OA18219A

OA18219A - Methods and compositions for HIV-related disorders.

Info

Publication number: OA18219A
Application number: OA1201700016
Authority: OA
Inventors: Celia Dominguez; Ignacio Muñoz-Sanjuan; Leticia Toledo-Sherman
Original assignee: Chdi Foundation, Inc.
Priority date: 2014-07-17
Filing date: 2015-07-17
Publication date: 2018-09-04

Abstract

Certain adjunctive therapies comprising a kynurenine-3-monooxygenase inhibitor and an antiviral agent for treating HIV-related disorders are provided herein. These disorders include AIDS dementia complex, AIDS-induced encephalopathy, HIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, minor neurocognitive disorder, minor cognitive motor disorder, vacuolar myelopathy, peripheral neuropathies, and polymyositis. Also provided are pharmaceutical compositions comprising a kynurenine-3-monooxygenase inhibitor and an antiviral agent.

Description

[001] This application claims the benefit of U.S. Provisional Appln. No. 62/025,840, filed July 17, 2014, which is incorporated herein by reference for all purposes.

[002] Provided herein are certain adjunctive thérapies for HIV-related disorders comprising administering a kynurenine-3-monooxygenase inhibitor with an antiviral agent. Also provided herein are pharmaceutical compositions comprising a kynurenine-3-monooxygenase inhibitor and an antiviral agent.

[003] Inflammatory processes contribute significantly to the progression and manifestations of a broad spectrum of central nervous system (CNS) diseases, including acute and chronic microbial infections, autoimmune processes, stroke, and physical trauma to the CNS. There are many mechanisms by which inflammation could cause neurological disease, including the production of neurotoxic agents by the host or invading microbes. Identification of such mediators and the processes that lead to their production and accumulation are important steps in developing rational approaches to therapy. Motor abnormalities, cognitive déficits, and dementia (encephalopathy) are frequent complications of infection with the human immunodeficiency virus (HIV) and can occur independently of opportunistic CNS infections. The most frequent neuropathologic substrate associated with neurological symptoms is HIV encephalitis, an inflammatory condition characterized by the presence of HIV-infected macrophages, astrogliosis, white matter pallor, and neuronal injury (loss of neurons and synapses). The production of toxins by microglia/macrophages has been hypothesized as a possible mechanism responsible for neurological dysfunction and neurodegeneration, because HIV is localized predominantly in microglia/macrophages and because macrophage-tropic isolâtes are associated with neurological disease to a greater extent than T cell tropic isolâtes. Potential host-coded neurotoxins include the NMDA receptor agonist quinolinic acid (QUIN). [004] QUIN is an excitotoxic métabolite ofthe tryptophan-kynurenine pathway. In models of inflammatory neurological disorders such as experimental allergie encephalitis, bacterial and viral infections, forebrain global ischemia or spinal trauma, brain QUIN levels are extremely elevated. This increased brain QUIN concentration could be due to either an elevated circulating concentration ofthe excitotoxin orto an increased de novo synthesis in activated microglia or in infiltrating macrophages. QUIN is an agonist of a subgroup of NMDA receptors and when directly injected into brain areas it destroys most neuronal cell bodies sparing fibers en passant and neuronal terminais. QUIN is a relatively poor agonist ofthe NMDA receptor complex containing either NR2C or NR2D subunits, while it interacts with higher affînity with the NR2A subunit (7-10 pmol) and the NR2B subunit (100 pmol). In vitro, the neurotoxic effects ofthe compound hâve been studied in different model Systems with variable results: chronic exposure of organotypic cortico-striatal cultures to submicromolar concentration of QUIN causes histological signs of pathology; similar results hâve been obtained after chronic exposure of cultured neuronal cells.

[005] Sustained increases in the concentrations of QUIN occur in cérébral spinal fluid (CSF) and blood of HIV-infected patients and macaques infected with the simian immunodeficiency virus (SIV), and begin soon after primary infection. Elevated CSF QUIN is associated with motor déficits and virus recovery from the CNS in the early asymptomatic stages of disease, and correlate with quantitative measures of neuropsychologic déficits, striatal and limbic atrophy, and markers of intrathecal immune activation (CSF p₂-microglobulin and neopterin concentrations) in late stage patients. One study reported that in HIV-infected patients, brain QUIN concentrations were elevated by > 300-fold, to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. Furthermore, in retrovirus-infected macaques, the largest kynurenine pathway responses in brain and CSF were associated with retrovirus-induced encephalitis. Direct measures ofthe amount of QUIN in brain derived from blood in a macaque with encephalitis showed that almost ail QUIN (98%) was synthesized locally within the brain. In contrast to the brain changes, there was no différence in any systemic measure between macaques with encephalitis and those without. These results demonstrate a rôle for induction of indoleamine-2,3-dioxygenase (IDO) in accelerating the local formation of QUIN within the brain tissue, particularly in areas of encephalitis, rather than entry of QUIN into the brain from the méningés or blood. In fact, robust increases in the activities of IDO, and two other enzymes in the kynurenine pathway of tryptophan metabolism, kynurenine-3-monooxygenase (KMO) and kynureninase (KYNU) hâve been found in areas of brain inflammation. Accordingly, strategies to reduce QUIN production, targeted at intracérébral sites, are potential approaches to therapy. [006] The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4(+) T cell déplétion and chronic T cell activation, leading ultimately to AIDS. CD4(+) T helper (T(H)) cells provide protective immunity and immune régulation through different immune cell functional subsets, including T(H)1, T(H)2, T regulatory (T(reg)), and interleukin-17 (IL-17)secreting T(H)17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T(H)17 cells may foster microbial translocation and sustained inflammation. It has been found that in HIV-seropositive subjects progressive disease is associated with the loss of T(H)17 cells and a reciprocal increase in the fraction ofthe immunosuppressive T(reg) cells both in peripheral blood and in rectosigmoid biopsies. The loss of T(H)17/T(reg) balance is associated with induction of indoleamine-2,3dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T(H)17/T(reg) balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid (3-OH-AA). It has been postulated that induction of IDO may represent a critical initiating event that results in inversion of the T(H)17/T(reg) balance and in the conséquent maintenance of a chronic inflammatory state in progressive HIV disease. Accordingly, strategies to lower 3-OHAA levels are predicted to eliminate orameliorate systemic inflammation after HIV infection. [007] KMO catalyzes the conversion of kynurenine (KYN) into 3-hydroxykynurenine (3-HK or 3-OH-KYN), which is further degraded by KYNU to 3-hydroxyanthranilic acid, and then to QUIN. 3-OH-KYN and QUIN act synergistically, i.e. 3-OH-KYN significantly potentiates the excitotoxic actions of QUIN. Studies from several laboratories hâve provided evidence that the shift of KYN pathway metabolism away from the 3-OH-KYN/QUIN branch to increase the formation of the neuroprotectant KYNA (kynurenic acid) in the brain leads to neuroprotection.

[008] In addition to having effects in the brain, the inhibition of KMO is further contemplated to impact peripheral tissues. Based on the rôle of 3-OH-AA in the modulation of T(H)17 cells and IL-17/IL-23 balance in HIV pathogenesis, KMO inhibitors are predicted to prevent increase in microbial translocation across the gastrointestinal mucosa and systemic inflammation in longterm progressors. Thus, the inhibition of KMO may be useful in the treatment of peripheral HIVrelated disorders as well as diseases of the brain.

[009] Compounds and pharmaceutically acceptable salts thereof described herein that inhibit KMO are disclosed in PCT patent publications WO2013/033068 and WO2013/033085, each of which is incorporated herein by reference in its entirety.

[010] There remains a need for methods and compositions that are effective in adjunctively treating disorders associated with HIV infection.

[011] Accordingly, provided is a method of treating an HIV-related disorder in a subject infected with HIV, comprising adjunctively administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:

R²

Formula I or a pharmaceutically acceptable sait thereof;

wherein the subject is also being administered an antiviral agent; and further wherein:

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C-iC4 alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo.

[012] Also provided is a composition comprising an antiviral agent and a compound of Formula I:

Formula I or a pharmaceutically acceptable sait thereof;

wherein:

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C1C₄ alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo.

BRIEF DESCRIPTION OF THE DRAWINGS [013] FIG 1. shows the dose dépendent increase of kynurenine (KYN) in the striatum extracellular space following dosing of Compound 6.

[014] FIG 2. shows the dose dépendent increase of kynurenic acid (KYNA) in the striatum extracellular space following dosing of Compound 6.

[015] FIG 3. shows the dose dépendent increase of anthranilic acid (AA) in the striatum extracellular space following dosing of Compound 6.

[016] FIG 4. shows insufficient modulation of 3-hydroxykynurenine (3-HKor3-OH-KYN) in the striatum extracellular space following dosing of Compound 6.

[017] FIG 5. shows the dose dépendent increase of kynurenine pathway (KP) métabolites in the striatum following dosing of Compound 6 in wild type mice.

[018] FIG 6. shows the dose dépendent increase of kynurenine pathway métabolites in the striatum following dosing of Compound 6 in Q175_KI homozygous mice.

[019] FIG 7. shows the modulation of KYN in the striatum following dosing of Compound 6, KYN, and (Compound 6 + KYN).

[020] FIG 8. shows the modulation of KYNA in the striatum following dosing of Compound 6, KYN, and (Compound 6 + KYN).

[021] FIG 9. shows the modulation of anthranilic acid (AA) in the striatum following dosing of Compound 6, KYN, and (Compound 6 + KYN).

[022] FIG 10. shows the modulation of 3-OH-KYN in the striatum following dosing of Compound 6, KYN, and (Compound 6 + KYN).

[023] FIG 11. shows the modulation of quinolinic acid (QA) in the striatum following dosing of Compound 6, KYN, and (Compound 6 + KYN).

[024] As used in the présent spécification, the following words, phrases and symbols are generally intended to hâve the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms hâve the indicated meanings throughout:

[025] A dash (“—”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH₂ is attached through the carbon atom. [026] The term “alkoxy” refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, terf-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. By “cycloalkoxy” is meant a cycloalkyl group, as defined herein, that is likewise attached through an oxygen bridge.

[027] The term “alkyl” encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example C1-C6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. When an alkyl residue having a spécifie number of carbons is named, ail géométrie isomers having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and tertbutyl; “propyl” includes n-propyl and isopropyl.

[028] The term “cycloalkyl” refers to a saturated hydrocarbon ring group, having the specified number of carbon atoms,, usually from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and caged saturated ring groups such as norbomane.

[029] The term “halo” refers to fluoro, chloro, bromo, and iodo.

[030] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable. [031] The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a sélection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When a substituent is oxo (i.e., =O) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations resuit in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subséquent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

[032] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution ofthe racemates. Resolution ofthe racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high- pressure liquid chromatography (HPLC) column. The term “isomers” refers to different compounds that hâve the same molecular formula. The term “stereoisomers” refers to isomers that differ only in the way the atoms are arranged in space. The term “enantiomers” refers to stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The symbol “(+)” may be used to designate a racemic mixture where appropriate. The term “diastereoisomers” refers to stereoisomers that hâve at least two asymmetric atoms, but which are not mirror-images of each other. The term “meso compound” or “meso isomer” refers to a non-optically active member of a set of stereoisomers. Meso isomers contain two or more stereocenters but are not chiral (i.e., a plane of symmetry exists within the molécule). The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized lightatthewavelength ofthe sodium D line.

[033] Where compounds described herein exist in various tautomeric forms, the term “compound” includes ail tautomeric forms ofthe compound. Such compounds also include crystal forms including polymorphs and clathrates. Similarly, the term “sait” includes ail tautomericforms and crystal forms ofthe compound. The term “tautomers” refers to structurally distinct isomers that interconvert by tautomerization. Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acidbase chemistry. Prototropic tautomerization or proton-shift tautomerization involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A spécifie example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A spécifie example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)“°ne tautomers.

[034] Pharmaceutically acceptable forms ofthe compounds recited herein include pharmaceutically acceptable salts, prodrugs, and mixtures thereof. In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts and prodrugs. [035] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stéarate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium. In addition, if the compounds described herein are obtained as an acid addition sait, the free base can be obtained by basifÿing a solution ofthe acid sait. Conversely, if the product is a free base, an addition sait, particularly a pharmaceutically acceptable addition sait, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic méthodologies that may be used to préparé non-toxic pharmaceutically acceptable addition salts.

[036] The term “prodrug” refers to a substance administered in an inactive or less active form that is then transformed (e.g., by metabolic processing of the prodrug in the body) into an active compound. The rationale behind administering a prodrug is to optimize absorption, distribution, metabolism, and/or excrétion of the drug. Prodrugs may be obtained by making a dérivative of an active compound (e.g., a compound of Formula I or another compound disclosed and/or described herein) that will undergo a transformation under the conditions of use (e.g., within the body) to form the active compound. The transformation of the prodrug to the active compound may proceed spontaneously (e.g., by way of a hydrolysis reaction) or it can be catalyzed or induced by another agent (e.g., an enzyme, light, acid or base, and/or température). The agent may be endogenous to the conditions of use (e.g., an enzyme présent in the cells to which the prodrug is administered, or the acidic conditions of the stomach) or the agent may be supplied exogenously. Prodrugs can be obtained by converting one or more functional groups in the active compound into another functional group, which is then converted back to the original functional group when administered to the body. For example, a hydroxyl functional group can be converted to a sulfonate, phosphate, ester or carbonate group, which in turn can be hydrolyzed in vivo back to the hydroxyl group. Similarly, an amino functional group can be converted, for example, into an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl functional group, which can be hydrolyzed in vivo back to the amino group. A carboxyl functional group can be converted, for example, into an ester (including silyl esters and thioesters), amide or hydrazide functional group, which can be hydrolyzed in vivo back to the carboxyl group. Examples of prodrugs include, but are not limited to, phosphate, acetate, formate and benzoate dérivatives of functional groups (such as alcohol or amine groups) présent in the compounds of Formula I and other compounds disclosed and/or described herein. In some embodiments, the “prodrugs” described herein include any compound that becomes a compound of Formula I when administered to a patient, e.g., upon metabolic processing ofthe prodrug. Examples of prodrugs include dérivatives of functional groups, such as a carboxylic acid group, in the compounds of Formula I. Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid dérivatives. Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include metabolically labile amides that are formed, for example, with an amine and a carboxylic acid. Exemplary amines include NH₂, primary, and secondary amines such as NHR^X, and NR^xR^y, wherein R^x is hydrogen, (C-i-C-ie)-alkyl, (C3-C7) cycloalkyl, (C₃-C7)-cycloalkyl-(Ci-C4)-alkyl—, (C₆-Ci4)-aryl which is unsubstituted or substituted by a residue (Ci-C₂)-alkyl, (Ci-C2)-alkoxy, fluoro, or chloro; heteroaryl, (C₆- C-i4)-aryl-(C-i-C4)alkyl—where aryl is unsubstituted or substituted by a residue (Ci-C2)-alkyl, (Ci-C2)-alkoxy, fluoro, or chloro; or heteroaryl-(Ci-C4)-alkyl— and in which R^y has the meanings indicated for R^xwith the exception of hydrogen or wherein R^x and R^y, together with the nitrogen to which they are bound, form an optionally substituted 4- to 7- membered heterocycloalkyl ring which optionally includes one or two additional heteroatoms chosen from nitrogen, oxygen, and sulfur. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Sériés, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[037] The compounds described herein can be enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein. Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2), 9-32.

[038] A “solvaté” refers to an entity formed by the interaction of a solvent and a compound or a pharmaceutically acceptable sait thereof. The term “compound” is intended to include solvatés of compounds. Similarly, “salts” includes solvatés of salts. Suitable solvatés are pharmaceutically acceptable solvatés, such as hydrates, including monohydrates and hemihyd rates.

[039] A “chelate” refers to an entity formed by the coordination of a compound to a métal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “salts” includes chelates of salts.

[040] A “non-covalent complex” refers to an entity formed by the interaction of a compound and another molécule wherein a covalent bond is not formed between the compound and the molécule. For example, complexation can occur through van derWaals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term “compound”.

[041] The term “hydrogen bond” refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in médicinal chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”, Accounts of Chemical Research, 17, pp. 320326 (1984)).

[042] “Hydrogen bond acceptor” refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp²-hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[043] The term “hydrogen bond donor” refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

[044] As used herein the terms “group”, “radical” or “fragment” refer to a functional group or fragment of a molécule attachable to a bond or other fragments of molécules.

[045] The term “active agent” refers to a compound or a pharmaceutically acceptable sait thereof which has biological activity. In some embodiments, an “active agent” is a compound or a pharmaceutically acceptable sait thereof having pharmaceutical utility. For example an active agent may be an anti-neurodegenerative therapeutic or an antiviral therapeutic.

[046] The term “therapeutically effective amount” of a compound, or a pharmaceutically acceptable sait thereof, described herein, refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prévention of disease e.g., a therapeutically effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of KMO activity and modulation of kynurenine pathway métabolites (such as kynurenine, kynurenic acid, anthranilic acid, 3-OH-kynurenine, 3-OH anthranilic acid, or quinolinic acid). In some embodiments, a therapeutically effective amount is an amount sufficient to treat the symptoms of an HIV-related disorder. In some embodiments a therapeutically effective amount is an amount sufficient to reduce the signs or side effects of an HIV-related disorder. In some embodiments, a therapeutically effective amount of a compound or a pharmaceutically acceptable sait thereof is an amount sufficient to prevent a significant increase or significantly reduce the level of HIV-related neuronal cell death. In some embodiments, a therapeutically effective amount of a compound or a pharmaceutically acceptable sait thereof is an amount sufficient to prevent a significant increase or significantly reduce the level of QUIN associated with HIV-related neuronal cell death. In some embodiments, a therapeutically effective amount is an amount sufficient to effect an increase in the level of KYNA associated with neuronal cell health in an HIV-infected patient. In some embodiments, a therapeutically effective amount is an amount sufficient to increase the anticonvulsant and neuroprotective properties associated with lowered levels of QUIN and increased levels of KYNA in an HIV-infected patient. In some embodiments, a therapeutically effective amount is an amount sufficient to modulate an inflammatory process in an HIV-infected patient, including but not limited to inflammation in the brain, spinal cord, and peripheral nervous system, or méningés. In methods described herein for adjunctively treating an HIV-related disorder, a therapeutically effective amount may also be an amount sufficient, when administered to a patient, to detectably slowthe progression ofthe HIV-related disorder, or preventthe patienttowhom the composition is given from presenting symptoms ofthe HIVrelated disorder. In some methods described herein for treating an HIV-related disorder, a therapeutically effective amount may also be an amount sufficient to produce a détectable decrease in the level of HIV-related neuronal cell death. For example, in some embodiments a therapeutically effective amount is an amount sufficient to significantly decrease the level of HIV-related neuronal death by effecting a détectable decrease in the amount of QUIN, and an increase in the amount of kynurenine, KYNA, oranthranilic acid. In addition, an amount is considered to be a therapeutically effective amount if it is characterized as such by at least one of the above criteria or experimental conditions, regardless of any inconsistent or contradictory results under a different set of criteria or experimental conditions.

[047] The term “inhibition” indicates a significant decrease in the baseline activity of a biological activity or process. “Inhibition of KMO activity” refers to a decrease in KMO activity as a direct or indirect response to the presence of at least one compound or a pharmaceutically acceptable sait thereof described herein, relative to the activity of KMO in the absence of at least one compound or a pharmaceutically acceptable sait thereof. The decrease in activity may be due to the direct interaction of the compound or a pharmaceutically acceptable sait thereof with KMO, or due to the interaction ofthe compound or a pharmaceutically acceptable sait thereof described herein with one or more other factors that in turn affect KMO activity. For example, the presence ofthe compound or a pharmaceutically acceptable sait thereof may decrease KMO activity by directly binding to the KMO, by causing (directly or indirectly) another factor to decrease KMO activity, or by (directly or indirectly) decreasing the amount of KMO présent in the cell or organism. Inhibition of KMO activity also refers to an observable inhibition of 3-HK and QUIN production in a standard assay such as the assays described below. The inhibition of KMO activity also refers to an observable increase in the production of KYNA. In some embodiments, the compound or a pharmaceutically acceptable sait thereof described herein has an IC50 value less than orequal to 1 micromolar. In some embodiments, the compound or a pharmaceutically acceptable sait thereof has an IC50 value less than or equal to less than 100 micromolar. In some embodiments, the compound or a pharmaceutically acceptable sait thereof has an IC50 value less than or equal to 10 nanomolar. Inhibition of KMO activity also refers to activation, redistribution, reorganization, or capping of one or more various KMO membrane-associated proteins (such as those receptors found in the mitochondria), or binding sites can undergo redistribution and capping that can initiate signal transduction. KMO activity also can modulate the availability of kynurenine, which can effect the synthesis or production of QUIN, KYNA, anthranilic acid, and/or 3-HK.

[048] A “disease responsive to inhibition of KMO activity” refers to a disease in which inhibiting KMO provides a therapeutic benefit such as an amelioration of symptoms, decrease in disease progression, prévention ordelay of disease onset, prévention or amelioration of an inflammatory response, or inhibition of aberrant activity and/or death of certain cell-types (such as neuronal cells).

[049] “Treatment” or “treating” refers to any treatment of a disease in a patient, including: a) preventing the disease, that is, causing the clinical symptoms ofthe disease not to develop; b) inhibiting the progression ofthe disease; c) slowing orarresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the régression of clinical symptoms. [050] “Subject” or “patient¹ refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; and in some embodiments the subject is human.

[051] The term “disease” refers to an abnormal condition of the human or animal body or of one or more of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to hâve a reduced duration or quality of life. As used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition).

[052] The term “adjunctively” refers to the administering to a patient, or treating a patient with, at least one compound, or a pharmaceutically acceptable sait thereof, described herein, in addition to an antiviral agent, either simultaneously, orat intervals prior to, during, or following administration of the antiviral agent to achieve the desired therapeutic effect.

[053] The term “viral load” refers to the concentration of a virus, such as HIV, in the blood. [054] Provided is a composition comprising an antiviral agent and a compound of Formula I:

R²

Formula I or a pharmaceutically acceptable sait thereof;

wherein:

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C-iC₄ alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo.

[055] In some embodiments, R¹ is C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent.

[056] In some embodiments, R¹ is C1-C4 alkoxy.

[057] In some embodiments, R¹ is sec-butoxy.

[058] In some embodiments, R¹ is (R)-sec-butoxy.

[059] In some embodiments, R¹ is (S)-sec-butoxy.

[060] In some embodiments, R¹ is isopropoxy.

[061] In some embodiments, R¹ is C1-C4 alkoxy substituted with one C₃-C₆ cycloalkyl substituent.

[062] In some embodiments, R¹ is cyclopropylmethoxy.

[063] In some embodiments, R¹ is C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy and C₃-C₆ cycloalkoxy.

[064] In some embodiments, R¹ is C1-C4 alkyl substituted with one C1-C4 alkoxy substituent. [065] In some embodiments, R¹ is 1-methoxyethyl.

[066] In some embodiments, R¹ is methoxymethyl.

[067] In some embodiments, R¹ is C-1-C4 alkyl substituted with one C3-C6 cycloalkoxy substituent.

[068] In some embodiments, R¹ is 1-cyclopropoxyethyl.

[069] In some embodiments, R¹ is cyclopropoxymethyl.

[070] In some embodiments, R¹ is C3-C6 cycloalkoxy.

[071] In some embodiments, R¹ is cyclobutoxy.

[072] In some embodiments, R¹ is cyclopentyloxy.

[073] In some embodiments, R¹ is cyclopropoxy.

[074] In some embodiments, R¹ is halo.

[075] In some embodiments, R¹ is chloro.

[076] In some embodiments, R¹ is fluoro.

[077] In some embodiments, R² is selected from: C1-C4 alkoxy, C₃-C₆ cycloalkoxy, and halo.

[078] In some embodiments, R² is C1-C4 alkoxy.

[079] In some embodiments, R² is isobutoxy.

[080] In some embodiments, R² is isopropoxy.

[081] In some embodiments, R² is methoxy.

[082] In some embodiments, R² is C₃-C₆ cycloalkoxy.

[083] In some embodiments, R² is cyclopropoxy.

[084] In some embodiments, R² is halo.

[085] In some embodiments, R² is chloro.

[086] In some embodiments, R² is fluoro.

[087] In some embodiments, R¹ is selected from C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C-1-C4 alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo; and R² is selected from: C1-C4 alkoxy, C3-C₆ cycloalkoxy, and halo.

[088] In some embodiments, R¹ is selected from sec-butoxy, chloro, cyclobutoxy, cyclopentyloxy, cyclopropoxy, 1-cyclopropoxyethyl, cyclopropylmethoxy, cyclopropoxymethyl, fluoro, methoxy, 1-methoxyethyl, and methoxymethyl; and R² is selected from: chloro, cyclopropoxy, fluoro, isobutoxy, isopropoxy, and methoxy.

[089] In some embodiments, the compound of Formula I is selected from: 6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-isopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid; (S)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid; (R)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-cyclobutoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(1-methoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(1-cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-isopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-fluorophenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-fluorophenyl)pyrimidine-4-carboxylic acid;

6-(3,4-dichlorophenyl)pyrimidine-4-carboxylic acid;

6-(3,4-difluorophenyl)pyrimidine-4-carboxylic acid; and

6-(3-chloro-4-methoxy)pyrimidine-4-carboxylic acid.

[090] In some embodiments, the compound of Formula I is 6-(4-chloro-3methoxyphenyl)pyrimidine-4-carboxylic acid.

[091] In some embodiments, the compound of Formula I is 6-(3-chloro-4isopropoxyphenyl)pyrimidine-4-carboxylic acid.

[092] In some embodiments, the compound of Formula I is 6-(3-chloro-4(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid.

[093] In some embodiments, the compound of Formula I is (S)-6-(4-sec-butoxy-3chlorophenyl)pyrimidine-4-carboxylic acid.

[094] In some embodiments, the compound of Formula I is (R)-6-(4-sec-butoxy-3chlorophenyl)pyrimidine-4-carboxylic acid.

[095] In some embodiments, the compound of Formula I is 6-(3-chloro-4cyclopropoxyphenyl)pyrimidine-4-carboxylic acid.

[096] In some embodiments, the compound of Formula I is 6-(3-chloro-4cyclobutoxyphenyl)pyrimidine-4-carboxylic acid.

[097] In some embodiments, the compound of Formula I is 6-(3-chloro-4(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid.

[098] In some embodiments, the compound of Formula I is 6-(3-chloro-4(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid.

[099] In some embodiments, the compound of Formula I is 6-(3-chloro-4-(1methoxyethyl)phenyl)pyrimidine-4-carboxylic acid.

[0100] In some embodiments, the compound of Formula I is 6-(3-chloro-4(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid.

[0101] In some embodiments, the compound of Formula I is 6-(3-chloro-4-(1cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid.

[0102] In some embodiments, the compound of Formula I is 6-(4-chloro-3cyclopropoxyphenyl)pyrimidine-4-carboxylic acid.

[0103] In some embodiments, the compound of Formula I is 6-(4-chloro-3isopropoxyphenyl)pyrimidine-4-carboxylic acid.

[0104] In some embodiments, the compound of Formula i is 6-(4-chloro-3fluorophenyl)pyrimidine-4-carboxylic acid.

[0105] In some embodiments, the compound of Formula I is 6-(3-chloro-4fluorophenyl)pyrimidine-4-carboxylic acid.

[0106] In some embodiments, the compound of Formula I is 6-(3,4-dichlorophenyl)pyrimidine-4carboxylic acid.

[0107] In some embodiments, the compound of Formula I is 6-(3,4-difluorophenyl)pyrimidine-4carboxylic acid.

[0108] In some embodiments, the compound of Formula I is 6-(3-chloro-4-methoxy)pyrimidine4-carboxylic acid.

[0109] Also provided is a composition comprising an antivirai agent and a compound selected from the compounds shown in Table A below, or a pharmaceutically acceptable sait thereof.

Table A

Compound No.	Chemical Structure	Chemical Name
1	N^N ci^y ° /O	6-(4-chloro-3-methoxy- phenyl)pyrimidine-4-carboxylic acid
2	N^N Cl	6-(3-chloro-4-isopropoxy- phenyl)pyrimidine-4-carboxylic acid
3	ΝΆ A_ojÇAï Cl	6-(3-chloro-4-(cyclopentyloxy)- phenyl)pyrimidine-4-carboxylic acid

Compound No.	Chemical Structure	Chemical Name
4	N^N Cl	(S)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid
5	N^N u-_ov^i Cl	(R)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid
6	N^N AAf* ° Cl	6-(3-chloro-4-cyclopropoxy- phenyl)pyrimidine-4-carboxylic acid
7	ΝΆ a_ol/ï Cl	6-(3-chloro-4-cyclobutoxy- phenyl)pyrimidine-4-carboxylic acid
8	N^N z^JUk/OH ^V Cl	6-(3-chloro-4-(cyclopropylmethoxy)- phenyl)pyrimidine-4-carboxyiic acid
9	N^N 0 Cl	6-(3-chloro-4-(methoxymethyl)- phenyl)pyrimidine-4-carboxylic acid
10	N^N /^AA/h 0 I Cl	6-(3-chloro-4-(1-methoxyethyl)- phenyl)pyrimidine-4-carboxylic acid
11	N^N ^ΑΑ+Ααπ _/O^LJ 0	6-(3-chloro-4-(cyclopropoxymethyl)- phenyl)pyrimidine-4-carboxylic acid

Compound No.	Chemical Structure	Chemical Name
12	ΝΎ __0 % TT	6-(3-chloro-4-(1-cyclopropoxyethyl)- phenyl)pyrimidine-4-carboxylic acid
13	N^N CI-Y ⁰ Y	6-(4-chloro-3-cyclopropoxy- phenyl)pyrimidine-4-carboxylic acid
14	N^Y c,YS Y	6-(4-chloro-3-isopropoxy- phenyl)pyrimidine-4-carboxylic acid
15	ΝΎ x“	6-(4-chloro-3-isobutoxy- phenyl)pyrimidine-4-carboxylic acid
16	N^N YY^^\r^0H CI-V F	6-(4-chloro-3-fluoro- phenyl)pyrimidine-4-carboxylic acid
17	N^N Cl	6-(3-chloro-4-fluoro- phenyl)pyrimidine-4-carboxylic acid
18	N^N z+X+Jk/OH _αγγ Cl	6-(3,4-dichloro-phenyl)pyrimidine-4carboxylic acid

Compound No.	Chemical Structure	Chemical Name
19	N^N F	6-(3,4-difluoro-phenyl)pyrimidine-4carboxylic acid
20	N^N Cl	6-(3-chloro-4-methoxy)pyrimidine-4carboxylic acid

[0110] Methods forobtaining the compounds, or pharmaceutically acceptable salts thereof, described herein will be apparent to those of ordinary skill in the art, suitable procedures being described, for example, in examples below, and in the référencés cited herein.

[0111] Provided is a method of treating a disorder in a subject infected with HIV, comprising adjunctively administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:

Formula I or a pharmaceutically acceptable sait thereof;

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C-iC₄ alkoxy and C₃-C₆ cycloalkoxy, C₃-C₆ cycloalkoxy, and halo.

[0112] Provided is a method of lowering HIV viral load in a subject infected with HIV, comprising adjunctively administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:

Formula I or a pharmaceutically acceptable sait thereof;

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C1C₄ alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo.

[0113] HIV drugs are classified into six drug classes on the basis of how each drug interfères with the HIV life cycle. These six classes include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pis), fusion inhibitors, CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs). HIV uses reverse transcriptase (RT) to convert its RNA into DNA (reverse transcription). Blocking RT and reverse transcription prevents HIV from replicating. NRTIs lack a 3’ hydroxyl group and are metabolically activated by host cellular kinases to their corresponding 5’-triphosphate forms, which are subsequently incorporated into DNA by HIV reverse transcriptase (RT) and which act as chain terminators of DNA synthesis. Examples of NRTIs include amdoxovir, Combivir®, Emtriva®, Epivir®, Epzicom®, Retrovir®, tenofovir alafenamide fumarate, Trizivir®, Truvada®, Videx®, Videx® EC, Viread®, Zerit®, and Ziagen®. NNRTIs are noncompetitive inhibitors of DNA polymerization, binding to a hydrophobie pocket in RT near the polymerase active site. Examples of NRTIs include Edurant®, Intelence®, lersivirine, Rescriptor®, Sustiva®, Viramune®, and Viramune® XR. After transcription in the nucléus, viral mRNA enters the cytoplasm and uses the host's cellular machinery to manufacture virus proteins. The viral components then gather at the cell membrane and immature viruses bud off the cell. Core proteins are produced as part of long polypeptides, which must be eut into smaller fragments by the enzyme protease in order to form mature, functional proteins. Pis bind to the site where protein cutting occurs, and so prevent the enzyme from releasing the individual core proteins. In this way the new viral particles are unable to mature or become infectious. Examples of Pis include Aptivus®, Crixivan®, Invirase®, Kaletra®, Lexiva®, Norvir®, Prezista®, Reyataz®, and Viracept®. Fusion inhibitors block the HIV envelope from merging with the host cell membrane (fusion), which prevents HIV from entering the host cell. Examples of fusion inhibitors include Fuzeon®. CCR5 antagonists block the CCR5 receptor on the surface of certain immune cells, such as CD4+ cells, which prevents HIV from entering the cell. Examples of CCR5 antagonists include cenicriviroc and Selzentry®. INSTIs block integrase, an enzyme HIV uses to insert (integrate) its viral DNA into the DNA of the host cell. Blocking integrase prevents HIV from replicating. Examples of INSTIs include Isentress®, Tivicay®, and Elvitegravir®. Multi-class combination drugs include Atripla® (efavirenz + tenofovir + emtricitabine), Comptera® (rilpivirine + tenofovir + emtricitabine), Stribild® (elvitegravir + cobicistat + tenofovir + emtricitabine), and Trii™ (dolutegravir + abacavir + lamivudine). Recommended antirétroviral therapy (ART) regimens for the treatment of HIV involve using a combination of three or more antirétroviral (ARV) drugs from at least two different HIV drug classes. The current standard of care for HIV/AIDS in the developed world is highly active antirétroviral therapy (HAART) therapy, usually a combination of two reverse transcriptase inhibitors and a protease inhibitor. Class-sparing regimens purposefully exclude ail ARV drugs from a spécifie drug class to save spécifie ARV drugs for future use in case a regimen needs to be changed because of toxicity or drug résistance. A class-sparing regimen may also be used to avoid adverse effects associated with a spécifie drug class. Certain HIV ART regimens include a pharmacokinetic enhancerthat increases the level of certain ARVs in the blood and make them more effective. Examples of pharmacokinetic enhancers include Cobicistat®, a component of the approved fixed-dose combination tablet Stribild®; ritonavir, a PI that improves the pharmacokinetic (PK) profites of concomitant Pis; and SPI-452. Experimental immune-based HIV thérapies include, Aralen®, DermaVir®, interleukin-7, lexgenleucel-T, Plaquenil®, Proleukin®, and SB-728-T. Entry inhibitors are a class of ARVs that include fusion inhibitors, CCR5 antagonists, and glycosidase inhibitors. Maturation inhibitors are a class of ARVs that target the gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles during maturation.

[0114] In some embodiments, the antiviral agent is selected from: entry inhibitors, fusion inhibitors, glycosidase inhibitors, CCR5 antagonists, immune-based thérapies, integrase inhibitors, maturation inhibitors, multi-class combination drugs, non-nucleoside reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, pharmacokinetic enhancers, and protease inhibitors, and combinations thereof.

[0115] In some embodiments, the antiviral agent is selected from: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists, and integrase strand transfer inhibitors, and combinations thereof.

[0116] In some embodiments, the antiviral agent is selected from: amdoxovir, Aptivus®, Aralen®, Atripla®, cenicriviroc, Cobicistat®, Combivir®, Complera®, Crixivan®, DermaVir®, Edurant®, elvitegravir, Emtriva®, Epivir®, Epzicom®, Fuzeon®, ibalizumab, Intelence®, interleukin-7, Invirase®, Isentress®, Kaletra®, lersivirine, lexgenleucel-T, Lexiva®, Norvir®, Plaquenil®, Proleukin®, Prezista®, PRO 140, Rescriptor®, Retrovir®, Reyataz®, SB-728-T, Selzentry®, SPI-452, Stribild®, Sustiva®, tenofovir alafenamide fumarate, Tivicay®, Trii™, Trizivir®, Truvada®, Videx®, Videx® EC, Viracept®, Viramune®, Viramune® XR, Viread®, Zerit®, and Ziagen®, and combinations thereof.

[0117] In some embodiments, the antiviral agent is HAART.

[0118] Human Immunodeficiency Virus (HIV) is the virus that causes Acquired Immunodeficiency Syndrome (AIDS), which is the most advanced stage of HIV infection. HIV destroys the CD4(+) T lymphocytes (CD4(+) cells) ofthe immune system, leaving the body vulnérable to life-threatening infections and cancers. HIV is a retrovirus that occurs as two types: HIV-1 and HIV-2. Both types are transmitted through direct contact with HIV-infected body fluids, such as blood, semen, and génital sécrétions, or from an HIV-infected motherto her child during pregnancy, birth, or breastfeeding (through breast milk). HIV-1 can be classified into four groups: M Group, N Group, O Group, and P Group. Viruses within each group can then be further classified by subtype. For example, the HIV-1 M group includes at least nine subtypes: A1, A2, B, C, D, F1, F2, G, H, J, and K. HIV-2 infection is endemicto West Africa. It generally takes longer to progress to symptomatic HIV/AIDS and has a lower mortality rate than HIV-1 infection.

[0119] In some embodiments, the HIV is HIV-1.

[0120] In some embodiments, the HIV is HIV-1 M group.

[0121] In some embodiments, the HIV is HIV-1 M group subtype A1.

[0122] In some embodiments, the HIV is HIV-1 M group subtype A2.

[0123] In some embodiments, the HIV is HIV-1 M group subtype B.

[0124] In some embodiments, the HIV is HIV-1

M group subtype C.

[0125] In some embodiments, the HIV is HIV-1 M group subtypeD.

[0126] In some embodiments, the HIV is HIV-1 M group subtypeF1.

[0127] In some embodiments, the HIV is HIV-1 M group subtypeF2.

[0128] In some embodiments, the HIV is HIV-1

M group subtype G.

[0129] In some embodiments, the HIV is HIV-1 M group subtype H.

[0130] In some embodiments, the HIV is HIV-1 M group subtype J.

[0131] In some embodiments, the HIV is HIV-1 M group subtype K.

[0132] In some embodiments, the HIV is HIV-1 N Group.

[0133] In some embodiments, the HIV is HIV-1 O Group.

[0134] In some embodiments, the HIV is HIV-1 P Group.

[0135] In some embodiments, the HIV is HIV-2.

[0136] HIV enters the central nervous system (CNS) early in the course of the infection and causes several important CNS conditions over the course of the disease, such as HIV encephalopathy and AIDS dementia complex. As part of the acute HIV syndrome during séroconversion, patients may expérience HIV encephalopathy. HIV-associated progressive encephalopathy (HPE) is a syndrome complex with cognitive, motor, and behavioral features seen in children. Prior to the advent of highly active antirétroviral therapy (HAART), dementia was a common source of morbidity and mortality in HIV-infected patients. It was usually observed in the late stages of AIDS, when CD4(+) lymphocyte counts fall below 200 cells/mL, and was seen in up to 50% of patients prior to their deaths. In 1986, the term AIDS dementia complex (ADC) was introduced to describe a unique constellation of neurobehavioral findings. HIV associated neurocognitive disorder (HAND) encompasses a hierarchy of progressively more severe patterns of neurological involvement. It can range from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to more severe HIVassociated dementia (HAD) (also called AIDS dementia complex [ADC] or HIV encephalopathy). ADC is considered a single entity with a broad and varied spectrum of clinical manifestations and severity. ADC is characterized by cognitive, motor, and behavioral features in adults, usually those with advanced AIDS. With the advent of HAART, a less severe dysfunction, minor cognitive motor disorder (MCMD), has become more common than ADC. The overall psychosocial and emotional burden on the family and friends of patients with HIV dementia is tremendous, far beyond that of a cognitively intact patient with AIDS. Patients with cognitive difficulties hâve problems with compliance and adhérence to their médication regimen. Because of their neuropsychiatrie problems, these patients are likely to be less inhibited and are more prone to HIV-related risk behavior (e.g., unprotected intercourse), and they therefore pose a greater risk of transmission of the virus. In addition to HIV itself, other causes of neurologie complications in HIV-infected individuals include opportunistic infections, tumors, and antirétroviral drugs. Other neurologie complications that arise from primary HIV infection include vacuolar myelopathy, peripheral neuropathies, and polymyositis.

[0137] In some embodiments, the HIV-related disorder is an opportunisme infection selected from: candidiasis, coccidioidomycosis, cryptococcosis, cryptosporidiosis, cytomégalovirus, herpes simplex virus, herpes zoster, histoplasmosis, isosporiasis, mycobacterium avium complex, pneumocystis pneumonia, bacterial pneumonia, progressive multifocal leukoencephalopathy Salmonella, toxoplasmosis, and tuberculosis.

[0138] In some embodiments, the HIV-related disorder is an AIDS-related cancer selected from: cervical cancer, Kaposi sarcoma, and lymphomas.

[0139] In some embodiments, the HIV-related disorder is an AIDS-defining illnesses selected from: candidiasis ofthe esophagus, bronchi, trachea, or lungs, invasive cervical cancer, disseminated or extrapulmonary coccidioidomycosis, extrapulmonary cryptococcosis, chronic intestinal cryptosporidiosis, cytomégalovirus disease (other than liver, spleen, or nodes), cytomégalovirus retinitis with loss of vision, HIV related-encephalopathy, herpes simplex (with chronic ulcers, bronchitis, pneumonitis, oresophagitis), disseminated or extrapulmonary histoplasmosis, chronic intestinal isosporiasis, Kaposi sarcoma, Burkitt's lymphoma, immunoblastic lymphoma, primary lymphoma of brain, disseminated or extrapulmonary mycobacterium avium complex or M. kansasii, pulmonary or extrapulmonary mycobacterium tuberculosis, disseminated or extrapulmonary mycobacterium species, pneumocystis jiroveci pneumonia, récurrent pneumonia, progressive multifocal leukoencephalopathy, récurrent salmonella septicemia, toxoplasmosis of brain, and wasting syndrome due to HIV.

[0140] In some embodiments, the HIV-related disorder is a neurological disorder. [0141] In some embodiments, the neurological disorder is selected from: AIDS dementia complex, AIDS-induced encephalopathy, HIV encephalopathy, HIV-associated progressive encephalopathy, HIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia, minor cognitive motor disorder, vacuolar myelopathy, peripheral neuropathies, and polymyositis.

[0142] In some embodiments, the neurological disorder is AIDS dementia complex.

[0143] In some embodiments, the neurological disorder is AIDS-induced encephalopathy. [0144] In some embodiments, the neurological disorder is HIV encephalopathy.

[0145] In some embodiments, the neurological disorder is HIV-associated progressive encephalopathy.

[0146] In some embodiments, the neurological disorder is HIV-associated neurocognitive disorder.

[0147] In some embodiments, the neurological disorder is asymptomatic neurocognitive impairment.

[0148] In some embodiments, the neurological disorder is minor neurocognitive disorder. [0149] In some embodiments, the neurological disorder is minor cognitive motor disorder. [0150] In some embodiments, the neurological disorder is vacuolar myelopathy.

[0151] In some embodiments, the neurological disorder is peripheral neuropathy.

[0152] In some embodiments, the neurological disorder is polymyositis.

[0153] The association of a compound, or a pharmaceutically acceptable sait thereof, described herein and an antiviral agent in a composition may be physical or non-physical. Examples of physically associated compositions include: compositions (e.g. unitary formulations) comprising a compound, or pharmaceutically acceptable sait thereof, described herein and an antiviral agent in admixture (for example within the same unit dose); compositions comprising material in which a compound, or pharmaceutically acceptable sait thereof, described herein and an antiviral agent are chemically/physicochemically linked (for example by crosslinking, molecular agglomération or binding to a common vehicle moiety); compositions comprising material in which a compound, or pharmaceutically acceptable sait thereof, described herein and an antiviral agent are chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or émulsion droplets); and pharmaceutical kits, pharmaceutical packs or patient packs in which a compound, or pharmaceutically acceptable sait thereof, described herein and an antiviral agent are copackaged or co-presented (e.g. as part of an array of unit doses).

[0154] Examples of non-physically associated compositions include: material (e.g. a non-unitary formulation) comprising a compound, or pharmaceutically acceptable sait thereof, described herein or an antiviral agent together with instructions for the extemporaneous association ofthe compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent to form a physical association ofthe two; material (e.g. a non-unitary formulation) comprising a compound, or pharmaceutically acceptable sait thereof, described herein or an antiviral agent together with instructions for adjunctive therapy with the compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent; material comprising a compound, or pharmaceutically acceptable sait thereof, described herein or an antiviral agent with instructions for administration to a patient population in which the other ofthe compound, or pharmaceutically acceptable sait thereof, described herein or the antiviral agent hâve been (or are being) administered; and material comprising a compound, or pharmaceutically acceptable sait thereof, described herein or an antiviral agent in an amount or in a form which is specifically adapted for use in combination with the other ofthe compound, or pharmaceutically acceptable sait thereof, described herein or the antiviral.

[0155] Also provided are packaged compositions. Such packaged compositions include a pharmaceutical composition comprising at least one compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent and instructions for using the composition to treat a subject (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject suffering an HIVrelated disorder. In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject suffering an HIV-related neurological disorder. The packaged pharmaceutical composition can include providing prescribing information; for example, to a patient or health care provider, or as a label in a packaged pharmaceutical composition. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical composition. [0156] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are: a) in admixture; b) chemically/physicochemically linked; c) chemically/physicochemically co-packaged; ord) unmixed but co-packaged orco-presented.

[0157] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are in admixture.

[0158] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are chemically/physicochemically linked. [0159] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are chemically/physicochemically copackaged.

[0160] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are unmixed but co-packaged or copresented.

[0161] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are co-packaged in a single container or in a plurality of containers within a single outer package.

[0162] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein is administered before the antiviral agent.

[0163] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein is administered after the antiviral agent.

[0164] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein and the antiviral agent are administered simultaneously.

[0165] In some embodiments, the antiviral agent and the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein, are administered simultaneously in a unitary formulation.

[0166] In some embodiments, the antiviral agent and the compound of Formula I, or a pharmaceutically acceptable sait thereof, described herein, are administered simultaneously in different formulations.

[0167] In some embodiments, the antiviral agent and the compound of Formula I or a pharmaceutically acceptable sait thereof, described herein are in a co-packaged drug product. [0168] In general, the compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent will be administered in therapeutically effective amounts by any of the accepted modes of administration for agents that serve similar utilities. The actual amounts of the compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent, i.e., the active ingrédients, will dépend upon numerous factors such as the severity ofthe disease to be treated, the âge and relative health of the subject, the potency ofthe compound used, the route and form of administration, and other factors well know to the skilled artisan. The active ingrédients can be administered at least once a day, such as once or twice a day.

[0169] In some embodiments, the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent are administered as pharmaceutical compositions. Accordingly, provided are pharmaceutical compositions comprising a compound, or a pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.

[0170] Pharmaceutically acceptable vehicles must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated. The vehicle can be inert or it can possess pharmaceutical benefits. The amount of vehicle employed in conjunction with the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent is sufficient to provide a practical quantity of material for administration per unit dose ofthe compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent.

[0171] Exemplary pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its dérivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnésium stéarate; calcium sulfate; synthetic oils; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycérine, sorbitol, mannitol, and polyethylene glycol; alginic acid; phosphate buffer solutions; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonie saline; and phosphate buffer solutions.

[0172] Optional active agents may be included in a pharmaceutical composition, which do not substantially interfère with the activity of the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent.

[0173] Effective concentrations of the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent are mixed with a suitable pharmaceutically acceptable vehicle. In instances in which the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent exhibits insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate.

[0174] Upon mixing or addition ofthe compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent, the resulting mixture may be a solution, suspension, émulsion orthe like. The form ofthe resulting mixture dépends upon a numberof factors, including the intended mode of administration and the solubility ofthe compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent in the chosen vehicle. The effective concentration sufficient for ameliorating the symptoms of the disease treated may be empirically determined.

[0175] The compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent may be administered orally, topically, parenterally, intravenously, by intramuscular injection, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations.

[0176] Pharmaceutical compositions may be formulated for oral use, such as for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, émulsions, hard or soft capsules, orsyrups or élixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically élégant and palatable préparations. In some embodiments, oral pharmaceutical compositions contain from 0.1 to 99% of a compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent. In some embodiments, oral pharmaceutical compositions contain at least 5% (weight %) of a compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent. Some embodiments contain from 25% to 50% or from 5% to 75 % of a compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent.

[0177] Orally administered pharmaceutical compositions also include liquid solutions, émulsions, suspensions, powders, granules, élixirs, tinctures, syrups, and the like. The pharmaceutically acceptable carriers suitable for préparation of such compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste-masking agents, and coloring agents. [0178] Typical components of carriers for syrups, élixirs, émulsions and suspensions include éthanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Syrups and élixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such pharmaceutical compositions may also contain a demulcent. [0179] The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent can be incorporated into oral liquid préparations such as aqueous or oily suspensions, solutions, émulsions, syrups, or élixirs, for example. Moreover, pharmaceutical compositions containing a compound, or pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid préparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stéarate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).

[0180] Fora suspension, typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.

[0181] Aqueous suspensions contain the pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents; may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stéarate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan substitute. The aqueous suspensions may also contain one or more preservatives, for example ethyl, orn-propyl p-hydroxybenzoate.

[0182] Oily suspensions may be formulated by suspending the active ingrédients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a minerai oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral préparations. These pharmaceutical compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0183] Pharmaceutical compositions may also be in the form of oil-in-water émulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a minerai oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.

[0184] Dispersible powders and granules suitable for préparation of an aqueous suspension by the addition of water provide the active ingrédient in admixture with a dispersing orwetting agent, suspending agent and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those already mentioned above.

[0185] Tablets typically comprise conventional pharmaceutically acceptable adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnésium stéarate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics ofthe powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The sélection of carrier components often dépends on secondary considérations like taste, cost, and shelf stability.

[0186] Such pharmaceutical compositions may also be coated by conventional methods, typically with pH ortime-dependent coatings, such that the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit® coatings, waxes and shellac.

[0187] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules wherein the active ingrédient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0188] Pharmaceutical compositions may be in the form of a stérile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that hâve been mentioned above. The stérile injectable préparation may also be stérile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringeris solution, and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be useful in the préparation of injectables.

[0189] The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may be administered parenterally in a stérile medium. Parentéral administration includes subeutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parentéral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parentéral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, éthanol, and sesame oil.

[0190] The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary températures but liquid at rectal température and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0191] The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye. Topical pharmaceutical compositions may be in any form including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and the like.

[0192] Such solutions may be formulated as 0.01% -10% isotonie solutions, pH 5-7, with appropriate salts. The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may also be formulated for transdermal administration as a transdermal patch.

[0193] Topical pharmaceutical compositions comprising at least one compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent can be admixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycérine, vitamin A and E oils, minerai oil, propylene glycol, PPG-2 myristyl propionate, and the like.

[0194] Other materials suitable for use in topical carriers include, for example, émollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:

[0195] Représentative émollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, minkoil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stéarate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stéarate, butyl stéarate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, minerai oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate;

propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloïdal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnésium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.

[0196] The compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may also be topically administered in the form of liposome delivery Systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholestérol, stearylamine or phosphatidylcholines.

[0197] Other pharmaceutical compositions useful forattaining systemic delivery ofthe compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent include sublingual, buccal and nasal dosage forms. Such pharmaceutical compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0198] Pharmaceutical compositions for inhalation typically can be provided in the form of a solution, suspension or émulsion that can be administered as a dry powder or in the form of an aérosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).

[0199] The pharmaceutical compositions may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molécules that function in different ways to enhance or be independent oftherapeutic effects ofthe compound, orpharmaceutically acceptable sait thereof, described herein and/or the antiviral agent. Particular classes of activity enhancers include skin pénétration enhancers and absorption enhancers.

[0200] Pharmaceutical compositions may also contain additional active agents that can be chosen from a wide variety of molécules, which can function in different ways to enhance the therapeutic effects of the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent. These optional other active agents, when présent, are typically employed in the pharmaceutical compositions at a level ranging from 0.01% to 15%. Some embodiments contain from 0.1% to 10% by weight ofthe composition. Otherembodiments contain from 0.5% to 5% by weight ofthe composition.

[0201] In ail of the foregoing the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent can be administered in combination with other active agents.

[0202] When used in combination with one or more additional pharmaceutical agent or agents, the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent may be administered priorto, concurrently with, orfollowing administration ofthe additional pharmaceutical agent or agents.

[0203] The dosages ofthe compounds described herein dépend upon a variety of factors including the particularsyndrome to be treated, the severity ofthe symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile ofthe compound, and the presence of any deleterious side-effects, among other considérations.

[0204] The compound, or pharmaceutically acceptable sait thereof, described herein and the antiviral agent are typically administered at dosage levels and in a manner customary for KMO inhibitors and antiviral agents respectively. For example, the compound, or pharmaceutically acceptable sait thereof, described herein and/or the antiviral agent can be administered, in single or multiple doses, by oral administration at a dosage level of generally 0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, such as 0.1-70 mg/kg/day, for example, 0.5-10 mg/kg/day. Unit dosage forms can contain generally 0.01-1000 mg of a compound, or pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent for example, 0.1-50 mg of at least one compound, or pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent. For intravenous administration, the at least one compound, or pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, for example, 0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of a compound, or pharmaceutically acceptable sait thereof, described herein and/or an antiviral agent.

[0205] In carrying out the procedures ofthe methods described herein, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include ail related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will hâve sufficient knowledge of such Systems and méthodologies so as to be able, without undue expérimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.

EXAMPLES

The compounds, pharmaceutically acceptable salts and prodrugs thereof, described herein, compositions, and methods described herein are further illustrated by the following nonlimiting examples.

As used herein, the following abbreviations hâve the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

DCM		dichloromethane
DMF	=	N,N-dimethylformamide
DMSO	=	dimethylsulfoxide
EtOAc	=	ethyl acetate
g	=	g ram
hr	=	hour
hrs	=	hours
LC/MS	=	liquid chromatography / mass spectrometry
mg	=	milligram
min	=	minutes
mL	=	milliliter
mmol	=	millimoles
mM	=	millimolar
nm	=	nanometer
rt	=	room température
TBME	=	t-butyl methyl ether
THF	=	tetrahydrofuran
pL	=	microliter
pM	=	micromolar
1g/1mL	=	1 vol

Experimental [0206] Commercially available reagents and solvents (HPLC grade) were used without further purification.

[0207] Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F254 (Merck) plates and visualized using UV light. Microwave reactions were carried out using CEM focused microwaves.

[0208] Analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, Systems using reverse phase Atlantis dC18 columns (5 pm, 2.1 x 50 mm), gradient 5-100% B ( A = water/0.1% formic acid, B= acetonitrile/0.1% formic acid) over 3 minutes, injection volume 3 pL, flow =1.0 mL/min. UV spectra were recorded at 215 nm using a Waters 2487 dual wavelength UV detectororthe Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second using Waters ZMD and over m/z 100 to 1000 at a sampling rate of 2 Hz using Electrospray Ionisation, by a Shimadzu 2010 LC-MS system, or analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu 2010, Systems using reverse phase Water Atlantis dC18 columns (3 pm, 2.1 χ 100 mm), gradient 5-100% B (A = water/0.1% formic acid, B= acetonitrile/0.1% formic acid) over 7 min, injection volume 3pL, flow = 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array or on the Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of2 scans per second using Waters ZQ and over m/z 100 to 1000 ata sampling rate of 2 Hz using Electrospray Ionisation, by a Shimadzu 2010 LC-MS system. Data were integrated and reported using OpenLynx and OpenLynx Browser software or via Shimadzu PsiPort software.

Example 1

Reaction Scheme 1

Stage 1

Stage 2

N

R² [0209] Referring to Reaction Scheme 1, Stage 1, to a stirred suspension of dichloropyrimidine (1 eq) in 1,4-dioxane (15 vol) was added boronic acid (0.7 eq) and Pd(PPh3)4 (0.025 eq). A 2 M K2CO3 solution (7.5 vol) was added to the resulting mixture, which was heated at 90 °C overnight under an atmosphère of N2. The reaction mixture was cooled to room température and concentrated in vacuo. The residue was dissolved in EtOAc:water (1:1) (100 vol) and the resulting solution filtered through celite. The organic layer was separated and the aqueous layer further extracted with EtOAc (50 vol). The combined organic layers were washed with saturated aqueous NaCI (20 vol), dried over Na2SÜ4, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (eluent: [0:1 to 1:19] EtOAc:heptane) to afford the required target compounds.

[0210] Referring to Reaction Scheme 1, Stage 2, 4-chloro-6-substituted-phenyl-pyrimidine (1 eq), PdCI₂(dppf).DCM (0.05 eq) and triethylamine (2 eq) were suspended in degassed MeOH (50 vol) in a bomb fitted with a magnetic stirrer bar. The atmosphère in the reaction vessel was replaced with N₂ by successive évacuation and charging with N2 gas (this process was repeated three times). The bomb was then flushed with CO by successive charging with CO and évacuation. The vessel was pressurized to 5 bar of CO and heated at 50 °C with stirring for 5 hours. The reaction vessel was allowed to cool to room température before venting CO and flushing with N2. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc (30 vol) and water (30 vol). The solution was filtered through cotton wool and the organic layer was separated, washed with saturated aqueous NaCI (15 vol), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (eluent: [0:1 to 1:9] EtOAc:heptane) yielded the target compounds.

[0211] Referring to Reaction Scheme 1, Stage 3, 6-substituted-phenyl-pyrimidine-4-carboxylic acid methyl ester (1 eq) was suspended in MeOH (20 vol), 1 M NaOH solution (20 vol) and stirred at room température for 4 hours. The reaction mixture was acidified with 2 M HCl.

Soluble products were extracted with DCM (2 χ 20 vol) and the combined organic layers were dried over MgSO₄, filtered and concentration under reduced pressure afforded the target compounds. Insoluble products were filtered, washed with water (3x10 vol) and heptane (3 χ 10 vol) before drying in vacuo to yield the target compounds.

[0212] The following compounds were prepared substantially as described above.

Compound No.	Chemical Structure	Molecular Weight	Mass Spec Resuit
1	N^N ⁰ /O	264.67	[M+H]⁺ = 265/267, 100% @ rt = 3.53 and 3.70 min
16	N^N F	252.63	[M+H]⁺ = 253, 100% @ rt = 4.06 min
17	N^N Cl	252.63	[M+H]⁺= 253, 100% @rt = 3.92-4.23 min
18	N^N ci^Y ⁰ Cl	269.09	[M+H]⁺= 269, 100%@rt = 4.04 min
19	N^N F^V ° F	236.18	[M+H]⁺= 237, 100% @ rt = 3.74 min
20	N^N Cl	264.67	[M+H]⁺= 265, 100%@rt = 3.73-4.10 min

Example 2

Reaction Scheme 2

[0213] Referring to Reaction Scheme 2, Stage 1, R-OH (1 eq) in DCM (70 vol) at O °C was added dibromo triphenyl phosphorane (1.2 eq). The reaction mixture was allowed to warm to room température and stirred for 16 hrs. The solvent removed in vacuum. DCM (10 vol) was added to the reaction mixture. The precipitate was filtered to afford the target compound. The crude mixture was used in the next step without further purification.

[0214] Referring to Reaction Scheme 2, Stage 2, R-Br (1.1 eq) in DMF (15 vol) were added 2chloro-4-iodophenol (1 eq) and CS2CO3 (2.5 eq). The reaction mixture was refluxed for 3 hours under nitrogen. The reaction mixture was allowed to cool to room température and EtOAc (40 vol) and aq ammonia (40 vol) were added. The organic layer was separated and the aqueous layer further extracted with EtOAc (50 vol). The combined organic layers were washed with saturated aqueous NaCI (20 vol), dried over Na2CO₃, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (eluent: [3:1]

EtOAc:heptane) to afford the required target compound.

[0215] Referring to Reaction Scheme 2, Stage 3, to a stirred suspension of 4- subtituted-3 chloro-iodobenzene (1 eq) in degassed DMF (15 vol) was added bis-diborane (1.05 eq), Pd(OAc)2 (0.04 eq) and KOAc (3.0 eq). The reaction mixture was heated at 90 °C for 5 hrs under an atmosphère of N₂. The reaction mixture was cooled to room température and filtered through celite then concentrated in vacuo to give crude product. Crude was used in the next step without further purification.

[0216] Referring to Reaction Scheme 2, Stage 4, to a stirred suspension of dichloropyrimidine (1 eq) in 1,4-dioxane (90vol) was added boronic ester (1.0 eq) and Pd(PPh₃)4 (0.03eq). A 2 M K2CO₃ (3 eq) solution was added to the resulting mixture, which was heated at 90 °C for 16 hrs under an atmosphère of N2. The reaction mixture was cooled to room température and concentrated in vacuo. The residue was dissolved in EtOAciwater (1:1) (100 vol) and the resulting solution filtered through celite. The organic layer was separated and the aqueous layer further extracted with EtOAc (50 vol). The combined organic layers were washed with saturated aqueous NaCI (20 vol), dried over Na2SO4, filtered and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography (eluent: [3:1] EtOAc:heptane) to afford the required target compound.

[0217] Referring to Reaction Scheme 2, Stage 5, 4-chloro-6-substituted-phenyl-pyrimidine (1 eq), PdCI₂(dppf).DCI\/l (0.05 eq) and triethylamine (2 eq) were suspended in degassed MeOH (50 vol) in a bomb fïtted with a magnetic stirrer bar. The atmosphère in the reaction vessel was replaced with N2 by successive évacuation and charging with N2 gas (this process was repeated three times). The bomb was then flushed with CO by successive charging with CO and évacuation. The vessel was pressurized to 5 bar of CO and heated at 50 °C with stirring for 16 hours. The reaction vessel was allowed to cool to room température before venting CO and flushing with N2. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc (30 vol) and water (30 vol). The organic layer was separated, washed with saturated aqueous NaCI (15 vol), dried over Na2SO₄, filtered and concentrated under reduced pressure. Purification by re-crystallization using MeOH yielded the target compound.

[0218] Referring to Reaction Scheme 2, Stage 6, 6-substituted-phenyl-pyrimidine-4-carboxylic acid methyl ester (1 eq) was suspended in THF (20 vol), 2 M NaOH (2.5 eq) and stirred at room température for 4 hours. Solvent (THF) was removed and reaction mixture was acidified with 2 M HCl. Resulting solid was filtered and was with water to give desired product.

[0219] The following compounds were prepared substantially as described above.

Compound No.	Chemical Structure	Molecular Weight	Mass Spec Resuit
2	N^N Cl	292.72	[M+H]⁺= 293/295, 100% @ rt = 4.18 min
3	An A₀JÇAj Cl	318.76	[M+H]⁺=319, 100% @rt = 4.61 min

Compound No.	Chemical Structure	Molecular Weight	Mass Spec Resuit
4	ΝΆ Cl	306.75	[M+H]⁺ = 307/309, 100% @ rt = 4.37 min
5	N^N AV¹ Cl	306.75	[M+H]⁺ = 307/309, 100% @ rt = 4.37 min
6	nA \Çtï Cl	290.71	[M+H]⁺= 291/293, 100% © rt = 3.93 min
7	N^N AVS Cl	304.79	[M+H]⁺= 305/307, 100% @ rt = 4.20 min
8	An ^V Cl	302.72	[M-Naf = 303/305, 100% © rt = 4.14 min

Example 3

Reaction Scheme 3

[0220] Referring to Reaction Scheme 3, Stage 1. Triethylamine (19.01 mL, 146.92 mmol) was added dropwise to a solution of diethyl but-2-ynedioate (25.0 g, 146.92 mmol) and formamidine hydrochloride (11.83 g, 146.92 mmol) in acetonitrile (500 mL). The resulting red solution was heated at 80 °C for 2.5 hours. After this time the reaction mixture was cooled to 5 °C using a saturated NaCI/ice bath and the reaction was stirred at this température for 25 minutes. After this time the resulting solid precipitate was collected under suction and dried on a sinterfunnel for 30 minutes under vacuum at room température before drying in the vacuum oven at room température for 3 hours to give the desired compound (21.3 g, 86% yield) as a pale brown solid. Tr = 0.85 min (3.5 minute method) mlz (ES+) [M+H]⁺ 169.

[0221] Referring to Reaction Scheme 3, Stage 2. Ethyl 6-hydroxypyrimidine-4-carboxylate (21.3 g, 126.67 mmol) was dissolved in dry DMF (100 mL) in a 2 neck flask. The flask was purged with a stream of nitrogen while cooling in an ice bath for 10 minutes. After this time, thionyl chloride (15.6 mL, 215.6 mmol) was added dropwise over 20 minutes, before being warmed to room température and stirred under a nitrogen atmosphère for 2 hours. After this time, the reaction mixture was carefully poured onto ~100 mL ice water. TBME (100 mL) was added, the organic layer was separated and the aqueous extracted with further TBME (3 x 100 mL). The combined organic layers were washed consecutively with water (2 x 100 mL), and brine (100 mL) before being dried (MgSO₄), filtered and concentrated to give the desired compound (8.8 g, 37% yield) as a light orange powder. δΗ (500 MHz, DMSO) 9.23 (d, J= 0.95 Hz, 1 H), 8.16 (d, J = 1.10 Hz, 1 H), 4.39 (q, J=7.09 Hz, 2 H), 1.34 (t, J=7.17 Hz, 3 H). Tr= 1.43 min (3.5 minute method) mlz (ES+) [M+H]⁺ 187 [0222] Referring to Reaction Scheme 3, Stage 3. Tripotassium phosphate (1.12 g, 5.63 mmol) was added in one portion to a stirred solution ofthe dioxaborolane (3.75 mmol) and ethyl 6chloropyrimidine-4-carboxylate (0.7 g, 3.75 mmol) in DMF (20 mL). The mixture was degassed with nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.14 g, 0.19 mmol) was added in one portion, the mixture was then heated to 80 °C and stirred at this température for 16 hours under a nitrogen atmosphère. After this time the reaction mixture was cooled to room température and partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed sequentially with water (100 mL) then brine (100 mL) before being dried (MgSCL), filtered and concentrated. The resulting brown solid was purified by flash column chromatography (elution: 40% EtOAc, 60% Heptane) to give the desired compound.

[0223] Referring to Reaction Scheme 3, Stage 4. NaOH (2 M solution, 0.63 mL, 1.27 mmol) was added in one portion to a stirred solution of ethyl 6-substituted pyrimidine-4-carboxylate (1.15 mmol) in THF (10 mL) and the mixture was stirred at room température for 16 hours before being heated to reflux for 2 hours. After this time, the reaction mixture was cooled to room température and the resulting precipitate was collected by filtration, washed with THF (20 mL) before being dried under vacuum to give the desired compound.

[0224] The following compounds were prepared substantially as described above.

Compound No.	Chemical Structure	Molecular Weight	Mass Spec Resuit
9	N^N /oJU ° Cl	278.04	[M+H]⁺= 279/281, 100% @ rt = 3.65 min

Example 4

Reaction Scheme 4

[0225] Referring to Reaction Scheme 4, Stage 1. Méthylmagnésium bromide (1.4M in toluene/THF, 1.5 mL, 0.046 mol) was added drop wise over 1 hourto a cold (-78 °C), stirred solution of 4-bromo-2-chlorobenzaldehyde (5.0 g, 0.023 mol) in THF (100 mL) and the mixture was stirred at this température under a nitrogen atmosphère for 1 hour. After this time, the reaction mixture was allowed to warm to room température over 1 hour before being stirred for a further 1.5 hours. The reaction mixture was then cooled to 5 °C in an ice bath and stirred for 10 minutes before saturated ammonium chloride (40 mL) was added drop wise and stirring continued at this température for a further 10 minutes before being allowed to warm to room température. The resulting mixture was then extracted with ethyl acetate (1 χ 100 mL), the organic layer was washed sequentially with water (100 mL), and brine (100 mL) before being dried (MgSO₄), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 10% ethyl acetate, 90% heptanes) to give the desired compound (4.33 g, 81% yield) as a colourless oil. δΗ (500 MHz, DMSO) 7.64 (d, J=1.58 Hz, 1 H) 7.49 - 7.60 (m, 2 H) 5.47 (d, J= 3.00 Hz, 1 H) 4.96 (dd, J = 6.07, 2.60 Hz, 1 H) 1.28 (d, J = 6.31 Hz, 3 H).

[0226] Referring to Reaction Scheme 4, Stage 2. Sodium hydride (60% in oil, 0.38 g, 9.6 mmol) was added portion wise over 5 minutes to a cooled (0 °C), stirred solution of 1-(4-bromo-2chlorophenyl)ethan-1-ol (1.5 g, 6.4 mmol) in DMF (15 mL) and the reaction was stirred at this température for 20 minutes under a nitrogen atmosphère. After this time, methyl iodide (0.48 mL, 7.6 mmol) was added in one portion and the reaction mixture was allowed to warm to room température before being stirred for a further 18 hours. The reaction was quenched by the drop wise addition of water (15 mL) over 10 minutes and the resulting solution was extracted with ethyl acetate (2 χ 30 mL). The combined organic extracts were washed sequentially with water (100 mL) and brine (10 mL) before being dried (MgSCU), filtered and concentrated to give the desired compound (1.5 g, 99% yield) as a yellow oil. δΗ (500 MHz, DMSO) 7.71 (d, J =1.89 Hz, 1 H) 7.60 (dd, J =8.35, 1.89 Hz, 1 H) 7.39 (d, J =8.35 Hz, 1 H) 4.63 (q, J =6.46 Hz, 1 H) 3.16 (s, 3 H) 1.26-1.38 (m, 3 H).

[0227] Referring to Reaction Scheme 4, Stages 3, 4 & 5 were carried out as described in Reaction Scheme 3 [0228] The following compounds were prepared substantially as described above.

Compound No.	Chemical Structure	Molecular Weight	Mass Spec Resuit
10	N^N o ' Cl	292.72	[M+H]⁺= 293/295, 100% @ rt = 3.72 min

Example 5 [0229] The following compounds may be prepared substantially as described above.

Compound No.	Chemical Structure	Chemical Name
11	N^N __O	6-(3-chloro-4-(cyclopropoxymethyl)- phenyl)pyrimidine-4-carboxylic acid
12	N^N __O	6-(3-chloro-4-(1-cyclopropoxyethyl)- phenyl)pyrimidine-4-carboxylic acid
13	N^N	6-(4-chloro-3-cyclopropoxy- phenyl)pyrimidine-4-carboxylic acid

Compound No.	Chemical Structure	Chemical Name
14	N^N Y	6-(4-chloro-3-isopropoxy- phenyl)pyrimidine-4-carboxylic acid
15	N Y X	6-(4-chloro-3-isobutoxy- phenyl)pyrimidine-4-carboxylic acid

Example 6 [0230] A generalized procedure for monitoring L-Kynurenine (KYN) hydroxylation to form product 3-Hydroxy-Kynurenine (3OH-KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring using MS.

Key reagents:

Compound: Stock concentrations: 10 mM in 100% DMSO

Cell line: CHO GST HIS KMO cell line, 1E4 cells/well/100 pl_ in 96well cell plate

Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration:

mM in 100 mM potassium phosphate buffer, pH 7.4)

Assay conditions:

Medium:	OptiMem (Reduced Sérum Medium Ix, +L-Glutamine + HEPES - Phénol Red; GIBCO: Cat# 11058)
Assay Volume:	200 pL
Plate Format:	96 well plate, transparent (Corning)
Read-Out:	product (3OH-KYN) quantification using product spécifie MRM
Reader:	LC/MS/MS

Assay protocol:

o préparé serial dilution (factor 3) of compound in 100% DMSO (top concentration = 6.67 mM,

100% DMSO) [8 points: 6.67 mM; 2.22 mM; 0.74 mM; 0.247 mM; 0.082 mM; 0.027 mM; 0.009 mM; 0.003mM] o préparé 300-fold concentrated solution of each compound concentration (top concentration

22.22 pM, 0.3% DMSO) in OptiMem medium [22.2 pM; 7.41 pM; 2.47 pM; 0.82 pM; 0.27 pM; 0.09 pM; 0.03 pM; 0.01 pM] o préparé substrate ( 10 mM) at concentration of 1.1 mM in medium o medium of cell plate is drawed off o cells are washed with OptiMem (100 pL/well) and drawed off again o assay mix: 90 pL OptiMem/well + 90 pL compound/well of each concentration [final compound top concentration: 10 pM; 0.15% DMSO] [final compound bottom concentration: 0.004 pM; 0.15% DMSO] o pre-incubation: 30min at 37 °C o add 20pLwell ofthe 1.1 mM substrate solution (final assay concentration: 100 pM) o positive control: 200 pL OptiMem o négative control: 180 pL OptiMem + 20 pL 1.1 mM substrate o incubate ~24h at 37 °C o transfer 100 pL of each well in a transparent 96 well plate (Coming) o add 100 pL/well 10% trichloro acetic acid (TCA) in water o centrifugate plate for 3 min at 4000 rpm o detect product by LC/MS (injection of 50 pL/well; 2.5 fold overfill of the 20 pL sample loop)

Data analysis: ICso’s are calculated using automated fitting algorithm (A+ Analysis)

Example 7 [0231] A method of monitoring L-Kynurenine (KYN) hydroxylation to form product 3-HydroxyKynurenine (3OH-KYN) by LC/MS is described below. Product is quantified by multiple reaction monitoring.

Key reagents:

Compound: Stock concentrations: 10 mM in 100% DMSO

Enzyme: KMO enzyme prepared at Evotec via mitochondria isolation from CHOGST HIS KMO cells

Substrate: L-Kynurenine (Sigma: Cat# K3750) [stock concentration: 10 mM in 100 mM potassium phosphate buffer, pH

7.4]

Assay conditions:

Buffer:	100 mM potassium phosphate, pH 7.4, 200pM NADPH, 0.4U/ml G6P-DH (Glucose 6-phosphate dehydrogenase), 3mM G6P (D-Glucose 6phosphate)
Assay Volume:	40 pL
Plate Format:	384 well plate, transparent (Matrix)
Read-Out:	product (3OH-KYN) quantification using product spécifie MRM
Reader:	LC/MS/MS

Assay protocol:

o préparé serial dilution (factor 3) of compound in 100% DMSO (top concentration = 10 mM, 100% DMSO) [8 points: 10 mM; 3.33 mM; 1.11 mM; 0.37 mM; 0.12 mM; 0.04 mM; 0.0137 mM; 0.0045 mM, 0.0015 mM] o préparé 3.33 -fold concentrated solution of each compound concentration (top concentration 300μΜ, 3% DMSO)in assay buffer [concentrations: 300 μΜ; 100 μΜ; 33.3 μΜ; 11.1 μΜ; 3.70 ρΜ; 1.23 μΜ; 0.41 μΜ; 0.137 μΜ] ο préparé substrate (10 mM) at concentration of 1 mM in assay buffer o assay mix: 4 pL compound/well of each concentration + 24 pl_ assay buffer/well + 8 pl_ KMO human enzyme + 4 pL 1 mM substrate (final concentration = 100 pM) [final compound top concentration: 30 pM; 0.3% DMSO] [final compound bottom concentration: 0.0137 pM; 0.3% DMSO] o positive control: 4 pL 50 pM FCE28833 in assay buffer [0.5%DMSO] (final assay concentration = 5 pM) + 24 pL assay buffer/well + 8 pL KMO human enzyme + 4 pL 1 mM substrate (final concentration = 100 pM) o négative control: 28 pL assay buffer/well + 8 pL KMO human enzyme + 4 pL 1 mM substrate (final concentration = 100 pM) o incubate 400min at RT o add 40 pL/well 10% trichloro acetic acid in water to stop the assay and precipitate protein o centrifuge plate for 3 min at 4000 rpm o product détection by LC/MS (injection of 50 pL/well; 2.5 fold overfill of the 20 pL sample loop)

Data analysis:

ICso’s are calculated using automated fitting algorithm (A+ Analysis).

Example 8 [0232] A method of monitoring L-Kynurenine (KYN) hydroxylation to form 3- HydroxyKynurenine (3OH-KYN) by LC/MS is described. Product is quantified by multiple reaction monitoring (MRM method).

Key reagents:

Compound:	Stock concentrations: 10 mM in 100% DMSO
Enzyme:	KMO enzyme prepared at Evotec from mouse Iiver (4-6 weeks old) via mitochondria isolation as described in the literature
Substrate:	L-Kynurenine (Sigma: Cat# K3750, stock concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4)

Assay conditions:

Buffer:	100 mM potassium phosphate, pH 7.4, 200 μΜ NADPH, 0.4 U/mL G6P- DH (Glucose 6-phosphate Dehydrogenase), 3 mM G6P (D-Glucose 6phosphate)
Assay Volume:	40 pL
Plate Format:	384 well plate, transparent (Matrix)
Read-Out:	product (3OH-KYN) quantification using product spécifie MRM
Reader:	LC/MS/MS

Assay protocol:

o préparé serial dilution (factor 3) of compound in 100% DMSO (top concentration = 10 mM, 100% DMSO) [8 points: 10 mM; 3.33 mM; 1.11 mM; 0.37 mM; 0.12 mM; 0.04 mM; 0.0137 mM; 0.0045 mM, 0.0015 mM] o préparé 3.33 -fold concentrated solution of each compound concentration (top concentration

300 μΜ, 3% DMSO) in assay buffer [concentrations: 300 μΜ; 100 μΜ; 33.3 μΜ; 11.1 μΜ; 3.70 μΜ; 1.23 μΜ; 0.41 μΜ; 0.137 μΜ] o préparé substrate (10 mM) at concentration of 1 mM in assay buffer o assay mix: 4 μΙ_ compound/well of each concentration + 24 pL assay buffer/well + 8 μΙ_ KMO mouse enzyme + 4 μΙ_ 1 mM substrate (final concentration = 100 μΜ) [final compound top concentration: 30 μΜ; 0.3% DMSO] [final compound bottom concentration: 0.0137 μΜ; 0.3% DMSO] o positive control: 4 μΙ_ 50μΜ FCE28833 in assay buffer, 0.5% DMSO [final assay concentration = 5μΜ] + 24 μΙ_ assay buffer/well + 8 μΙ_ KMO mouse enzyme + 4 μΙ_ 1 mM substrate [final concentration = 100 μΜ] o négative control: 28 μΙ_ assay buffer/well + 8 μΙ_ KMO mouse enzyme + 4 μΙ_ 1 mM substrate [final concentration = 100 μΜ] o incubate 40 min at RT o add 40 pL/well10% trichloro acetic acid in water to stop the assay and precipitate protein o centrifuge plate for 3 min at 4000 rpm o product détection by LC/MS (injection of20 pl_/well, 2 fold overfill ofthe 10 pL sample loop)

Data analysis: ICso’s are calculated using automated fitting algorithm (A+ Analysis).

Example 9 [0233] Using procedures similar to those described herein, the following compounds were assayed for activity.

lUPAC name	% Inhibition at 10 μΜ*
6-(4-chloro-3-methoxy- phenyl)pyrimidine-4-carboxylic acid	99.62
6-(3-chloro-4-isopropoxy- phenyl)pyrimidine-4-carboxylic acid	100
6-(3-chloro-4-(cyclopentyloxy)- phenyl)pyrimidine-4-carboxylic acid	97
(S)-6-(4-sec-butoxy-3-chlorophe nyl) py ri m i d i n e-4-carboxy I ic acid	100
(R)-6-(4-sec-butoxy-3-chloro- phenyl)pyrimidine-4-carboxylic acid	100

IUPAC name	% Inhibition at 10 μΜ*
6-(3-chloro-4-cyclopropoxy- phenyl)pyrimidine-4-carboxylic acid	100
6-(3-chloro-4-cyclobutoxy- phenyl)pyrimidine-4-carboxylic acid	100
6-(3-chloro-4-(cyclopropylmethoxy)- phenyl)pyrimidine-4-carboxylic acid	101
6-(4-chloro-3-fluoro-phenyl)pyrimidine- 4-carboxylic acid	102.645

Example 10

MICRODIALYSIS PROCEDURE FOR MOUSE STUDIES [0234] Animais were anesthetized using isoflurane (2%, 800 mL/min 02). Bupivacain/epinephrine was used for local analgesia, finadyne or carprophen for peri-/postoperative analgesia. The animais were placed in a stereotaxic frame (Kopf instruments, USA). Ishaped probes (membrane: polyacrylonitrile, 3 mm exposed surface; Brainlink, the Netherlands) were inserted in the striatum. After surgery, animais were kept individually in cages; provided food and water ad libitum.

[0235] Experiments were performed one day after surgery. On the day of the experiment, the probes of the animais were connected with flexible PEEK tubing to a microperfusion pump (Harvard PHD 2000 Syringe pump, Holliston, MA or similar). The l-shaped microdialysis probes were perfused with aCSF containing 147 mM NaCI, 3.0 mM KCI, 1.2 mM CaCI2 and 1.2 mM MgCI2, at a flow rate of 1.5 pL/min. Microdialysis samples were collected at 20-minute intervals by an automated fraction collecter (820 Microsampler, Univentor, Malta or similar) into mini-vials already containing 10 pL 0.02 M formic acid (FA) and 0.04% ascorbic acid in ultrapurified H2O. At t = -30 min vehicle or KMO inhibitor were be administered, to ensure central and peripheral inhibition of KMO at the time of administration of kynurenine. At t = 0 vehicle or kynurenine were administered. Microdialysate samples were collected for 240 min after administration of kynurenine. Ail the dialysis samples were stored at -80 °C awaiting their analysis. Dialysate levels of any or ail of KP métabolites KYN, KYNA, 3-OH-KYN, AA and QA were quantified by LC-MS/MS at by Brains On-Line. After the experiment, the mice were sacrificed and terminal brain (striatum + cortex), liver, kidney, plasma and CSF samples were collected for analysis of KP métabolites. Levels of KP métabolites were measured in terminal brain (striatum + cortex), liver, kidney, plasma and CSF samples at Brains On-Line. Finally, levels of kynurenine and KMO inhibitors in dose formulation samples were quantified by Brains On-Line.

Example 11 [0236] A method of examining the modulation of KYN, KYNA, AA, and 3-HK via KMO inhibition with Compound 6 in striatum extracellular space is disclosed. Specifically, this experiment is aimed at demonstrating the dose dépendent différences in central KP métabolite (KYN, KYNA, AA, 3-HK) élévations between dosing of Compound 6 at various levels in an animal brain. Following the microdialysis procedure described herein, dialysate levels of KP métabolites KYN, KYNA, 3-HK, and AA were quantified by LC-MS/MS at by Brains On-Line.

[0237] When microdialysis after PO dosing Compound 6 at various dosage levels (3 mg/kg, 10 mg/kg, or 30 mg/kg) was performed, Compound 6 showed dose dépendent increases KYN (see FIG. 1), as well as protective métabolites KYNA (see FIG. 2) & AA (see FIG. 3) in mouse striatum, while there was little or no effect on harmful métabolite 3-HK (see FIG. 4).

Example 12 [0238] A method of examining the modulation of KP métabolites in HD animais similar to WT contrais is disclosed. Specifically, this experiment is aimed at demonstrating that Compound 6 modulâtes the différences in KYNA élévations in an animal brain. Following the microdialysis procedure described herein, dialysate levels of KP métabolite KYNA was quantified by LCMS/MS at by Brains On-Line.

[0239] When microdialysis after PO dosing of Compound 6 at either 3 mg/kg or 10 mg/kg was performed, it was shown that Compound 6 increases KYNA in both WT (see FIG. 5) and HD animais (see FIG. 6), with little différence between the two.

Example 13 [0240] A method of examining the pharmacodynamie effects of kynurenine (30 mg/kg, p.o.) and Compound 6 (30 mg/kg, p.o.) on extracellular levels of KYN, KYNA, 3-OH-KYN, AA and QA in the striatum (STR) of adult male WT mice either co-dosed ordosed independently is disclosed. Specifically, this experiment is aimed at demonstrating the différences in central KP métabolite élévations between Kynurenine dosing versus dosing a KMO inhibitor expected to block kynurenine catabolism downstream of KMO in an animal brain.

[0241] When microdialysis after PO dosing of kynurenine (30 mg/kg, p.o.), Compound 6 (30 mg/kg, p.o.), or kynurenine and Compound 6 co-dosed (30 mg/kg, p.o. each) was performed, it was shown that Compound 6 increases KYN (see FIG. 7), as well as protective métabolites KYNA (see FIG. 8) & AA (see FIG. 9) in mouse striatum, while kynurenine alone has little or no effect on these métabolites. Furthermore, PO administration of Compound 6 blocks toxic métabolites 3-OH-KYN (see FIG. 10) and QA (see FIG. 11), whereas kynurenine dosing increases them, due to kynurenine catabolism in mice brain.

[0242] While some embodiments hâve been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope ofthe invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the spécification be read into the claims. Accordingly, it is to be understood that the présent invention has been described by way of illustration and not limitations on the scope ofthe claims.

Claims

What is claimed is:

1. Use of a compound of Formula I:

Formula I or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating an HIV-related disorder in a subject infected with HIV, wherein the médicament is formulated for adjunctive administration with an antiviral agent and further wherein

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent, C-Ca alkyl substituted with one substituent selected from C1-C4 alkoxy and C₃-C₆ cycloalkoxy, C₃-C₆ cycloalkoxy, and halo.
2. The use according to claim 1, wherein R¹ is Ci-C₄ alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent.
3. The use according to claim 2, wherein R¹ is alkoxy.
4. The use according to claim 3, wherein R¹ is sec-butoxy.
5. The use according to claim 4, wherein R¹ is (R)-sec-butoxy.
6. The use according to claim 4, wherein R¹ is (S)-sec-butoxy.
7. The use according to claim 3, wherein R¹ is isopropoxy.
8. The use according to claim 2, wherein R¹ is C1-C4 alkoxy substituted with one C₃-C6 cycloalkyl substituent.
9. The use according to claim 8, wherein R¹ is cyclopropylmethoxy.

WO 2016/011316 PCT/US201S/040848
10. The use according to claim 1, wherein R¹ is C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy and C3-C6 cycloalkoxy.
11. The use according to claim 10, wherein R¹ is C1-C4 alkyl substituted with one C1-C4 alkoxy substituent.
12. The use according to claim 11, wherein R¹ is 1-methoxyethyl.
13. The use according to claim 11, wherein R¹ is methoxymethyl.
14. The use according to claim 10, wherein R¹ is C1-C4 alkyl substituted with one C3-C6 cycloalkoxy substituent.
15. The use according to claim 14, wherein R¹ is 1-cyclopropoxyethyl.
16. The use according to claim 14, wherein R¹ is cyclopropoxymethyl.
17. The use according to claim 1, wherein R¹ is C₃-C₆ cycloalkoxy.
18. The use according to claim 17, wherein R¹ is cyclobutoxy.
19. The use according to claim 17, wherein R¹ is cyclopentyloxy.
20. The use according to claim 17, wherein R¹ is cyclopropoxy.
21. The use according to claim 1, wherein R¹ is halo.
22. The use according to claim 21, wherein R¹ is chloro.
23. The use according to claim 21, wherein R¹ is fluoro.
24. The use according to any one of claims 1 to 23, wherein R² is selected from: C1-C4 alkoxy, C3-C6 cycloalkoxy, and halo.

WO 2016/011316 PCT/US2015/040848
25. The use according to claim 24, wherein R² is C1-C4 alkoxy.
26. The use according to claim 25, wherein R² is isobutoxy.
27. The use according to claim 25, wherein R² is isopropoxy.
28. The use according to claim 25, wherein R² is methoxy.
29. The use according to claim 24, wherein R² is C₃-C₆ cycloalkoxy.
30. The use according to claim 29, wherein R² is cyclopropoxy.
31. The use according to claim 24, wherein R² is halo.
32. The use according to claim 31, wherein R² is chloro.
33. The use according to claim 31, wherein R² is fluoro.
34. The use according to claim 1, wherein:

R¹ is selected from C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C-1-C4 alkoxy and C3-C6 cycloalkoxy, C3-C6 cycloalkoxy, and halo; and

R² is selected from: C1-C4 alkoxy, C₃-C₆ cycloalkoxy, and halo.
35. The use according to claim 1, wherein:

R¹ is selected from sec-butoxy, chloro, cyclobutoxy, cyclopentyloxy, cyclopropoxy, 1-cyclopropoxyethyl, cyclopropylmethoxy, cyclopropoxymethyl, fluoro, methoxy, 1-methoxyethyl, and methoxymethyl; and

R² is selected from: chloro, cyclopropoxy, fluoro, isobutoxy, isopropoxy, and methoxy.
36. The use according to claim 1, wherein said compound of Formula I is selected from:

6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid;

WO 2016/011316 PCT/US2015/040848

6-(3-chloro-4-isopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid; (S)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid;

(R)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-cyclobutoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(1-methoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(1-cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(4-chloro-3-isopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(4-chloro-3-fluorophenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-fluorophenyl)pyrimidine-4-carboxylic acid; 6-(3,4-dichlorophenyl)pyrimidine-4-carboxylic acid;

6-(3,4-difluorophenyl)pyrimidine-4-carboxylic acid; and 6-(3-chloro-4-methoxy)pyrimidine-4-carboxylic acid.
37. The use according to any one of claims 1 to 36, wherein said médicament and said antiviral agent are: a) in admixture; b) chemically/physicochemically linked; c) chemically/physicochemically co-packaged; or d) unmixed but co-packaged orcopresented.
38. The use according to claim 37, wherein said médicament and said antiviral agent are copackaged in a single container or in a plurality of containers within a single outer package.
39. The use according to claim 37, wherein said médicament is administered before said antiviral agent.
40. The use according to claim 37, wherein said médicament is administered after said antiviral agent.

WO 2016/011316 PCT/US2015/040848
41. The use according to claim 37, wherein said médicament and said antiviral agent are administered simultaneously.
42. The use according to claim 41, wherein the antiviral agent and the médicament are administered simultaneously in a unitary formulation.
43. The use according to claim 41, wherein the antiviral agent and the médicament are administered simultaneously in different formulations.
44. The use according to any one of claims 1 to 43, wherein said HIV is HIV-1.
45. The use according to claim 44, wherein said HIV is HIV-1 group M.
46. The use according to any one of claims 1 to 45, wherein said antiviral agent is selected from: entry inhibitors, fusion inhibitors, glycosidase inhibitors, CCR5 antagonists, immune-based thérapies, integrase inhibitors, maturation inhibitors, multi-class combination drugs, non-nucleoside reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, pharmacokinetic enhancers, and protease inhibitors.
47. The use according to any one of claims 1 to 45, wherein said antiviral agent is selected from: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists, and integrase strand transfer inhibitors, and combinations thereof.
48. The use according to any one of claims 1 to 45, wherein said antiviral agent is selected from: amdoxovir, Aptivus®, Aralen®, Atripla®, cenicriviroc, Cobicistat®, Combivir®, Complera®, Crixivan®, DermaVir®, Edurant®, elvitegravir, Emtriva®, Epivir®, Epzicom®, Fuzeon®, ibalizumab, Intelence®, interleukin-7, Invirase®, Isentress®, Kaletra®, lersivirine, lexgenleucel-T, Lexiva®, Norvir®, Plaquenil®, Proleukin®, Prezista®, PRO 140, Rescriptor®, Retrovir®, Reyataz®, SB-728-T, Selzentry®, SPI452, Stribild®, Sustiva®, tenofovir alafenamide fumarate, Tivicay®, Trii™, Trizivir®, Truvada®, Videx®, Videx® EC, Viracept®, Viramune®, Viramune® XR, Viread®, Zerit®, and Ziagen®.

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49. The use according to any one of claims 1 to 45, wherein said antiviral agent is highly active antirétroviral therapy.
50. The use according to any one of claims 1 to 49, wherein said HIV-related disorder is a neurological disorder.
51. The use according to claim 50, wherein said neurological disorder is selected from: AIDS dementia complex, AIDS-induced encephalopathy, HIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, minor neurocognitive disorder, minor cognitive motor disorder, vacuolar myelopathy, peripheral neuropathies, and polymyositis.
52. A composition comprising an antiviral agent and a compound of Formula I:

Formula I or a pharmaceutically acceptable sait thereof;

wherein:

R¹ and R² are each independently selected from C1-C4 alkoxy optionally substituted with one C₃-C₆ cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy and C3-C6 cycloalkoxy, C₃-C₆ cycioalkoxy, and halo.
53. The composition according to claim 52, wherein R¹ is C1-C4 alkoxy optionally substituted with one C3-C₆ cycloalkyl substituent.
54. The composition according to claim 53, wherein R¹ is C1-C4 alkoxy.
55. The composition according to claim 54, wherein R¹ is sec-butoxy.
56. The composition according to claim 55, wherein R¹ is (R)-sec-butoxy.

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57. The composition according to claim 55, wherein R¹ is (S)-sec-butoxy.
58. The composition according to claim 54, wherein R¹ is isopropoxy.
59. The composition according to claim 53, wherein R¹ is C1-C4 alkoxy substituted with one

C3-C6 cycloalkyl substituent.
60. The composition according to claim 59, wherein R¹ is cyclopropylmethoxy.
61. The composition according to claim 52 wherein R¹ is C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy and C3-C6 cycloalkoxy.
62. The composition according to claim 61, wherein R¹ is C1-C4 alkyl substituted with one C1-C4 alkoxy substituent.
63. The composition according to claim 62, wherein R¹ is 1-methoxyethyl.
64. The composition according to claim 62, wherein R¹ is methoxymethyl.
65. The composition according to claim 61, wherein R¹ is C1-C4 alkyl substituted with one

C3-C6 cycloalkoxy substituent.
66. The composition according to claim 65, wherein R¹ is 1-cyclopropoxyethyl.
67. The composition according to claim 65, wherein R¹ is cyclopropoxymethyl.
68. The composition according to claim 52, wherein R¹ is C3-C6 cycloalkoxy.
69. The composition according to claim 68, wherein R¹ is cyclobutoxy.
70. The composition according to claim 68, wherein R¹ is cyclopentyloxy.
71. The composition according to claim 68, wherein R¹ is cyclopropoxy.

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72. The composition according to claim 52, wherein R¹ is halo.
73. The composition according to claim 72, wherein R¹ is chloro.
74. The composition according to claim 72, wherein R¹ is fluoro.
75. The composition according to any one of claims 52 to 74, wherein R² is selected from:

C1-C4 alkoxy, C3-C6 cycloalkoxy, and halo.
76. The composition according to claim 75, wherein R² is C1-C4 alkoxy.
77. The composition according to claim 76, wherein R² is isobutoxy.
78. The composition according to claim 76, wherein R² is isopropoxy.
79. The composition according to claim 76, wherein R² is methoxy.
80. The composition according to claim 75, wherein R² is C₃-Cs cycloalkoxy.
81. The composition according to claim 80, wherein R² is cyclopropoxy.
82. The composition according to claim 75, wherein R² is halo.
83. The composition according to claim 82, wherein R² is chloro.
84. The composition according to claim 82, wherein R² is fluoro.
85. The composition according to claim 52, wherein:

R¹ is selected from C1-C4 alkoxy optionally substituted with one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy and C₃-C₆ cycloalkoxy, C₃-C₆ cycloalkoxy, and halo; and

R² is selected from: C1-C4 alkoxy, C₃-C₆ cycloalkoxy, and halo.

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86. The composition according to claim 52, wherein:

R¹ is selected from sec-butoxy, chloro, cyclobutoxy, cyclopentyloxy, cyclopropoxy, 1-cyclopropoxyethyl, cyclopropylmethoxy, cyclopropoxymethyl, fluoro, methoxy, 1-methoxyethyl, and methoxymethyl; and

R² is selected from: chloro, cyclopropoxy, fluoro, isobutoxy, isopropoxy, and methoxy.
87. The composition according to claim 52, wherein said compound of Formula I is selected from:

6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-isopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid;

(S)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid;

(R)-6-(4-sec-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-cyclobutoxyphenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(1-methoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-(1-cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-isopropoxyphenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-isobutoxy-phenyl)pyrimidine-4-carboxylic acid;

6-(4-chloro-3-fluorophenyl)pyrimidine-4-carboxylic acid;

6-(3-chloro-4-fluorophenyl)pyrimidine-4-carboxylic acid;

6-(3,4-dichlorophenyl)pyrimidine-4-carboxylic acid; 6-(3,4-difluorophenyl)pyrimidine-4-carboxylic acid; and 6-(3-chloro-4-methoxy)pyrimidine-4-carboxylic acid.
88. The composition according to any one of claims 52 to 87, comprising said antiviral agent and said compound of Formula I or a pharmaceutically acceptable sait thereof, in a copackaged drug product.

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89. The composition according to any one of claims 52 to 88, wherein said antiviral agent is selected from: entry inhibitors, fusion inhibitors, glycosidase inhibitors, CCR5 antagonists, immune-based thérapies, integrase inhibitors, maturation inhibitors, multiclass combination drugs, non-nucleoside reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, pharmacokinetic enhancers, and protease inhibitors.
90. The composition according to any one of claims 52 to 88, wherein said antiviral agent is selected from: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 antagonists, and integrase strand transfer inhibitors, and combinations thereof.
91. The composition according to any one of claims 52 to 88, wherein said antiviral agent is selected from: amdoxovir, Aptivus®, Aralen®, Atripla®, cenicriviroc, Cobicistat®, Combivir®, Complera®, Crixivan®, DermaVir®, Edurant®, elvitegravir, Emtriva®, Epivir®, Epzicom®, Fuzeon®, ibalizumab, Intelence®, interleukin-7, Invirase®, Isentress®, Kaletra®, lersivirine, lexgenleucel-T, Lexiva®, Norvir®, Plaquenil®, Proleukin®, Prezista®, PRO 140, Rescriptor®, Retrovir®, Reyataz®, SB-728-T, Selzentry®, SPI-452, Stribild®, Sustiva®, tenofovir alafenamide fumarate, Tivicay®, Trii™, Trizivir®, Truvada®, Videx®, Videx® EC, Viracept®, Viramune®, Viramune® XR, Viread®, Zerit®, and Ziagen®, and combinations thereof.
92. The composition according to any one of claims 52 to 88, wherein said antiviral agent is highly active antirétroviral therapy.