gout. The anti-psychotic drug haloperidol has been associated with a reduced risk of incident rheumatoid arthritis. Inflammasome activation plays a role in both rheumatoid arthritis as well as gout, making haloperidol a potential treatment for those and other diseases where inflammasome-activation plays a role.

[0059] In one aspect, the haloperidol derivative compounds have a formula represented by structure I, or the pharmaceutically acceptable salt thereof: where each R1can be or a C1 to C6 alkylgroup; R2can be hydrogen or oxygen (when R2is oxygen, then there is a double bond between O and C and C does not have a hydrogen bonded to it); n can be an integer from 0 to 10 or 1 to 8, 1 to 6, or 2 to 4; and R3a, R3b, R3c, R3d, and R3ecan be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group. In some aspects, n can be an integer from 0 to 10. In other aspects, n can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4 or 1 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3. In some aspects, the compound is not one of the following: ,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0060] In some aspects, each R1can be independently selected from hydrogen, a halogen, or a C1 to C3 alkyl group. In further aspects, each R1can be independently selected from hydrogen, a halogen, or a methyl group. In other aspects, one of R1can be a C1 to C6 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1can be a C1 to C3 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1is a methyl group and the other of R1are hydrogen or a halogen.

[0061] In some aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a substituted or unsubstituted aryl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be an aryl group substituted with at least one C1 to C6 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a substituted or unsubstituted phenyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one C1 to C6 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In further aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one C1 to C3 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In further aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one methyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or a halogen. In some aspects, R3a, R3b, R3c, R3d, and / or R3ecan be independently selected from hydrogen and one of the following:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .

[0062] In otherand the other of

[0063] In one aspect, the haloperidol derivative compounds have a formula represented by structure II, or the pharmaceutically acceptable salt thereof:   R3b1R3b2where each R1can beor a C1 to C6 alkyl group; each R2aand R2bcan be hydrogen or oxygen (when R2ais oxygen, then there is a double bond between O and C and R2bis not present); n can be an integer from 0 to 10, 1 to 8, 2 to 6, or 2 to 4; and R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, or a substituted orTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) unsubstituted aryl group. In some aspects, n can be an integer from 0 to 10. In other aspects, n can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4 or 1 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3.

[0064] In some aspects, each R1can be independently selected from hydrogen, a halogen, or a C1 to C3 alkyl group. In further aspects, each R1can be independently selected from hydrogen a halogen, or methyl. In other aspects, one of R1can be a C1 to C6 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1can be a C1 to C3 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1is a methyl and the other of R1are hydrogen or a halogen.

[0065] In some aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a substituted or unsubstituted aryl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be an aryl group substituted with at least one C1 to C6 alkyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a substituted or unsubstituted phenyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one C1 to C6 alkyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In further aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one C1 to C3 alkyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In further aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one methyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In some aspects, R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be independently selected from hydrogen or one of the following:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .

[0066] In otherand the other ofhydrogen or a halogen.

[0067] FIG.10 shows families of haloperidol derivatives. Each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 can be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group. In some aspects, n can be an integer from 0 to 8 or 0 to 10. In other aspects, n can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4 or 1 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3.

[0068] In yet another aspect, this disclosure provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject. In some aspects, the pharmaceutical composition can include a therapeutically effective amount of a haloperidol derivative compound to treat a condition (e.g., inflammatory arthritis) in a subject (e.g., animal or human subject). In some aspects, the pharmaceutical composition also includes a pharmaceutically acceptable carrier. In other aspects, the pharmaceutical composition is formulated for administering to a subject. In some aspects, the compound of the pharmaceutical composition has a formula represented by structure III or the pharmaceutically acceptable salt thereof:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) where each R1can beand a C1 to C6 alkyl group; R2can be hydrogen or oxygen (when R2 is oxygen, then there is a double bond between O and C and C does not have a hydrogen bonded to it); n can be an integer from 0 to 10, 1 to 8, 2 to 6, or 2 to 4; and R3a, R3b, R3c, R3d, and R3ecan be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, and a substituted or unsubstituted aryl group. In some aspects, n can be an integer from 0 to 10. In other aspects, n can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3. In some aspects, the compound is not one of the following:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .some can selected from hydrogen, halogen, or a C1 to C3 alkyl group. In further aspects, each R1can be independently selected from hydrogen, halogen, or methyl. In other aspects, one of R1can be a C1 to C6 alkyl group and the other of R1are hydrogen or halogen. In further aspects, one of R1can be a C1 to C3 alkyl group and the other of R1are hydrogen or halogen. In further aspects, one of R1is a methyl and the other of R1are hydrogen or halogen.

[0070] In some aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a substituted or unsubstituted aryl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be an aryl group substituted with at least one C1 to C6 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a substituted or unsubstituted phenyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one C1 to C6 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In further aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one C1 to C3 alkyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In further aspects, one of R3a, R3b, R3c, R3d, or R3ecan be a phenyl group substituted with at least one methyl group and the other of R3a, R3b, R3c, R3d, and R3eare hydrogen or halogen. In some aspects, R3a, R3b, R3c, R3d, and R3ecan be independently selected from hydrogen or one of the following: .TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0071] In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be one of the following: and the other of

[0072] In yet another aspect, this disclosure provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject. In some aspects, the pharmaceutical composition can include a therapeutically effective amount of a haloperidol derivative compound to treat a condition (e.g., inflammatory arthritis) in a subject (e.g., animal or human subject). In some aspects, the pharmaceutical composition also includes a pharmaceutically acceptable carrier. In other aspects, the pharmaceutical composition is formulated for administering to a subject. In some aspects, the compound of the pharmaceutical composition has a formula represented by structure IV or the pharmaceutically acceptable salt thereof:   R3b1R3b2where each R1can be or a C1 to C6 alkyl group; each R2aandthen there is a double bond between O and C and R2bis not present); n can be an integer from 0 to 10, 1 to 8, 2 to 6, or 2 to 4; and R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group. In some aspects, n can be an integer from 0 to 10. In other aspects, nTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4 or 1 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3.

[0073] In some aspects, each R1can be independently selected from hydrogen, a halogen, and a C1 to C3 alkyl group. In further aspects, each R1can be independently selected from hydrogen a halogen, and methyl. In other aspects, one of R1can be a C1 to C6 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1can be a C1 to C3 alkyl group and the other of R1are hydrogen or a halogen. In further aspects, one of R1is a methyl and the other of R1are hydrogen or a halogen.

[0074] In some aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a substituted or unsubstituted aryl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be an aryl group substituted with at least one C1R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a substituted or unsubstituted phenyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In other aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one C1 to C6 alkyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In further aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one C1 to C3 alkyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In further aspects, one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be a phenyl group substituted with at least one methyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are hydrogen or a halogen. In some aspects, R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2can be independently selected from hydrogen or one of the following: .TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0075] In other aspects, one of R3a, R3b, R3c, R3d, or R3ecan be one of the following: and theR3e2are hydrogen or a halogen.

[0076] In yet another aspect, this disclosure provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject. In some aspects, the pharmaceutical composition can include a therapeutically effective amount of a haloperidol derivative compound to treat a condition (e.g., inflammatory arthritis) in a subject (e.g., animal or human subject). In some aspects, the pharmaceutical composition also includes a pharmaceutically acceptable carrier. In other aspects, the pharmaceutical composition is formulated for administering to a subject. In some aspects, the compound of the pharmaceutical composition has a formula represented by the structures in Figure 10 or the pharmaceutically acceptable salt thereof. As described previously, FIG.10 shows families of haloperidol derivatives. Each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 can be independently selected from hydrogen, halogen, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group. In some aspects, n can be an integer from 0 to 8 or 0 to 10. In other aspects, n can be an integer from 2 to 10. In some aspects, n can be an integer from 0 to 4 or 1 to 4. In other aspects, n can be an integer from 1 to 3. In further aspects, n is 3.

[0077] The present disclosure also provides for a method for treating a condition including administering to a subject in need thereof, a pharmaceutical composition including a therapeutically effective amount of any one of the haloperidol derivative compounds or related pharmaceutical composition disclosed herein. In some aspects, the condition to be treated is inflammatory arthritis. In further aspects, the condition to be treated is gout. In other aspects, the condition to be treated is any inflammation-related disease, such as those caused at least in part by or contributed to by inflammasomes.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) Pharmaceutical Formulations and Routes of Administration

[0078] Embodiments of the present disclosure include the agent (e.g., haloperidol derivatives) as identified herein and can be formulated with one or more pharmaceutically acceptable excipients, diluents, carriers and / or adjuvants. In addition, embodiments of the present disclosure include the agent formulated with one or more pharmaceutically acceptable auxiliary substances. In particular the agent can be formulated with one or more pharmaceutically acceptable excipients, diluents, carriers, and / or adjuvants to provide an embodiment of a composition of the present disclosure.

[0079] A wide variety of pharmaceutically acceptable excipients are known in the art. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7thed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3rded. Amer. Pharmaceutical Assoc.

[0080] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[0081] In an embodiment of the present disclosure, the agent can be administered to the subject using any means capable of resulting in the desired effect. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. For example, the agent can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[0082] In pharmaceutical dosage forms, the agent may be administered in the form of its pharmaceutically acceptable salts, or a subject active composition may be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[0083] For oral preparations, the agent can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such asTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0084] Embodiments of the agent can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0085] Embodiments of the agent can be utilized in aerosol formulation to be administered via inhalation. Embodiments of the agent can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.

[0086] Furthermore, embodiments of the agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Embodiments of the agent can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[0087] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more compositions. Similarly, unit dosage forms for injection or intravenous administration may comprise the agent in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[0088] Embodiments of the agent can be formulated in an injectable composition in accordance with the disclosure. Typically, injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or the active ingredient (triamino-pyridine derivative and / or the labeled triamino-pyridine derivative) encapsulated in liposome vehicles in accordance with the present disclosure.

[0089] In an embodiment, the agent can be formulated for delivery by a continuous delivery system. The term “continuous delivery system” is used interchangeably herein with “controlled delivery system” and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0090] Mechanical or electromechanical infusion pumps can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos.4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, delivery of the agent can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. In some embodiments, the agent can be in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.

[0091] In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to, a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are used in some embodiments because of convenience in implantation and removal of the drug delivery device.

[0092] Drug release devices suitable for use in the disclosure may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.

[0093] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos.4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, a subject treatment method can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are used in some embodiments due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97 / 27840 and U.S. Pat. Nos.5,985,305 and 5,728,396). ExemplaryTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) osmotically-driven devices suitable for use in the disclosure include, but are not necessarily limited to, those described in U.S. Pat. Nos.3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.

[0094] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted herein, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.

[0095] In some embodiments, the agent can be delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of the agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos.4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present disclosure is the Synchromed infusion pump (Medtronic).

[0096] Suitable excipient vehicles for the agent are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents. Methods of preparing such dosage forms are known, or will be apparent upon consideration of this disclosure, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 17th edition, 1985. The composition or formulation to be administered will, in any event, contain a quantity of the agent adequate to achieve the desired state in the subject being treated.

[0097] Compositions of the present disclosure can include those that comprise a sustained- release or controlled release matrix. In addition, embodiments of the present disclosure can be used in conjunction with other treatments that use sustained-release formulations. As used herein, a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-based hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylacticTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxcylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. Illustrative biodegradable matrices include a polylactide matrix, a polyglycolide matrix, and a polylactide co-glycolide (co-polymers of lactic acid and glycolic acid) matrix.

[0098] In another embodiment, the pharmaceutical composition of the present disclosure (as well as combination compositions) can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (Sefton (1987). CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al. (1980). Surgery 88:507; Saudek et al. (1989). N. Engl. J. Med.321:574). In another embodiment, polymeric materials are used. In yet another embodiment a controlled release system is placed in proximity of the therapeutic target thus requiring only a fraction of the systemic dose. In yet another embodiment, a controlled release system is placed in proximity of the therapeutic target, thus requiring only a fraction of the systemic. Other controlled release systems are discussed in the review by Langer (1990). Science 249:1527-1533.

[0099] In another embodiment, the compositions of the present disclosure (as well as combination compositions separately or together) include those formed by impregnation of the agent described herein into absorptive materials, such as sutures, bandages, and gauze, or coated onto the surface of solid phase materials, such as surgical staples, zippers and catheters to deliver the compositions. Other delivery systems of this type will be readily apparent to those skilled in the art in view of the instant disclosure. Dosages

[0100] Embodiments of the agent (e.g., haloperidol derivatives) can be administered to a subject in one or more doses. Those of skill will readily appreciate that dose levels can vary as a function of the specific the agent administered, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0101] In an embodiment, multiple doses of the agent are administered. The frequency of administration of the agent can vary depending on any of a variety of factors, e.g., severity of the symptoms, and the like. For example, in an embodiment, the agent can be administered once per month, twice per month, three times per month, every other week (qow), once perTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid). As discussed above, in an embodiment, the agent is administered continuously.

[0102] The duration of administration of the agent, e.g., the period of time over the agent is administered, can vary, depending on any of a variety of factors, e.g., patient response, etc. For example, the agent in combination or separately, can be administered over a period of time of about one day to one week, about two weeks to four weeks, about one month to two months, about two months to four months, about four months to six months, about six months to eight months, about eight months to 1 year, about 1 year to 2 years, or about 2 years to 4 years, or more.

[0103] Dosage at concentrations as high as 60 micrograms / kilograms that are non-toxic. Also lower concentrations, such as 1-4 micrograms / kilogram, show biological activity in in vivo systems. The concentration in in vitro established at 10-9-10-6M are active and this concentration is expected to be achieved in the cell environment. (See Slominski AT, Janjetovic Z, Fuller BE, Zmijewski MA, Tuckey RC, et al. (2010) Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity. PLoS ONE 5(3): e990; Slominski AT, Kim T-K., Janjetovic Z, Tuckey RC, Bieniek, R, Yue Y, Li W, Chen J, Miller D, Chen T, Holick M (2011) 20- hydroxyvitamin D2 is a non-calcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells. Am J Physiol: Cell Physiol 300:C526-C541; Wang J, Slominski AT, Tuckey RC, Janjetovic Z, Kulkarni A, Chen J, Postlethwaite A, Miller D, Li W (2012) 20-Hydroxylvitamin D3possesses high efficacy against proliferation of cancer cells while being non-toxic. Anticancer Res 32: 739-746; Slominski A, Janjetovic Z, Tuckey RC, Nguyen MN, Bhattacharya KG, Wang J, Li W, Jiao Y, Gu W, Brown M, Postlethwaite AE (2013) 20-hydroxyvitamin D3, noncalcemic product of CYP11A1 action on vitamin D3, exhibits potent antifibrogenic activity in vivo. J Clin Endocrinol Metab 98, E298-E30; Chen, J., J. Wang, T. Kim, E. Tieu, E. Tamg, Lin Z, D. Kovacic, D. Miller, A. Postlethwaite, R. Tuckey, A. Slominski and W. Li (2014). Novel Vitamin D Analogs as Potential Therapeutics: The Metabolism, Toxicity Profiling, and Antiproliferative Activity. Anticancer Res 34: 2153-2163.)

[0104] In an aspect, the dosage for administering to a subject (e.g., a mammal such as a human) having a condition (e.g., gout) of any single agent of the present disclosure is about 2TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) to 60 micrograms / kilogram or a combination of agents, each agent can be about 2 to 60 micrograms / kilogram. Routes of Administration

[0105] Embodiments of the present disclosure provide methods and compositions for the administration of the agent (e.g., haloperidol derivatives) to a subject (e.g., a human) using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as systemic and localized routes of administration.

[0106] Routes of administration include intranasal, intramuscular, intratracheal, subcutaneous, intradermal, topical application, intravenous, rectal, nasal, oral, and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the agent and / or the desired effect. An agent can be administered in a single dose or in multiple doses.

[0107] Embodiments of the agent can be administered to a subject using available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes. In general, routes of administration contemplated by the disclosure include, but are not limited to, enteral, parenteral, or inhalational routes.

[0108] Parenteral routes of administration other than inhalation administration include, but are not limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes, i.e., any route of administration other than through the alimentary canal. Parenteral administration can be conducted to effect systemic or local delivery of the agent. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.

[0109] In an embodiment, the agent can also be delivered to the subject by enteral administration. Enteral routes of administration include, but are not limited to, oral and rectal (e.g., using a suppository) delivery.

[0110] Methods of administration of the agent through the skin or mucosa include, but are not limited to, topical application of a suitable pharmaceutical preparation, transdermal transmission, injection and epidermal administration. For transdermal transmission, absorption promoters or iontophoresis are suitable methods. Iontophoretic transmission may be accomplished using commercially available "patches" that deliver their product continuously via electric pulses through unbroken skin for periods of several days or more.

[0111] While embodiments of the present disclosure are described in connection with the Examples and the corresponding text and figures, there is no intent to limit the disclosure toTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) the embodiments in these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.

[0112] While embodiments of the present disclosure are described in connection with the Examples and the corresponding text and figures, there is no intent to limit the disclosure to the embodiments in these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure. EXAMPLE 1

[0113] Gout is the most common form of inflammatory arthritis and is estimated to affect 2 to 3% of the world’s population (1). Over the last three decades, the incidence of gout has roughly doubled in most of the world (2). Typically, gout it is characterized by episodic acute inflammatory events, which are termed gout flares (3). A common feature of gout is the deposition of monosodium urate (MSU) crystals deposition in and around joints (4). A principal therapy for gout is the reduction of serum urate levels to enable dissolution of deposited crystals (5, 6). Other first-line therapies include non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids to limit the inflammation and pain that accompany gout flares. Unfortunately, many patients tolerate these therapies poorly or respond inadequately (7). Urate crystals activate the NLRP3 inflammasome (8) and inhibitors of interleukin-1β (IL- 1β), a cytokine released by inflammasome activation (9), are also part of the therapeutic armamentarium against gout (10, 11). However, IL-1β inhibitors carry a high economic cost as well as a serious adverse event profile.

[0114] Although several drugs are approved for the management of gout, most have significant potential side effects. Further, to date no medications have been approved for reducing the risk of gout or preventing the disease. Therefore, there is a need to explore alternate therapeutic strategies. One such approach is to identify existing FDA-approved therapies that could be repurposed as treatments for new indications (12) by analyzing drug- disease associations using health insurance databases. Recently, we reported that exposure to haloperidol, an FDA-approved drug for the treatment of schizophrenia or Tourette’s disorder, reduced the risk of incident rheumatoid arthritis (13). Since inflammasome activation plays a critical role in rheumatoid arthritis as well (14), we studied whether haloperidol use might also protect against the development of gout. We also investigated potential mechanisms underlying the anti-inflammatory effect of haloperidol.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) Methods and Materials Health Insurance Claims Databases Analyses

[0115] Health insurance database information contains de-identified data that are Health Insurance Portability and Accountability Act (HIPAA)-compliant and were deemed by the University of Virginia Institutional Review Board (IRB) as exempt from IRB approval requirements. The retrospective study used claims data from the PearlDiver Mariner database, which contains data on health care claims and medication usage for persons in provider networks over the time period 2010 to 2022.

[0116] Patients were included in the analysis if they had continuous enrollment in the plan for at least 6 months, were at least 18 years of age at baseline, and were confirmed to have schizophrenia or Tourette’s disorder (diagnosed on at least 2 separate occasions). Individuals with pre-existing gout prior to diagnosis of schizophrenia or Tourette’s disorder were excluded. Disease claims were identified by International Classification of Diseases (ICD)-9- CM and ICD-10-CM codes. Exposure to Haloperidol or other anti-psychotics – the independent variable – was determined by whether patients filled pharmacy prescriptions for generic or brand versions, as identified by National Drug Codes. Time from diagnosis of Schizophrenia or Tourette’s to initial diagnosis of gout was the dependent variable.

[0117] Analyses were performed using R Studio, Version 2023.06.0+421 (the R project). To analyze the risk of gout between haloperidol users and haloperidol non-users (those who used other anti-psychotics), an adjusted Cox proportional hazards regression analysis was performed, and the hazard ratio was analyzed. The adjusted model included these confounding variables: Age, Sex, Smoking, Body Mass Index, and Charlson Comorbidity Index, and Year of plan entry. The haloperidol Yes and haloperidol No groups were also matched for these variables using greedy nearest neighbor propensity score matching using the R package MatchIt. Cox models were analyzed by chi square test. Patients were censored when they developed gout, left the plan, or switched to the other class of anti-psychotic. Statistical tests were 2-sided. P values < 0.05 were considered statistically significant. Cell culture studies

[0118] All cell culture experiments were compliant with University of Virginia Institutional Biosafety Committee regulations. Human THP-1 macrophages were cultured in RMPI-1640 media (ThermoFisher) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin– streptomycin. Human fibroblasts (Cell Applications) were cultured in HFLS medium (Cell Applications). Cells were maintained at 37 °C in a 5% CO2environment. ASC speck imagingTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0119] THP-1 cells were seeded on chambered coverslips (30,000 cells / well) for 12 h were pretreated with Haloperidol (1 μM, Sigma-Aldrich) or 0.1% DMSO (control) for 2 h. Cells were treated with LPS (125 ng / mL) for 4 h and ATP (5 mM) for 15 min. Coverslips were fixed with 2% PFA (15 min at room temperature), washed with PBS, permeabilized, blocked with blocking buffer (PBS, 0.1% TX-100, 5% normal rabbit serum; 1 h at 4 °C), incubated with rabbit anti-human ASC antibody (AdipoGen, 1:200) with blocking buffer, and visualized with goat anti-rabbit-488 (ThermoFisher, 1:500). DAPI-stained slides were mounted using Fluoromount-G (Southern Biotech) and imaged by confocal microscopy (Nikon A1R). The number of ASC specks per 0.09 mm2field was quantified. Means were compared using two-tailed Student t test. Caspase-1 western blotting

[0120] THP-1 cells were treated with LPS and ATP and pre-treated with Haloperidol (0.1–1 μM) for 1 h. Proteins from the cell-free supernatant were precipitated by adding sodium deoxycholate (0.15% final), followed by adding TCA (7.2% final) and incubating on ice overnight. Samples were spun down at 12000g for 30 min and pellets were washed 2 times with ice-cold acetone. Precipitated proteins solubilized in 4X LDS Buffer with 2- mercaptoethanol were resolved by SDS-PAGE on Novex® Tris-Glycine Gels (Invitrogen) and transferred onto low fluorescence PVDF membranes (Biorad). The transferred membranes were blocked with LI-COR block for 1 h at room temperature and then incubated with anti-human caspase-1 antibody (AdipoGen, 1:1000) at 4 °C overnight. The immunoreactive bands were visualized using species-specific secondary antibodies conjugated with IRDye®. Blot images were captured using an Odyssey® imaging system. IL-1β and IL-6 ELISA

[0121] THP-1 cells and fibroblasts were treated with LPS and ATP and treated with haloperidol (0.01–100 µM) as above. Secreted IL-β and IL-6 in the conditioned cell culture media were detected using ELISA kits (R&D Systems) according to the manufacturer's instructions. Means were compared using two-tailed Student t test or one-way ANOVA with post hoc Tukey’s test. Biotin-Haloperidol synthesisTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0122] Haloperidol (I) (150 mg, 0.4 mmol) was dissolved in anhydrous dichloromethane (DCM, 10 mL). To the solution, p-nitrophenyl chloroformate (160 mg, 0.8 mmol) and triethylamine (Et3N, 139 μL, 1.0 mmol) were added. The reaction was stirred for 1 hour at RT and then added dropwise to a solution of ethylenediamine (EDA, 267 μL, 4 mmol) in dimethylformamide (DMF, 20 mL). The reaction was stirred overnight. The haloperidol- amino ethyl carbamate (haloperidol-AEC) (II) product was purified by washing with 0.1 M sodium hydrocarbonate (3 × 200 mL), followed by chromatography on a SiO2 column (30 × 2.5 cm) eluted with a chloroform-methanol mixture (90 : 10 to only methanol) and determined by TLC analysis. Streptavidin pulldown

[0123] To detect binding partners of Haloperidol, LPS-primed wild-type mouse BMDMs lysed with NP-40 lysis buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% NP-40, 5 mM EDTA and 0.1% Triton-X 100) on wet ice, and centrifuged 12,000 rpm for 15 minutes at 4°C. The supernatant lysates were then pre-cleaned by streptavidin magnetic beads (88816, Thermo Fisher) to remove unspecific binding. These pre-treated proteins were incubated with free haloperidol and biotinylated haloperidol, as indicated, for 1 hour on ice bath. Then, these samples were incubated with pre-activated streptavidin magnetic beads overnight at 4°C with rotation. On the next day, the beads were washed with lysis buffer for three times, and thenTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) boiled with SDS sample buffer (LC2676, Thermo Fisher) for further mass spectrometry analysis. Untargeted Protein Identification and Label-free Quantification via Tandem Mass Spectrometry

[0124] Immunoprecipitated samples were submitted on beads and supernatant was exchanged for 100 mM ammonium bicarbonate, pH 7.5. Samples were reduced with 5 mM dithiothreitol for 90 min at room temperature, and alkylated with 10 mM iodoacetamide for 45 min at room temperature, protected from light. Modified porcine trypsin protease (Promega #V5113) was added at a ratio of 1:20 w / w enzyme:protein at 37°C and incubated overnight, and the digestion was quenched with formic acid. Peptides were then desalted by reverse-phase chromatography using Pierce peptide desalting spin columns (Thermo Fisher part #89852), dried completely, and resuspended in Solvent A (0.1% formic acid in Fisher Optima LC / MS grade water). Samples were quantified by A280 absorbance and total injection amount was normalized.

[0125] Samples were subjected to mass analysis using a Thermo Scientific Ultimate 3000 RSLCnano ultra-high performance liquid chromatography (UPLC) system coupled to a high- resolution Thermo Scientific Eclipse Tribrid Orbitrap mass spectrometer. These analyses were performed at the University of Connecticut Proteomics & Metabolomics Facility. Each sample was injected onto a nanoEase M / Z Peptide BEH C18 column (1.7 μm, 75 μm x 250 mm, Waters Corporation) and separated by reversed-phase UPLC using a gradient of 4-90% Solvent B (0.1% formic acid in Fisher Optima LC / MS grade acetonitrile) over a 60-min gradient at 300 nL / min flow, followed by a 10-min wash and 20-min column re-equilibration. Peptides were eluted directly into the Eclipse using positive mode nanoflow electrospray ionization with source spray voltage set to 2200 V. MS1 scans were acquired at 120,000 resolution, with AGC target set to Standard, maximum injection time set to Auto, RF lens set at 30%, and scan range set for 300-1800 m / z. Data-dependent MS2 scans were collected for ions in charge states 2-8 at a minimum intensity of 5.0e4. Scans were acquired in the Orbitrap at 15,000 resolution, with AGC target set to Standard, maximum injection time set to Dynamic, isolation window set to 1.6 m / z, for a cycle time of 3 sec. Fragmentation was performed using HCD at 30% energy. Dynamic exclusion was enabled after 1 observation, for 30 sec, with a tolerance window of 20 ppm total.

[0126] Peptides were identified using MaxQuant (v1.6.10.43) and its embedded Andromeda search engine and quantified by label-free quantification (15). The raw data were searched against both the complete UniProt Mus Musculus reference proteome (identifierTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) UP000000589, accessed 12 Jan 2022) and the MaxQuant contaminants database. Variable modifications allowed oxidation of Met, acetylation of protein N-termini, deamidation of Asn / Gln, and peptide N-terminal Gln to pyroGlu conversion. Carbamidomethylation of Cys was set as a fixed modification. Protease specificity was set to trypsin / P with a maximum of 2 missed cleavages. All results were filtered to a 1% false discovery rate at the peptide and protein levels using the target-decoy approach; all other parameters were kept at default values. MaxQuant output files were imported into Scaffold (Proteome Software, Inc.) for data visualization and subsequent analyses. Results Haloperidol associated with reduced risk of gout

[0127] We evaluated haloperidol, in the PearlDiver Mariner (151 million people from 2010 to 2022) database by comparing patients diagnosed with schizophrenia or Tourette’s disorder (the population at risk) on the basis of use of haloperidol versus use of other anti-psychotic drugs. We performed a retrospective, longitudinal cohort analysis using a Cox proportional hazards regression analyses to estimate the hazard of gout in relation to haloperidol use. Since individuals in this database were not randomly assigned to haloperidol treatment, we performed propensity score matching, a causal inference approach (16), to assemble cohorts with similar baseline characteristics, thereby reducing possible bias in estimating treatment effects. Additionally, to control for any residual covariate imbalance, we adjusted for confounders associated with gout: age, sex, smoking, and body mass index, Charlson comorbidity index (a measure of overall health), and year of entry into the database. The adjusted Cox proportional hazards regression model in the propensity-score-matched populations showed a protective association of haloperidol use against incident gout (aHR = 0.762; 95% CI, 0.713, 0.813; P < 0.001) (Table 1). Table 1 HR (95% CI)Haloperidol 0.762 (0.713–0.813)TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) HR, hazard ratio. CI, confidence interval. BMI, body mass index. CCI, Charlson comorbidity index Haloperidol inhibits inflammasome activation

[0128] Since haloperidol use was associated with reduced risk of rheumatoid arthritis (13) and gout, we sought to understand the mechanisms by which haloperidol could confer such protection. Inflammasome activation is considered a key driver of rheumatoid arthritis and gout since patients with rheumatoid arthritis and gout exhibit high levels of the inflammasome constituents NLRP3, ASC, or Caspase-1 (14, 17). In addition, lipopolysaccharide (LPS) and adenosine triphosphate (ATP), which activate the inflammasome (18), are also elevated in patients with rheumatoid arthritis (19–21). Similarly, uric acid, which also activates the inflammasome (8), is elevated in patients with gout (4).

[0129] First, we tested whether haloperidol could inhibit inflammasome assembly by monitoring ASC speck formation (22) in human THP-1 macrophages using immunofluorescence. Haloperidol inhibited LPS and ATP-induced ASC speck formation (FIG.1) (P = 0.007), indicating that haloperidol blocked inflammasome assembly.

[0130] Next, we monitored inflammasome activation by assessing cleavage of inactive pro- caspase-1 into active caspase-1 (18) in macrophages, using western blotting. Haloperidol robustly inhibited LPS and ATP-induced caspase-1 cleavage, confirming that haloperidol inhibits inflammasome activation (FIG.2).

[0131] Finally, we used ELISA to quantify levels of interleukin (IL)-1β, a cardinal inflammasome output, and IL-6, which lies mechanistically downstream of IL-1β, both of which are elevated in rheumatoid arthritis patients (23) and gout (24, 25). In rheumatoid arthritis, the principal cellular source of IL-1β is macrophages and that of IL-6 is synovial (joint) fibroblasts (26). We found that IL-1β release in macrophages was robustly induced by LPS and ATP stimulation, and it was reduced by exposure to Haloperidol in a dose- dependent manner (P < 0.05) (FIG.3A). The downstream impact of inflammasome activation was assessed in human synovial fibroblasts by measuring IL-6 secretion. IL-6 release was robustly induced by LPS and ATP stimulation, and it was reduced by haloperidol in a dose-dependent manner (FIG.3B).

[0132] Similarly, IL-1β release in macrophages was robustly induced by MSU stimulation, and it too was reduced by exposure to Haloperidol in a dose-dependent manner (P < 0.05) (FIG.4). These data demonstrate that haloperidol inhibits inflammasome activation and subsequent inflammatory pathways.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) Haloperidol – Mass spectrometry

[0133] Haloperidol is presumed to exert its anti-psychotic effects via its antagonism of the D2 dopamine receptor. Given this novel inflammasome-inhibitory activity we identified, we sought to determine whether haloperidol might have another receptor. Therefore, we performed mass spectrometry proteomics using a pull-down strategy with a biotin-conjugated haloperidol affinity probe. We synthesized this probe using an intermediate aminoethylcarbamate derivative of haloperidol, which provided a handle upon which a biotin linker could be attached (Methods). We then incubated LPS-primed wild-type mouse bone marrow derived macrophage lysates with biotinylated haloperidol and performed a streptavidin pull down. To identify specific binding partners, we performed a competition control with free (unconjugated) haloperidol. We also used a biotin alone pull down as a negative control. Using tandem mass spectrometry, we found the top specific hit to be the lysosomal protein LAMTOR1 (FIG.5). Multiple peptides corresponding to LAMTOR1, collectively comprising 52% coverage of the protein, were identified in the pull down with biotinylated haloperidol. In contrast, no peptides corresponding to LAMTOR1 were identified in the pull downs with biotin alone or when biotin-haloperidol was incubated along with an excess of free haloperidol as a competitor. Table 2 Exclusive Exclusive Total LAMTOR1 unique LAMTOR1 unique LAMTOR1TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0134] We found this interesting as LAMTOR1 was recently identified to be a binding partner for NLRP3 that was also critical for inflammasome activation (27). We found that LPS+ATP induced peri-nuclear aggregation of NLRP3 and LAMTOR1 in human THP-1 cells, confirming the recent report. Interestingly, treatment with haloperidol markedly reduced the aggregation of NLRP3 and LAMTOR1 (FIG.6). These data are compatible with haloperidol binding LAMTOR1 and disrupting its association with NLRP3, thereby reducing inflammasome activation. Haldol – LAMTOR1 docking model

[0135] To better understand the interaction between haloperidol and LAMTOR1, we performed a protein-ligand docking study using the SeamDock web server (28). LAMTOR1 exists in a complex with LAMTOR2, LAMTOR3, LAMTOR4, and LAMTOR5 in a structure known as the Ragulator complex (29). Therefore, we submitted the axial conformation of haloperidol and the 5YK3 PDB structure of the Ragulator complex (29) to the SeamDock docking engine. An energetically favorable docking complex was identified with a Gibbs free energy of –8.1 kcal / mol (FIG.7). This high-affinity complex corresponds to a dissociation constant (Kd) of ~2 ^M at 37 ^C, which is compatible with the observed IC50of ~8 ^M for haloperidol in inhibiting IL-1^ release in cell culture models.

[0136] In this model, haloperidol binds to 5 amino acids of LAMTOR1 and 2 amino acids of LAMTOR3. This binding is sustained by 6 hydrophobic bonds and 6 hydrogen bonds. Hydrophobic bonds were identified between haloperidol and LAMTOR1 (amino acids 93, 94, 95) and LAMTOR3 (amino acid 119). Hydrogen bonds were identified between haloperidol and LAMTOR1 (amino acids 93, 94, 97, 98) and LAMTOR3 (amino acid 3). Another docking complex in an alternate pose with a Gibbs free energy of –7.9 kcal / mol in a very similar pose was also identified with interactions in similar regions (FIG.8). Derivatives of Haloperidol

[0137] Haloperidol is known to antagonize the D2 dopamine receptor. In this study, we identified LAMTOR1 as a novel interacting partner of haloperidol. D2 dopamine blockade by haloperidol is thought to be responsible for much of its undesirable side effects. Therefore, we propose the following new chemical entities (FIGS.9, 10 and Table 3), which are derivatives of haloperidol designed to preserve binding to LAMTOR1, based on our docking models, and minimize binding to the D2 dopamine receptor, based on a crystal structure of haloperidol bound to it (30).TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) Table 3 Nf t t^ ^Discussion

[0138] We identified a significant association between haloperidol use and a reduced risk of incident gout. A strength of the insurance database analysis is its large size, which constitutes a majority of all U.S. adults. Another strength is adjustment for confounders and propensity score matching, which simulates randomization and increases the validity of the conclusion. Nevertheless, as this retrospective study was not randomized, there could be residual confounding or selection bias.

[0139] We also present biochemical evidence that haloperidol reduces inflammasome activation in cell culture systems. Our discovery of LAMTOR1 as a novel interacting partner of haloperidol could provide further insight into the full spectrum of this drug’s effects. Given that LAMTOR1 is a chaperone for NLRP3, haloperidol could also be used as a tool toTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) dissect inflammasome assembly and activation. Further, the new chemical derivatives we designed could retain activity against inflammasome activation and avoid dopamine antagonism.

[0140] These investigations collectively suggest a potential beneficial effect of haloperidol in forestalling gout onset. These studies also provide a rationale for performing randomized controlled trials of haloperidol for gout, which can provide insights into causality. Traditional approaches to drug development consume more than a decade and nearly $3 billion, with more than 99% of drug candidates failing (31). Our identification of this unrecognized activity of an existing FDA-approved drug could accelerate a new therapeutic approach for gout.

[0141] The tissue concentration of haloperidol in schizophrenia patients is 10 µM (32, 33). We found that lower concentrations of haloperidol (0.1–1 µM) also could reduce inflammasome activation. Therefore, doses of haloperidol lower than currently prescribed for mental disorders might be beneficial for gout. As haloperidol is a cell-permeable small molecule, another potential mode of delivery is a sustained release implant or transdermal patch. Alternatively, it could be directly injected into affected joints. Such strategies could limit potential side effects. References for Example 1 1. M. Dehlin, L. Jacobsson, E. Roddy, Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol 16, 380–390 (2020). 2. Z. Jin, et al., Incidence trend of five common musculoskeletal disorders from 1990 to 2017 at the global, regional and national level: results from the global burden of disease study 2017. Ann Rheum Dis 79, 1014–1022 (2020). 3. D. Bursill, et al., Gout, Hyperuricaemia and Crystal-Associated Disease Network (G- CAN) consensus statement regarding labels and definitions of disease states of gout. Ann Rheum Dis 78, 1592–1600 (2019). 4. D. J. Mccarty, J. L. Hollander, Identification of urate crystals in gouty synovial fluid. Ann Intern Med 54, 452–460 (1961). 5. J. D. FitzGerald, et al., 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken) 72, 744–760 (2020). 6. P. Richette, et al., 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 76, 29–42 (2017).TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) 7. R. T. Keenan, et al., Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med 124, 155–163 (2011). 8. F. Martinon, V. Pétrilli, A. Mayor, A. Tardivel, J. Tschopp, Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). 9. F. Martinon, K. Burns, J. Tschopp, The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10, 417–426 (2002). 10. F. Sivera, M. D. Wechalekar, M. Andrés, R. Buchbinder, L. Carmona, Interleukin-1 inhibitors for acute gout. Cochrane Database Syst Rev, CD009993 (2014). 11. N. Schlesinger, Anti-interleukin-1 therapy in the management of gout. Curr Rheumatol Rep 16, 398 (2014). 12. M. S. Boguski, K. D. Mandl, V. P. Sukhatme, Drug discovery. Repurposing with a difference. Science 324, 1394–1395 (2009). 13. Ambati, V. L., et al., Association between haloperidol use and risk of rheumatoid arthritis. Medcomm Fut Med 2, e66 (2023). 14. R. J. Mathews, et al., Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis 73, 1202–1210 (2014). 15. J. Cox, M. Mann, MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26, 1367–1372 (2008). 16. P. R. Rosenbaum, D. B. Rubin, The central role of the propensity score in observational studies for causal effects. Biometrika 70, 41–55 (1983). 17. N. Dalbeth, et al., Gout. Nat Rev Dis Primers 5, 69 (2019). 18. S. Mariathasan, et al., Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004). 19. A. Tripathy, P. Padhan, N. Swain, S. K. Raghav, B. Gupta, Increased Extracellular ATP in Plasma of Rheumatoid Arthritis Patients Activates CD8+T Cells. Arch Med Res 52, 423–433 (2021). 20. M. Arabski, et al., The presence of anti-LPS antibodies and human serum activity against Proteus mirabilis S / R forms in correlation with TLR4 (Thr399Ile) gene polymorphism in rheumatoid arthritis. Clin Biochem 45, 1374–1382 (2012).TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) 21. J. Parantainen, et al., The biological activity of serum bacterial lipopolysaccharides associates with disease activity and likelihood of achieving remission in patients with rheumatoid arthritis. Arthritis Res Ther 24, 256 (2022). 22. J. Masumoto, et al., ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem 274, 33835–33838 (1999). 23. N. Komatsu, H. Takayanagi, Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol 18, 415–429 (2022). 24. J.-Y. Choe, G. H. Lee, S.-K. Kim, Radiographic bone damage in chronic gout is negatively associated with the inflammatory cytokines soluble interleukin 6 receptor and osteoprotegerin. J Rheumatol 38, 485–491 (2011). 25. P.-C. Tsai, C.-J. Chen, H.-M. Lai, S.-J. Chang, Analysis of polymorphisms in the promoter region and protein levels of interleukin-6 gene among gout patients. Clin Exp Rheumatol 26, 841–847 (2008). 26. F. Zhang, et al., Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol 20, 928–942 (2019). 27. K. Tsujimoto, et al., The lysosomal Ragulator complex activates NLRP3 inflammasome in vivo via HDAC6. EMBO J 42, e111389 (2023). 28. S. Murail, S. J. de Vries, J. Rey, G. Moroy, P. Tufféry, SeamDock: An Interactive and Collaborative Online Docking Resource to Assist Small Compound Molecular Docking. Front Mol Biosci 8, 716466 (2021). 29. Z. Mu, L. Wang, W. Deng, J. Wang, G. Wu, Structural insight into the Ragulator complex which anchors mTORC1 to the lysosomal membrane. Cell Discov 3, 17049 (2017). 30. L. Fan, et al., Haloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands. Nat Commun 11, 1074 (2020). 31. J. A. DiMasi, H. G. Grabowski, R. W. Hansen, Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ 47, 20–33 (2016). 32. B. Swathy, M. Banerjee, Haloperidol induces pharmacoepigenetic response by modulating miRNA expression, global DNA methylation and expression profiles of methylation maintenance genes and genes involved in neurotransmission in neuronal cells. PLoS One 12, e0184209 (2017). 33. J. Kornhuber, et al., Persistence of haloperidol in human brain tissue. Am J Psychiatry 156, 885–890 (1999).TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) EXAMPLE 2

[0142] Mouse model of gout

[0143] To induce a mouse model of gout, C57BL / 6J mice (6-8 weeks old) were anesthetized with intraperitoneal injection of 100 mg / kg ketamine hydrochloride (Ft. Dodge Animal Health) and 10 mg / kg xylazine (Phoenix Scientific). Monosodium urate (MSU) crystals were injected into the right ankle joint at a concentration of 25 mg / mL in 20 µL of sterile saline. A control group was injected with saline. For haloperidol treatment, mice were pretreated with 10mg / kg of haloperidol in 50μl of 0.1% DMSO solution at 1 hour before MSU injection. The haloperidol treatment was administered twice a day after MSU injection. The vehicle group received 50 µL of 0.1% DMSO solution. Ankle swelling was measured using a digital caliper. The ankle joints were collected for biochemical and histological analysis. All procedures were approved by the University of Virginia’s Institutional Animal Care & Use Committee.

[0144] NLRP3 inflammation detection in ankle joints

[0145] To measure NLRP3 inflammasome activation, the collected ankle joints were lysed using RIPA Lysis and Extraction Buffer (ThermoFisher). Total protein concentration was determined using Pierce™ BCA Protein Assay Kits (ThermoFisher). The expression levels of NLRP3, LAMTOR1, and pro- and cleaved caspase-1 were determined by western blotting with specific antibodies: anti-mouse NLRP3 (AdipoGen, 1:1000), anti-mouse caspase-1 (AdipoGen, 1:1000), and anti-human LAMTOR1 (Cell Signaling Technology). One hundred micrograms of total protein were used to determine IL-1β production in ankle joints using ELISA kits (R&D Systems) according to the manufacturer's instructions.

[0146] Neutrophile staining

[0147] To detect neutrophil infiltration, immunofluorescent staining was performed with an anti-human myeloperoxidase (MPO) antibody (Abcam), which recognizes MPO, a specific marker for activated neutrophils. Briefly, the collected ankle joints were fixed with 4% paraformaldehyde (PFA) and processed for paraffin sectioning. The paraffin sections were deparaffinized by immersing the slides in xylene and an alcohol series (100%, 95%, 70%, and 50%). Antigen retrieval was performed using retrieval buffer (sodium citrate, pH 6.0) in a vegetable steamer for 20 minutes. Sections were then blocked with blocking buffer (PBS, 0.1% TX-100, 5% normal rabbit serum) for 1 hour at 4°C, incubated with rabbit anti-human MPO antibody (Abcam, 1:200) in blocking buffer, and visualized with goat anti-rabbit-555 (ThermoFisher, 1:500). DAPI-stained slides were mounted using Fluoromount-G (Southern Biotech) and imaged by confocal microscopy (Nikon A1R).TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0148] Figures 11A to 11D illustrate NLRP3 inflammasome activation in monosodium urate (MSU)-induced mouse model of gout. Figure 11A is a schematic of the MSU-induced mouse model of gout. Figure 11B illustrates ankle swelling measurement at various timepoints after MSU injections. Figure 11C illustrate immunoblotting analysis of NLRP3 and LAMTOR1 of tissue lysates from ankles at various timepoints after PBS or MSU injections. Figure 11D illustrates ELISA measurement of IL-1β productions in tissue lysates from ankles at various timepoints after PBS or MSU injections.

[0149] Figures 12A to 12C illustrate that haloperidol reduces inflammation and Ankle swelling in MSU-induced mouse model of gout. Figure 12A illustrates ankle swelling measurement of vehicle- or haloperidol-treated groups at various timepoints after PBS or MSU injections. Two-way ANOVA, *p<0.05, **p<0.01. Figure 12B illustrates immunoblotting analysis of LAMTOR1, pro-caspase-1 (45kD) and cleaved caspase-1 (20kD) of tissue lysates from vehicle- or haloperidol-treated groups at various timepoints after PBS or MSU injections. Figure 12C illustrates ELISA measurement of IL-1β productions in tissue lysates from vehicle- or haloperidol-treated groups at various timepoints after PBS or MSU injections. Two-way ANOVA, *p<0.05.

[0150] Figure 13 illustrates that haloperidol reduces neutrophil infiltration in MSU-induced mouse model of gout. Figure 13 illustrates confocal images of Myeloperoxidase (MPO) positive neutrophils in ankles tissues at 12 and 24 hours after PBS or MSU injections following treatment of vehicle or haloperidol.

[0151] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a concentration range of “about 0.1 percent to about 5 percent” should be interpreted to include not only the explicitly recited concentration of about 0.1 weight percent to about 5 weight percent but also include individual concentrations (e.g., 1 percent, 2 percent, 3 percent, and 4 percent) and the sub- ranges (e.g., 0.5 percent, 1.1 percent, 2.2 percent, 3.3 percent, and 4.4 percent) within the indicated range. The term “about” can include traditional rounding according to significant figures of the numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)

[0152] Many variations and modifications may be made to the above-described aspects. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) CLAIMS What is claimed:

1. A compound having a formula represented by structure II or the pharmaceutically acceptable salt thereof:  wherein each R1is independently selected from hydrogen, a halogen, or a C1 to C6 alkyl group; R2aand R2bare each independently selected from hydrogen or oxygen, when R2ais oxygen, oxygen has a double bond to the carbon atom and the carbon atom is not bonded to R2bdue to the double bond to carbon; n is an integer from 0 to 8; and R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are each independently selected from hydrogen, halogen, -OH, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group, and wherein the compound is not one of the following: ,TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)2. The compound of claim 1, wherein each R1is independently selected from hydrogen or a C1 to C3 alkyl group.

3. The compound of claim 1, wherein each R1is independently selected from hydrogen or a methyl group.

4. The compound of claim 1, wherein one of R1is a C1 to C6 alkyl group and the other of R1are hydrogen.

5. The compound of claim 1, wherein one of R1is a methyl and the other of R1are hydrogen.

6. The compound of any one of the preceding claims, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is a substituted or unsubstituted aryl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are hydrogen.

7. The compound of any one of the preceding claims, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is a substituted or unsubstituted phenyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are hydrogen.

8. The compound of any one of claims 1-5, wherein R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are independently selected from hydrogen and one of the following:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .

9. The compound of any one of claims 1-5, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is one of the following: and the other of hydrogen.

10. The compound of any one of the preceding claims, wherein n is an integer from 0 to 4.

11. The compound of any one of the preceding claims, wherein n is 4.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound to treat a condition in a subject, wherein the compound has a formula represented by structure II or the pharmaceutically acceptable salt thereof:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03)wherein each R1is independently selected from hydrogen, halogen, or a C1 to C6 alkyl group; R2aand R2bare each independently selected from hydrogen or oxygen, when R2ais oxygen, oxygen has a double bond to the carbon atom and the carbon atom is not bonded to R2bdue to the double bond to carbon; n is an integer from 0 to 8; and R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1and R3e2are independently selected from hydrogen, halogen, -OH, a C1 to C6 alkyl group, or a substituted or unsubstituted aryl group, and wherein the compound is not one of the following: orTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .

13. The pharmaceutical composition of claim 12, wherein each R1is independently selected from hydrogen or a C1 to C3 alkyl group.

14. The pharmaceutical composition of claim 12, wherein each R1is independently selected from hydrogen or a methyl group.

15. The pharmaceutical composition of claim 12, wherein one of R1is a C1 to C6 alkyl group and the other of R1are hydrogen.

16. The pharmaceutical composition of claim 12, wherein one of R1is a methyl and the other of R1are hydrogen.

17. The pharmaceutical composition of any one of claims 12-16, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is a substituted or unsubstituted aryl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are hydrogen.

18. The pharmaceutical composition of any one of claims 12-16, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is a substituted or unsubstituted phenyl group and the other of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are hydrogen.

19. The pharmaceutical composition of any one of claims 12-16, wherein R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2are independently selected from hydrogen and one of the following:TH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) .

20. The pharmaceutical composition of any one of claims 12-16, wherein one of R3a1, R3a2, R3b1, R3b2, R3c1, R3c2, R3d1, R3d2, R3e1or R3e2is one of the following: and the other21. The pharmaceutical composition of any one of claims 12-16, wherein n is an integer from 0 to 4.

22. The pharmaceutical composition of any one of claims 12-16, wherein n is 4.

23. The pharmaceutical composition of any one of claims 12-22, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of any one of claims 12-22, wherein the pharmaceutical composition is formulated for administering to a subject.

25. A method for treating a condition comprising: administering to a subject in need thereof, a pharmaceutical composition, wherein the pharmaceutical composition comprises aTH 222117-2460 UVA LVG Ref. AMBATI-LAMTOR1 (02989-03) therapeutically effective amount of the compound or the pharmaceutical composition of any one of claims 1-24.

26. The method of claim 25, wherein the condition is gout.

27. The method of claim 25, wherein the condition is an inflammatory arthritis, gout, or an inflammation-related disease.

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