Soluble epoxide hydrolase inhibitors and methods of use therof

Abstract

In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds and compositions that inhibit soluble epoxide hydrolase (sEH) and methods of using the compounds to treat diseases. In one aspect, the compounds described herein when administered with EC5026 provide synergistic results with respect to inhibiting soluble epoxide hydrolase and treating or preventing diseases associated with soluble epoxide hydrolase activity.

Description

ATTORNEY DOCKET NO.930503-2010 SOLUBLE EPOXIDE HYDROLASE INHIBITORS AND METHODS OF USE THEROF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No.63 / 643,978, filed on May 8, 2024, the contents of which are incorporated by reference herein in their entireties. BACKGROUND

[0002] Epoxide hydrolases (EHs) catalyze the hydration of aliphatic epoxides or arene oxides to their corresponding diols by the addition of water. Some EHs play an important role in the metabolism of a variety of compounds including hormones, chemotherapeutic drugs, carcinogens, environmental pollutants, mycotoxins, and other harmful foreign compounds. There are two well-studied EHs in mammals: microsomal epoxide hydrolase (mEH, EC 3.3.2.9) and soluble epoxide hydrolase (sEH, EC3.3.2.10). These enzymes are very distantly related, have different subcellular localization, and are members of α / β hydrolase fold family, and have different but partially overlapping substrate selectivity. The soluble and microsomal EH forms are known to complement each other in degrading some plant natural products.

[0003] The major role of the sEH is in the metabolism of lipid epoxides, including epoxides of arachidonic acid, linoleic acid, and other fatty acids, some of which are endogenous chemical mediators. Lipid epoxides, such as epoxides of arachidonic acid (cis-epoxyeicosatrienoic acids or EETs), and other lipid epoxides are known effectors of blood pressure, and modulators of vascular permeability. The vasodilatory properties of EETs are associated with an increased open-state probability of calcium-activated potassium channels leading to hyperpolarization of the vascular smooth muscle. Metabolism of the EETs by sEH diminishes these activities. Metabolism of EETs by sEH also prevents their incorporation into coronary endothelial phospholipids, suggesting a regulation of endothelial function by sEH. It has been shown that treatment of spontaneous hypertensive rats (SHRs) with selective sEH inhibitors significantly reduces their blood pressure. In addition, it was claimed that male knockout sEH mice have significantly lower blood pressure than wild-type mice, however subsequent studies with back breeding into C57B mice demonstrated that 20-HETE levels increased compensating for the increase of EETs in plasma.ATTORNEY DOCKET NO.930503-2010

[0004] The EETs have also demonstrated anti-inflammatory properties in endothelial cells. In contrast, diols derived from epoxy-linoleate (EpOME) perturb membrane permeability and calcium homeostasis, which results in inflammation that is modulated by nitric oxide synthase and endothelin-1. Micromolar concentrations of 9,10 EpOME (leukotoxin) reported in association with inflammation and hypoxia and depression of mitochondrial respiration in vitro, and mammalian cardiopulmonary toxicity in vivo. Leukotoxin toxicity presents symptoms suggestive of multiple organ failure and acute respiratory distress syndrome (ARDS). In both cellular and organismal models, leukotoxin-mediated toxicity is dependent upon the conversion of leukotoxin into the corresponding diol, suggesting roles for sEH in the regulation of inflammation and vascular permeability. The bioactivity of these epoxy fatty acids suggests that inhibition of formation of the corresponding vicinal-dihydroxy-lipids may have therapeutic value, making sEH a promising pharmacological target.

[0005] 1,3-Disubstituted ureas, carbamates, and amides have been reported as potent inhibitors of sEH. These compounds are competitive tight-binding inhibitors often with subnanomolar KIs that interact stoichiometrically with purified recombinant human sEH. Based on the X-ray crystal structures of sEH complexed with inhibitors, urea-based sEH inhibitors were shown to establish strong hydrogen bonds between the urea group of the inhibitors and residues of the sEH active site, mimicking features encountered in the reaction coordinate of epoxide ring opening by this enzyme. These inhibitors efficiently reduced lipid epoxide metabolism in several in vitro and in vivo models.

[0006] Despite the high activity associated with these inhibitors, there exists a need for compounds possessing similar or increased activities, preferably with improved water solubil- ity and / or pharmacokinetic properties to facilitate formulation and delivery. SUMMARY

[0007] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to compounds and compositions that inhibit soluble epoxide hydrolase (sEH) and methods of using the compounds to treat diseases. In one aspect, the compounds described herein when administered with EC5026 provide synergistic results with respect to inhibiting soluble epoxide hydrolase and treating or preventing diseases associated with soluble epoxide hydrolase activity.

[0008] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, andATTORNEY DOCKET NO.930503-2010 advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0010] FIG.1 shows the structure of several compounds described herein.

[0011] FIG. 2 shows the plasma concentrations of EC5026, M3a, and M3b, after administrating a single dose of 1 mg / kg by oral gavage to separate groups of male rats.

[0012] FIGS.3A-3B show the concentration of EC5026 detected in healthy humans after (A) a single and (B) repeat dose in relation to the predicted concentration needed for efficacy.

[0013] FIG 4. shows tested inhibition of sEH activity from healthy humans administered a once daily oral dose of EC5026.

[0014] FIG. 5 shows detected concentrations of EC5026 and M3a and M3b in healthy humans.

[0015] FIG.6 shows isolobologram results of IC50 calculated for sEH inhibitors administered alone and together.

[0016] FIGS.7A-7B show updated predicted efficacious concentrations based on synergism of EC5026, M3a and M3b.

[0017] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.ATTORNEY DOCKET NO.930503-2010 DETAILED DESCRIPTION

[0018] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0019] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0020] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0021] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0022] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0023] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly usedATTORNEY DOCKET NO.930503-2010 dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0024] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions

[0025] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0026] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” include, but are not limited to, mixtures or combinations of two or more such excipients, and the like.

[0027] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0028] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greaterATTORNEY DOCKET NO.930503-2010 than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0029] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. Thus, for example, if a component is in an amount of about 1%, 2%, 3%, 4%, or 5%, where any value can be a lower and upper endpoint of a range, then any range is contemplated between 1% and 5% (e.g., 1% to 3%, 2% to 4%, etc.).

[0030] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0031] As used herein, “IC50,” is intended to refer to the concentration of a substance (e.g., aATTORNEY DOCKET NO.930503-2010 compound or a drug) that is required for 50% inhibition of a biological process, or component of a process. For example, IC50refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.

[0032] As used herein, “area under the curve” or “AUC” is the concentration of a compound described herein in a patient sample, (e.g., blood, plasma) as a function of time.

[0033] As used herein, “Cmax” is the maximum (or peak) concentration in a patient sample (e.g., blood, serum) that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose.

[0034] As used herein, “half-life” is the time taken for concentration of a compound or drug to decrease from its maximum concentration (Cmax) to half of Cmaxin a sample (e.g., blood, serum).

[0035] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0036] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated toATTORNEY DOCKET NO.930503-2010 the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0037] The position of a substituent can be defined relative to the positions of other substituents in an aromatic ring. For example, as shown below in relationship to the “R” group, a second substituent can be “ortho,” “para,” or “meta” to the R group, meaning that the second substituent is bonded to a carbon labeled ortho, para, or meta as indicated below. Combinations of ortho, para, and meta substituents relative to a given group or substituent are also envisioned and should be considered to be disclosed.

[0038] In defining various used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0039] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0040] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can alsoATTORNEY DOCKET NO.930503-2010 be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0041] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0042] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0043] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groupsATTORNEY DOCKET NO.930503-2010 including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0044] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH2— (methylene), —CH2CH2—, — CH2C(CH3)2CH2—, and —CH2CH2CH2— are non-limiting examples of alkanediyl groups.

[0045] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0046] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0047] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.ATTORNEY DOCKET NO.930503-2010

[0048] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0049] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0050] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0051] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.ATTORNEY DOCKET NO.930503-2010 Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.

[0052] The term “aldehyde” as used herein is represented by the formula -C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0053] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0054] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) and —N(-alkyl)2, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0055] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0056] The term “ester” as used herein is represented by the formula —OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0057] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.

[0058] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0059] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0060] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, whereinATTORNEY DOCKET NO.930503-2010 the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0061] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2- a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0062] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2- C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2- C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl,ATTORNEY DOCKET NO.930503-2010 dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0063] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H- pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0064] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0065] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula —OH.

[0066] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0067] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0068] The term “nitro” as used herein is represented by the formula —NO2.

[0069] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0070] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.ATTORNEY DOCKET NO.930503-2010

[0071] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0072] The term “thiol” as used herein is represented by the formula -SH.

[0073] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0074] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0075] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^;ATTORNEY DOCKET NO.930503-2010 –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; – C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; – OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; – C(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; – C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4straight or branched alkylene)O–N(R^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0076] Suitable monovalent substituents on R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, – 0–alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0077] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or anATTORNEY DOCKET NO.930503-2010 unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0078] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0079] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] Suitable substituents on the aliphatic group of R†are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] The term “leaving group” refers to the electron-withdrawing group, such as an atom or a group of atoms, that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.ATTORNEY DOCKET NO.930503-2010

[0082] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (Z / E) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0083] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0084] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold- Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.ATTORNEY DOCKET NO.930503-2010

[0085] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36Cl, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0086] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0087] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and theATTORNEY DOCKET NO.930503-2010 imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0088] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0089] In some aspects, a structure of a compound can be represented by a formula: ,

[0090] which is understood to be,

[0091] wherein n is typically anunderstood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), and Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0092] The term “substantially R or substantially S” is used when referring to the stereochemistry of a particular carbon atom is defined as a carbon atom having at least 95% enantiomeric excess (ee) at the carbon atom.

[0093] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous,ATTORNEY DOCKET NO.930503-2010 intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0094] The term “subject” as used herein refers to any individual or patient to which the subject methods are performed. Generally, the subject is human or a non-human mammal. Illustrative non-human mammals who can benefit from the present methods include, e.g., Equidae (e.g., horse, ass, zebra), Bovidae (e.g., cattle, bison, sheep, goat, yak, impala, antelope, hartebeest, wildebeest, gnu, gazelle, water buffalo, duiker), Cervidae (e.g., deer, elk, moose, reindeer, pudu, bororo, brocket, guemal, muntjac), Suidae (e.g., pig, hog, boar), Canidae (domesticated dog, wolf, fox, coyote, jackel), Felidae (e.g., domesticated cat, cheetah, ocelot, lynx, bobcat, mountain lion, leopard, puma, lion, jaguar, tiger), Rodentia (e.g., mouse, rat, guinea pig, chinchilla, agouti, porcupine, beaver, gopher), Lagomorpha (e.g., rabbit, jackrabbit, hare, pika), Camelidae (e.g., camel, llama, alpaca, guanaco, vicugna), Ursidae (e.g., bear, panda), Procyonidae (e.g., raccoon, coati, olingo), Mustelidae (polecat, weasel, ferret, mink, fisher, badger, otter, wolverine, marten, sable, ermine), Elephantidae (e.g., elephant), rhinoceros, hippopotamus and non-human primates (e.g., chimpanzee, bonobo, macaque, ape).

[0095] “Soluble epoxide hydrolase” (“sEH”) is an enzyme which in endothelial, smooth muscle and other cell types converts EETs to the corresponding diol compounds called dihydroxyeicosatrienoic acids (“DHETs”). The cloning and sequence of the murine sEH is set forth in Grant et al., J. Biol. Chem.268(23):17628-17633 (1993). The cloning, sequence, and accession numbers of the human sEH sequence are set forth in Beetham et al., Arch. Biochem. Biophys.305(1):197-201 (1993). The amino acid sequence of human sEH is also set forth as SEQ ID NO:2 of U.S. Pat. No.5,445,956; the nucleic acid sequence encoding the human sEH is set forth as nucleotides 42-1703 of SEQ ID NO:1 of that patent. The evolution and nomenclature of the gene is discussed in Beetham et al., DNA Cell Biol. 14(1):61-71 (1995). Soluble epoxide hydrolase represents a single highly conserved gene product with over 90% homology between rodent and human (Arand et al., FEBS Lett., 338:251-256 (1994)).

[0096] As used herein, the term “sEH-mediated disease or condition” and the like refers to a disease or condition characterized by less than or greater than normal, sEH activity. A sEH- mediated disease or condition is one in which modulation of sEH results in some effect on the underlying condition or disease (e.g., a sEH inhibitor or antagonist results in someATTORNEY DOCKET NO.930503-2010 improvement in patient well-being in at least some patients).

[0097] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a hematological malignancy, breast cancer, and / or another solid malignancy. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a hematological malignancy, breast cancer, and / or another solid tumor in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0098] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0099] The term “therapeutically effective amount” refers to the amount of a subject compound that will elicit the biological or medical response in a tissue, system, animal or human that is being sought by administering said compound. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome. Such amount should be sufficient to inhibit sEH activity to some degree (e.g., partial to complete inhibition).

[0100] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single doseATTORNEY DOCKET NO.930503-2010 compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0101] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0102] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0103] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0104] The term “modulate” refers to the ability of a compound to increase or decrease the function, or activity, of the associated activity (e.g., soluble epoxide hydrolase). “Modulation”, as used herein in its various forms, is meant to include antagonism and partial antagonism of the activity associated with sEH. Inhibitors of sEH are compounds that, e.g., bind to, partially or totally block the enzyme’s activity.

[0105] As used herein, the term “contacting” refers to the process of bringing into contact at least two distinct species such that they can react. However, it should be appreciated the resulting reaction product can be produced directly from a reaction between the addedATTORNEY DOCKET NO.930503-2010 reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0106] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0107] Pharmaceutically acceptable salts of compounds described herein include conventional nontoxic salts or quaternary ammonium salts of a compound, e.g., from non- toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. In other cases, described compounds may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

[0108] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).ATTORNEY DOCKET NO.930503-2010

[0109] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0110] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0111] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0112] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if aATTORNEY DOCKET NO.930503-2010 class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0113] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0114] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0115] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere). Soluble Epoxide Hydrolase Inhibitors and Methods of Making and Using the Compounds

[0116] Soluble epoxide hydrolase (sEH) inhibitors have been actively pursued as a therapeutic target for a number of different medical conditions (or multiple indications) including cardiovascular diseases, pain management, and inflammatory conditions. One such sEH inhibitor is EC5026 as shown below: .ATTORNEY DOCKET NO.930503-2010

[0117] EC5026 is an orally active sEH inhibitor developed by the Applicant. EC5026 treats inflammation and neuropathic pain without the need of addictive opioids. EC5026 is currently testing in several clinical trials.

[0118] It has been unexpectedly discovered that the compounds described herein have significantly improved pharmacokinetic properties compared to EC5026. In one aspect, disclosed herein is a unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; andATTORNEY DOCKET NO.930503-2010 wherein when there is only one compound, the compound is not EC5026.

[0119] In one aspect, the pharmaceutical compositions described herein can include any combination of compounds having the formula I, II, and III, where the composition does not only include EC5026 (i.e., a pharmaceutical composition containing only EC5026). In one aspect, the pharmaceutical composition includes two or more compounds having the formula I.

[0120] In one aspect, the compound is formula I, wherein X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen. In another aspect, the compound is formula I, wherein X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen. In another aspect, the compound is formula I, wherein X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, X4is hydrogen, and the stereochemistry at carbon a is substantially S or substantially R.

[0121] In one aspect, the compound is formula I, wherein the compound has the formula IV (also referred to herein as M3a)

[0122] Inhas the formula V (also referred to herein as M3b) OOH

[0123] Ina mixture of compounds IV and V. In one aspect, the molar ratio of IV to V is from 10:1 to 1:10. In another aspect, molar ratio of IV to V is from 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, where any value can be a lower and upper endpoint of aATTORNEY DOCKET NO.930503-2010 range (e.g., 2:1 to 1:3).

[0124] In one aspect, the pharmaceutical composition includes a mixture of compound IV and EC5026. In another aspect, the pharmaceutical composition includes a mixture of compound V and EC5026. In another aspect, the pharmaceutical composition includes a mixture of compound IV, V, and EC5026.

[0125] In one aspect, the compound is formula I, wherein X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen. In another aspect, the compound is formula I, wherein X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, X4is hydrogen, and the stereochemistry at carbon a is substantially S or substantially R. In another aspect, the compound is formula I, wherein the compound is .

[0126] Ingroup, and X2- X4are hydrogen. In another aspect, the compound is formula I, wherein X1is a hydroxymethyl group, and X2- X4are hydrogen. In another aspect, the compound is formula I, wherein X1is a hydroxyalkyl group, X2- X4are hydrogen, and the stereochemistry at carbon a is substantially R or substantially S. In another aspect, the compound is formula I, wherein the compound is .

[0127] is hydrogen,ATTORNEY DOCKET NO.930503-2010 X3is hydrogen, and X4is a hydroxyl group. In another aspect, the compound is formula I, wherein X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group. In another aspect, the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydrogen, X4is a hydroxyl group, and the stereochemistry at carbon a is substantially R or substantially S. In another aspect, the compound is formula I, wherein the compound is

[0128] Ingroup, X2is a hydroxyl group, and X3and X4are hydrogen. In another aspect, the compound is formula I, wherein X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen. In another aspect, the compound is formula I, wherein X1is a hydroxyl alkyl group, X2is a hydroxyl group, X3and X4are hydrogen, and the stereochemistry at carbon a is substantially S or substantially R. In another aspect, the compound is formula I, wherein the compound is .

[0129] InIn another aspect, the compound is formula II, wherein X1is an alkyl group, X2is an alkyl group, and X3is hydrogen. In another aspect, the compound is formula II, wherein X1is a methyl group, X2is a methyl group, and X3is hydrogen. In another aspect, the compound is formula II, wherein X1is an alkyl group, X2is hydrogen, and X3is an alkyl group. In another aspect, the compound is formula II, wherein X1is a methyl group, X2is hydrogen, and X3is a methyl group.

[0130] In one aspect, the compound is formula III, wherein X2is hydrogen and X3is an alkyl group. In another aspect, the compound is formula III, wherein X2is hydrogen and X3is hydrogen.

[0131] As discussed above, it has been unexpectedly discovered that the compounds described herein have significantly improved pharmacokinetic properties when compared to EC5026. Thus, the compounds described herein are more potent inhibitors of sEH whenATTORNEY DOCKET NO.930503-2010 formulated as pharmaceutical compositions.

[0132] It has been unexpectedly discovered that the compounds described herein have a longer half-life than EC5026. Not wishing to be bound by theory, metabolism of xenobiotic compounds occurs in two stages: phase 1 metabolism forms water-soluble compounds, while Phase 2 metabolism adds polar groups through glucuronidation and sulfation that increase water-solubility and accelerate elimination. It was unexpectedly observed that no Phase 2 metabolism of occurred. This results in the compounds being surprisingly stable in vivo, which can make them more potent compared to EC5026.

[0133] Evidence is strong that the residence time of the sEH inhibitor on the target enzyme is one of the most important parameters affecting in vivo efficacy. Inhibitors with a long half-life time have long duration of action on the enzyme target, which translates to long in vivo efficacy. However, most of the sEH inhibitors reported to date do not have optimum residence time on the enzyme.

[0134] In one aspect, the compounds described herein have a half-life that is at least two times greater than the half-life of EC5026 at the same dosage in a male rat. In another aspect, the compounds described herein have a half-life that is two times to seven times greater than the half-life of EC5026 at the same dosage in a male rat, or two times, three times, four times, five times, six times, or seven times, greater than the half-life of EC5026 at the same dosage, where any value can be a lower and upper endpoint of a range (e.g., three times to seven times).

[0135] Due to the improved half-life of the compounds described herein, the compounds and pharmaceutical compositions have improved potency and efficacy when compared to EC5026. In one aspect, the compounds described herein have a Cmaxthat is at least two times greater than the Cmaxof EC5026 at the same dosage in a male rat. In another aspect, the compounds described herein have a Cmaxthat is two times to twenty five times greater than the Cmaxof EC5026 at the same dosage in a male rat, or two times, five times, ten times, five times, fifteen times, twenty times, or twenty five times, greater than the Cmaxof EC5026 at the same dosage, where any value can be a lower and upper endpoint of a range (e.g., five times to twenty times).

[0136] In one aspect, the compounds described herein have an area under the curve (AUC) that is at least two times greater than the AUC of EC5026 at the same dosage in a male rat. In another aspect, the compounds described herein have an AUC that is two times to fifty times greater than the AUC of EC5026 at the same dosage in a male rat, or two times, five times, ten times, twenty times, thirty times, forty times, or fifty five times, greater than the AUCATTORNEY DOCKET NO.930503-2010 of EC5026 at the same dosage, where any value can be a lower and upper endpoint of a range (e.g., ten times to forty times).

[0137] In one aspect, the therapeutically effective amount of the compound having the formula I-III in the unit dose composition is up to 100% less than the therapeutically effective amount of EC5026 in a unit dose composition. In another aspect, the therapeutically effective amount of the compound having the formula I-III in the unit dose composition is from 10% to 100% less than the therapeutically effective amount of EC5026 in a unit dose composition, or 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than the therapeutically effective amount of EC5026 in a unit dose composition, where any value can be a lower and upper endpoint of a range (e.g., 20% to 60%).

[0138] In one aspect, the compounds having the formula I, II, or III as described herein can be co-administered with EC5026. The compound having the formula I, II, or III when administered with EC5026 provides synergistic results. In one aspect, the combination of a compound having the formula I, II, or III with EC5026 can inhibit soluble epoxide hydrolase below efficacious levels of EC5026 alone to achieve inhibition of enzyme activity at lower effective concentrations of EC5026. Additionally, a compound having the formula I, II, or III when administered with EC5026 can improve potency and safety of EC5026.

[0139] In one aspect, a compound having the formula I, II, or III is administered sequentially or concurrently with EC5026. In one aspect, the compound having the formula I, II, or III is formulated with EC5026 in a single unit dose composition. In another aspect, a kit comprising a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III and a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier can be used to sequentially or concurrently administer the compounds.

[0140] In one aspect, EC5026 is co-administered with M3a, M3b, or a combination thereof. In one aspect, the weight ratio of EC5026 to the compound of formula I (e.g., M3a, M3b, or a combination thereof) is from 1:1 to 1:20. In another aspect, the weight ratio of EC5026 to the compound of formula I (e.g., M3a, M3b, or a combination thereof) is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20, where any value can be a lower and upper endpoint of a range (e.g., 1:5 to 1:15, 1:8 to 1:12, 1:9 to 1:11, etc.).

[0141] In one aspect, EC5026 is co-administered with M3a at a weight ratio of EC5026 / M3a of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20, where any value can be a lower and upper endpoint of a range (e.g., 1:5 to 1:15, 1:8 to 1:12, 1:9 to 1:11, etc.).ATTORNEY DOCKET NO.930503-2010

[0142] In one aspect, EC5026 is co-administered with M3b at a weight ratio of EC5026 / M3a of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20, where any value can be a lower and upper endpoint of a range (e.g., 1:5 to 1:15, 1:8 to 1:12, 1:9 to 1:11, etc.).

[0143] In one aspect, EC5026 is co-administered with M3a plus M3b at a weight ratio of EC5026 / M3a + M3b of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20, where any value can be a lower and upper endpoint of a range (e.g., 1:5 to 1:15, 1:8 to 1:12, 1:9 to 1:11, etc.).

[0144] In one aspect, the sum of the compound of formula I (e.g., M3a, M3b, or a combination thereof) and EC5026 is from about 0.5 mg to 100 mg per unit dose composition, or about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, where any value can be a lower and upper endpoint of a range (e.g., 1 mg to 10 mg, 3 mg to 8 mg, etc.). General Synthetic Method

[0145] Exemplary methods for producing compounds described herein, as well as characterization information, are provided in the Examples. Solvents, temperatures, presence or absence of protecting groups, and other reaction conditions may vary according to the specific substituents in the compound being synthesized. Pharmaceutical Compositions

[0146] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0147] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although theATTORNEY DOCKET NO.930503-2010 most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratumorally.

[0148] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0149] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0150] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non- aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, theATTORNEY DOCKET NO.930503-2010 compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0151] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0152] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0153] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (MackATTORNEY DOCKET NO.930503-2010 Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).

[0154] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0155] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0156] The disclosed pharmaceutical compositions in an oral dosage form can comprise oneATTORNEY DOCKET NO.930503-2010 or more pharmaceutical excipient and / or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters and polyglycerol esters of saturated fatty acids C12H24O2to C18H36O2and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium- viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

[0157] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and / or methacrylic acid and / or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example EudragitR RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalicATTORNEY DOCKET NO.930503-2010 acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl- acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0158] Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl- , triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl- phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0159] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0160] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0161] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, forATTORNEY DOCKET NO.930503-2010 example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0162] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0163] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0164] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate- phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol.22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.

[0165] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcelluloseATTORNEY DOCKET NO.930503-2010 phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid.

[0166] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For example, a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

[0167] For the preparation of solutions or suspensions it is, for example, possible to use water, particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulfoxide, triglycerides and the like.

[0168] In the case of a liquid dosage form such as a drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1- C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as ethylene diamine, hydroxyethyl theophylline, tromethamine (for example as 0.1 to 20% aqueous solution), aliphatic amino acids.

[0169] In preparing the disclosed liquid dosage form can comprise solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization ofATTORNEY DOCKET NO.930503-2010 which generally lies between 2 and 40 and in particular between 10 and 20. Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P. Fiedler “Lexikon der Hillsstoffe für Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195.

[0170] In various aspects, a liquid dosage form can further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like. Complex formers which may be for example be considered are: chelate formers such as ethylene diamine retrascetic acid, nitrilotriacetic acid, diethylene triamine pentacetic acid and their salts.

[0171] It may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9. Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8).

[0172] In order to enhance the solubility and / or the stability of a disclosed compound in a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g., 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β- cyclodextrin. Also co-solvents such as alcohols may improve the solubility and / or the stability of the compounds according to the present disclosure in pharmaceutical compositions.

[0173] In various aspects, a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0174] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0175] Pharmaceutical compositions of the present disclosure suitable for parenteralATTORNEY DOCKET NO.930503-2010 administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0176] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In some aspects, a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.

[0177] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.

[0178] In addition to the pharmaceutical compositions described herein above, the disclosed compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscularATTORNEY DOCKET NO.930503-2010 injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0179] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present invention may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0180] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0181] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsionsATTORNEY DOCKET NO.930503-2010 or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.

[0182] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0183] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and / or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.

[0184] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.

[0185] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene- polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylATTORNEY DOCKET NO.930503-2010 methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0186] Sprays generally provide the active agent in an aqueous and / or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration.

[0187] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.

[0188] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage.

[0189] Examples of patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multi-layer drug-in-adhesive patch a membrane is disposed between two distinct drug- in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backingATTORNEY DOCKET NO.930503-2010 film.

[0190] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present invention include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2- methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

[0191] Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0192] Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present invention is a matrix system design which is characterizedATTORNEY DOCKET NO.930503-2010 by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

[0193] Pharmaceutical compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0194] Pharmaceutical compositions containing a compound of the present disclosure, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0195] The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.

[0196] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0197] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or aATTORNEY DOCKET NO.930503-2010 stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0198] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0199] In one aspect, an appropriate dosage level will generally be about 0.01 to 1000 mg of a compound described herein per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0200] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, generalATTORNEY DOCKET NO.930503-2010 health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

[0201] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

[0202] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

[0203] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0204] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

[0205] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure. Methods of Use

[0206] The compounds and pharmaceutical compositions described herein are efficacious as soluble epoxide hydrolase inhibitors. The present disclosure provides methods for inhibiting soluble epoxide hydrolase inhibitors.

[0207] In one aspect, the compounds and pharmaceutical compositions described herein can be administered to treat or prevent a disorder or disease in which modulation of sEH results in some effect on the underlying condition or disease (e.g., a sEH inhibitor or antagonist results in some improvement in patient well-being in at least some patients). Such disorders andATTORNEY DOCKET NO.930503-2010 diseases may include, but is not limited to, renal, hepatic, or pulmonary hypertension, chronic pain, acute pain, neuropathic pain, inflammatory pain, inflammation, neuroinflammation, renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation, acute respiratory distress syndrome, sepsis, burn, diabetic complications, end stage renal disease, ocular disease, Raynaud syndrome, osteoarthritis, autoimmune disease, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain Barre Syndrome, Wilson's disease, Niemann-Pick disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies and neuronal ceroid lipofuscinosis.

[0208] In another aspect, the compounds and pharmaceutical compositions described herein can treat or prevent an endoplasmic stress related disease or disorder selected from the group consisting of diabetes, atherosclerosis, obesity, liver disease, viral infection, cancer, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autoimmune disease, neurodegeneration, heart disease and stroke.

[0209] In another aspect, the compounds and pharmaceutical compositions described herein can treat or prevent a central nervous system disease. In one aspect, the compounds described herein can pass the blood brain barrier, which makes them suitable for treating a variety of CNS diseases and disorders.

[0210] In one aspect, the compounds and pharmaceutical compositions described herein are efficacious in alleviating, reducing, inhibiting and preventing pain and / or inflammation in humans or non-human mammals, particularly painful and inflammatory conditions that could not be effectively treated using currently employed medications (e.g., non-steroidal anti- inflammatory drugs and / or analgesics were inefficacious), and / or in non-human mammals (e.g., felines, canines) in whom currently employed medications (e.g., non-steroidal anti- inflammatory drugs and / or analgesics) are toxic.

[0211] In one aspect, the compositions and methods described herein prevent, reduce, inhibit and / or reversing pain and / or inflammation in a non-human mammal. In various aspects, the non-human mammal is an ungulate, e.g., equine, bovine, ovine or porcine. In some embodiments, the non-human mammal is canine or feline.ATTORNEY DOCKET NO.930503-2010

[0212] In other aspects, the compositions and methods described herein provide relief from pain and / or inflammation in humans or non-human mammals who have received an inefficacious course of treatment for a painful and / or inflamed lesion (e.g., administration of a regime of non- steroidal anti-inflammatory drugs (NSAIDS) or another currently used medication was inefficacious). Inflammatory conditions in non-human animals that can be prevented, reduced, alleviated and / or mitigated by administration of an inhibitor of sEH include without limitation injury or trauma, osteopathic conditions (joint inflammation, panosteitis, osteoarthritis, hip dysplasia), allergic reactions, blockages in the lymphatic system, high blood pressure, heart failure, thyroid disease, liver disease, inflammatory bowel disease, pancreatic inflammation, and chronic kidney disease. The inflammation may be acute or chronic.

[0213] In other aspects, the compositions and methods described herein provide relief from pain and / or inflammation for humans or non-human mammals who cannot tolerate therapeutically effective doses of NSAIDs or other active agents other than an inhibitor of sEH for the treatment of pain and / or inflammation (e.g., due to toxicity and / or an inability to metabolize currently available medications). For example, in some embodiments, the humans or non-human mammal received a course of treatment of one or more NSAIDs, as sole active agent or in combination with another active agent other than an inhibitor of sEH, and the course of treatment of one or more NSAIDs did not result in the prevention, reduction, inhibition or reversal of the inflammatory and / or neuropathic pain condition. In some embodiments, an effective regime of one or more NSAIDs cannot be administered to the human or non-human animal (e.g., would be toxic), and other active agents (that are not an NSAID and are not an inhibitor of sEH) are ineffective in providing the non-human mammal with relief from the painful and / or inflammatory condition. In some embodiments, the humans or non-human mammal has a painful and / or inflammatory condition that could not be effectively prevented, reduced, inhibited and / or reversed by administration of a NSAID co- administered with a gamma-aminobutyric acid (GABA) analog (e.g., gabapentin or pregabalin, or analogs or pro-drugs thereof).

[0214] In one aspect, the subject mammal suffers from tendonitis or arthritis. In some aspects, the subject suffers from a chronic inflammatory condition with a neuropathic pain component. Inflammatory pain that has not been treated successfully can evolve into a more chronic pain condition which remains even if the inflammation is resolved. Such chronic or neuropathic pain cannot be effectively reduced, inhibited or reversed by administration of NSAIDS but can be effectively reduced, inhibited or reversed by administration of an inhibitor of sEH as a sole active agent, or coadministered with another anti-inflammatory and / or analgesic agent (e.g.,ATTORNEY DOCKET NO.930503-2010 a therapeutic or sub-therapeutic amount of an NSAID and / or a gamma-aminobutyric acid (GABA) analog (e.g., gabapentin or pregabalin, or analogs or pro-drugs thereof).

[0215] In other aspects, the non-human mammal is an ungulate and suffers from laminitis. Laminitis is a severely debilitating, excruciatingly painful, and life-threatening disease of the soft tissues of the foot of an ungulate, particularly the foot of an equine. Although laminitis has traditionally been viewed as an inflammatory disease, the disorder is far more complex than a simple inflammatory process. The equine foot, complex in both anatomy and physiology, integrates multiple organ systems, including the musculoskeletal, integumentary, nervous, immune, gastrointestinal and cardiovascular systems. Thus, the similarities that are often encountered between animal and human diseases do not occur with equine laminitis. The mode of weight bearing in horses, for example, is fundamentally different from that which occurs in the plantigrade foot. Equines are also unique among ungulates (i.e., cattle, sheep, goats, pigs, etc.) regarding the susceptibility to laminitis. Notwithstanding having structurally similar digit as equines, other ungulates are either not susceptible to laminitis or it occurs to a much lesser degree. Not surprisingly, the precise mechanism underlying laminitic pain remains unclear yet pain control is the single most important task in the clinical management of laminitic horses. Approximately 75% of horses afflicted with laminitis are euthanized due to the seriousness of the disease coupled with lack of efficacious therapies, especially currently available analgesics. Consequently, laminitis is widely considered as one of the most important diseases of horses and a global welfare problem.

[0216] In other aspects, the non-human mammal suffers from tendonitis or osteoarthritis. Other painful inflammatory diseases such as osteoarthritis (OA) are highly prevalent in domestic animal species (e.g., horses, cats, dogs) and humans. The non- steroidal anti- inflammatory drugs (NSAIDs) are currently the most important class of systemic analgesics to treat OA pain in humans. However, NSAIDs have a relatively narrow safety margin and may have severe toxic side effects when recommended dosages are exceeded and / or prolonged use and / or in susceptible non-human mammals. These adverse effects include gastrointestinal ulceration, renal papillary necrosis, hepatocellular injury, and thrombosis, and are potentially lethal. Among animals, cats are exquisitely sensitive to the toxic effects of NSAIDs.

[0217] In one aspect, the compounds and pharmaceutical compositions described herein have an IC50of less than about 100 μΜ, for example, an IC50of less than about 75 μΜ, 50 μΜ, 25 μΜ, 10 μΜ, 1 μΜ, 100 nΜ, 10 nΜ or 1 nΜ. As appropriate, the IC50for inhibition of sEH is determined with respect to the sEH enzyme from the same species as the human or non- human mammal receiving the inhibitor of sEH (e.g., IC50for inhibition of sEH is determinedATTORNEY DOCKET NO.930503-2010 with respect to the species subject to treatment, e.g., with respect to the sEH enzyme from equine, bovine, ovine, porcine, canine, feline, etc., for subjects who are equine, bovine, ovine, porcine, canine, feline, respectively).

[0218] In another aspect, the compounds and pharmaceutical compositions described herein inhibit sEH without also significantly inhibiting mEH. In one aspect, at concentrations of 100 μΜ, the compounds and pharmaceutical compositions described herein inhibit sEH activity by at least 50% while not inhibiting mEH activity by more than 10%.

[0219] The pharmaceutical compositions described herein may additionally include an additional agent or therapy. Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells; hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and / or chemotherapeutics of neoplastic disease. Other pharmacological therapies can include any other drug or biologic found in any drug class. For example, other drug classes can comprise allergy / cold / ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma / pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine / metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies. Other examples of agents or therapies that can be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.

[0220] In other aspects, the pharmaceutical compositions described herein can be administered sequentially or concurrently with other agents to the patient.

[0221] The pharmaceutical compositions described herein with a compound of formula I-III can be administered to a subject at a dose of from 0.1 to 500 mg / kg per day. In one aspect, The dose range for adult humans is from about 5 mg / day to about 5 g / day, or 5 mg / day, 0.5 mg / day, 0.5 g / day, 1.0 g / day, 1.5 g / day, 2.0 g / day, 2.5 g / day, 3.0 g / day, 3.5 g / day, 4.0 g / day, 4.5 g / day, or 5.0 g / day, where any value can be a lower and upper endpoint of a range (e.g., 1.0 g / day to 2.5 g / day). In one aspect, tablets, capsules, or other oral formulations of the pharmaceutical compositions described herein can contain an amount of one or more compounds of formula I-III per unit dose at a dosage of about 5 mg to about 500 mg, or 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, where any value can be a lower and upper endpoint of a range (e.g., 150 mg to 250 mg).ATTORNEY DOCKET NO.930503-2010

[0222] In another aspect, the compounds and pharmaceutical compositions described herein can improve organ or stem cell transplantation. In one aspect, the compounds and pharmaceutical compositions described herein can be administered to a subject while the subject is undergoing organ or stem cell transplantation. Not wishing to be bound by theory, epoxy fatty acid substrates EpFAs play an important role in resolving inflammation and regulating other biological processes. However, their effectiveness is limited by sEH, which rapidly metabolizes EpFAs into inactive or even inflammatory diols. The compounds and pharmaceutical compositions described herein can inhibit sEH, which in turn can promote cell and tissue growth in a subject once stem cells or an organ have been transplanted in a subject. The compounds and pharmaceutical compositions described herein can be administered before, during, after, or any combination thereof in conjunction with the transplantation.

[0223] In one aspect, described herein is a method for improving stem cell growth in a subject, the method comprising administering stem cells to the subject and the unit dose composition as described herein to the subject. In one aspect, the improvement is compared the same subject (e.g., rat) that was not administered the unit dose composition as described herein.

[0224] In one aspect, described herein is a method for improving tissue growth in a subject, the method comprising transplanting the tissue in the subject and administering the unit dose composition as described herein to the subject. In one aspect, the improvement is compared the same subject (e.g., rat) that was not administered the unit dose composition as described herein.

[0225] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. Aspects

[0226] Aspect 1. A unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:ATTORNEY DOCKET NO.930503-2010 O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and wherein when there is only one compound, the compound is not EC5026.

[0227] Aspect 2. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has a half-life that is at least two times greater than the half-life of EC5026 at the same dosage in a male rat.ATTORNEY DOCKET NO.930503-2010

[0228] Aspect 3. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has a half-life that is two times to seven times greater than the half-life of EC5026 at the same dosage in a male rat.

[0229] Aspect 4. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has a Cmaxthat is at least two times greater than the Cmaxof EC5026 at the same dosage in a male rat.

[0230] Aspect 5. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has a Cmaxthat is two times to twenty five greater than the Cmaxof EC5026 at the same dosage in a male rat.

[0231] Aspect 6. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has an area under the curve (AUC) that is at least two times greater than the AUC of EC5026 at the same dosage in a male rat.

[0232] Aspect 7. The composition of Aspect 1, wherein the compound having the formula I- III in the unit dose composition has an area under the curve (AUC) that is two times to fifty times greater than the AUC of EC5026 at the same dosage in a male rat.

[0233] Aspect 8. The composition of Aspect 1, wherein the therapeutically effective amount of the compound having the formula I-III in the unit dose composition is up to 100% less than the therapeutically effective amount of EC5026 in a unit dose composition.

[0234] Aspect 9. The composition of any one of Aspects 1-8, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0235] Aspect 10. The composition of any one of Aspects 1-8, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0236] Aspect 11. The composition of Aspect 9 or 10, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0237] Aspect 12. The composition of any one of Aspects 1-8, wherein the compound is ,ATTORNEY DOCKET NO.930503-2010 , or

[0238] Aspect 13. The composition of any one of Aspects 1-8, wherein the compound is , orATTORNEY DOCKET NO.930503-2010

[0239] Aspect 14. The composition of any one of Aspects 1-8, wherein the composition comprises a mixture of compounds having the Formula IV and Vand .

[0240] Aspect 15. The composition of Aspect 14, wherein the molar ratio of IV to V is from 10:1 to 1:10.

[0241] Aspect 16. The composition of any one of Aspects 12-15, wherein the composition further comprises EC5026.

[0242] Aspect 17. The composition of any one of Aspects 1-8, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

[0243] Aspect 18. The composition of Aspect 17, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0244] Aspect 19. The composition of any one of Aspects 1-8, wherein the compound isATTORNEY DOCKET NO.930503-2010 .

[0245] is formula I, X1is a hydroxyalkyl group, and X2- X4are hydrogen.

[0246] Aspect 21. The composition of any one of Aspects 1-8, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

[0247] Aspect 22. The composition of Aspect 20 or 21, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0248] Aspect 23. The composition of any one of Aspects 1-8, wherein the compound is .

[0249] compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

[0250] Aspect 25. The composition of any one of Aspects 1-8, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

[0251] Aspect 26. The composition of Aspect 24 or 25, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0252] Aspect 27. The composition of any one of Aspects 1-8, wherein the compound isATTORNEY DOCKET NO.930503-2010 .

[0253] compound isformula I, X1is a hydroxyl alkyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0254] Aspect 29. The composition of any one of Aspects 1-8, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0255] Aspect 30. The composition of Aspect 28 or 29, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0256] Aspect 31. The composition of any one of Aspects 1-8, wherein the compound is .

[0257] compound is formula II, X1is an alkyl group.

[0258] Aspect 33. The composition of any one of Aspects 1-8, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

[0259] Aspect 34. The composition of any one of Aspects 1-8, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.

[0260] Aspect 35. The composition of any one of Aspects 1-8, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.

[0261] Aspect 36. The composition of any one of Aspects 1-8, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

[0262] Aspect 37. The composition of any one of Aspects 1-8, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.ATTORNEY DOCKET NO.930503-2010

[0263] Aspect 38. The composition of any one of Aspects 1-8, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.

[0264] Aspect 39. The composition of any one of Aspects 1-38, wherein the composition further comprises EC5026.

[0265] Aspect 40. The composition of Aspect 1, wherein the composition comprises a compound of formula I and EC5026.

[0266] Aspect 41. The composition of Aspect 40, wherein the compound of formula I is , or

[0267] Aspect 42. The composition of Aspect 40 or 41, wherein the composition consists of the compound of formula I, EC5026, and the pharmaceutically acceptable carrier.

[0268] Aspect 43. The composition of any one of Aspects 40-42, wherein a weight ratio of EC5026 to the compound of formula I is from 1:1 to 1:20.

[0269] Aspect 44. The composition of any one of Aspects 40-43, wherein a sum of the compound of formula I and EC5026 is from about 0.5 mg to 100 mg per unit dose composition.

[0270] Aspect 45. The composition of any one of Aspects 1-44, wherein the unit dose composition comprises an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.ATTORNEY DOCKET NO.930503-2010

[0271] Aspect 46. The composition of any one of Aspects 1-44, wherein the unit dose composition comprises an oral unit dose composition.

[0272] Aspect 47. A kit comprising (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof: O X2X4X3X3a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group;ATTORNEY DOCKET NO.930503-2010 the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

[0273] Aspect 48. The kit of Aspect 47, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0274] Aspect 49. The kit of Aspect 47, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0275] Aspect 50. The kit of Aspect 48 or 49, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0276] Aspect 51. The kit of Aspect 47, wherein the compound is , ,ATTORNEY DOCKET NO.930503-2010 or

[0277] Aspect 52. The kit of Aspect 47, wherein the compound is , or

[0278] Aspect 53. The kit of Aspect 47, wherein the composition comprises a mixture of compounds having the Formula IV and VATTORNEY DOCKET NO.930503-2010 .

[0279] from 10:1 to1:10.

[0280] Aspect 55. The kit of Aspect 47, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

[0281] Aspect 56. The kit of Aspect 55, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0282] Aspect 57. The kit of Aspect 47, wherein the compound is .

[0283] I, X1is a hydroxyalkyl group, and X2- X4are hydrogen.

[0284] Aspect 59. The kit of Aspect 47, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

[0285] Aspect 60. The kit of Aspect 58 or 59, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0286] Aspect 61. The kit of Aspect 47, wherein the compound is .ATTORNEY DOCKET NO.930503-2010

[0287] Aspect 62. The kit of Aspect 47, wherein the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

[0288] Aspect 63. The kit of Aspect 47, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

[0289] Aspect 64. The kit of Aspect 62 or 63, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0290] Aspect 65. The kit of Aspect 47, wherein the compound is .

[0291] is a hydroxyl alkyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0292] Aspect 67. The kit of Aspect 47, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0293] Aspect 68. The kit of Aspect 66 or 67, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0294] Aspect 69. The kit of Aspect 47, wherein the compound is .

[0295] X1is an alkyl group.

[0296] Aspect 71. The kit of Aspect 47, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

[0297] Aspect 72. The kit of Aspect 47, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.ATTORNEY DOCKET NO.930503-2010

[0298] Aspect 73. The kit of Aspect 47, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.

[0299] Aspect 74. The kit of Aspect 47, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

[0300] Aspect 75. The kit of Aspect 47, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.

[0301] Aspect 76. The kit of Aspect 47, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.

[0302] Aspect 77. The kit of Aspect 47, wherein the compound has formula I.

[0303] Aspect 78. The kit of Aspect 77, wherein the compound of formula I is , or

[0304] Aspect 79. The kit of any one of Aspects 77-78, wherein a weight ratio of EC5026 to the compound of formula I is from 1:1 to 1:20.

[0305] Aspect 80. The kit of any one of Aspects 47-79, wherein the first and second unit dose composition comprises, independently, an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.

[0306] Aspect 81. The kit of any one of Aspects 47-79, wherein the first and second unit dose composition comprises, independently, an oral unit dose composition.ATTORNEY DOCKET NO.930503-2010

[0307] Aspect 82. A method of inhibiting soluble epoxide hydrolase (sEH) in a subject, the method comprising administering to the subject the unit dose composition of any one of Aspects 1-46.

[0308] Aspect 83. A method of treating or preventing a disease or disorder in a subject by inhibiting soluble epoxide hydrolase (sEH), the method comprising administering to the subject the unit dose composition of any one of Aspects 1-46, thereby treating or preventing the disease or disorder in the subject.

[0309] Aspect 84. The method of Aspect 83, wherein the disease is a central nervous system disease, a dermatologic inflammatory disorder, a dermatologic autoimmune disorder, or a cardiovascular disease.

[0310] Aspect 85. The method of Aspect 83, wherein the disease or disorder is selected from the group consisting of renal, hepatic, or pulmonary hypertension, chronic pain, acute pain, neuropathic pain, inflammatory pain, inflammation, neuroinflammation, renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation, acute respiratory distress syndrome, sepsis, burn, diabetic complications, end stage renal disease, ocular disease, Raynaud syndrome, osteoarthritis, autoimmune disease, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain Barre Syndrome, Wilson's disease, Niemann-Pick disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies and neuronal ceroid lipofuscinosis.

[0311] Aspect 86. The method of Aspect 83, wherein the disease or disorder is an endoplasmic stress related disease or disorder selected from the group consisting of diabetes, atherosclerosis, obesity, liver disease, viral infection, cancer, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autoimmune disease, neurodegeneration, heart disease and stroke.

[0312] Aspect 87. A method for improving stem cell growth in a subject, the method comprising administering stem cells to the subject and the unit dose composition of any one of Aspects 1-46 to the subject.ATTORNEY DOCKET NO.930503-2010

[0313] Aspect 88. A method for improving tissue growth in a subject, the method comprising transplanting a tissue in the subject and administering the unit dose composition of any one of Aspects 1-46 to the subject.

[0314] Aspect 89. The method of Aspect 88, wherein the unit dose composition is administered before, during, or after the transplantation of the tissue to the subject.

[0315] Aspect 90. The method of any one of Aspects 82-89, wherein the unit composition is administered orally, topically, or intravenously.

[0316] Aspect 91. A method of inhibiting soluble epoxide hydrolase (sEH) in a subject, the method comprising administering to the subject concurrently or sequentially (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:ATTORNEY DOCKET NO.930503-2010 O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

[0317] Aspect 92. A method of treating or preventing a disease or disorder in a subject by inhibiting soluble epoxide hydrolase (sEH), the method comprising administering to the subject concurrently or sequentiallyATTORNEY DOCKET NO.930503-2010 (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof: O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.ATTORNEY DOCKET NO.930503-2010

[0318] Aspect 93. The method of Aspect 92, wherein the disease is a central nervous system disease, a dermatologic inflammatory disorder, a dermatologic autoimmune disorder, or a cardiovascular disease.

[0319] Aspect 94. The method of Aspect 92, wherein the disease or disorder is selected from the group consisting of renal, hepatic, or pulmonary hypertension, chronic pain, acute pain, neuropathic pain, inflammatory pain, inflammation, neuroinflammation, renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation, acute respiratory distress syndrome, sepsis, burn, diabetic complications, end stage renal disease, ocular disease, Raynaud syndrome, osteoarthritis, autoimmune disease, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain Barre Syndrome, Wilson's disease, Niemann-Pick disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies and neuronal ceroid lipofuscinosis.

[0320] Aspect 95. The method of Aspect 92, wherein the disease or disorder is an endoplasmic stress related disease or disorder selected from the group consisting of diabetes, atherosclerosis, obesity, liver disease, viral infection, cancer, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autoimmune disease, neurodegeneration, heart disease and stroke.

[0321] Aspect 96. A method for improving tissue growth in a subject, the method comprising transplanting a tissue in the subject and administering to the subject concurrently or sequentially (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:ATTORNEY DOCKET NO.930503-2010 O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

[0322] Aspect 97. The method of Aspect 96, wherein the tissue is an organ.ATTORNEY DOCKET NO.930503-2010

[0323] Aspect 98. The method of any one of Aspects 91-97, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0324] Aspect 99. The method of any one of Aspects 91-97, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

[0325] Aspect 100. The method of Aspect 98 or 99, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0326] Aspect 101. The method of any one of Aspects 91-97, wherein the compound is , orATTORNEY DOCKET NO.930503-2010 any combination thereof.

[0327] Aspect 102. The method of any one of Aspects 91-97, wherein the compound is , or

[0328] Aspect 103. The method of any one of Aspects 91-97, wherein the composition comprises a mixture of compounds having the Formula IV and Vand .ATTORNEY DOCKET NO.930503-2010 V

[0329] Aspect 104. The method of Aspect 103, wherein the molar ratio of IV to V is from 10:1 to 1:10.

[0330] Aspect 105. The method of any one of Aspects 91-97, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

[0331] Aspect 106. The method of Aspect 105, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0332] Aspect 107. The method of any one of Aspects 91-97, wherein the compound is .

[0333] is formula I, X1is a hydroxyalkyl group, and X2- X4are hydrogen.

[0334] Aspect 109. The method of any one of Aspects 91-97, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

[0335] Aspect 110. The method of Aspect 108 or 109, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0336] Aspect 111. The method of any one of Aspects 91-97, wherein the compound is .

[0337] compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.ATTORNEY DOCKET NO.930503-2010

[0338] Aspect 113. The method of any one of Aspects 91-97, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

[0339] Aspect 114. The method of Aspect 112 or 113, wherein the stereochemistry at carbon a is substantially R or substantially S.

[0340] Aspect 115. The method of any one of Aspects 91-97, wherein the compound is .

[0341] compound is formula I, X1is a hydroxyl alkyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0342] Aspect 117. The method of any one of Aspects 91-97, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

[0343] Aspect 118. The method of Aspect 116 or 117, wherein the stereochemistry at carbon a is substantially S or substantially R.

[0344] Aspect 119. The method of any one of Aspects 91-97, wherein the compound is .

[0345] compound is formula II, X1is an alkyl group.

[0346] Aspect 121. The method of any one of Aspects 91-97, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

[0347] Aspect 122. The method of any one of Aspects 91-97, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.ATTORNEY DOCKET NO.930503-2010

[0348] Aspect 123. The method of any one of Aspects 91-97, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.

[0349] Aspect 124. The method of any one of Aspects 91-97, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

[0350] Aspect 125. The method of any one of Aspects 91-97, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.

[0351] Aspect 126. The method of any one of Aspects 91-97, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.

[0352] Aspect 127. The method of any one of Aspects 91-97, wherein the compound has formula I.

[0353] Aspect 128. The method of Aspect 127, wherein the compound of formula I is , or

[0354] Aspect 129. The method of any one of Aspects 91-128, wherein the first and second unit dose composition comprises, independently, an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.

[0355] Aspect 130. The method of any one of Aspects 91-128, wherein the first and second unit dose composition comprises, independently, an oral unit dose composition.

[0356] Aspect 131. The method of any one of Aspects 91-128, wherein the first and second unit dose compositions are administered orally, topically, or intravenously.ATTORNEY DOCKET NO.930503-2010

[0357] Aspect 132. The method of any one of Aspects 82-131, wherein the subject is a human or non-human mammal.

[0358] Aspect 133. The method of any one of Aspects 82-131, wherein the subject is a domesticated mammal, a farm mammal, or wild mammal.

[0359] Aspect 134. The method of any one of Aspects 82-131, wherein the subject is an equine and the disease or disorder is pain, inflammation, or laminitis. EXAMPLES

[0360] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure.

[0361] METHODS

[0362] Preparation of 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-((2S,3R)-3-hydroxy- 2-methylbutanoyl)piperidin-4-yl)urea (M3a).

[0363] To a solution(piperidin-4-yl)urea (1.0 g, 3.11 mmol) and (2S, 3R)-3-hydroxy-2-methylbutanoic acid (0.44 g, 3.74 mmol) in DMF (15 mL) were added PyBOP (1.94 g, 3.74 mmol) followed by Et3N (0.65 mL, 4.67 mmol) at 0oC. The reaction mixture was warmed to room temperature. After stirring overnight, 50 mL of EtOAc was added and the organic layer was washed twice with water. After drying the organic layer with MgSO4, the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (10% MeOH in EtOAc as eluent) to obtain the desired product (1.1 g, 83.9% yield) as a white solid. mp 45.3-47.2oC.1H NMR (600 MHz, DMSO-d6) δ 8.76 (d, J = 19 Hz, 1H), 7.67 (d, J = 14 and 3 Hz, 1H), 7.38 (td, J = 9 and 1 Hz, 1H), 7.11 (ddd, J = 9, 3 and 1 Hz, 1H), 6.39 (dd, J = 11 and 8 Hz, 1H), 4.60 (br s, 1H), 4.22 (t, J = 15ATTORNEY DOCKET NO.930503-2010 Hz, 1H), 3.98-3.85 (m, 1H), 3.77-3.60 (m, 2H), 3.22-3.07 (m, 1H), 2.85-2.73 (m, 1H), 2.72- 2.63 (m, 1H), 1.92-1.75 (m, 2H), 1.38-1.13 (m, 2H), 1.08-0.95 (m, 6H). HRMS (m / z): [M-1]- calcd for C18H23F4N3O4, 420.1546; found, 420.1550. ^^^^ଶୈହ= +10.56 (0.506 g / 100 mL (EtOH))

[0364] Preparation of 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-((2S,3S)-3-hydroxy- 2-methylbutanoyl)piperidin-4-yl)urea (M3b).

[0365] To a solution of(piperidin-4-yl)urea and (2S, 3S)-3-hydroxy-2-methylbutanoic acid (0.09 g, 0.74 mmol) in DMF (6 mL) were added PyBOP (0.42 g, 0.81 mmol) followed by Et3N (0.13 mL, 0.93 mmol) at 0oC. The reaction mixture was warmed to room temperature. After stirring overnight, 20 mL of EtOAc was added and the organic layer was washed twice with water. After drying the organic layer with MgSO4, the solvent was removed using a rotary evaporator. The residue was purified by column chromatography with 10% MeOH in EtOAc to obtain the desired product (0.21 g, 82.0% yield) as a white solid. mp 148.7 -153.1oC.1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 20 Hz, 1H), 7.67 (dd, J = 13 and 3 Hz, 1H), 7.38 (t, J = 9 Hz, 1H), 7.11 (d, J = 9 Hz, 1H), 6.43-6.32 (m, 1H), 4.55 (br s, 1H), 4.22 (t, J = 15 Hz, 1H), 4.01 – 3.86 (m, 1H), 3.71 (q, J = 7 Hz, 2H), 3.16 (t, J = 13 Hz, 1H), 2.86-2.71 (m, 2H), 1.92-1.75 (m, 2H), 1.43-1.15 (m, 2H), 1.04 (dd, J = 9 and 6 Hz, 3H), 0.92 (t, J = 7 Hz, 3H). HRMS (m / z): [M-1]- calcd for C18H23F4N3O4, 420.1183; found, 420.1191. ^^^^ଶୈହ= +11.60 (0.506 g / 100 mL (EtOH))

[0366] Comparative Studies vs. EC5026

[0367] In vitro potency

[0368] Select sEH inhibitors were assayed separately and together for potency against inhibition of sEH activity. Briefly, inhibitors were serially diluted in DMSO to 100-fold the desired final concentration. Enzymes were diluted to the desired dilution in sodium phosphate buffer (0.1M pH 7.4) containing 0.1 mg / mL of BSA to a final concentration of 1% DMSO. Conditions used gave rates that were linear both with time and enzyme concentration and that resulted in at least 10% but not more than 20% hydrolysis of the substrate.

[0369] Single compound IC50s were evaluated over 8 serial 1:1 dilutions starting at 0.5 nM for EC5026, 5 nM for M3a, 5 nM for M3b, 2.5 nM each of a 1:1 mixture of M3a and M3b (described as Met Mix), and 62.5 nM TPPU as a reference inhibitor. To determine additive effects, EC5026 was added at a concentration of 0.01, 0.02, or 0.05 nM to varying concentrations of the other sEH inhibitors.ATTORNEY DOCKET NO.930503-2010

[0370] Enzyme inhibition was measured using CNPC and data were plotted as a percent of inhibition (100% activity measured in absence of inhibitor but 1% DMSO) as a function of the concentration of inhibitor. The IC50 values (the concentration of inhibitor that reduces enzyme activity by 50%) were determined by non-linear regression of the data, using SigmaPlot curve fitting of the data into a sigmoidal, logistic 3 parameters equation. Overall, r2 above 0.98 were obtained.

[0371] In vivo PK and toxicology studies

[0372] PK: Rodents: Non-fasted male Sprague-Dawley rats were administered EC5026, M3a or M3b by oral gavage (1 mg / kg) in PEG 400. Blood samples were collected over 72 hr and concentrations in the blood were determined by LC / MS / MS.

[0373] Toxicology: EC5026, M3a and M3b were administered separately to 3 male and 3 female rats by oral gavage at a dose of 30 mg / kg (female) and 60 mg / kg (male) for 7-days. Three hours post the last dose, blood was collected for PK, and target organs previously identified for the most sensitive findings were collected and analyzed by histology.

[0374] Human Study

[0375] Study EC5026-01-02 was a Phase 1b, single-center, double-blind, randomized, placebo-controlled Phase 1b MAD study to investigate the safety, tolerability, and PK of 2 escalating dose regimens of oral EC5026 in healthy male and female participants. EC5026 and placebo tablets were administered as a single oral dose daily, for 7 consecutive days. Participants assigned to the active drug received a single loading dose on Day 1 and a single maintenance dose on Days 2 through 7. The following dose regimens (loading dose / maintenance dose) were evaluated: 4 mg / 2 mg (Cohort 1, total cumulative 7-day oral dose of 16 mg) and 8 mg / 4 mg (Cohort 2, total cumulative 7-day oral dose of 32 mg). Each study participant participated in only 1 dose cohort. Each cohort of 8 participants enrolled 2 participants to receive placebo and 6 participants to receive active drug product (EC5026). All 16 participants who received treatment completed the study. The study consisted of a screening stage, inpatient treatment stage, and outpatient follow-up stage. Participants remained in confinement at the clinical research unit for 8.5 consecutive days and returned to the unit as specified in the protocol for additional laboratory tests and safety evaluations during an initial 30-day period, and for a final end of study visit at Day 30 ± 2 days. Participants were administered study drug on-site by the study staff on Days 1 through 7; no take-home medications were provided. EC5026, M3a and M3b were evaluated at prespecified timepoints by validated HPLC / MS / MS methods.

[0376] sEH activity was monitored in the blood at prespecified timepoints. Blood was collectedATTORNEY DOCKET NO.930503-2010 into tubes containing EDTA and immediately spiked with 0.3mM exogenous deuterated 14,15 EpETrE, an sEH substrate, and allowed to incubate at 37C for 20 min before terminating the reaction with 3.3 mM zinc sulfate, mixing, and freezing at -80°C until analysis by HPLC. Conversion of 14,15 EET-d11 to the sEH product,14,15 DiHETrE-d11, was monitored as a function of sEH activity. A separate tube containing 10 µM of a potent sEH inhibitor was also collected to serve as a positive control for non-sEH mediated hydrolysis.

[0377] RESULTS

[0378] Several different compounds were evaluated and compared to EC5026 (structures provided in (FIG.1). Surprisingly, several of the compounds not only maintain their potency on the sEH enzyme (Table 1), but also increase potency when added in combination (Table 2). Moreover, when EC5026 was added to a concentration gradient of M3a and M3b at concentrations below the predetermined IC50, the combination of inhibitors was more potent than either inhibitor evaluated alone. Table 1 Human sEH mouse sEH Rat sEHTable 2 IC50(nM) of each compound aloneATTORNEY DOCKET NO.930503-2010 1.65 ± 0.38 2.58 ± 1.09 1.95 ± 0.38 0.65 ± 0.2IC50(nM) of each compound with additional EC5026nd = not determined

[0379] The nature of inhibition was evaluated using an isobologram analysis (https: / / www.mdpi.com / 1999-4923 / 11 / 5 / 208 ) to determine if M3a and M3b increase potency of EC5026 beyond expected additive effects (FIG. 6). The isobologram is a quantitative method for measuring interactions between drugs where dose-effect relationships are depicted in a multi-dimensional array with lines connecting dose pairs that are equieffective in relationship to a common pharmacological endpoint. In this instance, inhibition of sEH is used to estimate activity at a common level of activity (IC50 concentration) for the two component drugs separately and for each fixed dose-ratio combination. In the isobolographic figure, areas of dose addition, synergism, and / or antagonism are clearly defined by reference to the theoretical "IC50 Addition Line." According to Loewe's isobolographic theory, IC50's falling under the curve (between the IC50 Addition would represent unexpectedly enhanced analgetic activity and combination EDSO's located above the line would represent unexpectedly diminished analgetic activity. A separate sEH inhibitor, TPPU, was included as a positive control to evaluate synergy of an sEH inhibitor in a different chemical class. Regression analysis was used to determine goodness of fit of the polynomial synergy line against the null hypothesis of a linear additive line. Based on this analysis, the preferred model for M3a, M3b and the metabolites when combined with EC5026 sas the polynomial synergy line. In contrast, the preferred model for TPPU was the additive linear model.

[0380] Using the Loewe isobole equation for additive behavior of two drugs with concentration (^^1,^^2)( ^^1, ^^2), synergy can be calculated by ^^1 / ^^1+^^2 / ^^2 <1 where ^^1 and ^^2 are the concentrations of the agents that produce the same amount of effect as the combination, when they act as single drug. Data <1 represents synergistic effects, data = 1 are additive, and data >1 are antagonistic. These data confirm the isobole graphs demonstrating that independent sEH inhibitor, TPPU has expected additive effects, but m3a and M3b unexpectedly show synergy for enzyme inhibition.ATTORNEY DOCKET NO.930503-2010 Table 3 Loewe Additivity Model (<1.0 = synergy) M3a M3b M3a+M3b TPPU

[0381] Modifying the chemical structure through allosteric mechanisms can tailor the binding dynamics and biological effects on hsEH greater than using a combination of orthostatic inhibitors. As expected, orthostatic inhibitors, such as EC5026 and TPPU, display additive inhibition; while the addition of allosteric compounds would increase potency above what is expected, as is seen with M3a and M3b when combined with EC5026.

[0382] Furthermore, the compounds are not rapidly eliminated as expected for phase 1 compounds, which are anticipated to be rapidly conjugated as glucuronides and sulphates. The compounds also unexpectedly have a longer half-life than EC5026.

[0383] In a comparative PK study, separate groups of rats were administered a single oral dose of 1 mg / kg EC5026 or M3a or M3b (FIG.2). It was unexpectedly discovered that M3a and M3b each have a longer half-life than EC5026. Not wishing to be bound by theory, metabolism of xenobiotic compounds occurs in two stages: phase 1 metabolism forms water- soluble compounds, while Phase 2 metabolism adds polar groups through glucuronidation and sulfation that increase water-solubility and accelerate elimination. It was unexpectedly observed that no Phase 2 metabolism of M3a and M3b occurred. This results in M3a and M3b being surprisingly stable in vivo, which makes them surprisingly and significantly more potent when compared to EC5026.

[0384] Table 4 provides the pharmacokinetic (PK) properties of EC5026, M3a, and M3b in male rats after a single oral administration of 1 mg / kg. The results indicate M3a and M3b each have significantly improved PK properties when compared to EC5026. Table 4 EC5026 M3a M3bATTORNEY DOCKET NO.930503-2010 Cmax (ng / mL) 168 3,452 298 AUC0-inf(hr*ng / mL) 1,188 47,051 2,942

[0385] TabM3b in healthy humans after a once-daily oral dose of EC5026 for 7-days. Consistent with data in rodents, the results indicate M3a and M3b each have significantly improved PK properties when compared to EC5026. FIG.5 shows detected concentrations of EC5026 and M3a and M3b in healthy humans. Table 5 IC50AUC0-inf(hr*ng / mL) % Formed T1 / 2 (h) (nM) 7)

[0386] Based on the synergistic effects of M3a and M3b, sEH activity was monitored in humans as a function of EC5026 exposure. The unbound concentration of EC5026 in plasma can be used as a reliable surrogate for the unbound concentration in target tissues. Predicted efficacious concentrations were calculated based on free plasma concentrations required to inhibit 90% of enzyme activity in vitro (estimated at 10x the IC50). With the assumption that the in vivo IC90 of EC5026 in humans is similar to the in vitro IC50, the effective unbound concentration is estimated to be ≥28 ng / mL or ≥672*hr / mL to maintain target inhibition over 24 hours when the plasma unbound fraction in humans (0.025) is taken into consideration.

[0387] In a Phase 1b clinical study, healthy humans were administered EC5026 at either 2 or 4 mg for 6 days after receiving a 2x loading dose on day 1. Based on exposure data observed in a Phase 1b clinical trial in healthy humans after once daily oral dosing, the minimumATTORNEY DOCKET NO.930503-2010 efficacious dose required to achieve effective sEH inhibition is an 8 mg single dose, or 2 mg dose at steady state. Enzyme inhibition is predicted for approximately 2-days after the last 2 mg dose, and 3-days after the last 4 mg dose at steady state (FIGS.3A-3B).

[0388] However, sEH activity assays monitored during the Phase 1 study demonstrated significant inhibition beyond expected efficacious concentrations. The low dose group demonstrated significant inhibition of sEH activity on day 1, even though concentrations were below the expected therapeutic level. Furthermore, sEH activity was significantly inhibited up to 21-days post last dose even though modeling predicted that concentrations would drop below predicted efficacious concentrations 2-3 days after the last dose (FIG.4).

[0389] Recalculating predicted efficacious concentrations using free plasma concentrations (2.5% for EC5026 and 9.8% for M3a and 10.7% for M3b) and multiplying the IC50 by 10 (https: / / www.sciencedirect.com / science / article / abs / pii / B9780123860095000096). Table 6 provides the predicted levels consistent with what is observed from the clinical trial data (FIGS. 7A-7B). Table 6 IC50 (nM) Predicted efficacious human actual concentration (ng / mL)

[0390] Finally, M3a and M3b were compared to EC5026 for safety profile against the target organ toxicity. Using organ weight as a marker of toxic effect, EC5026 increases the weight of two target organs. Although the observation is not clinically evident, the compounds have a lesser effect on increasing organ weight in one system, and no effect on the other organ of interest. On a histological scale of 0-3, EC5026 caused level 3 vacuolation of the target organ in all animals after 1-week of dosing; whereas, both compounds showed level 1-2 at the sameATTORNEY DOCKET NO.930503-2010 doses. Furthermore, free drug concentrations of M3a and M3b were approximately 7x higher than EC5026 further supporting a wide safety profile of M3a and M3b. Due to the increased potency when combined with EC5026, the addition of M3a and / or M3b can be used to justify lower clinical doses and improve the safety profile of EC5026.

[0391] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

1. ATTORNEY DOCKET NO.930503-2010 CLAIMS 1. A unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof: O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; andATTORNEY DOCKET NO.930503-2010 wherein when there is only one compound, the compound is not EC5026.

2. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has a half-life that is at least two times greater than the half-life of EC5026 at the same dosage in a male rat.

3. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has a half-life that is two times to seven times greater than the half-life of EC5026 at the same dosage in a male rat.

4. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has a Cmaxthat is at least two times greater than the Cmaxof EC5026 at the same dosage in a male rat.

5. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has a Cmaxthat is two times to twenty five greater than the Cmaxof EC5026 at the same dosage in a male rat.

6. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has an area under the curve (AUC) that is at least two times greater than the AUC of EC5026 at the same dosage in a male rat.

7. The composition of claim 1, wherein the compound having the formula I-III in the unit dose composition has an area under the curve (AUC) that is two times to fifty times greater than the AUC of EC5026 at the same dosage in a male rat.

8. The composition of claim 1, wherein the therapeutically effective amount of the compound having the formula I-III in the unit dose composition is up to 100% less than the therapeutically effective amount of EC5026 in a unit dose composition.

9. The composition of claim 1, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

10. The composition of claim 1, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

11. The composition of claim 9, wherein the stereochemistry at carbon a is substantially S or substantially R.

12. The composition of claim 1, wherein the compound isATTORNEY DOCKET NO.930503-2010 , or13. The composition of claim 1, wherein the compound isATTORNEY DOCKET NO.930503-2010 , or a14. The composition of claim 1, wherein the composition comprises a mixture of compounds having the Formula IV and V.ATTORNEY DOCKET NO.930503-2010 15. The composition of claim 14, wherein the molar ratio of IV to V is from 10:1 to 1:

10.

16. The composition of any one of claim 12, wherein the composition further comprises EC5026.

17. The composition of claim 1, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

18. The composition of claim 17, wherein the stereochemistry at carbon a is substantially S or substantially R.

19. The composition of claim 1, wherein the compound is .

20. The composition of claim 1, wherein the compound is formula I, X1is a hydroxyalkyl group, and X2- X4are hydrogen.

21. The composition of claim 1, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

22. The composition of claim 20, wherein the stereochemistry at carbon a is substantially R or substantially S.

23. The composition of claim 1, wherein the compound is .

24. The group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

25. The composition of claim 1, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.ATTORNEY DOCKET NO.930503-2010 26. The composition of claim 24, wherein the stereochemistry at carbon a is substantially R or substantially S.

27. The composition of claim 1, wherein the compound is .

28. is a hydroxyl alkylgroup, a group, are 29. The composition of claim 1, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

30. The composition of claim 28, wherein the stereochemistry at carbon a is substantially S or substantially R.

31. The composition of claim 1, wherein the compound is . 32.an alkyl group.

33. The composition of claim 1, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

34. The composition of claim 1, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.

35. The composition of claim 1, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.

36. The composition of claim 1, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

37. The composition of claim 1, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.ATTORNEY DOCKET NO.930503-2010 38. The composition of claim 1, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.

39. The composition of claim 1, wherein the composition further comprises EC5026.

40. The composition of claim 1, wherein the composition comprises a compound of formula I and EC5026.

41. The composition of claim 40, wherein the compound of formula I is , or a42. The composition of claim 40, wherein the composition consists of the compound of formula I, EC5026, and the pharmaceutically acceptable carrier.

43. The composition of claim 40, wherein a weight ratio of EC5026 to the compound of formula I is from 1:1 to 1:

20.

44. The composition of claim 40, wherein a sum of the compound of formula I and EC5026 is from about 0.5 mg to 100 mg per unit dose composition.

45. The composition of claim 1, wherein the unit dose composition comprises an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.

46. The composition of claim 1, wherein the unit dose composition comprises an oral unit dose composition.

47. A kit comprisingATTORNEY DOCKET NO.930503-2010 (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof: O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.ATTORNEY DOCKET NO.930503-2010 48. The kit of claim 47, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

49. The kit of claim 47, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

50. The kit of claim 48, wherein the stereochemistry at carbon a is substantially S or substantially R.

51. The kit of claim 47, wherein the compound is , orATTORNEY DOCKET NO.930503-2010 any combination thereof.

52. The kit of claim 47, wherein the compound is , or 53.having the Formula IV and VATTORNEY DOCKET NO.930503-2010 . 54.

55. The kit of claim 47, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

56. The kit of claim 55, wherein the stereochemistry at carbon a is substantially S or substantially R.

57. The kit of claim 47, wherein the compound is . 58.group, and X2- X4are hydrogen.

59. The kit of claim 47, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

60. The kit of claim 58, wherein the stereochemistry at carbon a is substantially R or substantially S.

61. The kit of claim 47, wherein the compound is .ATTORNEY DOCKET NO.930503-2010 62. The kit of claim 47, wherein the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

63. The kit of claim 47, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

64. The kit of claim 62, wherein the stereochemistry at carbon a is substantially R or substantially S.

65. The kit of claim 47, wherein the compound is . 66.group, X2is a hydroxyl group, and X3and X4are hydrogen.

67. The kit of claim 47, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

68. The kit of claim 66, wherein the stereochemistry at carbon a is substantially S or substantially R.

69. The kit of claim 47, wherein the compound is .

70. The71. The kit of claim 47, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

72. The kit of claim 47, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.

73. The kit of claim 47, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.ATTORNEY DOCKET NO.930503-2010 74. The kit of claim 47, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

75. The kit of claim 47, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.

76. The kit of claim 47, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.

77. The kit of claim 47, wherein the compound has formula I.

78. The kit of claim 77, wherein the compound of formula I is , or a79. The kit of claim 77, wherein a weight ratio of EC5026 to the compound of formula I is from 1:1 to 1:

20.

80. The kit of claim 47, wherein the first and second unit dose composition comprises, independently, an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.

81. The kit of claim 47, wherein the first and second unit dose composition comprises, independently, an oral unit dose composition.

82. A method of inhibiting soluble epoxide hydrolase (sEH) in a subject, the method comprising administering to the subject the unit dose composition of any one of claims 1- 46.ATTORNEY DOCKET NO.930503-2010 83. A method of treating or preventing a disease or disorder in a subject by inhibiting soluble epoxide hydrolase (sEH), the method comprising administering to the subject the unit dose composition of any one of claims 1-46, thereby treating or preventing the disease or disorder in the subject.

84. The method of claim 83, wherein the disease is a central nervous system disease, a dermatologic inflammatory disorder, a dermatologic autoimmune disorder, or a cardiovascular disease.

85. The method of claim 83, wherein the disease or disorder is selected from the group consisting of renal, hepatic, or pulmonary hypertension, chronic pain, acute pain, neuropathic pain, inflammatory pain, inflammation, neuroinflammation, renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation, acute respiratory distress syndrome, sepsis, burn, diabetic complications, end stage renal disease, ocular disease, Raynaud syndrome, osteoarthritis, autoimmune disease, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS- associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain Barre Syndrome, Wilson's disease, Niemann-Pick disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies and neuronal ceroid lipofuscinosis.

86. The method of claim 83, wherein the disease or disorder is an endoplasmic stress related disease or disorder selected from the group consisting of diabetes, atherosclerosis, obesity, liver disease, viral infection, cancer, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autoimmune disease, neurodegeneration, heart disease and stroke.

87. A method for improving stem cell growth in a subject, the method comprising administering stem cells to the subject and the unit dose composition of any one of claims 1-46 to the subject.

88. A method for improving tissue growth in a subject, the method comprising transplanting a tissue in the subject and administering the unit dose composition of any one of claims 1- 46 to the subject.ATTORNEY DOCKET NO.930503-2010 89. The method of claim 88, wherein the unit dose composition is administered before, during, or after the transplantation of the tissue to the subject.

90. The method of claim 82, wherein the unit composition is administered orally, topically, or intravenously.

91. A method of inhibiting soluble epoxide hydrolase (sEH) in a subject, the method comprising administering to the subject concurrently or sequentially (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof: O X2X4X3X3IIIATTORNEY DOCKET NO.930503-2010 wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

92. A method of treating or preventing a disease or disorder in a subject by inhibiting soluble epoxide hydrolase (sEH), the method comprising administering to the subject concurrently or sequentially (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:ATTORNEY DOCKET NO.930503-2010 O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

93. The method of claim 92, wherein the disease is a central nervous system disease, a dermatologic inflammatory disorder, a dermatologic autoimmune disorder, or a cardiovascular disease.ATTORNEY DOCKET NO.930503-2010 94. The method of claim 92, wherein the disease or disorder is selected from the group consisting of renal, hepatic, or pulmonary hypertension, chronic pain, acute pain, neuropathic pain, inflammatory pain, inflammation, neuroinflammation, renal inflammation, hepatic inflammation, vascular inflammation, and lung inflammation, acute respiratory distress syndrome, sepsis, burn, diabetic complications, end stage renal disease, ocular disease, Raynaud syndrome, osteoarthritis, autoimmune disease, myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS- associated dementia, other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Guillain Barre Syndrome, Wilson's disease, Niemann-Pick disease, encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity, tremor, retinitis pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies and neuronal ceroid lipofuscinosis.

95. The method of claim 92, wherein the disease or disorder is an endoplasmic stress related disease or disorder selected from the group consisting of diabetes, atherosclerosis, obesity, liver disease, viral infection, cancer, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autoimmune disease, neurodegeneration, heart disease and stroke.

96. A method for improving tissue growth in a subject, the method comprising transplanting a tissue in the subject and administering to the subject concurrently or sequentially (a) a first unit dose pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds having Formula I, II, or III, a pharmaceutically acceptable salt thereof or a prodrug thereof:ATTORNEY DOCKET NO.930503-2010 O X2X4X3X3wherein X1, X2, X3, and X4are, independently, hydrogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an ester group, an ether group, an amine group, or an amide group; the stereochemistry at carbon a and b is racemic, substantially R, or substantially S; and the compound is not EC5026; and (b) a second unit dose composition comprising EC5026 and a pharmaceutically acceptable carrier.

97. The method of claim 96, wherein the tissue is an organ.

98. The method of any one of claims 91-97, wherein the compound is formula I, X1is an alkyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.ATTORNEY DOCKET NO.930503-2010 99. The method of any one of claims 91-97, wherein the compound is formula I, X1is a methyl group, X2is a hydroxyl group, X3is hydrogen, and X4is hydrogen.

100. The method of claim 98, wherein the stereochemistry at carbon a is substantially S or substantially R.

101. The method of any one of claims 91-97, wherein the compound is , or102. The method of any one of claims 91-97, wherein the compound isATTORNEY DOCKET NO.930503-2010 , or a103. The method of any one of claims 91-97, wherein the composition comprises a mixture of compounds having the Formula IV and V.ATTORNEY DOCKET NO.930503-2010 104. The method of claim 103, wherein the molar ratio of IV to V is from 10:1 to 1:

10.

105. The method of any one of claims 91-97, wherein when the compound is formula I, X1is an alkyl group, X2is hydrogen, X3is hydroxyl group, and X4is hydrogen.

106. The method of claim 105, wherein the stereochemistry at carbon a is substantially S or substantially R.

107. The method of any one of claims 91-97, wherein the compound is . 108.I, X1is a hydroxyalkyl group, and X2- X4are hydrogen.

109. The method of any one of claims 91-97, wherein the compound is formula I, X1is a hydroxymethyl group, and X2- X4are hydrogen.

110. The method of claim 108, wherein the stereochemistry at carbon a is substantially R or substantially S.

111. The method of any one of claims 91-97, wherein the compound is .

112. TheI, X1is an alkyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

113. The method of any one of claims 91-97, wherein when the compound is formula I, X1is a methyl group, X2is hydrogen, X3is hydrogen, and X4is a hydroxyl group.

114. The method of claim 112, wherein the stereochemistry at carbon a is substantially R or substantially S.

115. The method of any one of claims 91-97, wherein the compound isATTORNEY DOCKET NO.930503-2010 .

116. formula I, X1is agroup, a group, are 117. The method of any one of claims 91-97, wherein the compound is formula I, X1is a hydroxyl methyl group, X2is a hydroxyl group, and X3and X4are hydrogen.

118. The method of claim 116, wherein the stereochemistry at carbon a is substantially S or substantially R.

119. The method of any one of claims 91-97, wherein the compound is . 120.X1is an alkyl group.

121. The method of any one of claims 91-97, wherein the compound is formula II, X1is an alkyl group, X2is an alkyl group, and X3is hydrogen.

122. The method of any one of claims 91-97, wherein the compound is formula II, X1is a methyl group, X2is a methyl group, and X3is hydrogen.

123. The method of any one of claims 91-97, wherein the compound is formula II, X1is an alkyl group, X2is hydrogen, and X3is an alkyl group.

124. The method of any one of claims 91-97, wherein the compound is formula II, X1is a methyl group, X2is hydrogen, and X3is a methyl group.

125. The method of any one of claims 91-97, wherein the compound is formula III, X2is hydrogen and X3is an alkyl group.

126. The method of any one of claims 91-97, wherein the compound is formula III, X2is hydrogen and X3is hydrogen.ATTORNEY DOCKET NO.930503-2010 127. The method of any one of claims 91-97, wherein the compound has formula I.

128. The method of claim 127, wherein the compound of formula I is , or a129. The method of any one of claims 91-97, wherein the first and second unit dose composition comprises, independently, an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, a lozenge, an ointment, a cream, a patch, or a galenic formulation.

130. The method of any one of claims 91-97, wherein the first and second unit dose composition comprises, independently, an oral unit dose composition.

131. The method of any one of claims 91-97, wherein the first and second unit dose compositions are administered orally, topically, or intravenously.

132. The method of any one of claims 82-131, wherein the subject is a human or non-human mammal.

133. The method of any one of claims 82-131, wherein the subject is a domesticated mammal, a farm mammal, or wild mammal.

134. The method of any one of claims 82-131, wherein the subject is an equine and the disease or disorder is pain, inflammation, or laminitis.

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