WO2014085791A2 - Compositions and uses thereof for treating multiple myeloma - Google Patents

Description

COMPOSITIONS AND USES THEREOF FOR TREATING MULTIPLE MYELOMA

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. provisional application number 61/732,014, filed November 30, 2012, the entirety of which is hereby incorporated by reference.

BACKGROUND

[0002] Multiple myeloma (MM) is a cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies. Multiple myeloma is the most common primary tumor of bone and is found in the spine, skull, ribs, sternum and pelvis but may affect any bone with hematopoietic red marrow. In multiple myeloma, collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells. Bone damage is common and can be severe in MM, and a large percentage of patients will develop pathologic fractures. In addition, multiple myeloma can metastasize throughout the body. It is well known that many cancer deaths arise as a consequence of metastatic disease, rather than from the primary tumor. In appreciation of this fact, there is a strong clinical interest in preventing or halting metastasis as a means of treating cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0003] Figure 1 sets forth in tabular form the IC₅₀ values for various compounds against the multiple myeloma cell lines ARP, CAG, MM I S and SKO007. Fludelone is the compound of formula I-b; iso-fludelone is the compound of formula I-f; iso-dehydelone is the compound of formula I-e; and dEpoB is 12, 13-desoxyepothilone B (also known as epothilone D).

[0004] Figure 2A depicts the biological activity of known microtubule inhibitors on cellular proliferation of ARP multiple myeloma cells.

[0005] Figure 2B depicts the proliferation index of known multiple myeloma chemotherapeutic agents and iso fludelone (I-f) in ARP multiple myeloma cells.

[0006] Figure 3A depicts the biological activity of known microtubule inhibitors on cellular proliferation of CAG multiple myeloma cells. [0007] Figure 3B depicts the proliferation index of known multiple myeloma chemotherapeutic agents and isofludelone (I-f) in CAG multiple myeloma cells.

[0008] Figure 4A depicts the biological activity of known microtubule inhibitors on cellular proliferation of MM IS multiple myeloma cells.

[0009] Figure 4B depicts the proliferation index of known multiple myeloma chemotherapeutic agents and isofludelone (I-f) in MM IS multiple myeloma cells.

[0010] Figure 5 A depicts the biological activity of known microtubule inhibitors on cellular proliferation of SKO001 multiple myeloma cells.

[0011] Figure 5B depicts the proliferation index of known multiple myeloma chemotherapeutic agents and isofludelone (I-f) in SKO007 multiple myeloma cells.

[0012] Figure 6 presents toxicity data (LD₅₀) of migrastatin analogs Ml, M2, M3, M4, Migrastatin Ether (ME) and Carboxy-Methyl Migrastatin Ether (CME) on multiple myeloma (MM) cell lines.

[0013] Figure 7 presents the inhibition of CAG multiple myeloma cell migration by ME and CME migrastatin analogs.

[0014] Figure 8 presents the inhibition of H929 multiple myeloma cell migration by migrastatin ether (ME) and carboxy-methyl migrastatin ether (CME) analogs.

[0015] Figure 9 presents the inhibition of multiple myeloma cell migration by macroether migrastatin.

DEFINITIONS

[0016] Certain compounds of the present disclosure, and definitions of specific functional groups are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0017] As used herein, the following definitions shall apply unless otherwise indicated. [0018] The term "acyl," used alone or a part of a larger moiety, refers to groups formed by removing a hydroxy group from a carboxylic acid. Non-limiting exemplary acyl groups include carboxylic acids, esters, amides, and carbamates.

[0019] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0020] The term "alicyclic", as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH₂- cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl-n, cyclohexyl, -CH₂- cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[0021] The term "alkyl," as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1-12 carbon atoms. In certain embodiments, alkyl groups contain 1-8 carbon atoms. In certain embodiments, alkyl groups contain 1-6 carbon atoms. In some embodiments, alkyl groups contain 1-5 carbon atoms, in some embodiments, alkyl groups contain 1-4 carbon atoms, in some embodiments alkyl groups contain 1-3 carbon atoms, and in some embodiments alkyl groups contain 1-2 carbon atoms. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

[0022] The term "alkenyl," as used herein, denotes a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Unless otherwise specified, alkenyl groups contain 2-12 carbon atoms. In certain embodiments, alkenyl groups contain 2-8 carbon atoms. In certain embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms, in some embodiments, alkenyl groups contain 2-4 carbon atoms, in some embodiments alkenyl groups contain 2-3 carbon atoms, and in some embodiments alkenyl groups contain 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.

[0023] The term "alkynyl," as used herein, refers to a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Unless otherwise specified, alkynyl groups contain 2-12 carbon atoms. In certain embodiments, alkynyl groups contain 2-8 carbon atoms. In certain embodiments, alkynyl groups contain 2-6 carbon atoms. In some embodiments, alkynyl groups contain 2-5 carbon atoms, in some embodiments, alkynyl groups contain 2-4 carbon atoms, in some embodiments alkynyl groups contain 2-3 carbon atoms, and in some embodiments alkynyl groups contain 2 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0024] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and polycyclic ring systems having a total of five to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like. In certain embodiments, the term "6- to 10-membered aryl" refer to a phenyl or an 8- to 10-membered polycyclic aryl ring.

[0025] The terms "cycloaliphatic", "carbocycle", or "carbocyclic", used alone or as part of a larger moiety, refer to a saturated or partially unsaturated cyclic aliphatic monocyclic or polycyclic ring systems, as described herein, having from 3 to 12 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloaliphatic", "carbocycle" or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. In certain embodiments, the terms "3- to 14-membered carbocycle" and "C₃_i₄ carbocycle" refer to a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7- to 14-membered saturated or partially unsaturated polycyclic carbocyclic ring.

[0026] The term "halogen" means F, CI, Br, or I.

[0027] The term "heteroaliphatic," as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, or phosphorus. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" groups.

[0028] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. In certain embodiments, the term "5- to 12-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

[0030] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-14-membered poly cyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). In some embodiments, the term "3- to 7-membered heterocyclic" refers to a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, the term "3- to 12-membered heterocyclic" refers to a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- to 12-membered saturated or partially unsaturated poly cyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical," are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0032] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0033] In another aspect, the present disclosure provides "pharmaceutically acceptable" compositions, which comprise a therapeutically effective amount of one or more of the compounds described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.

[0034] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0035] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other nontoxic compatible substances employed in pharmaceutical formulations. [0036] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0037] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each stereocenter, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0038] If, for instance, a particular enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis, chiral chromatography, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0039] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0040] One of ordinary skill in the art will appreciate that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term "protecting group," as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized. By way of non-limiting example, hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), /?-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p- AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1 -methyl- 1-benzyloxyethyl, 1 -methyl- l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl)ethyl, t-butyl, allyl, /?-chlorophenyl, /?-methoxyphenyl, 2,4-dinitrophenyl, benzyl, /?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, /?-nitrobenzyl, /?-halobenzyl, 2,6- dichlorobenzyl, /?-cyanobenzyl, /?-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N- oxido, diphenylmethyl, p,p '-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a- naphthyldiphenylmethyl, /?-methoxyphenyldiphenylmethyl, di(/ methoxyphenyl)phenylmethyl, tri(/?-methoxyphenyl)methyl, 4-(4 ' -bromophenacyloxyphenyl)diphenylmethyl, 4,4 ' ,4 " -tris(4,5- dichlorophthalimidophenyl)methyl, 4,4 ' ,4 " -tris(levulinoyloxyphenyl)methyl, 4,4 ' ,4 " - tris(benzoyloxyphenyl)methyl, 3 -(imidazol- 1 -yl)bis(4 ' ,4 ' ' -dimethoxyphenyl)methyl, 1 , 1 -bis(4- methoxyphenyl)-l '-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-/?-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2- trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl /?-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl /?-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl /?-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-( 1 , 1 ,3 ,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1- dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkyl Ν,Ν,Ν',Ν'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0041] For protecting 1,2- or 1,3-diols, the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, /?-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1- methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1 ,2-dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, l-(N,N-dimethylamino)ethylidene derivative, a-(N,N'- dimethylamino)benzylidene derivative, 2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS), l,3-(l,l,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t- butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0042] Amino-protecting groups include methyl carbamate, ethyl carbamante, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-( 10,10-dioxo- 10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2- haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), 1 -(3,5-di- t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), /?-nitobenzyl carbamate, /?-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(/?-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-/?-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, N'-/?-toluenesulfonylaminocarbonyl derivative, N'-phenylaminothiocarbonyl derivative, t-amyl carbamate, 5^*-benzyl thiocarbamate, /?-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, /?-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-( V,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p '-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p- phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, /?-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, /?-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N - oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5 ,5 -dimethyl-3 -oxo- 1 - cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3 ,5 ,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Exemplary protecting groups are detailed herein, however, it will be appreciated that the present disclosure is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present disclosure. Additionally, a variety of protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.

[0043] As described herein, compounds of the disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. 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 embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0044] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH₂)o-4R°; -(CH₂)₀^OR°; -O(CH₂)₀_4R°, -O- (CH₂)o-4C(0)OR°; -(CH₂y₄CH(OR°)₂; -(CH₂)₀^SR°; -(CH₂)₀^Ph, which may be substituted with R°;

which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH₂)o_₄0(CH₂)₀_i-pyridyl which may be substituted with R°; -N0₂; -CN; -N₃; -(CH₂)o_₄N(R°)₂; -(CH₂)₀_₄N(R^o)C(O)R°; -N(R°)C(S)R°; -(CH₂)₀_₄N(R^o)C(O)NR°₂; -N(R°)C(S)NR°₂; -(CH₂)₀_₄N(R^o)C(O)OR^o; -N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR°₂; -N(R°)N(R°)C(0)OR⁰; -(CH₂)₀_₄C(O)R°; -C(S)R°; -(CH₂)₀_₄C(O)OR°; -(CH₂)₀_₄C(O)SR°; -(CH₂)o_₄C(0)OSiR°₃; -(CH₂)_{0 4}OC(0)R°; -OC(O)(CH₂)_{0 4}SR- SC(S)SR°; -(CH₂)_{0 4}SC(0)R°; -(CH₂)o ₄C(0)NR°₂; -C(S)NR°₂; -C(S)SR°; -SC(S)SR°, -(CH₂)₀_₄OC(O)NR°₂; -C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH₂C(0)R°; -C(NOR°)R°; -(CH₂)₀^SSR°; -(CH₂)_{0 4}S(0)₂R°; -(CH₂)_{0 4}S(0)₂OR°; -(CH₂)o^OS(0)₂R°; -S(0)₂NR°₂; -(CH₂)₀^S(O)R°; -N(R°)S(0)₂NR°₂; - N(R°)S(0)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(0)₂R°; -P(0)R°₂; -OP(0)R°₂; -OP(0)(OR°)₂; SiR°₃; straight or branched alkylene)0-N(R°)₂; or -(Ci_₄ straight or branched alkylene)C(0)0-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, Ci_₆ aliphatic, -CH₂Ph, -O(CH₂)₀ iPh, -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.

[0045] 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 2}R*, -(haloR*), -(CH₂)_{0 2}OH, -(CH₂)_{0 2}OR*, -(CH₂)_{0 2}CH(OR*)₂; -O(haloR'), -CN, -N₃, -(CH₂)_{0 2}C(0)R*, -(CH₂)_{0 2}C(0)OH, -(CH₂)_{0 2}C(0)OR*, -(CH₂)_{0 2}SR*, -(CH₂)o ₂SH, -(CH₂)o ₂NH₂, -(CH₂)_{0 2}NHR*, -(CH₂)_{0 2}NR*₂, -N0₂, -SiR*₃, -OSiR*₃, -C(0)SR* -(Ci_₄ straight or branched alkylene)C(0)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from

aliphatic, -CH₂Ph, -O(CH₂)₀-iPh, 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 =0 and =S. [0046] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR^* ₂, =NNHC(0)R^*, =NNHC(0)OR^*, =NNHS(0)₂R^*, =NR^*, =NOR^*, -0(C(R^* ₂))_{2 3}0- or -S(C(R^* ₂))₂_₃S-, wherein each independent occurrence of R is selected from hydrogen, Ci_₆ aliphatic 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: -0(CR ₂)_{2 3}0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic 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.

[0047] Suitable substituents on the aliphatic group of R^* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, -NHR*, -NR*₂, or -N0₂, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_₄ aliphatic, -CH₂Ph, -O(CH₂)₀-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R^†, -NR^† ₂, -C(0)R^†, -C(0)OR^†, -C(0)C(0)R^†, -C(0)CH₂C(0)R^†, -S(0)₂R^†, -S(0)₂NR^† ₂, -C(S)NR^† ₂, -C(NH)NR^† ₂, or -N(R^†)S(0)₂R^†; wherein each R^† is independently hydrogen, Ci_₆ aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0049] Suitable substituents on the aliphatic group of R^† are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, -NHR*, -NR*₂, or -N0₂, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_₄ aliphatic, -CH₂Ph, -O(CH₂)₀ iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to those salts 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, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0051] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and

salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0052] When used as a chemical bond, "·~»~ " shall be understood to depict a single carbon- carbon bond with undefined stereochemistry at a carbon center. Thus, a substituent attached to a carbon atom with a "·~>~ " bond refers to embodiments where the substituent is coming out of the plane of the paper, embodiments where the substituent is going behind the plane of the paper, and combinations (i.e., stereochemical mixtures) thereof. A "·~>~ " attached to a double bond refers to both the Z and E isomers.

[0053] As used herein and in the claims, the singular forms "a", "an", and "the" include the plural reference unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds.

[0054] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0055] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0056] The term "palliative" refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.

[0057] As used herein, the term "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0058] As used herein, the term "treat," "treatment," or "treating" refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.

[0059] The expression "unit dose" as used herein refers to a physically discrete unit of a formulation appropriate for a subject to be treated. It will be understood, however, that the total daily usage of a formulation of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts. A particular unit dose may or may not contain a therapeutically effective amount of a therapeutic agent.

[0060] An individual who is "suffering from" a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of the disease, disorder, and/or condition.

[0061] An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0062] The present invention encompasses the recognition that there remains a need for chemotherapeutic compounds that are useful in the treatment of cancer and/or effective at inhibiting cancer metastasis.

[0063] The present invention provides, among other things, novel compounds and compositions for use in the treatment of cancer. In some embodiments, such compounds and compositions are useful in treating multiple myeloma. In some embodiments, such compounds and compositions are useful in inhibiting and/or preventing metastasis of multiple myeloma. The present invention further provides new and/or improved methods of treating cancer. In certain embodiments, such methods are useful for treating multiple myeloma. In certain embodiments, such methods are useful for treating metastatic spread of multiple myeloma. Such compounds and methods are described in greater detail, below.

[0064] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I:

I

or a pharmaceutically acceptable derivative thereof, wherein:

Ri^e is hydrogen or lower alkyl;

R₂ ^e is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; R₅ ^e and R6^e are each independently hydrogen or a protecting group; X^e is O, S, C(R₇ ^e)₂, or NR₇ ^e, wherein each occurrence of R₇ ^e is independently hydrogen or lower alkyl;

R_B ^s is, independently for each occurrence, hydrogen; halogen; -ORB'^e; -SRB'^e; -N(RB'^e)₂;

-C(Y^e)₃, -CH(Y^e)₂, -CH₂Y^e, where Y^e is F, Br, CI, I, OR_B"=, NHR_B e, N(R_B"=)₂, or SR_B"=;

N₃; N₂R_B' ^e; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic,

heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -OR_B"=; -SR_B"=; -N(R_B« ₂; -C(0)OR_B ; -C(0)R_B e; -CONHR_B e; -0(C=0)R_B e;

N₃; N₂RB'^e; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; wherein each occurrence of R_B' ^e is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic,

heteroaliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and

m is 1, 2, 3, or 4.

[0065] Compounds of Formula I have been previously described in, for example, WO 2004/018478, published on March 4, 2004 and incorporated herein by reference in its entirety. It has now been surprisingly found that such compounds and compositions thereof are useful in inhibiting and/or preventing metastasis of multiple myeloma.

[0066] As described generally above for Formula I, X^e is O, S, C(R₇ ^e)₂, or NR₇ ^e, wherein each occurrence of R₇ ^e is independently hydrogen or lower alkyl. In some embodiments of Formula I, X^e is O. In some embodiments of Formula I, X^e is S. In some embodiments of Formula I, X^e is C(R₇ ^e)₂, wherein each occurrence of R₇ ^e is independently hydrogen or lower alkyl. In some such embodiments, X^e is C(R₇ ^e)₂, wherein each occurrence of R₇ ^e is hydrogen. In some embodiments of Formula I, X^e is C(R₇ ^e)₂, wherein each occurrence of R₇ ^e is lower alkyl.

[0067] As described generally above for Formula I, R₅ ^e and R₆ ^e are each independently hydrogen or a protecting group. In some embodiments of Formula I, Rs^e and R₆ ^e are each hydrogen. In some embodiments of Formula I, Rs^e and R₆ ^e are each a protecting group. [0068] As described generally above for Formula I, Ri^e is hydrogen or lower alkyl. In some embodiments of Formula I, Ri^e is hydrogen. In some embodiments of Formula I, Ri^e is lower alkyl. In some such embodiments, Ri^e is methyl.

[0069] As described generally above for Formula I, R₂ ^e is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety. In some embodiments of Formula I, R₂ ^e is a substituted or unsubstituted heteroaryl moiety. In some embodiments of Formula I, R₂ ^e is a substituted heteroaryl moiety. In some such embodiments, R₂ ^e is a thiazolyl moiety substituted with a methyl group. In some such embodiments, R₂ ^e is a oxazolyl moiety substituted with a methyl group. In some such embodiments, R₂ ^e is a isoxazolyl moiety substituted with a methyl group. In some embodiments of Formula I, R₂ ^e is an unsubstituted heteroaryl moiety. In some such embodiments, R₂ ^e is a thiazolyl moiety. In some embodiments of Formula I, R₂ ^e is an oxazolyl moiety. In some embodiments of Formula I, R₂ ^e is an isoxazolyl moiety.

[0070] In some embodiments of Formula I, R₂ ^e is selected from:

[0071] In some embodiments of Formula I, R₂ ^e is a substituted or unsubstituted aryl moiety. In some embodiments of Formula I, R₂ ^e is an unsubstituted aryl moiety. In some embodiments of Formula I, R₂ ^e is a substituted aryl moiety.

[0072] As described generally above for Formula I, R_B ^e is, independently for each occurrence, hydrogen; halogen; -OR_B e; -SR_B"=; -N(R_B"=)₂; -C(Y^e)₃, -CH(Y^e)₂, -CH₂Y^e, where Y^e is F, Br, CI, I, OR_B ^e, NHR_B e, N(R_B' ^e)₂, or SR_B' ^e; -C(0)OR_B<e; -C(0)R_B<e; -CONHR_B e;

N₃; N₂R_B e; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -OR_B ^e; -SR_B e; -N(R_B>e)₂; -C(0)OR_B e; -C(0)R_B e; -CONHR_B e;

N₃; N₂R_B<e; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; wherein each occurrence of R_B' ^S is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety. In some embodiments of Formula I, R_B ^e is hydrogen. In some embodiments of Formula I, R_B ^s is methyl. In some embodiments of Formula I, R_B ^s is selected from -C(Y^e)₃, -CH(Y^e)₂, -CH₂Y^e, where Y^e is F, Br, CI, I. In some embodiments of Formula I, R_B ^s is selected from -C(Y^e)₃, -CH(Y^e)₂, -CH₂Y^e, where Y^e is F. In some embodiments of Formula I, R_B ^E is -C(Y^e)₃, where Y^e is F. In some such embodiments, R_B ^s is -CF₃. In some embodiments of Formula I, R_B ^s is -CH(Y^e)₂, where Y^e is F. In some embodiments of Formula I, R_B ^E is -CH₂Y^e, where Y^e is F.

[0073] As described generally above for Formula I, m is 1, 2, 3 or 4. In some embodiments of Formula I, m is 1. In some embodiments of Formula I, m is 2. In some embodiments of Formula I, m is 3. In some embodiments of Formula I, m is 4.

[0074] In some embodiments, a compound of Formula I is selected from:

I-d I-e I-f

[0075] In some embodiments, a compound of Formula I is selected from:

[0076] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with a compound of Formula II:

II

armaceutically acceptable derivative thereof;

wherein Ri^m and R₂ ^m are each independently hydrogen, halogen, -CN, -S(0)_{1 2}R , -N0₂, -

, IB 1A, , IB

COR^1A, -C0₂R^1A, NR^1AC(=0)R^1C, -NR^1AC(=0)OR -CONR R , an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR ; wherein W is independently -0-, -S- or -NR^1C-, wherein each occurrence of R^1A, R^1B and R^1C is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Ri^m and R₂ ^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

R₃ ^m is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl

moiety; or a prodrug moiety or an oxygen protecting group;

R₄ ^m is halogen, -OR^4A, -OC(=0)R^4A or -NR^4AR^4B; wherein R^4A and R^4B are independently

hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; a prodrug moiety, a nitrogen protecting group or an oxygen protecting group; or R^4A and R^4B, taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or R₄ ^m, taken together with the carbon atom to which it is attached forms

R₅ ^m is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Re^m is hydrogen, halogen, -CN, -SCO^R^, -N0₂, -COR^6A, -C0₂R^6A, -NR^6AC(=0)R^6B, -

NR^6AC(=0)OR^6B, -CONR^6AR^6B, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^6A; wherein W is independently -0-, -S- or -NR^6C-, wherein each occurrence of R^6A, R^6B and R^6C is independently hydrogen, or an aliphatic,

heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or R₆ ^m and Rc^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Ra^m and each occurrence of Rt,^m are independently hydrogen, halogen, -CN, -S(0)₁_₂R^al, -N0₂, - COR^al, -C0₂R^al, -NR^alC(=0)R^a2, -NR^alC(=0)OR^a2, -CONR^alR^a2, an aliphatic,

heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^al; wherein W is independently -0-, -S- or -NR^a3-, wherein each occurrence IS

independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or R_a ^m and the adjacent occurrence of R_t,^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rc^m is hydrogen, halogen, -CN, -S(0)₁_₂R^cl, -N0₂, -COR^cl, -C0₂R^cl, -NR^clC(=0)R^c2, -

NR^clC(=0)OR^c2, -CONR^clR^c2; an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^cl; wherein W is independently -0-, -S- or -NR^c3-, wherein each occurrence of R^cl, R^c2 and R^c3 is independently hydrogen, or an aliphatic,

heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or R_c ^m and R₆ ^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

n is an integer from 1 to 5;

Χ is O, S, NR^X1 or CR^X1R^¾; wherein R^X1 and R^X2 are independently hydrogen, halogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or a nitrogen protecting group;

Q^m is hydrogen, halogen, -CN, -S(0)₁_₂R^Q1, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, -

NR^Q1C(=0)OR^Q2, -CONR^Q1R^Q2, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^Q1; wherein W is independently -0-, -S- or -NR^Q3-, wherein each occurrence of R^¹, R^² and R^³ is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Yi^m and Y₂ ^m are independently hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or -WR^Y1; wherein W is independently -0-, -S- or -NR^Y2-, wherein each occurrence of R^Y1 and R^Y2 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Yi and Y₂ together with the carbon atom to which they are attached form a moiety having the structure:

[0077] Compounds of Formula II have been previously described in, for example, WO 2004/087673, published on October 14, 2004 and incorporated herein by reference in its entirety. It has now been surprisingly found that such compounds and compositions thereof, in combination with a compound of Formula I, are useful in inhibiting and/or preventing metastasis of multiple myeloma.

[0078] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with at least one compound selected from Formulae Il-a, Il-b and II-c:

Il-a Il-b II-c

or a pharmaceutically acceptable derivative thereof, wherein:

the bond is a single bond or a double bond

Ri^m and R₂ ^m are hydrogen or lower alkyl;

R₃ ^m R₅ ^m and Re^m are Ci_₆ alkyl; R4^m is halogen, -OR , -OC(=0)R^4A or -M R ; wherein R and R are independently hydrogen; a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative or an oxygen protecting group selected from a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ether, an ester, a carbonate, a cyclic acetal or a ketal; or R^4A and R^4B, taken together with the nitrogen atom to which they are attached, form a C₃_₂o heterocyclic or C₃_i₄ heteroaryl moiety; or R₄, taken together with the carbon atom to which it is attached forms a moiety having the structure:

independently a Ci_₆ alkyl group optionally substituted with one or more of Ci_₂o aliphatic; C_3-14 aryl; C₃_i₄ heteroaryl; Ci_₂o alkylC₃_i₄aryl; Ci_₂o alkylC₃_i₄heteroaryl, C₃_i₄ aryloxy; Ci_₂₀ heteroalkoxy, C₃_i₄ heteroaryloxy; Ci_₂₀ alkylthio; C₃_i₄ arylthio; heteroCi_ 2₀alkylthio; heteroC₃_i₄arylthio; F; CI; Br; I; -OH; -N0₂; -CN; -CF₃; -CH₂CF₃; -CHC1₂; - CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂S0₂CH₃; -C(0)R_x; -C0₂(R_x); -CON(R_x)₂; - OC(0)R_x; - OC0₂R_x; -OCON(R_x)₂; -N(R_X)₂; S(0)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x is independently Ci_₂₀ aliphatic, heteroCi_₂₀aliphatic, C₃_i₄ aryl, C₃_i₄ heteroaryl, Ci_₂o alkylC₃_i₄aryl or Ci_₂o alkylC₃_i₄heteroaryl;

Χ is O, S, NR^X1 or CR^X1R^¾; wherein R^X1 and R^X2 are independently hydrogen, halogen, or a substituted or unsubstituted Ci_₂o alkyl, heteroCi_₂oalkyl, cycloC₃_ioalkyl, heterocyclo C₃_i₀alkyl, C₃_i₄ aryl or C₃_i₄ heteroaryl, or a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative;

Q^m is hydrogen, halogen, -CN, -S(0)₁_₂R^Q1, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, - NR^Q1C(=0)OR^Q2, -CONR^Q1R^Q2, or a substituted or unsubstituted Ci_₂₀ aliphatic, heteroCi_₂oaliphatic, C₃_₂o alicyclic, heteroC₃_₂oalicyclic, C₃_i₄ aryl or C₃_i₄ heteroaryl moiety, or -WR^Q1; wherein W is independently O, S or NR^Q3 and each occurrence of R^Q1, R^Q2 and R^Q3 is independently hydrogen, or a substituted or unsubstituted Ci_₂₀ aliphatic, heteroCi_₂oaliphatic, C₃_₂o alicyclic, heteroC₃_₂o alicyclic, C₃_i₄aryl or C₃_i₄ heteroaryl moiety; Y₂ ^m is hydrogen, or a substituted or unsubstituted Ci_₂o alkyl, heteroCi_₂oalkyl, cyclo C₃_ i₀alkyl, heterocycloC₃_i₀alkyl, C₃_i₄aryl, or C₃_i₄ heteroaryl moiety; or -WR^Y1;

W is O or NH; and

R^Y1 and R^Y2 are independently hydrogen, or a substituted or unsubstituted Ci_₂o aliphatic, heteroCi_₂oaliphatic, C₃_₂o alicyclic, heteroC₃_₂oalicyclic, C₃_i₄ aryl or C₃_i₄ heteroaryl moiety.

[0079] In some embodiments of Formula Il-a, X^lm is O. In some embodiments of Formula

Il-a, the bond is a double bond. In some embodiments of Formula Il-a, Q is hydrogen, halogen, -CN, -S(0)₁_₂R^Q1, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, -NR^Q1C(=0)OR^Q2, -CONR^Q1R^Q2, or -WR^Q1. In some embodiments of Formula Il-a, wherein W is independently O, S or NR^Q3 and each occurrence of R^Q1, R^Q2 and R^Q3 is independently hydrogen, or a substituted or unsubstituted Ci_₂o aliphatic, heteroCi_₂oaliphatic, C₃_₂o alicyclic, heteroC₃_₂₀ alicyclic, C₃_i₄aryl or C₃_i₄ heteroaryl moiety.

[0080] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with a compound of Formula III:

III

or a pharmaceutically acceptable salt thereof; wherein:

Ri^m is hydrogen or optionally substituted Ci_₆ aliphatic;

R₂ ^m is an oxygen protecting group, hydrogen, or optionally substituted Ci_₆ aliphatic;

R₃ ^m and R₅ ^m are each independently optionally substituted Ci_₆ aliphatic; and

R4^m is hydrogen or -T^m-Y^m;

-T^m- is an optionally substituted Ci_8 bivalent saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or more methylene units are optionally and

independently replaced by -NR^m-, -N(R^m)C(0)-, -C(0)N(R^m)-, -N(R^m)S0₂-, -S0₂N(R^m)- , -0-, -C(O)-, -OC(O)-, -OC(0)0-, -C(0)0-, -OC(0)N(R^m)-, -S-, -SO-, or -S0₂-; each R^m is independently -H, or an optionally substituted group selected from the group consisting of Ci-₂o aliphatic, Ci-₂o heteroaliphatic, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, 3- to 14-membered carbocycle, 3- to 12-membered heterocyclic; and

Y^m is hydrogen or acyl.

[0081] In some embodiments of Formula III, Ri^m is Ci_₃ aliphatic substituted with one or more halogens. In some embodiments of Formula III, R₄ ^m is -T^m-Y^m. In some such embodiments, -T^m- is CH₂ and -Y^m is acyl.

[0082] In some embodiments of Formula III, Ri^m is -CF₃. In some embodiments of Formula III, R⁴ is -T^m-Y^m. In some such embodiments, -T^m- is CH₂ and -Y^m is -C0₂H.

[0083] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with at least one compound selected from Formulae IV, V and VI:

or a pharmaceutically acceptable salt thereof, wherein each of Ri^m, R₂ ^m, R₃ ^m, R₄ ^m and R₅ ^m are as defined above and described herein.

[0084] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with at least one compound selected from Formulae IV-a, V-a and Vl-a:

IV-a V-a Vl-a or a pharmaceutically acceptable salt thereof, wherein each of Ri^m, R₂ ^m, R₃ ^m and R₅ ^m are as defined above and described herein.

[0085] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with at least one compound selected from:

Dehydro migraether (DHME) Methyl-cis-dehydromigraether Methyl-trans-dehydromigraether

or a pharmaceutically acceptable salt thereof. [0086] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I in combination with at least one compound selected from:

Migrastatin ether Carboxymethyl migraether

(ME) _or (CMME)

or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound of Formula II.

[0088] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound selected from Formulae Il-a, Il-b or II-c.

[0089] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound selected from Formulae IV, V and VI.

[0090] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound of Formulae IV-a, V-a and Vl-a. [0091] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. [0092] In some embodiments, the present invention provides a method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound selected from Formulae I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt thereof, in combination with a compound selected from:

Migrastatin ether Carboxymethyl migrastatin ether

(ME) _or (CME)

[0093] Multiple Myeloma (MM) is a B-cell malignancy characterized by the occurrence of plasma cell tumor within the bone marrow that causes severe osteolytic bone lesions with rapid dissemination to distant medullary sites and more rarely metastatic deposits outside the bone marrow. Although new therapeutic options have recently emerged leading to improved response rates, MM still remains incurable. This study aims to develop new combination small-molecule therapy preventing both tumor growth and dissemination. Epothilone and Migrastatin are promising biologically active natural products that display potent anti-tumor activity. Upon completing their total synthesis and in the light of extensive in vitro screening of synthetic analogs generated by Diverted Total Synthesis (DTS), Iso-fludelone (I-f) and the migrastatin core ether (ME) derivatives were selected for their higher in vitro inhibitory activity, enhanced biostability and therapeutic index. While Iso-fludelone (I-f) is a third generation microtubule stabilizing epothilone, showing remarkable anti-tumor potency in solid tumors (Chou, PNAS 2008), the two promising ether-derivative migrastatin analogs, the migrastatin core ether (ME) and the carboxymethyl-ME (CME), are potent tumor cell migration inhibitors (Lecomte, PNAS 2011).

[0094] In cytotoxicity assay with a panel of 9 MM cell lines, Iso-fludelone (I-f) exhibits a remarkable in vitro potency to kill tumor cells with IC₅₀ values in the nanomolar range, markedly enhanced compared with established microtubule-targeting agents, such as taxanes (paclitaxel and docetaxel) and vinca alkaloids (vincristine and vinblastine) and with other anti-myeloma drugs including melphalan, thalidomide and bortezomib. We next investigated the capacity of Migrastatin analogs to inhibit the MM transmigration. Both compounds CME and ME display high efficacy in blocking tumor cell migration in vitro with IC50 values in the micromolar range, more than two orders of magnitude less than the LD50 values. In the light of these results, in vivo efficacy of these compounds as monotherapy or in combination in inhibiting tumor growth and dissemination was assessed in human MM xenograft models established in NOD/SCID IL2R gamma null (NSG) mice. Very encouraging findings will be presented at the 2012 ASH annual meeting and suggest that combining iso-fludalone and migrastatin analogs can achieve great response in multiple myeloma treatment.

Example 1

[0095] Biological Assay. CAG, ARP, MM IS and SKO007 cells were cultured in IMDM supplemented with 10% FBS (Gemcell), 1% Pen-Strep (Gibco) and 1% glutamine. 200 to 1000 cells were plated into each well of 384-well black plates with clear bottom (Corning) in 30 μΐ corresponding culture media and were placed in a 37 °C incubator. 16 hours later, 50μ1 of compounds at various concentrations (14 concentration range from ΙΟΟμΜ to ΙΟρΜ) were added and the plates were returned to 37 °C for 72 hours later.

[0096] At the endpoint, 20μί of Alamar Blue (Invitrogen) at 5X were added in each well. The plates were returned at 37 °C for 8 to 12 hours and then the fluorescence emitted by metabolically active cells was quantified at 590nm. Curve fits and IC₅₀ values were then determined. Results are presented in Figures 1-5.

Example 2

[0097] The potential toxicity of Migrastatin Ether (ME) and Carboxy-Methyl Migrastatin Ether (CME) on multiple myeloma (MM) cell lines (RPMI8226, MM1S, ARP, CAG, OPM2, SKO-007, U266 and MM1R) was determined. Cells were exposed to migrastatin analogs over a concentration range from 0.96fM to 750μΜ. Cell proliferation and viability were assessed at 18 hours and 48 hours. DMSO vehicle was used as control. Table 1 sets forth the migrastatin analogs screened against multiple myeloma cell lines.

Table 1.

Analog # Structure

[0098] Results are presented in Figure 6. No cytotoxicity was observed up to 300μΜ with mean values for lethal dose 50 (LD₅₀) of 500μΜ and 800μΜ for ME and CME respectively. Comparatively, CME compound exhibits lower cytotoxicity than ME.

[0099] We next investigated the ability of ME and CME to inhibit MM cell migration in chemotaxis assay performed towards a SDF-1 gradient in a modified Boy den chamber consisting of a cell culture insert (6.4 mm diameter, 8-μιη pore polyethylene terephthalate membrane, [Becton Dickenson]) seated in each well of a 24-well companion plate (Becton Dickinson). Briefly, multiple myeloma cells were grown as subconfluent cultures then starved for 24 hours in serum-free IMDM medium. 8 hours prior to the assay, cells were pretreated with migrastatin analogs. After dissociation, mechanically and with 5mM EDTA, single-cell suspensions were prepared by filtration through a 35μιη mesh cell strainer (Becton Dickinson). Cells were counted and a total of 5x104 cells suspended in serum- free medium were seeded into the upper chamber of an insert, then positioned in a 24-well plate, containing medium with or without SDF-1 at 200ng/mL. When used, migrastatin analogs or DMSO (vehicle) were added to the medium at 0.1% (v/v) in both chambers. Migration assays were carried out for 6 hours in a humidified incubator at 37 °C with 5% C0₂. At the end of the incubation period, medium from the lower chamber was collected and centrifuged. The migrating cells were then resuspended and enumerated following trypan blue staining in a standard microscope-counting chamber. The migration in response to the test condition was calculated relative to the DMSO vehicle control. As shown in Figures 7 and 8, ME and CME efficiently blocked the migration of CAG and H929 MM cells in response to SDF-1 gradient with IC₅₀ close to ΙΟμΜ range.

[00100] Figure 9 presents the migration inhibitory potential of the macroether migrastatin analog on 3 MM cell lines. Macroether migrastatin blocked RPMI8226 and CAG MM migration at submicromolar IC₅₀. Comparatively, higher drug concentration were necessary to inhibit migration MM IS cells.

Claims

1. A method of treating multiple myeloma comprising administering to a subject suffering from or susceptible to multiple myeloma a therapeutically effective amount of a compound of Formula I:

I

or a pharmaceutically acceptable derivative thereof;

wherein Ri^e is hydrogen or lower alkyl;

R₂ ^e is a substituted or unsubstituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl moiety; R₅ ^e and R are each independently hydrogen or a protecting group;

X^e is O, S, C(R₇ ^e)₂, or NR₇ ^e, wherein each occurrence of R₇ ^e is independently hydrogen or lower alkyl;

RB^s is, independently for each occurrence, hydrogen; halogen; -ORB'^E; -SRB'^E; -N(RB'^E)₂; -

C(Y^e)₃, -CH(Y^e)₂, -CH₂Y^e, where Y^e is F, Br, CI, I, OR_B"=, NHR_B-e, N(R_B"=)₂, or

SR_B<e; -C(0)OR_B<e; -C(0)R_B e; -CONHR_B<e; -0(C=0)R_B e; -0(C=0)OR_B"=;

-NRB'^E

N₃; N₂RB'^E; cyclic acetal; or cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl, optionally substituted with one or more of hydrogen; halogen; -OR_B"=; -SR_B ^«=; -N(R_B"=)₂; -C(0)OR_B"=; -C(0)R_B"=; -CONHR_B"=; -0(C=0)R_B e; -0(C=0)OR_B"=; -NR_B«= (C=0)R_B e; N₃; N₂R_B"=; cyclic acetal; or cyclic or acyclic, linear or branched substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; wherein each occurrence of RB'^E is independently hydrogen; a protecting group; a linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl moiety; and m is 1, 2, 3, or 4. The method according to claim 1, wherein X^e is O.

The method according to claim 2, wherein Rs^e and R6^e are each hydrogen.

The method according to claim 3, wherein R_B ^s is methyl.

The method according to claim 3, wherein R_B ^s is -CF₃.

The method according to either claim 4 or claim 5, wherein Ri^e is methyl.

The method according to claim 6, wherein R₂ ^e is a substituted heteroaryl moiety.

I-d I-e I-f or a pharmaceutically acceptable salt thereof. The method according to claim 9, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

11. The method according to any of claims 1-10, further comprising administering a therapeutically effective amount of a compound of Formula II:

or a pharmaceutically acceptable derivative thereof;

wherein Ri^m and R₂ ^m are each independently hydrogen, halogen, -CN, -S(0)₁_₂R^1A, -N0₂, -COR^1A, -C0₂R^1A, -NR^1AC(=0)R^1B, -NR^1AC(=0)OR^1B, -CONR^1AR^1B, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^1A; wherein W is independently -0-, -S- or -NR^1C-, wherein each occurrence of R^1A, R^1B and R is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Ri^m and R₂ ^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

R₃ ^m is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or a prodrug moiety or an oxygen protecting group; R4^m is halogen, -OR , -OC(=0)R^4A or -M R ; wherein R^4A and R^4B are

independently hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; a prodrug moiety, a nitrogen protecting group or an oxygen protecting group; or R^4A and R^4B, taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or R₄ ^m, taken together with the carbon atom to which it is attached forms a moiety having the structure:

Rs^m is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rs^m is hydrogen, halogen, -CN, -SCO^R^, -N0₂, -COR^6A, -C0₂R^6A, -NR^6AC(=0)R^6B, - NR^6AC(=0)OR^6B, -CONR^6AR^6B, an aliphatic, heteroaliphatic, alicyclic,

heteroalicyclic, aryl or heteroaryl moiety, or -WR^6A; wherein W is independently -O- , -S- or -NR^6C-, wherein each occurrence of R^6A, R^6B and R^6C is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Rg^m and R_c ^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Ra^m and each occurrence of Rt,^m are independently hydrogen, halogen, -CN, -S(0)_{1 2}R^al, - N0₂, -COR^al, -C0₂R^al, -NR^alC(=0)R^a2, -NR^alC(=0)OR^a2, -CONR^alR^a2, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^al;

wherein W is independently -0-, -S- or -NR^a3-, wherein each occurrence of R^al, R^a2 and R^a3 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or R_a ^m and the adjacent occurrence of Rt,^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Rc^m is hydrogen, halogen, -CN, -S(0)₁_₂R^cl, -N0₂, -COR^cl, -C0₂R^cl, -NR^clC(=0)R^c2, - NR^clC(=0)OR^c2, -CONR^clR^c2; an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or -WR^cl; wherein W is independently -0-, -S- or -NR^c3-, wherein each occurrence of R^cl, R^c2 and R^c3 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Rc^m and Re^m, taken together with the carbon atoms to which they are attached, form an alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

n is an integer from 1 to 5;

Χ is O, S, NR^X1 or CR^R*²; wherein R^X1 and R^X2 are independently hydrogen,

halogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety, or a nitrogen protecting group;

Q^m is hydrogen, halogen, -CN, -S(0)₁_₂R^Q1, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, - NR^Q1C(=0)OR^Q2, -CONR^Q1R^Q2, an aliphatic, heteroaliphatic, alicyclic,

heteroalicyclic, aryl or heteroaryl moiety, or -WR^¹; wherein W is independently -O- , -S- or -NR^Q3-, wherein each occurrence of R^Q1, R^Q2 and R^Q3 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety;

Yi^m and Y₂ ^m are independently hydrogen, an aliphatic, heteroaliphatic, alicyclic,

heteroalicyclic, aryl or heteroaryl moiety; or -WR^Y1; wherein W is independently -O- , -S- or -NR^Y2-, wherein each occurrence of R^Y1 and R^Y2 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl moiety; or Yi and Y₂ together with the carbon atom to which they are attached form a moiet

having the structure: ¾·

12. The method according to any of claims 1-10, further comprising administering a therapeutically effective amount of a compound having one of the following structures:

or a pharmaceutically acceptable salt thereof, wherein:

Ri^m and R₂ ^m are hydrogen or lower alkyl;

R₃ ^m R₅ ^m and Rs^m are Ci_₆ alkyl;

the bond is a single bond or a double bond;

R4^m is halogen, -OR^4A, -OC(=0)R^4A or -NR^4AR^4B; wherein R^4A and R^4B are

independently hydrogen; a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative or an oxygen protecting group selected from a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ether, an ester, a carbonate, a cyclic acetal or a ketal; or R^4A and R^4B, taken together with the nitrogen atom to which they are attached, form a C₃_₂o heterocyclic or C₃_i₄ heteroaryl moiety; or R₄, taken together with the carbon atom to which it is attached

forms a moiety having the structure: ^" , R^Y2, "

or

NHR Y1 or R⁴ and R^4B are independently a Ci_6 alkyl group optionally substituted with one or more of Ci_₂₀ aliphatic; C₃_i₄ aryl; C₃_i₄ heteroaryl; Ci_₂₀ alkylC₃_i₄aryl; Ci_₂o alkylC₃_i₄heteroaryl, C₃_i₄ aryloxy; Ci_₂o heteroalkoxy, C₃_i₄ heteroaryloxy; Ci_₂o alkylthio; C₃_i₄ arylthio; heteroCi_₂oalkylthio; heteroC₃_i₄arylthio; F; CI; Br; I; -OH; -N0₂; -CN; -CF₃; -CH₂CF₃; -CHC1₂; -CH₂OH; -CH₂CH₂OH; - CH₂NH₂; -CH₂S0₂CH₃; -C(0)R_x; -C0₂(R_x); -CON(R_x)₂; -OC(0)R_x; - OC0₂R_x; - OCON(R_x)₂; -N(R_X)₂; S(0)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x is independently Ci_₂o aliphatic, heteroCi_₂oaliphatic, C₃_i₄ aryl, C₃_i₄ heteroaryl, Ci_₂o alkylC₃_i₄aryl or Ci_₂o alkylC₃_i₄heteroaryl;

Χ is O, S, NR^X1 or CR^X1R^¾; wherein R^X1 and R^X2 are independently hydrogen,

halogen, or a substituted or unsubstituted Ci_₂o alkyl, heteroCi_₂oalkyl, cycloC₃_ loalkyl, heterocyclo C₃_ioalkyl, C₃_i₄ aryl or C₃_i₄ heteroaryl, or a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative; Q^m is hydrogen, halogen, -CN, -SCO)^¹, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, - NR^Q1C(=0)OR^Q2, -CONR^Q1R^Q2, or a substituted or unsubstituted Ci_₂₀ aliphatic, heteroCi_₂oaliphatic, C₃-₂₀ alicyclic, heteroC₃_₂oalicyclic, C_3-14 aryl or C_3-14 heteroaryl moiety, or -WR^Q1; wherein W is independently O, S or NR^Q3 and each occurrence of R^Q1, R^Q2 and R^Q3 is independently hydrogen, or a substituted or unsubstituted Ci_₂₀ aliphatic, heteroCi_₂oaliphatic, C3-20 alicyclic, heteroC3_₂o alicyclic, C3_i₄aryl or C_3-14 heteroaryl moiety;

Y₂ ^m is hydrogen, or a substituted or unsubstituted Ci_₂o alkyl, heteroCi_₂oalkyl, cyclo C_3- i₀alkyl, heterocycloC₃_i₀alkyl, C₃_i₄aryl, or C₃_i₄ heteroaryl moiety; or -WR^Y1;

W is O or NH; and

R^Y1 and R^Y2 are independently hydrogen, or a substituted or unsubstituted Ci_₂o aliphatic, heteroCi_₂oaliphatic, C₃-₂₀ alicyclic, heteroC₃_₂oalicyclic, C_3-14 aryl or C_3-14 heteroaryl moiety.

The method according to claim 12, wherein for the compound of formula Il-a, when X¹ is O and the bond is a double bond, Q is hydrogen, halogen, -CN,

-S(0)₁_₂R^Q1, -N0₂, -COR^Q1, -C0₂R^Q1, -NR^Q1C(=0)R^Q2, -NR^Q1C(=0)OR^Q2,

-CONR^Q1R^Q2, or -WR^Q1; wherein W is independently O, S or NR^Q3 and each occurrence of R^Q1, R^Q2 and R^Q3 is independently hydrogen, or a substituted or unsubstituted Ci_₂o aliphatic, heteroCi_₂₀aliphatic, C₃_₂₀ alicyclic, heteroC₃_₂₀ alicyclic, C₃_i₄aryl or C₃_i₄ heteroaryl moiety.

14. The method according to any of claims 1-10, further comprising administering a therapeutically effective amount of a compound of formula III:

III

or a pharmaceutically acceptable salt thereof; wherein: Ri^m is hydrogen or optionally substituted Ci_₆ aliphatic;

R₂ ^m is an oxygen protecting group, hydrogen, or optionally substituted Ci_₆ aliphatic;

R₃ ^m and R₅ ^m are each independently optionally substituted Ci_₆ aliphatic; and

R4^m is hydrogen or -T^m-Y^m;

-T^m- is an optionally substituted Ci_8 bivalent saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or more methylene units are optionally and

independently replaced by -NR^m-, -N(R^m)C(0)-, -C(0)N(R^m)-, -N(R^m)S0₂-, -S0₂N(R^m)- , -0-, -C(O)-, -OC(O)-, -OC(0)0-, -C(0)0-, -OC(0)N(R^m)-, -S-, -SO-, or -S0₂-;

each R^m is independently -H, or an optionally substituted group selected from the group consisting of Ci_₂₀ aliphatic, Ci_₂₀ heteroaliphatic, 6- to 10-membered aryl, 5- to 12- membered heteroaryl, 3- to 14-membered carbocycle, 3- to 12-membered heterocyclic; and

-Y^m is hydrogen or acyl.

15. The method according to claim 14, wherein R^lm is Ci_₃ aliphatic substituted with one or more halogens or R^4m is -T^m-Y^m wherein -T^m- is CH₂ and -Y^m is acyl.

16. The method according to claim 14, wherein R^lm is -CF₃ or R^4m is -T^m-Y^m wherein -T^m- is CH₂ and -Y^m is -C0₂H.

17. The method according to claim 14, wherein the compound is of formula IV, V, or VI:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 14, wherein the compound is of formula IV-a, V-a, or Vl-a:

IV-a V-a Vl-a or a pharmaceutically acceptable salt thereof.

19. The compound of claim 12 or 14, wherein = is a single or double bond, R^lm is hydrogen or methyl, R^2m, R^3m and R^5m are methyl, and R^4m is hydrogen or -T^m-Y^m, wherein - T^m- is -CH₂- and Y^m is -C0₂H.

20. The compound of claim 19, wherein, = is a single bond, R^lm is hydrogen, and R^2m, R^3m and R^5m are methyl, R^4m is -T^m-Y^m, wherein -T^m- is -CH₂- and Y^m is -C0₂H.

21. The compound of claim 14, wherein the compound is selected from:

Dehydro migraether (DHME) Methyl-cis-dehydromigraether Methyl-trans-dehydromigraether

harmaceutically acceptable salt thereof.

The method according to claim 12, wherein compound is selected from:

Migrastatin ether Carboxymethyl migraether (ME) _or (CMME)

or a pharmaceutically acceptable salt thereof.