Piperazinyl and morpholino hydroxylamines and methods for making the same

Abstract

In accordance with the purpose(s) of the present disclosure, described herein are synthetic methods for producing piperazinyl and morpholino hydroxylamines in large scale and high yield. The synthetic approach requires a minimal number of steps and can produce piperazinyl and morpholino hydroxylamines on a multi-gram scale.

Description

ATTORNEY DOCKET NO.222105-2080 PIPERAZINYL AND MORPHOLINO HYDROXYLAMINES AND METHODS FOR MAKING THE SAME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 582,382, filed on September 13, 2023, the contents of which are incorporated by reference herein in their entireties. BACKGROUND

[0002] The N,N,O-trisubstituted hydroxylamine moiety is a significantly underrepresented functional group in medicinal chemistry, perhaps due to the widespread perceptions of the mutagenicity of such compounds and the weakness and electrophilicity of heteroatom- heteroatom bonds as novel structural elements for drug discovery. Additionally, broader exploitation of the concept is limited by the paucity of synthetic methods for straightforward synthesis of the core functionality of this group.

[0003] Trisubstituted hydroxylamines are attractive as potential achiral replacements for stereogenic centers in natural product-like molecules, while maintaining biological activity. Piperazinyl and morpholino hydroxylamines have been demonstrated to enhance ADMET properties when introduced into existing drugs. Thus, it would be desirable to develop a facile method for synthesizing such trisubstituted hydroxylamines in high yield and large scale for drug discovery purposes. These needs and other needs are satisfied by the present disclosure. SUMMARY

[0004] In accordance with the purpose(s) of the present disclosure, described herein are synthetic methods for producing piperazinyl and morpholino hydroxylamines in large scale and high yield. The synthetic approach requires a minimal number of steps and can produce piperazinyl and morpholino hydroxylamines on a multi-gram scale.

[0005] 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, and 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 disclosureATTORNEY DOCKET NO.222105-2080 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

[0006] 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.

[0007] FIGS.1-3 show exemplary reaction schemes for making piperazinyl and morpholino analogues described herein.

[0008] 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. DETAILED DESCRIPTION

[0009] 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.

[0010] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0011] 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.ATTORNEY DOCKET NO.222105-2080

[0012] 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.

[0013] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0014] 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.

[0015] 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 used 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.

[0016] 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

[0017] 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 theATTORNEY DOCKET NO.222105-2080 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.

[0018] 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.

[0019] 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.

[0020] 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 greater 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’”.

[0021] 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 valuesATTORNEY DOCKET NO.222105-2080 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.).

[0022] 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.

[0023] 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 -OCH2CH2O- 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.

[0024] 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 andATTORNEY DOCKET NO.222105-2080 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 to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0025] 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.

[0026] In defining various terms, “A1,” “A2,” “A3,” and “A4” are 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.

[0027] 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,ATTORNEY DOCKET NO.222105-2080 alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0028] 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 also 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.

[0029] 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.

[0030] 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 asATTORNEY DOCKET NO.222105-2080 “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0031] 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 groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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,ATTORNEY DOCKET NO.222105-2080 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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 substitutedATTORNEY DOCKET NO.222105-2080 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. Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0044] 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.

[0045] 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.ATTORNEY DOCKET NO.222105-2080

[0046] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0047] 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.

[0048] 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, wherein 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.

[0049] 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.

[0050] 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-ATTORNEY DOCKET NO.222105-2080 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, 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.

[0051] 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.

[0052] 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.

[0053] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula —OH.

[0054] 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.ATTORNEY DOCKET NO.222105-2080

[0055] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0056] The term “nitro” as used herein is represented by the formula —NO2.

[0057] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0058] 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.

[0059] 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.

[0060] The term “thiol” as used herein is represented by the formula -SH.

[0061] “R1,” “R2,” “R3,”... “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0062] 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 inATTORNEY DOCKET NO.222105-2080 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).

[0063] 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.

[0064] 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 ^; –(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.ATTORNEY DOCKET NO.222105-2080

[0065] 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, – (CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–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.

[0066] 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 an 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.

[0067] 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.

[0068] 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,ATTORNEY DOCKET NO.222105-2080 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.

[0069] 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 C1–4 aliphatic, –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.

[0070] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability 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.

[0071] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) 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.

[0072] 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.

[0073] 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 ofATTORNEY DOCKET NO.222105-2080 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.

[0074] 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.ATTORNEY DOCKET NO.222105-2080

[0075] 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.

[0076] 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 the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0077] 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.

[0078] In some aspects, a structure of a compound can be represented by a formula: ,

[0079] which is understood to be,

[0080] wherein n is typically an understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), and Rn(e). By “independent substituents,” it is meant thatATTORNEY DOCKET NO.222105-2080 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.

[0081] 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.

[0082] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0083] 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.222105-2080

[0084] 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).

[0085] 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.

[0086] 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 a 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 combinationATTORNEY DOCKET NO.222105-2080 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.

[0087] 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.

[0088] 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.

[0089] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere). Synthesis of Piperazinyl and Morpholino Hydroxylamines

[0090] In one aspect, described herein are synthetic methods for producing piperazinyl and morpholino hydroxylamines in large scale and high yield. The synthetic approach requires a minimal number of steps and can produce piperazinyl and morpholino hydroxylamines on a multi-gram scale. The piperazinyl and morpholino hydroxylamines are useful intermediates for producing a number of different biological and pharmaceutical compounds.

[0091] FIGS. 1-2 provide exemplary general synthetic procedures for producing the piperazinyl and morpholino hydroxylamines.

[0092] Referring to FIG.1, four steps A-D are used to produce piperazinyl hydroxylamines having the structure X R7bR7cR7dXATTORNEY DOCKET NO.222105-2080 wherein R5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium,

[0093] In one aspect, the method for making the piperazinyl hydroxylamines having the structure X involves (A) reacting a compound having the structure XI with a compound having the structure XII in the presence of a base to produce a compound having the structure XIIIwherein R10is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, and LG is leaving group;ATTORNEY DOCKET NO.222105-2080 (B) reacting a compound having the structure XIII with a first oxidizing agent with heating to produce a compound having the structure XIV R7bR7cR7aR7dZ Z Z Z; (C) reacting a compound having the structure XIV with (i) a second oxidizing agent followed by (ii) a first reducing agent to produce a first intermediate; and (D) reacting the first intermediate with a second reducing agent to produce a compound having the structure X.

[0094] Step A involves reacting a compound having the structure XI with a compound having the structure XII in the presence of a base to produce a compound having the structure XIIIATTORNEY DOCKET NO.222105-2080wherein R5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; each Z is independently hydrogen or deuterium; R10is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, and LG is leaving group;

[0095] In one aspect, R10in structures XI and XIII s a C1-C5 linear or branched alkyl group. In another aspect, R10in structures XI and XIII is a C1-C5 linear or branched alkoxy group. In another aspect, R10in structures XI and XIII is a C1-C5 linear or branched alkoxy group substituted with an aryl group. In another aspect, R10in structures XI and XIII is a benzyloxy group.

[0096] Step A involves allylation of the compound having the structure XI with the allyl compound having the structure XII in the presence of a base. In one aspect, leaving group LG of the allyl compound XII is a halide, sulfonate, carbonate, or phosphate. In another aspect, the leaving group is bromide. In one aspect, the allyl compound XII can be partially or completely deuterated. In another aspect, each Z in allyl compound XII is hydrogen. The molar ratio of the compound having the structure XI to the allyl compound having the structure XII can be from 0.5:1 to 1:3, or 0.5:1, 1:1, 1:1.5, 1:2, 1:2.3, or 1:3, where any value can be a lower or upper endpoint of a range (e.g., 1:1.5 to 1:2).

[0097] Step A is conducted in an organic solvent. In one aspect, the organic solvent is an aprotic organic solvent such as, for example, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4-dioxane, 1,2-ATTORNEY DOCKET NO.222105-2080 dimethoxyethane, pentane, hexanes, heptanes, cyclohexanes, N,N′-dimethylpropyleneurea (DMPU), or a combination thereof.

[0098] The base is a compound that can deprotonate the amino proton on the piperazine ring of compound XI. In one aspect, the comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide. The molar ratio of the compound having the structure XI to the base can be from 0.5:1 to 1:3, or 0.5:1, 1:1, 1:1.5, 1:2, 1:2.3, or 1:3, where any value can be a lower or upper endpoint of a range (e.g., 1:1.5 to 1:2).

[0099] In one aspect, step A is conducted at elevated temperature. In one aspect, the reaction in step A is conducted at a temperature of from about 25oC to about 100oC, or 25oC, 35oC, 45oC, 55oC, 65oC, 75oC, 85oC, 95oC, or 100oC, where any value can be a lower or upper endpoint of a range (e.g., 55oC to 75oC). After step A, a compound having the structure XIV is produced. The compound having the structure XIII can be subsequently purified using techniques known in the art.

[0100] Step B involves oxidation of the compound having the structure XIII followed by Meisenheimer rearrangement to produce a compound having the structure XIV.

[0101] In one aspect, step B comprises the steps of (i) reacting a compound having the structure XIII with a first oxidizing agent in a first organic solvent to produce a first composition; (ii) adding an aqueous base to the first composition to produce a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to produce a residue; (v) dissolving the residue in a second organic solvent to produce a second composition; and (vi) heating the second composition from about 50oC to about 100oC to produce the compound having the structure XIV.

[0102] In one aspect, the first oxidizing agent in step B comprises a peroxyacid, oxone, or hydrogen peroxide / acetic acid. In another aspect, the first oxidizing agent in step B comprises meta-chloroperoxybenzoic acid. In another aspect, the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.05.

[0103] Step B is conducted in an organic solvent, where the solvent does not react with the first oxidant. In one aspect, the first organic solvent is dichloromethane. The first solvent can then be removed using techniques known in the art, the remaining residue is then dissolved in a second organic solvent to produce a second composition. In one aspect, second organicATTORNEY DOCKET NO.222105-2080 solvent is a higher boiling solvent such as, for example toluene. In one aspect, the second composition in step B is conducted at a temperature of from about 50oC to about 100oC, or 50oC, 60oC, 70oC, 80oC, 90oC, or 100oC, where any value can be a lower or upper endpoint of a range (e.g., 70oC to 90oC). During the heating step, Meisenheimer rearrangement occurs to produce a compound having the structure XIV. The compound having the structure XIIV can be subsequently purified using techniques known in the art.

[0104] Step C involves oxidation of the alkenyl group in the compound having the structure XIIV followed by reduction to produce a first intermediate.

[0105] In one aspect, step C comprises the steps of (i) reacting a compound having the structure XIV with a second oxidizing agent in a third organic solvent to produce a third composition; and (ii) mixing the first reducing agent with the third composition to produce the first intermediate.

[0106] In one aspect, the second oxidizing agent used in step C comprises ozone or osmium tetroxide with sodium metaperiodate. Step C is conducted in an organic solvent. In one aspect, third organic solvent comprises an alcohol (e.g., methanol, ethanol, butanol, or any combination thereof) and an aprotic solvent (e.g., tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-methyl THF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4- dioxane, 1,2-dimethoxyethane, pentane, hexanes, heptanes, cyclohexanes, N,N′- dimethylpropyleneurea (DMPU), or any combination thereof).

[0107] In one aspect, the compound having the structure XIV is reacted with the second oxidizing agent at a temperature of from about -50oC to about -100oC, or -50oC, -60oC, -70oC, -80oC, -90oC, or -100oC, where any value can be a lower or upper endpoint of a range (e.g., -70oC to -90oC).

[0108] After oxidation of the alkenyl group in the compound having the structure XIIV, a first reducing agent is subsequently added to the reaction to produce a first intermediate, which is a terminal alcohol as provided belowATTORNEY DOCKET NO.222105-2080 .

[0109] In onewhich is any compound that can deliver a hydrogen anion. In one aspect, the first reducing agent comprises a borohydride. In one aspect, the hydride is sodium borohydride, lithium aluminium hydride, or diisobutylaluminium hydride. The molar ratio of the first reducing agent to the compound having the structure XIV is from 1.5:1 to 2.5:1, or 1.5:1, 1.75:1, 2:1, 2.25:1, or 2.5:1, where any value can be a lower or upper endpoint of a range (e.g., 1.75:1 to 2:1). The first intermediate produced in step C can be subsequently purified using techniques known in the art prior to step D.

[0110] Step D involves reduction of the carbonyl group in the first intermediate to produce the piperazinyl hydroxylamine compound X.

[0111] In one aspect, step D comprises the steps of (i) dissolving the first intermediate in an aprotic solvent to produce a fourth composition; (ii) mixing the second reducing agent with the fourth composition to produce the compound having the structure X; and (iii) isolating and purifying the compound having the structure X.

[0112] The first intermediate is dissolved in an aprotic solvent (e.g., tetrahydrofuran (THF), 2- methyltetrahydrofuran (2-methyl THF), diethyl ether, methyl tert-butyl ether (MTBE), 1,4- dioxane, 1,2-dimethoxyethane, pentane, hexanes, heptanes, cyclohexanes, N,N′- dimethylpropyleneurea (DMPU), or any combination thereof) followed by the addition the second reducing agent. In one aspect, the hydride is sodium borohydride, lithium aluminium hydride, or diisobutylaluminium hydride. The molar ratio of the first reducing agent to the compound having the structure XIV is from 2:1 to 4:1, or 2:1, 2.5:1, 3:1, 3.5:1, or 4:1, where any value can be a lower or upper endpoint of a range (e.g., 2.5:1 to 3.5:1).

[0113] In one aspect, the first intermediate is reacted with the second reducing agent at a temperature of from about 10oC to about -50oC, or 10oC, 0oC, -10oC, -20oC, -30oC, -40oC, or -50oC, where any value can be a lower or upper endpoint of a range (e.g., -10oC to -ATTORNEY DOCKET NO.222105-2080 30oC). The piperazinyl hydroxylamine compound X produced in step D can be subsequently purified using techniques known in the art prior to step D.

[0114] Referring to FIG.2, three steps A-C are used to produce morpholino hydroxylamines having the structure XX R7b R7c7aR7dR whereinR7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium,

[0115] In one aspect, the method for making the morpholino hydroxylamines having the structure XX involves (A) reacting a compound having the structure XXI with a compound having the structure XXII in the presence of a base to produce a compound having the structure XXIII ZATTORNEY DOCKET NO.222105-2080wherein LG is leaving group; (B) reacting a compound having the structure XXIII with a first oxidizing agent to produce a compound having the structure XXIV (C) reacting thesecond oxidizing agent followed by (ii) a first reducing agent to produce a compound having the structure XX.

[0116] The same reaction conditions and reagents used in steps A-C for producing the piperazinyl hydroxylamines can be used to produce the morpholino hydroxylamines having the structure XX, where step D is not required to produce the morpholino hydroxylamines.

[0117] 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.

[0118] 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 toATTORNEY DOCKET NO.222105-2080 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 Aspect 1. A method for making a compound having the structure X R7bR7c7dR7aR X whereinR5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium, the method comprising (a) reacting a compound having the structure XI with a compound having the structure XII in the presence of a base to produce a compound having the structure XIIIATTORNEY DOCKET NO.222105-2080wherein R10is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, and LG is leaving group; (b) reacting a compound having the structure XIII with a first oxidizing agent with heating to produce a compound having the structure XIV R7bR7cR7aR7dZ Z Z Z; (c) reacting a compound having the structure XIV with (i) a second oxidizing agent followed by (ii) a first reducing agent to produce a first intermediate; and (d) reacting the first intermediate with a second reducing agent to produce a compound having the structure X. Aspect 2. The method of Aspect 1, wherein R10is a C1-C5 linear or branched alkyl group. Aspect 3. The method of Aspect 1, wherein R10is a C1-C5 linear or branched alkoxy group. Aspect 4. The method of Aspect 1, wherein R10is a C1-C5 linear or branched alkoxy group substituted with an aryl group. Aspect 5. The method of Aspect 1, wherein R10is a benzyloxy group.ATTORNEY DOCKET NO.222105-2080 Aspect 6. The method of any one of Aspects 1-5, wherein LG is a halide, sulfonate, carbonate, or phosphate. Aspect 7. The method of any one of Aspects 1-6, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide. Aspect 8. The method of any one of Aspects 1-7, wherein step (a) is conducted in an aprotic organic solvent. Aspect 9. The method of any one of Aspects 1-8, wherein step (a) is conducted at a temperature of from about 25oC to about 100oC. Aspect 10. The method of any one of Aspects 1-9, wherein step (b) comprises the steps of (i) reacting a compound having the structure XIII with a first oxidizing agent in a first organic solvent to produce a first composition; (ii) adding an aqueous base to the first composition to produce a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to produce a residue; (v) dissolving the residue in a second organic solvent to produce a second composition; and (vi) heating the second composition from about 50oC to about 100oC to produce the compound having the structure XIV. Aspect 11. The method of Aspect 10, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene Aspect 12. The method of any one of Aspects 1-11, wherein the first oxidizing agent in step (b) comprises a peroxyacid, oxone, or hydrogen peroxide / acetic acid. Aspect 13. The method of any one of Aspects 1-11, wherein the first oxidizing agent in step (b) comprises meta-chloroperoxybenzoic acid. Aspect 14. The method of any one of Aspects 1-11, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.05. Aspect 15. The method of any one of Aspects 1-14, wherein step (c) comprises the steps of (i) reacting a compound having the structure XIV with a second oxidizing agent in a third organic solvent to produce a third composition; and (ii) mixing the first reducing agent with the third composition to produce the first intermediate.ATTORNEY DOCKET NO.222105-2080 Aspect 16. The method of Aspect 15, wherein the second oxidizing agent comprises ozone or osmium tetroxide with sodium metaperiodate. Aspect 17. The method of Aspect 15 or 16, wherein the third organic solvent comprises an alcohol and an aprotic solvent. Aspect 18. The method of any one of Aspects 15-17, wherein the compound having the structure XIV is reacted with the second oxidizing agent at a temperature of from about -50oC to about -100oC. Aspect 19. The method of any one of Aspects 1-18, wherein the first reducing agent comprises a hydride. Aspect 20. The method of any one of Aspects 1-18, wherein the first reducing agent comprises a borohydride. Aspect 21. The method of any one of Aspects 1-20, wherein the molar ratio of the first reducing agent to the compound having the structure XIV is from 1.5:1 to 2.5:1. Aspect 22. The method of any one of Aspects 1-21, wherein the first intermediate is isolated prior to step (d). Aspect 23. The method of any one of Aspects 1-22, wherein step (d) comprises the steps of (i) dissolving the first intermediate in an aprotic solvent to produce a fourth composition; (ii) mixing the second reducing agent with the fourth composition to produce the compound having the structure X; and (iii) isolating and purifying the compound having the structure X. Aspect 24. The method of Aspect 23, wherein the second reducing agent is mixed with the fourth composition at a temperature of from about 10oC to about -50oC. Aspect 25. The method of any one of Aspects 1-24, wherein the second reducing agent comprises a hydride. Aspect 26. The method of any one of Aspects 1-24, wherein the second reducing agent comprises an aluminum hydride. Aspect 27. The method of any one of Aspects 1-26, wherein the molar ratio of the second reducing agent to the first intermediate is from 4:1 to 2:1. Aspect 28. The method of any one of Aspects 1-27, wherein R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen.ATTORNEY DOCKET NO.222105-2080 Aspect 29. The method of any one of Aspects 1-27, wherein R5is methyl and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen. Aspect 1. Aspect 30. A method for making a compound having the structure XX R7bR7c7R7dRawhereinR7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium, the method comprising (a) reacting a compound having the structure XXI with a compound having the structure XXII in the presence of a base to produce a compound having the structure XXIII ZATTORNEY DOCKET NO.222105-2080wherein LG is leaving group; (b) reacting a compound having the structure XXIII with a first oxidizing agent to produce a compound having the structure XXIV; and (c) reacting the compound having the structure XXIV with (i) a second oxidizing agent followed by (ii) a first reducing agent to produce a compound having the structure XX. Aspect 31. The method of Aspect 30, wherein LG is a halide, sulfonate, carbonate, or phosphate. Aspect 32. The method of Aspect 30 or 31, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide. Aspect 33. The method of any one of Aspects 30-32, wherein step (a) is conducted in an aprotic organic solvent. Aspect 34. The method of any one of Aspects 30-33, wherein step (a) is conducted at a temperature of from about 25oC to about 100oC. Aspect 35. The method of any one of Aspects 30-34, wherein step (b) comprises the steps ofATTORNEY DOCKET NO.222105-2080 (i) reacting a compound having the structure XXIII with a first oxidizing agent in a first organic solvent to produce a first composition; (ii) adding an aqueous base to the first composition to produce a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to produce a residue; (v) dissolving the residue in a second organic solvent to produce a second composition; and (vi) heating the second composition from about 50oC to about 100oC to produce the compound having the structure XXIV. Aspect 36. The method of Aspect 35, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene Aspect 37. The method of any one of Aspects 30-36, wherein the first oxidizing agent in step (b) comprises a peroxyacid, oxone, or hydrogen peroxide / acetic acid. Aspect 38. The method of any one of Aspects 30-37, wherein the first oxidizing agent in step (b) comprises meta-chloroperoxybenzoic acid. Aspect 39. The method of any one of Aspects 30-37, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.05. Aspect 40. The method of any one of Aspects 30-39, wherein step (c) comprises the steps of (i) reacting a compound having the structure XXIV with a second oxidizing agent in a third organic solvent to produce a third composition; and (ii) mixing the first reducing agent with the third composition to produce the compound having the structure XX; and (iii) isolating and purifying the compound having the structure XX. Aspect 41. The method of Aspect 40, wherein the second oxidizing agent comprises ozone or osmium tetroxide with sodium metaperiodate. Aspect 42. The method of Aspect 40 or 41, wherein third organic solvent comprises an alcohol and an aprotic solvent. Aspect 43. The method of any one of Aspects 40-42, wherein the compound having the structure XXIV is reacted with the second oxidizing agent at a temperature of from about -50oC to about -100oC. Aspect 44. The method of any one of Aspects 30-43, wherein the first reducing agent comprises a hydride.ATTORNEY DOCKET NO.222105-2080 Aspect 45. The method of any one of Aspects 30-43, wherein the first reducing agent comprises a borohydride. Aspect 46. The method of any one of Aspects 30-45, wherein the molar ratio of the first reducing agent to the compound having the structure XXIV is from 1.5:1 to 2.5:1. Aspect 47. The method of any one of Aspects 30-46, wherein R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen. Aspect 48. The method of any one of Aspects 1-27, wherein R5is methyl and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen. Aspect 49. A compound having the structure XXX whereinY is O or NR5, R5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium. EXAMPLES

[0119] 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.ATTORNEY DOCKET NO.222105-2080

[0120] Example 1

[0121] An exemplary synthetic scheme for making piperazinyl analogue described herein is provided in FIG.3. A [2,3]-Meisenheimer rearrangement is used to install the hydroxylamine unit.1-3Beginning with commercially available 1 that on allylation with allyl bromide under basic conditions gave the N-allyl derivative (2) in 72% yield. N-oxidation of 2 with meta- chloroperoxybenzoic acid (MCPBA) followed by [2,3]-Meisenheimer rearrangement gave 3 in 47% yield over 2 steps. The alkene present in 3 was then subjected to ozonolysis followed by reduction with sodium borohydride (NaBH4), after which, further reduction of the carboxybenzyl group with lithium aluminum hydride4(LiAlH4) gave the intended hydroxylamine precursor 4 in 50% yield over 2 steps.

[0122] Experimental

[0123] Synthesis of benzyl 4-allylpiperazine-1-carboxylate (2)

[0124] To a stirred solution of benzyl piperazine-1-carboxylate (15 g, 68.14 mmol, 1.0 eq.) in anhydrous THF (250 mL) at r.t. was added K2CO3(18.8 g, 136.28 mmol, 2.0 eq.) followed by slow addition of allyl bromide (11.8 mL, 136.28 mmol, 2.0 eq.). The solution was brought to 65 °C and stirred for 16 h, after which time, the mixture was cooled to r.t. and quenched via addition of 1M NaOH (200 mL). The layers were separated and the aqueous layer extracted with EtOAc (3x, 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica (eluent: 50:45:5 Hexanes:EtOAc:Et3N) to afford the title compound 2 (12.81 g, 49.2 mmol, 72 %) as a yellow oil. TLC Rf= 0.60 (50:45:5 Hexanes:EtOAc:Et3N; CAM, UV).1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.89-5.78 (m, 1H), 5.23-5.14 (m, 2H), 5.13 (br s, 2H), 3.56 (m, 4H), 3.00 (d, J = 6.6 Hz, 2H), 2.40 (br s, 4H).13C NMR (126 MHz, CDCl3) δ 155.4, 136.9, 134.7, 128.6, 128.1, 128.0, 118.5, 67.2, 61.8, 52.8, 43.9. HRMS-ESI (m / z) [M+H]+calculated for [C15H21N2O2]+: 261.1598, found: 261.1594.ATTORNEY DOCKET NO.222105-2080

[0125] Synthesis of benzyl 4-(allyloxy)piperazine-1-carboxylate (3)added MCPBA (70% mixture with 3-chlorobenzoic acid and water) (11.56 g, 46.9 mmol, 1.0 eq) portion-wise over a period of 5 min. After full addition, the reaction mixture was stirred at -30 °C for 1 h, then was quenched with aq. NaHCO3(150 mL) and the layers were separated. The organic layer was washed with NaHCO3(3x, 150 mL) after which the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was dissolved in toluene heated to 80 °C with stirring for 14 h. After such time, the mixture was cooled to r.t. and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica (eluent: 80:15:5 Hexanes:EtOAc:Et3N) to afford the title compound 3 (6.13 g, 22.2 mmol, 47%) as a clear oil. TLC Rf= 0.50 (30:70 EtOAc:Hexanes; CAM, UV).1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 5H) 5.99-5.88 (m, 1H), 5.27 (d, J = 17.3 Hz, 1H), 5.18 (d, J = 10.3 Hz, 1H), 5.13 (s, 2H), 4.21 (d, J = 6.1 Hz, 2H), 4.03 (s, 2H), 3.19-3.11 (m, 4H), 2.57 (s, 3H).13C NMR (126 MHz, CDCl3): δ 155.3, 136.8, 134.6, 128.7, 128.2, 128.1, 118.0, 73.2, 67.4, 55.3, 42.7. HRMS-ESI (m / z): [M+H]+calculated for [C15H21N2O3]+: 277.1547, found: 277.1540.

[0127] Synthesis of 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol (4)and methanol (50 mL) and cooled to -78 °C. Ozone was bubbled through the reaction mixture for 30 min until full consumption of starting material. On completion, as indicated by ESIMS, argon was bubbled through the reaction mixture to disperse residual ozone. NaBH4(1.53 g, 40.54 mmol, 2.0 eq.) was then added portion-wise at -78 °C and the solution was gradually warmed to r.t. and stirred for 1 h. After such time, the mixture was quenched with aq. NaHCO3(200 mL) and the layers separated. The aqueous layer was extracted with DCM (2x, 150 mL) and the combined organic layers washed with aq. brine (2x, 150 mL), dried over Na2SO4, filtered and concentrated in vacuo to directly afford the alcohol as a clear oil (5.26 g, 18.8ATTORNEY DOCKET NO.222105-2080 mmol, 93% crude yield). TLC Rf= 0.10 (70:30 EtOAc:Hexanes; CAM, UV).1H NMR (500 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.13 (s, 2H), 4.07 (s, 2H), 3.84-3.81 (m, 4H), 3.24-3.10 (m, 5H), 2.60-2.56 (m, 2H).13C NMR (126 MHz, CDCl3) δ 155.2, 136.6, 128.7, 128.3, 128.1, 71.9, 67.5, 65.3, 55.0, 42.7. HRMS-ESI (m / z) [M+H]+calculated for [C14H21O4N2]+: 281.1496, found: 281.1489.

[0129] The so obtained crude alcohol (5.26 g, 18.8 mmol, 1.0 eq.) obtained in the previous step was dissolved in anhydrous THF (68 mL) and cooled to 0 °C. LiAlH4(2.31 g, 60.81 mmol, 3.2 eq.) was then added portion-wise over a period of 5 min. After full addition, the solution was warmed to r.t. and stirred for 2 h. After such time, the reaction mixture was cooled back to 0 °C and quenched by slow addition of H2O. After effervescence ceased, the solution was acidified with concentrated HCl until pH ^ 2. The aqueous layer was then extracted with EtOAc (4x, 150 mL), after which, the aqueous layer was cooled to 0 °C and basified to pH ^ 10 by portion-wise addition of solid NaOH. The basified aqueous layer was extracted with EtOAc (4x, 100 mL) and the resulting organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound 4 (1.63 g, 10.2 mmol, 50% yield over 2 steps from 3) as a yellow oil with spectral data identical to that of an authentic sample.

[0130] 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. REFERENCES 1) Meisenheimer, J. Über eine eigenartige Umlagerung des Methyl-allyl-anilin-N-oxyds. Ber. Dtsch. Chem. Ges.1919, 52, 1667-1677. 2) Albini, A. Synthetic Utility of Amine N-Oxides. Synthesis 1993, 3, 263-277. 3) Hill, J.; Beckler, T. D.; Crich, D. Recent Advances in the Synthesis of Di- and Trisubstituted Hydroxylamines. Molecules 2023, 28, 2816. 4) Vallakati, R.; May, J. A. Biomimetic Synthesis of the Antimalarial Flindersial Alkaloids. J. Am. Chem. Soc.2012, 134, 6936-6939.

Claims

ATTORNEY DOCKET NO.222105-2080 CLAIMS 1. A method for making a compound having the structure X R7bR7c7R7dRaXwhereinR5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium, the method comprising (a) reacting a compound having the structure XI with a compound having the structure XII in the presence of a base to produce a compound having the structure XIIIATTORNEY DOCKET NO.222105-2080wherein R10is a substituted or unsubstituted linear or branched alkyl group, or a substituted or unsubstituted linear or branched alkoxy group, and LG is leaving group; (b) reacting a compound having the structure XIII with a first oxidizing agent with heating to produce a compound having the structure XIV R7bR7cR7aR7dZ Z Z Z; (c) reacting a compound having the structure XIV with (i) a second oxidizing agent followed by (ii) a first reducing agent to produce a first intermediate; and (d) reacting the first intermediate with a second reducing agent to produce a compound having the structure X.

2. The method of claim 1, wherein R10is a C1-C5 linear or branched alkyl group.

3. The method of claim 1, wherein R10is a C1-C5 linear or branched alkoxy group.

4. The method of claim 1, wherein R10is a C1-C5 linear or branched alkoxy group substituted with an aryl group.

5. The method of claim 1, wherein R10is a benzyloxy group.

6. The method of claim 1, wherein LG is a halide, sulfonate, carbonate, or phosphate.ATTORNEY DOCKET NO.222105-2080 7. The method of claim 1, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide.

8. The method of claim 1, wherein step (a) is conducted in an aprotic organic solvent.

9. The method of claim 1, wherein step (a) is conducted at a temperature of from about 25oC to about 100oC.

10. The method of claim 1, wherein step (b) comprises the steps of (i) reacting a compound having the structure XIII with a first oxidizing agent in a first organic solvent to produce a first composition; (ii) adding an aqueous base to the first composition to produce a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to produce a residue; (v) dissolving the residue in a second organic solvent to produce a second composition; and (vi) heating the second composition from about 50oC to about 100oC to produce the compound having the structure XIV.

11. The method of claim 10, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene 12. The method of claim 1, wherein the first oxidizing agent in step (b) comprises a peroxyacid, oxone, or hydrogen peroxide / acetic acid.

13. The method of claim 1, wherein the first oxidizing agent in step (b) comprises meta- chloroperoxybenzoic acid.

14. The method of claim 1, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.

05.

15. The method of claim 1, wherein step (c) comprises the steps of (i) reacting a compound having the structure XIV with a second oxidizing agent in a third organic solvent to produce a third composition; and (ii) mixing the first reducing agent with the third composition to produce the first intermediate.

16. The method of claim 15, wherein the second oxidizing agent comprises ozone or osmium tetroxide with sodium metaperiodate.

17. The method of claim 15, wherein the third organic solvent comprises an alcohol and an aprotic solvent.

18. The method of claim 15, wherein the compound having the structure XIV is reacted with the second oxidizing agent at a temperature of from about -50oC to about -100 oC.

19. The method of claim 1, wherein the first reducing agent comprises a hydride.ATTORNEY DOCKET NO.222105-2080 20. The method of claim 1, wherein the first reducing agent comprises a borohydride.

21. The method of claim 1, wherein the molar ratio of the first reducing agent to the compound having the structure XIV is from 1.5:1 to 2.5:

1.

22. The method of claim 1, wherein the first intermediate is isolated prior to step (d).

23. The method of claim 1, wherein step (d) comprises the steps of (i) dissolving the first intermediate in an aprotic solvent to produce a fourth composition; (ii) mixing the second reducing agent with the fourth composition to produce the compound having the structure X; and (iii) isolating and purifying the compound having the structure X.

24. The method of claim 23, wherein the second reducing agent is mixed with the fourth composition at a temperature of from about 10oC to about -50oC.

25. The method of claim 1, wherein the second reducing agent comprises a hydride.

26. The method of claim 1, wherein the second reducing agent comprises an aluminum hydride.

27. The method of claim 1, wherein the molar ratio of the second reducing agent to the first intermediate is from 4:1 to 2:

1.

28. The method of claim 1, wherein R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen.

29. The method of claim 1, wherein R5is methyl and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen.

30. A method for making a compound having the structure XX R7bR7cR7dwhereinR7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium, the method comprisingATTORNEY DOCKET NO.222105-2080 (a) reacting a compound having the structure XXI with a compound having the structure XXII in the presence of a base to produce a compound having the structure XXIII Zwherein LG is leaving group; (b) reacting a compound having the structure XXIII with a first oxidizing agent to produce a compound having the structure XXIV; andATTORNEY DOCKET NO.222105-2080 (c) reacting the compound having the structure XXIV with (i) a second oxidizing agent followed by (ii) a first reducing agent to produce a compound having the structure XX.

31. The method of claim 30, wherein LG is a halide, sulfonate, carbonate, or phosphate.

32. The method of claim 30, wherein the base in step (a) comprises a carbonate, hydroxide, phosphate, hydride, dialkylamide, or hexamethyldisilazide.

33. The method of claim 30, wherein step (a) is conducted in an aprotic organic solvent.

34. The method of claim 30, wherein step (a) is conducted at a temperature of from about 25oC to about 100oC.

35. The method of claim 30, wherein step (b) comprises the steps of (i) reacting a compound having the structure XXIII with a first oxidizing agent in a first organic solvent to produce a first composition; (ii) adding an aqueous base to the first composition to produce a second composition comprising an organic layer and an aqueous layer; (iii) separating the organic layer from the aqueous layer; (iv) removing the first organic solvent from the organic layer to produce a residue; (v) dissolving the residue in a second organic solvent to produce a second composition; and (vi) heating the second composition from about 50oC to about 100oC to produce the compound having the structure XXIV.

36. The method of claim 35, wherein the first organic solvent is dichloromethane and the second organic solvent is toluene 37. The method of claim 30, wherein the first oxidizing agent in step (b) comprises a peroxyacid, oxone, or hydrogen peroxide / acetic acid.

38. The method of claim 30, wherein the first oxidizing agent in step (b) comprises meta- chloroperoxybenzoic acid.

39. The method of claim 30, wherein the molar ratio of the first oxidizing agent to the compound having the structure XIII is from 0.95:1 to 1:1.

05.

40. The method of claim 30, wherein step (c) comprises the steps of (i) reacting a compound having the structure XXIV with a second oxidizing agent in a third organic solvent to produce a third composition; and (ii) mixing the first reducing agent with the third composition to produce the compound having the structure XX; and (iii) isolating and purifying the compound having the structure XX.

41. The method of claim 40, wherein the second oxidizing agent comprises ozone or osmium tetroxide with sodium metaperiodate.ATTORNEY DOCKET NO.222105-2080 42. The method of claim 40, wherein third organic solvent comprises an alcohol and an aprotic solvent.

43. The method of claim 40, wherein the compound having the structure XXIV is reacted with the second oxidizing agent at a temperature of from about -50oC to about -100 oC.

44. The method of claim 30, wherein the first reducing agent comprises a hydride.

45. The method of claim 30, wherein the first reducing agent comprises a borohydride.

46. The method of claim 30, wherein the molar ratio of the first reducing agent to the compound having the structure XXIV is from 1.5:1 to 2.5:

1.

47. The method of claim 30, wherein R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen.

48. The method of claim 1, wherein R5is methyl and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare each hydrogen.

49. A compound having the structure XXX whereinY is O or NR5, R5is a substituted or unsubstituted linear or branched alkyl group, and R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7hare independently hydrogen, deuterium, or a substituted or unsubstituted alkyl group; and each Z is independently hydrogen or deuterium.

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