Macrocyclic ketone compounds and applications thereof

Abstract

The present disclosure relates to macrocyclic ketone compounds that are analogs of the marine natural product halichondrin B, compositions thereof and methods of making and using the same. The compounds may interfere with the microtubular growth of cells, thereby becoming mitotic tubule inhibitors

Description

MACROCYCLIC KETONE COMPOUNDS AND APPLICATIONS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 598,372, filed November 13, 2023, the entire content of which is incorporated herein by reference.BACKGROUND

[0002] Eribulin mesylate is a synthetic analogue of halichondrin B which is a large poly ether macrolide derivative. Eribulin is reported to be a mitotic tubule inhibitor by inhibiting the dynamics of the microtubules, including suppressing the microtubule growth in the interphase cells without affecting the shortening phase and sequestering tubulin into non-productive aggregates. It may lead to G2 / M cell-cycle block and apoptosis. When used as an anti-cancer drug, observed adverse events may include neutropenia, neuropathy, leucopenia, anemia, and thrombocytopenia. Thus, although Eribulin is used in patients with metastatic breast cancer (MBC), it may be associated with an increased risk of hematologic toxi cities in patients.SUMMARY

[0003] The present disclosure provides macrocyclic ketone compounds, which are synthetic analogues of Eribulin, and derivatives thereof as mitotic tubule inhibitors, and compositions and applications thereof. These disclosed macrocyclic ketone compounds, and compositions and applications thereof, may effectively prevent or treat tumors or cancers.

[0004] In an aspect, provided herein is a compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, *– NR11– CR2R3–, –CR2R3–NR11–CR2R3–, *–O–CR2R3–, or –CR2R3–O–CR2R3–; * denotes a connection to R1; R1is ; RG is a reactive group; L is a linker connecting X and RG; RAis –CR4R5R6; each R2, R3, R4, R5and R6is independently hydrogen, halogen, –U, or –G; or L and R4, together with atoms to which they are attached, form a ring, wherein the ring is optionally substituted with 1, 2, or 3 R9; –U is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C2- C6 alkenyl, or C2-C6 alkynyl; wherein each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with 1, 2, or 3 R9and / or 1 or 2 –G; –G is independently C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; wherein each C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R11is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and R9is independently halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4heteroalkyl, –C(O)H, –C(O)OH, –CN, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, –C(O)(C1-C4 alkyl), –C(O)O(C1-C4 alkyl), –C(O)NH2, –C(O)NH(C1-C4 alkyl), –C(O)N(C1-C4alkyl)2, –NH2, –NH(C1-C4alkyl), –N(C1-C4alkyl)2, –NH(C2-C4alkylene)-OH, –NH(C2-C4alkylene)-O-(C1-C4alkyl), –OH, –O(C1-C4alkyl), –O(C1-C4haloalkyl), –O(C2-C4 alkylene)-NH2, –O(C2-C4 alkylene)-NH-(C1-C4 alkyl), –O(C2-C4 alkylene)-N-(C1-C4 alkyl)2, –O(C1-C4 alkylene)-C(O)OH, –O(C1-C4 alkylene)-C(O)O- (C1-C4alkyl), –O(C2-C4alkenyl), –O(C1-C4alkylene)-(C6-C10aryl), –O(C1-C4alkylene)- (5- to 10-membered heteroaryl), –O(C6-C10 aryl), –SH, S(O)2OH, –S(O)2(C1-C4 alkyl), – S(O)2NH2, –S(O)2NH(C1-C4 alkyl), or –S(O)2N(C1-C4 alkyl)2; or two R9, together with atoms to which they are attached, form a C3-C10cycloalkyl or a 3- to 10-membered heterocycloalkyl ring.

[0005] In another aspect, provided herein is a pharmaceutical composition comprising a compound of anyone disclosed herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.

[0006] In still another aspect, provided herein is a method of treating a cancer in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0007] In another aspect, provided herein is a method of treating a cancer in a mammal suffering therefrom with a conjugate of a compound disclosed herein linked with (i) a cell surface targeting agent, or (ii) a long acting reagent, comprising: administering to the mammal a therapeutically effective amount of (i) the conjugate of the compound disclosed herein or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or (ii) a pharmaceutical composition comprising the conjugate of the compound disclosed herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier, wherein the cell surface targeting agent is a small molecule, a polypeptide, or an antibody, and wherein the long acting reagent comprising a polymer, human serum albumin (HSA), or a nanoparticle.

[0008] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative instances of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different instances, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein) of which:

[0011] FIG. 1 illustrates cell viability data of two batches of LUX106-6.

[0012] FIG. 2 illustrates cell viability data of two batches of LUX106-6 and LUX106-8.

[0013] FIG. 3 illustrates cell viability data of two batches of LUX106-6 and LUX106-16.

[0014] FIG. 4 illustrates cell viability data of two batches of LUX106-6 and LUX106-25.

[0015] FIG. 5 illustrates cell viability data of two batches of LUX106-6 and LUX106-41.

[0016] FIG. 6 illustrates cell viability data of two batches of LUX106-6 and LUX106-51.

[0017] FIG. 7 illustrates cell viability data of two batches of LUX106-6 and LUX106-58.

[0018] FIG. 8 illustrates cell viability data of two batches of LUX106-6 and LUX115-20.

[0019] FIG. 9 illustrates cell viability data of Eribulin and LUX126-1.DETAILED DESCRIPTION

[0020] While various embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed.

[0021] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carboncarbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.Definitions

[0022] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise.

[0023] When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range is encompassed within the scope of the present disclosure. Where the stated rangeincludes upper or lower limits, ranges excluding either of those included limits are also included in the present disclosure. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0024] As used herein, the term “about” or “nearly” when referring to a number or a numerical range means that the number or numerical range generally referred to is within + / - 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the stated number or numerical range.

[0025] As used herein, the term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein.

[0026] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0027] As used herein, the term “C1-C6 alkyl” generally refers to a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms, and the straight or branched hydrocarbon chain is attached to the rest of the molecule by a single bond. Likewise, an alkyl group comprising up to 3 carbon atoms is a C1-C3 alkyl group, and an alkyl group comprising up to 4 carbon atoms is a C1-C4alkyl group. Examples of a C1-C6alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl. In some instances, a substituent of an alkyl group is specifically indicated. For example, “cyanoalkyl” refers to an alkyl group substituted with at least one cyano substituent.

[0028] The C1-C6alkyl group may be optionally substituted with a C1-C3alkoxy group. Examples include, but are not limited to, methoxyethyl, methoxypropyl, methoxyisopropyl, ethoxyethyl, ethoxypropyl, ethoxyisopropyl, propoxyethyl, propoxypropyl, and propoxyisopropyl.

[0029] The C1-C6 alkyl group may be optionally substituted with a C3-C6 cycloalkyl group. Examples include, but are not limited to, 1-methylcyclopropyl, 1-methylcyclobutyl, and 1- methylcyclohexyl.

[0030] As used herein, the term “C1-C6alkoxy” generally refers to a radical of the formula –OR wherein R is a C1-C6 alkyl group as defined. Likewise, an alkoxy group comprising up to 3 carbon atoms is a C1-C3alkoxy group. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy,isopentoxy, 2-methylbutoxy, neopentoxy, 1 -ethylpropoxy, n-hexyloxy, isohexyloxy, 4- methylpentoxy, 3 -methylpentoxy, 2-m ethylpentoxy, 1 -methylpentoxy, 3.3 -dimethylbutoxy, 2,2- dimethylbutoxy, 1,1 -dimethylbutoxy, 1,2-dimethylbutoxy, 1.3 -dimethylbutoxy, 2,3- dimethylbutoxy, and 2-ethylbutoxy.

[0031] The C1-C3 alkoxy group may be optionally substituted with a C1-C3 alkoxy group. Examples include, but are not limited to, methoxymethoxy, methoxy ethoxy, methoxypropoxy, methoxyisopropoxy, ethoxymethoxy, ethoxy ethoxy, ethoxypropoxy, ethoxyisopropoxy, propoxymethoxy, propoxy ethoxy, propoxypropoxy, and propoxyisopropoxy.

[0032] As used herein, the term “C3-C6 cycloalkylamino” is, for example, azacyclobutyl, pyrrolidino, piperidino, or hexamethylenimino.

[0033] As used herein, the term “C3-C6 cycloalkyl” generally refers to a monocyclic nonaromatic radical having from 3 to 6 ring atoms, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “cycloalkenyl” as used herein generally refers to a group that comprises one or more unsaturated rings in which all ring members are carbon. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted o

[0034] As used herein, the term “alkenyl” generally refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-8 alkenyl, C2-6 alkenyl and C2-4 alkenyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively, including, for example, ethenyl, allyl or isopropenyl. The term “alkynyl” as used herein generally refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C2-8 alkynyl, C2 -6 alkynyl and C2-4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.

[0035] As used herein, the term “halogen” or “halide” generally refers to fluorine, chlorine, bromine, and iodine. The term “haloalkyl” as used herein generally refers to an alkyl group that is substituted with one or more independently chosen halogens (e.g., “Ci-Ce haloalkyl” groups have from 1 to 6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; 2,2,2-trifluoroethyl;1,2-difluoroethyl; 3-bromo-2-fluoropropyl; 1,2-dibromoethyl; and 1,2,2,2-tetrafluoro-l- trifluoromethyl-ethyl.

[0036] As used herein, the term “heteroalkyl” generally refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some instances, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof. In some instances, a carbon atom or heteroatom is optionally oxidized (e.g., - C(O)OCH2-, -CH2OCH2-, -CH2S(O)2NHCH2-, -NHC(O)NHCH2-, -CH2NHC(O)CH2-). Further examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe.

[0037] As used herein, the term “heteroaryl” generally refers to a monocyclic aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazyl.

[0038] The terms “heterocyclic” or “heterocycle” or “heterocyclyl” or “cycloheteroalkyl” or “heterocycloalkyl” as used herein generally refer to a ring structure (monocycle or polycycle) containing 3-12 ring atoms (3-12 membered heterocycle), 3-8 ring atoms (3-8 membered heterocycle or 3-8 membered cycloheteroalkyl), 3-6 ring atoms (3-6 membered heterocycle or 3- 6 membered cycloheteroalkyl), or 5-6 ring atoms (5-6 membered heterocycle or 5-6 membered cycloheteroalkyl), in which at least one ring atom is carbon, and at least one ring atom is a heteroatom selected from N, O, and S, or a heteroatom group selected from C(=O), S(=O), and S(=O)2. A heterocyclic group may be aromatic or non-aromatic. Piperidine and oxetane are non- limiting examples of non-aromatic heterocycles. Thiazole and pyridine are non-limiting examples of aromatic heterocycles. Other examples of heterocycle include: aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone and caprolactone. Similarly, the term “cycloheteroalkenyl” refers to a monocycle or polycycle ring structure comprising carbon atom(s) and heteroatom(s) / heteroatom group(s), wherein the cycloheteroalkenyl comprises at least one C=C double bond, at least one ring atom that is carbon, and at least one ring atom that is a heteroatom selected from N, O, and S or a heteroatom group selected from C(=O), S(=O), and S(=O)2. Unless stated otherwise specifically in the specification, a heterocycle or heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe.

[0039] As used herein, the term “aryl” generally refers to an all-carbon monocyclic or fused- ring polycyclic groups of 6 to 12 (C6-12 aryl) or 6 to 10 carbon atoms (Ce-io aryl) having a completely conjugated pi-electron system. Examples include, but are not limited to, phenyl, naphthalenyl, tetrahydronaphthyl, indanyl, biphenyl, and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O -thiocarb amyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRXRY, wherein Rxand RYare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-membered heteroalicyclic ring. Illustrative substituted alkyl group include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, aminoethyl, hydoxymethyl, methoxymethyl, 2-fluoroethyl, and 2- methoxyethyl, etc.

[0040] The term “heteroaryl” as used herein generally refers to an aromatic group in which at least one aromatic ring comprises at least one heteroatom selected from N, O and S. Heteroaryls include, for example, 5-12 membered heteroaryls, 5-10 membered heteroaryls, 5-7 membered monocyclic structures or 7-12 membered bicyclic structures. The number of heteroatoms in a heteroaryl can be 1, 2, 3, 4, or more. Examples include, but are not limited to, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine-2(lH)-keto, pyridine-4(lH)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, imidazolyl, furanyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl , benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl,and quinazolinyl. The heteroaryl group may be substituted or un substituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRXRY, with Rxand RYas defined above.

[0041] As used herein, the term “amino” generally refers to primary amino group (-NH2),—l / secondary amino group (-NH-), and tertiary amino group ( \).

[0042] As used herein, the term “alkylamino” generally refers to a secondary or tertiary amine that has the general structure -NH-R1or -N(R1)(R2), respectively, wherein R1and R2are selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such alkylamino groups include, but are not limited to, mono- and di-(Ci-6 alkyl)amino groups, in which each C1-6 alkyl may be the same or different. In this case, the definition of “alkyl” as used in the term “alkylamino” differs from the definition of “alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups.

[0043] The term “alkylthio” as used herein generally refers to an alkyl-substituted thio group, wherein the term alkyl is as defined above o

[0044] The terms “substituent” and “substituted,” as used herein, generally denote that a molecular moiety is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom. A straight chain substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a straight chain.

[0045] The term “cycloalkylamine” as used herein generally refers to either a ring structure with an amino group attached to a carbon atom in the ring or a ring structure with a nitrogen atom as member of the ring.

[0046] As used herein, the term “C1-C4 alkylcarbonyl” generally refers to a carbonyl radical that is substituted by a C1-C4 alkyl radical as defined above. Examples include, but are not limited to, methylcarbonyl, ethyl carbonyl, n-propyl carbonyl, isopropylcarbonyl, butyl carbonyl, and tertbutyl carbonyl.

[0047] As used herein, the term “C1-C3 alkyl sulfonyl” generally refers to a sulfonyl radical that is substituted by a C1-C3 alkyl radical as defined above. Examples include, but are not limited to, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, and isopropanesulfonyl.

[0048] As used herein, the term “C1-C4 alkoxycarbonyl” generally refers to a carbonyl radical that is substituted by C1-C4 alkoxy radical, as defined above. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and tert-butoxy carbonyl.

[0049] As used herein, the term “monosaccharide” generally refers to a sugar a pentose, hexose, heptose, or octose sugar, analog, or derivative thereof, including, but not limited to, deoxy sugars, dideoxy sugars, amino sugars, and sugar acids. The term includes protected and unprotected forms of monosaccharides, i.e., wherein selected reactive groups, typically oxygen- or nitrogen-bearing groups, of the monosaccharide have been either temporarily blocked (“protected”) to prevent their undergoing a reaction under the conditions of a specific transformation or left exposed and available for possible participation in a reaction, respectively. Taking the hexose for example, hexoses many include, but are not limited to, glucose (Glc), galactose (Gal), mannose (Man), glucuronic acid (GlcA), and iduronic acid (IdoA). Monosaccharides also include hexoses substituted with hydroxy groups, oxo groups, amino groups, acetamido groups, and other functional groups. “Deoxy” hexose refer to monosaccharides having carbon atoms one or more carbon atoms in the hexose backbone having only hydrogen substituents. Hexoses also include, but are not limited to, glucosamine (2-amino- 2-deoxy-glucose; GlcN), N-acetylglucosamine (2-acetamido-2-deoxy-glucose; GlcNAc), galactosamine (2-amino-2-deoxy-galactose; GalN), N-acetylgalactosamine (2-acetamido-2- deoxy-galactose; GalNAc), mannosamine (2-amino-2-deoxy-mannose; ManN), and N- acetylmannosamine (2-acetamido-2-deoxy-mannose; ManNAc).

[0050] As used herein, the term “leaving group” generally refers to molecular fragment or stable species that can be detached from a molecule in a bond-breaking step. The leaving group, in accordance with the specification, is not particularly limited. The ability of a leaving group to depart is correlated with the pKa of the conjugate acid, with lower pKa being associated with better leaving group ability. Examples of leaving group include, without limitation, halide or a sulfonate. Halides is as defined above. Examples of sulfonates can include, without limitation, nonaflate, tritiate, fluorosulfonate, tosylate, mesylate or besylate. In one embodiment, for example and without limitation, the leaving group is chloride, mesylate or tosylate. The functional groups that can be converted into leaving groups, in accordance with the specification, are not particularly limited. In one embodiment, for example the functional group can be a hydroxyl group that can be converted into a leaving group as described above.

[0051] As used herein, the term “linker” generally refers to a molecule that joins two other molecules, either covalently, or through ionic, van der Waals or hydrogen bonds. In some cases, the linker uses covalent bonds to join the two other molecules. The term “cleavable linker” asused herein generally refers to a linker that can be degraded or otherwise severed to separate the two components connected by the cleavable linker. Cleavable linkers are generally cleaved by enzymes, typically peptidases, proteases, nucleases, lipases, and the like. Cleavable linkers may also be cleaved by environmental cues, such as, for example, changes in temperature, pH, salt concentration, etc., when there is such a change in environment following transcytosis of the compound disclosed herein across a polarized epithelial membrane.

[0052] As used herein, the term “conjugate” generally refers to a compounds disclosed herein linked to a cell surface targeting agent via a linker. In some cases, the linker can be a cleavable linker. In some cases, the linker can be a non-cleavable linker.

[0053] As used herein, the term “cell surface targeting agent” generally refers to an agent that binds to a cell surface, in particular, selectively binds to a particular cell surface, for example, by targeting a specific cell surface receptor or a unique cell surface motif. In some cases, the cell surface targeting agent can be a receptor binding domain. For example, the receptor binding domain can be any receptor binding domain known to one of skill in the art without limitation to bind to a cell surface receptor that is present on the apical membrane of an epithelial cell. In some cases, the receptor binding domain can bind specifically to the cell surface receptor. In some cases, the receptor binding domain can bind to the cell surface receptor with sufficient affinity to allow endocytosis of the conjugate. In some cases, the cell surface targeting agent can bind selectively to the surface of targeted cells. For example, the cell surface targeting agent may be a ligand that binds to the cell surface receptor found on a particular type of cell or expressed at a higher frequency on target cells than on other cells.

[0054] In some cases, the “cell surface targeting agent” can comprise a peptide, a polypeptide, a protein, a lipid, a carbohydrate, or a small organic molecule, or a combination thereof. In some cases, examples of each of these molecules can bind to cell surface receptors present on the apical membrane of epithelial cells. Examples of peptides or polypeptides include, but are not limited to, RGD-containing peptides, bombesin or gastrin-releasing peptide, bacterial toxin receptor binding domains, such as the receptor binding domains from Pseudomonas aeruginosa (PE), cholera toxin, Cholix toxin, botulinum toxin, diptheria toxin, shiga toxin, shiga-like toxin, etc.; fusion proteins (e.g., albumin fusions); antibodies, including monoclonal, polyclonal, and single-chain antibodies, or derivatives thereof (e.g., isotype immunoglobulin G (IgG) or derivatives thereof, or integrin alpha- 10 specific antibody), growth factors, such as EGF, IGF-I, IGF-II, IGF-III etc.; cytokines, such as IL-1, IL-2, IL-3, IL-6, etc.; chemokines, such as MIP-la, MIP-lb, MCAF, IL-8, etc.; and other ligands, such as CD4, cell adhesion molecules from the immunoglobulin superfamily, integrins, ligands specific for the IgA receptor, etc.

[0055] As used herein, the term “biological half-life” of a substance generally refers to a pharmacokinetic parameter which specifies the time required for one half of the substance to be removed from an organism following introduction of the substance into the organism.

[0056] As used herein, the term “long acting reagent” generally refers to reagents, when linked to another compound, can increase the biological half-life of the other compound. In some cases, an albumin protein or an albumin protein-binding peptide. The albumin protein or albumin protein-binding peptide may extend the half-life of the conjugate. In some cases, water soluble polymers such as polyethylene glycol (PEG) can be conjugated to the compounds disclosed herein. An increase in half-life, an increased solubility, and decreased clearance by the kidney and decreased enzymatic degradation may be attributed to conjugates of a variety of water soluble polymers and functional agents, including PEG conjugates to the compounds disclosed herein. In some cases, another approach to maintaining substance stability in the plasma is to form three-dimensional (3D) drug nanoparticles, which promote the formation of 3D intramolecular and / or intermolecular structures to block intramolecular cleavage sites. Encapsulation of substances in nanoparticles can reduce the apparent drug clearance from plasma, thereby enhancing the apparent drug circulation half-life and potential cumulative drug delivery to the target tissues.

[0057] The term “pharmaceutically acceptable” as used herein generally refers to a form of the compound that is safe for administration to a subject. For example, a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound described herein, which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.

[0058] Included in the compounds of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId are the pharmaceutically acceptable salt forms of the free- base compounds. The term “pharmaceutically-acceptable salts” as used herein generally refers to salts, commonly used to form alkali metal salts and to form addition salts of free acids or free bases, which have been approved by a regulatory agency. Salts are formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.

[0059] 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 subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. For example, Berge et al. describes pharmaceutically acceptable salts in detail in Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceuticallyacceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. 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, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, 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, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.

[0060] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and other amine salt. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, examples include, but are not limited to, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is ammonium, potassium, sodium, calcium, or magnesium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, andthe 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, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, diethyl amine, tri ethyl amine, tripropylamine, and ethanol amine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. Bis salts (i.e. , two counterions) and higher salts (e.g. , three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.

[0061] As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate”. Other solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0062] As used herein, and unless otherwise specified, “prodrug” refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. A discussion of prodrugs is provided in Higuchi, T., et al , “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId I-V in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve,VI, Via- Vic, VII, Vlla-VIId is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.

[0063] The term “isomers” as used herein generally refers to different compounds that have the same molecular formula, including any and all geometric isomers and stereoisomers. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. For example, “isomers” include geometric double bond cis- and trans-i somers, also termed E- and Z- isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure, unless specified otherwise. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).

[0064] In some embodiments, the compound(s) of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId is used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s), in one embodiment, is combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.

[0065] The term “excipient” as used herein generally refers to any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration purposes.

[0066] The term “diluent” as used herein generally refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition within granules in the form of a single compound or in the form of a mixture of compounds. Non-limiting examples of diluent include lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0067] The term “adjuvant,” as used herein generally refers to any substance or mixture of substances that increases the efficacy or potency of a compound disclosed herein on a target where the adjuvant is used together with the compound disclosed herein. However, when the adjuvant is used alone, no pharmacological effect is observed on the same target.

[0068] T lie phrase “effective amount” as used herein generally refers to quantifying the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse sideeffects typically associated with alternative therapies. The effective amount, in one embodiment, is administered in a single dosage form or in multiple dosage forms.

[0069] The terms “treat”, “treating,” “treatment,” and “therapy” as used herein generally refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals. Treatment includes the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0070] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0071] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those of skill in the art.Cytotoxic Properties

[0072] A possible mechanism that may explain the biological properties of the compounds disclosed herein is their binding to tubulins / microtubules having a key role in cell division. The binding to P-tubulin may promote the assembly of microtubules and may simultaneously inhibit disassembly, thereby stabilizing microtubule dynamics. Suppression of microtubule dynamics may result in the blockade of cell mitosis, thereby leading to apoptosis. The compounds disclosed herein may be microtubule targeting agent (MTA), causing mitotic blockade and the ensuing loss of cell viability. The compounds disclosed herein may be cytotoxic.Pharmaceutical Compositions / F ormulations

[0073] One embodiment provides a pharmaceutical composition comprising a compound of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0074] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), herein incorporated by reference for such disclosure.

[0075] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0076] T lie pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0077] All formulations for oral administration are in dosages suitable for such administration. Examples of such dosage units are tablets or capsules. In some embodiments, these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 rag. A suitable daily dose for a human or other mammal vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.

[0078] Conventional formulation techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.Numbered Embodiments

[0079] The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as depending from or relating to every previous or subsequent numbered embodiment, independent of their order as listed.

[0080] Embodiment 1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:X is a bond, -CH2-, -CH2-CH2-, -CR2R3-, - CR2R3-CR2R3-, -CR2=CR3-, *- NR11- CR2R3-, -CR2R3-NRU-CR2R3-, *-O-CR2R3-, or -CR2R3-O-CR2R3-;* denotes a connection to R1; R1is ; RG is a reactive group; L is a linker connecting X and RG; RAis –CR4R5R6; each R2, R3, R4, R5and R6is independently hydrogen, halogen, –U, or –G; or L and R4, together with atoms to which they are attached, form a ring, wherein the ring is optionally substituted with 1, 2, or 3 R9; –U is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2- C6 alkenyl, or C2-C6 alkynyl; wherein each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with 1, 2, or 3 R9and / or 1 or 2 –G; –G is independently C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; wherein each C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R11is independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and R9is independently halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 heteroalkyl, –C(O)H, –C(O)OH, –CN, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, –C(O)(C1-C4alkyl), –C(O)O(C1-C4alkyl), –C(O)NH2, –C(O)NH(C1-C4alkyl), –C(O)N(C1-C4 alkyl)2, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, –NH(C2-C4 alkylene)-OH, –NH(C2-C4 alkylene)-O-(C1-C4 alkyl), –OH, –O(C1-C4 alkyl), –O(C1-C4 haloalkyl), –O(C2-C4alkylene)-NH2, –O(C2-C4alkylene)-NH-(C1-C4alkyl), –O(C2-C4alkylene)-N-(C1-C4alkyl)2, –O(C1-C4alkylene)-C(O)OH, –O(C1-C4alkylene)-C(O)O- (C1-C4 alkyl), –O(C2-C4 alkenyl), –O(C1-C4 alkylene)-(C6-C10 aryl), –O(C1-C4 alkylene)- (5- to 10-membered heteroaryl), –O(C6-C10 aryl), –SH, S(O)2OH, –S(O)2(C1-C4 alkyl), – S(O)2NH2, –S(O)2NH(C1-C4alkyl), or –S(O)2N(C1-C4alkyl)2; or two R9, together with atoms to which they are attached, form a C3-C10 cycloalkyl or a 3- to 10-membered heterocycloalkyl ring.

[0081] Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula la:Formula la wherein each R1to R6is as defined in Embodiment 1.

[0082] Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula lb:wherein each RA, R2, R3, RG, and L is as defined in Embodiment 1.

[0083] Embodiment 4. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ic:wherein each RG and L is as defined in Embodiment 1; and wherein RDis hydrogen, halogen, – U, or –G.

[0084] Embodiment 5. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Id:wherein each RG and L is as defined in Embodiment 1.

[0085] Embodiment 6. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ie:wherein each R4, R5, RG, and L is as defined in Embodiment 1.

[0086] Embodiment 7. The compound of any one of Embodiments 1-6, wherein:# denotes a connection to RG; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene,C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10 aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; and each o and p is independently an integer of 1-6.

[0087] Embodiment 8. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula II:wherein: RG is as defined in Embodiment 1;heterocycle or heteroaryl; each L1and L2is independently a bond, –O–, –NH–, C1-C6alkylene, C1-C6haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6alkylene, C1-C6haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; n is an integer of 0-4; each o and p is independently an integer of 1-6; and each Rais independently R9.

[0088] Embodiment 9. The compound of Embodiment 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IIa:wherein: R5and R6are as defined in Embodiment 1; L1and L2are as defined in Embodiment 8; each o and p is independently an integer of 1-6; X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; Y is CH or N; Z is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; each Rais independently R9; and n is an integer of 0-4.

[0089] Embodiment 10. The compound of Embodiment 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IIb:wherein: L1and L2are as defined in Embodiment 9;each o and p is independently an integer of 1-6;Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

[0090] Embodiment 11. The compound of Embodiment 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula lie:Formula He wherein:L1and L2are as defined in Embodiment 9; each o and p is independently an integer of 1-6;Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

[0091] Embodiment 12. The compound of Embodiment 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula lid:Formula lid wherein:L1and L2are as defined in Embodiment 9; each o and p is independently an integer of 1-6;Y is -CH- or N; each Rais independently R9; and n is an integer of 0-4.

[0092] Embodiment 13. The compound of Embodiment 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, whereinheteroaryl.

[0094] Embodiment 15. The compound of any one of Embodiments 8-14, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 0.

[0095] Embodiment 16. The compound of any one of Embodiments 8-14, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 1.

[0096] Embodiment 17. The compound of Embodiment 16, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein Rais methyl, ethyl, trifluoromethyl, or halogen.

[0097] Embodiment 18. The compound of any one of Embodiments 1-17, wherein:RG is:LG is a leaving group; RBis independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; RCis independently C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; R9is as defined in Embodiment 1; each R12is independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and q is an integer of 0-3.

[0098] Embodiment 19. The compound of Embodiment 18, wherein LG is halide.

[0099] Embodiment 20. The compound of Embodiment 18, wherein LG is nonaflate, triflate, fluorosulfonate, tosylate, mesylate, or besylate.

[0100] Embodiment 21. The compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is:

[0101] Embodiment 22. A compound of any one of Formulas III- VI:Formula V Formula VI or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, *– NR11– CR2R3–, –CR2R3–NR11–CR2R3–, *–O–CR2R3–, or –CR2R3–O–CR2R3–; * denotes a connection to R1; R1is ; RG is a reactive group; L is a linker connecting X and RG; RAis –CR4R5R6; RNis –OH, –NH2, or –NH–C(O)OR20; each R2, R3, R4, R5and R6is independently hydrogen, halogen, –U, or –G; or L and R4, together with atoms to which they are attached, form a ring, wherein the ring is optionally substituted with 1, 2, or 3 R9; –U is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2- C6 alkenyl, or C2-C6 alkynyl; wherein each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with 1, 2, or 3 R9and / or 1 or 2 –G; –G is independently C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; wherein each C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R11is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; R9is independently halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4heteroalkyl, –C(O)H, –C(O)OH, –CN, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, – C(O)(C1-C4alkyl), –C(O)O(C1-C4alkyl), –C(O)NH2, –C(O)NH(C1-C4alkyl), –C(O)N(C1-C4alkyl)2, –NH2, –NH(C1-C4alkyl), –N(C1-C4alkyl)2, –NH(C2-C4alkylene)-OH, –NH(C2-C4alkylene)-O-(C1-C4 alkyl), –OH, –O(C1-C4 alkyl), –O(C1-C4 haloalkyl), –O(C2-C4 alkylene)- NH2, –O(C2-C4 alkylene)-NH-(C1-C4 alkyl), –O(C2-C4 alkylene)-N-(C1-C4 alkyl)2, –O(C1-C4 alkylene)-C(O)OH, –O(C1-C4alkylene)-C(O)O-(C1-C4alkyl), –O(C2-C4alkenyl), –O(C1-C4alkylene)-(C6-C10 aryl), –O(C1-C4 alkylene)-(5- to 10-membered heteroaryl), –O(C6-C10 aryl), – SH, S(O)2OH, –S(O)2(C1-C4 alkyl), –S(O)2NH2, –S(O)2NH(C1-C4 alkyl), or –S(O)2N(C1-C4 alkyl)2; or two R9, together with atoms to which they are attached, form a C3-C10cycloalkyl or a 3- to 10-membered heterocycloalkyl ring;R20is independently C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, or a monosaccharide, or a monosaccharide derivative; R22is –CR4R5R23; and R23is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with a hydroxy, or 1, 2, or 3 R9and / or 1 or 2 –G.

[0102] Embodiment 23. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to any one of Formulas IIIa-VIa:wherein each R1to R6, R22, and RNis as defined in Embodiment 22.

[0103] Embodiment 24. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to any one of Formulas IIIb-VIb:Formula Vb Formula Vlb wherein each RA, R2, R3, R22, RN, RG, and L is as defined in Embodiment 22.

[0104] Embodiment 25. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to an one of Formulas IIIc-VIc:wherein each R22, RN, RG and L is as defined in Embodiment 22; and wherein RDis hydrogen, halogen, -U, or -G.

[0105] Embodiment 26. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formulas Illd or Vd:wherein each RN, RG and L is as defined in Embodiment 22.

[0106] Embodiment 27. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formulas IIIe or Ve:wherein each R4, R5, RN, RG, and L is as defined in Embodiment 22.

[0107] Embodiment 28. The compound of any one of Embodiments 22-27, wherein: L is #–(L2)o–(L1)p–; # denotes a connection to RG; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10 aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6alkylene, C1-C6haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10 aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; and each o and p is independently an integer of 1-6.

[0108] Embodiment 29. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VII:wherein: RN, RG is as defined in Embodiment 22;heterocycle or heteroaryl; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10 aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10 aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; n is an integer of 0-4; each o and p is independently an integer of 1-6; and each Rais independently R9.

[0109] Embodiment 30. The compound of Embodiment 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIa:Formula VIIa wherein: each of RN, R5and R6is as defined in Embodiment 22; L1and L2are as defined in Embodiment 29; each o and p is independently an integer of 1-6; X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; Y is CH or N; Z is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; each Rais independently R9; and n is an integer of 0-4.

[0110] Embodiment 31. The compound of Embodiment 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIb:wherein: L1and L2are as defined in Embodiment 29; RNis as defined in Embodiment 22; each o and p is independently an integer of 1-6;Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

[0111] Embodiment 32. The compound of Embodiment 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIc:wherein: L1and L2are as defined in Embodiment 29; RNis as defined in Embodiment 22; each o and p is independently an integer of 1-6; Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

[0112] Embodiment 33. The compound of Embodiment 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIId:wherein: L1and L2are as defined in Embodiment 29;RNis as defined in Embodiment 22; each o and p is independently an integer of 1-6;Y is -CH- or N; each Rais independently R9; and n is an integer of 0-4.

[0113] Embodiment 34. The compound of Embodiment 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, whereinheteroaryl.

[0115] Embodiment 36. The compound of any one of Embodiments 29-35, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 0.

[0116] Embodiment 37. The compound of any one of Embodiments 29-35, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 1.

[0117] Embodiment 38. The compound of Embodiment 37, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein Rais methyl, ethyl, trifluoromethyl, or halogen.

[0118] Embodiment 39. The compound of any one of Embodiments 22-38, wherein:RG is:LG is a leaving group; RBis independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; RCis independently C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; R9is as defined in Embodiment 22; each R12is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and q is an integer of 0-3.

[0119] Embodiment 40. The compound of Embodiment 39, wherein LG is halide.

[0120] Embodiment 41. The compound of Embodiment 39, wherein LG is nonaflate, triflate, fluorosulfonate, tosylate, mesylate, or besylate.

[0121] Embodiment 42. The compound of Embodiment 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is:

[0122] Embodiment 43. A pharmaceutical composition comprising a compound of any one of Embodiments 1-42, or pharmaceutically acceptable salt, solvate, diastereom eric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.

[0123] Embodiment 44. A method of treating a cancer in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition of Embodiment 43.

[0124] Embodiment 45. A method of treating a cancer in a mammal suffering therefrom with a conjugate of a compound of any one of Embodiments 1-42 linked with (i) a cell surface targeting agent, or (ii) a long acting reagent, comprising: administering to the mammal a therapeutically effective amount of (i) the conjugate of the compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or (ii) a pharmaceutical composition comprising the conjugate of the compound of any one of Embodiments 1-42, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier, wherein the cell surface targeting agent is a small molecule, a polypeptide, or an antibody, and wherein the long acting reagent comprising a polymer, human serum albumin (HSA), or a nanoparticle.

[0125] Embodiment 46. A conjugate comprising:(i) a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof; and(ii) a cell surface targeting agent or a long acting reagent linked to the compound, wherein the cell surface targeting agent is a small molecule, a polypeptide, or an antibody, and wherein the long acting reagent comprising a polymer, human serum albumin (HSA), or a nanoparticle.

[0126] Embodiment 47. A pharmaceutical composition comprising a conjugate of Embodiment 46, and a pharmaceutically acceptable carrier.EXAMPLESChemical Synthesis

[0127] Methods of the present invention may include the use of at least one compound of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId, which inhibits programmed necrosis in the regulation of repair and / or functional performance of a wide range of cells, tissues and organs, and have therapeutic and cosmetic applications ranging from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. Accordingly, the methods and compositions of the present invention include the use of the subject inhibitors for all such uses as inhibitors of programmed necrosis may be implicated. Moreover, the subject methods can be performed on cells which are provided in culture (in vitro), or on cells in a whole animal (in vivo).

[0128] The examples and preparations provided below illustrated and exemplify the compounds described herein and methods of preparing such compounds. In general, the compounds described herein may be prepared by processes known in the general chemical arts.

[0129] T lie compounds of the present invention can be prepared using various synthetic routes, including those described below, starting from commercially available materials. Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Functional groups may be removed according to known procedures in the art.

[0130] The protection of functional groups by protecting groups, the protecting groups themselves, and their removal reactions (commonly referred to as “deprotection”) are described, for example, in standard reference works, such as J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T.W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J. Meienhofer editors, Academic Press, London and New York (1981).

[0131] All synthetic procedures described herein can be carried out under known reaction conditions, advantageously under those described herein, either in the absence or in the presence (usually) of solvents or diluents.

[0132] T lie invention further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all “intermediates” included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.

[0133] New7starting materials and / or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In select embodiments, such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).

[0134] Starting materials of the invention, are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above.

[0135] All reagents and solvents were obtained commercially unless stated otherwise. All commercial reagents and solvent were used without purification unless stated otherwise. When required, some reagents and solvents were purified by standard techniques. For example, tetrahydrofuran may be purified by distillation from sodium.

[0136] Reaction progress was monitored by reverse-phase HPLC and / or thin-layer chromatography (TLC). Liquid chromatography-mass spectrometry was performed using either Waters or Shimadzu 2010EV LCMS instruments using water and acetonitrile or methanol doped with 0.1% formic acid. TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography was performed using silica gel (32-63 pm particle size) or aluminum oxide (activated, basic, -150 mesh size). Automated chromatographic purification was carried out using pre-packed silica or Cl 8 cartridges (from RediSep and Luknova) and eluted using an ISCO Companion system. Reverse phase purifications were conducted usingwater and acetonitrile or methanol doped with 0.1% formic acid. All final product compounds were purified using one of these two chromatographic methods. Purity and characterization of compounds was established by a combination of TLC, liquid chromatography-mass spectroscopy (LC-MS) and Nuclear Magnetic Resonance (NMR) analytical techniques. 'H and13C NMR spectra were obtained on a Joel 400 spectrometer at 400 MHz and 101 MHz, respectively. Chemical shifts are reported in 5 (ppm) and were internally referenced to deuterated solvent signals.

[0137] The size and scale of the synthetic methods will vary depending on the desired amount of end product. It is understood that while specific reactants and amounts are provided in the Examples, one of skill in the art. knows other alternative and equally feasible sets of reactants that will also yield the same compounds. Thus, where general oxidizers, reducers, solvents of various nature (aprotic, apolar, polar, etc.) are utilized, equivalents will be known in the art and are herein contemplated for use in the present methods.

[0138] Many of the steps below indicate various work-ups following termination of the reaction. A work-up involves generally quenching of a reaction to terminate any remaining catalytic activity and starting reagents. This is generally followed by addition of an organic solvent and separation of the aqueous layer from the organic layer. The product is typically obtained from the organic layer and unused reactants and other spurious side products and unwanted chemicals are generally trapped in the aqueous layer and discarded. The work-up in standard organic synthetic procedures found throughout the literature is generally followed by drying the product by exposure to a drying agent, such as anhydrous Na2SO4, to remove any excess water or aqueous byproducts remaining partially dissolved in the organic layer and concentration of the remaining organic layer. Concentration of product dissolved in solvent may be achieved by any known means, such as evaporation under pressure, evaporation under increased temperature and pressure, and the like. Such concentrating may be achieved by use of standard laboratory equipment such as rotary-evaporator distillation, and the like. This is optionally followed by one or more purification steps which may include, but is not limited to, flash column chromatography, filtration through various media and / or other preparative methods known in the art and / or crystallization / recrystallization. (See, for instance, Addison Ault, “Techniques and Experiments for Organic Chemistry,” 6th Ed., University Science Books, Sausalito, Calif, 1998, Ann B. McGuire, Ed., pp.45-59).Examples of Novel Compounds

[0139] Eribulin is a chemotherapy drug that can be used to treat breast cancer or liposarcoma, among other indications. Common side effects include, but are not limited to: neutropenia, anemia, leukopenia, fatigue, alopecia, nausea, headaches, and constipation, among other things.

[0140] Eribulin contains many functional groups that can be modified as shown below:

[0141] 1) The primary amine group (-NH2) can be modified in various ways, including, but not limited to: alkylation (to make -NHRAor -NRARB), acylation (to make -NHC(O)RA), sulfonylation (to make -NHSO2RA), etc., wherein each of RAand RBis independently an unsubsititued alkyl group or substituted alkyl group, or a linker group, among other possible chemical groups.

[0142] 2) The secondary alcohol can be modified in various ways, including, but not limited to: oxidation to a carbonyl group, reduction to remove the hydroxyl group, substitution with other groups, alkylation on the oxygen atom with other groups, etc.

[0143] 3) Oxydative cleavage to remove the -CH2NH2 tail and form an aldehyde at the former secondary alcohol position, followed by a reductive amination to introduce a secondary amine at this position.

[0144] 4) The ketone group can be modified in various ways, including, but not limited to: reduction to a secondary alcohol, further alkylaltion of the secondary alcohol with other chemical groups including but not limited to, an alkyl group (substituted or unsub stitued), a carbohydrate (such as an unsubstituted or substituted monosaccharide), replacing the carbonyl (— C(=O)— ) group with an amine-containing group (to make: -CH(NHRA)-, -C(=NHOH)-, -C(=NH-NHRA)-, or -C(=NH-NH-C(=O)RN)-). Here, RAis an unsubsititued alkyl group or substituted alkyl group, or a linker group among other possible chemical groups; RNis an unsubsititued or substituted alkyl group, an unsubsititued or substituted alkoxy group, an unsubsititued or substituted carbohydrate group (including a monosaccharide and derivatives thereof), among other possible chemical groups.

[0145] Structures of selected compounds are summarized in Table 1. Additional molecules that are Eribulin-based analogues are possible.

[0146] Table 1. Examples of Selected Compounds.LC-MS Conditions

[0147] HPLC-MS analyses are performed on a Waters ACQUITY UPLC with SQ mass detector and PDA eZ. detector. The column used is a Phenom enex Kinetex C18 column (1.7um, 2.1 x 50 mm). The mobile phase consists of eluent A (water, 0.05% TFA) and eluent B (CH3CN, 0.05% TFA), and the elution proceeds at 0.5 mL / min. The initial conditions are 90% A, then 90% A to 10% A linearly decreased within 1.75 min, then from 10% A to 90% A within 0.25 min. The total run time is 2 minutes.General Synthetic Routes

[0148] There are many routes available to synthesize compounds of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va-Ve, VI, Via- Vic, VII, Vlla-VIId. Below are synthetic routes leading to specific compounds of Formulas I, la-Ie, II, Ila-IId, III, Illa-IIIe, IV, IVa-IVc, V, Va- Ve, VI, Via- Vic, VII, Vlla-VIId. The synthetic routes shown are not limiting but are examples from many available routes.

[0149] In one example, as shown in Scheme 1, the amino and hydroxy groups in Compound Fill can be transformed into tert-butyloxycarbonyl (BOC)-protected amino group and tosylate group, respectively, in Compound N-12. The tosylate group in Compound N-12 can react with a hydroxy group in Compound N-13 in an SN2 type of displacement to afford the cyclic amine Compound N-14. The secondary amine in Compound N-14 can react with the tosylate AB175- 11 to give Compounds N-15. Also shown in Scheme 1 are examples of specific examples of Compound N-13 which comprise a secondary hydroxy and secondary cyclic amine. Other example for Compound N-13 are possible.

[0150] Scheme 1 : Synthesis of Compound N-15Compound N-13

[0151] In another example, as shown in Scheme 2, the amino and hydroxy groups in Compound N-21 can be transformed into BOC-protected amino group and tosylate group, respectively, in Compound N-22. The tosylate group in Compound N-12 can react with a secondary amino group in Compound N-23 in an SN2 type of displacement to afford the cyclic amine Compound N-24. The remaining secondary amine in Compound N-24 can react with the tosylate AB175-11 to give Compounds N-25. Also shown in Scheme 2 are examples of specific examples of Compound N-23 which comprise two secondary amine in the same cyclic structure. Other example for Compound N-23 are possible.

[0152] Scheme 2: Synthesis of Compound N-25Compound N-23Compound N-21 Compound N-22 Compound N-24Compound N-23

[0153] Free primary or secondary amine can react with AB175-11. Routes A-F show some possible synthetic routes leading to secondary amine intermediates that can react with AB 175- 11. In Routes A-E, (1) Rxrepresents substitutions that is covalently linked to a cyclic amine structure and is not limiting; (2) although all the secondary amine intermediates made comprise azetidine, other cyclic amines such as those shown as Compound N-13 and Compound N-23 and their derivatives can be used in similar synthetic routes leading to other secondary amine intermediates comprising the corresponding cyclic amines with a free amine group; (3) for the other cyclic amine in the intermediates, although only piperidine and piperazine are shown as examples, other cyclic amines can be used in similar synthetic routes as well; (4) although only a bond, a methylene group, and an ethylene group are shown as the linker between the two cyclic amine moieties in the intermediates, other linkers can be used. In sum, Routes A-F are not limiting.

[0154] Route A :Compound N-31 Compound N-32 Compound N-33 Compound N-34

[0155] As shown in route A, reductive amination between a secondary cyclic amine Compound N-31 and a cyclic ketone Compound N-32 provides a linked bicyclic intermediate CompoundN-33. The BOC group in Compound N-33 is removed under acidic conditions to provide a secondary cyclic amine Compound N-34 ready to react with AB 175-11.

[0156] Route B :Compound N-41 Compound N-42 Compound N-43 Compound N-44

[0157] As shown in Route B, reductive amination between a secondary cyclic amine Compound N-41 and a cyclic ketone Compound N-42 provides a linked bicyclic intermediate Compound N-43. The linkage between the two heterocycles is a bond. The BOC group in Compound N-43 is removed under acidic conditions to provide a secondary cyclic amine Compound N-44 ready to react with AB175-11.

[0158] Compound N-51 Compound N-52 Compound N-53 Compound N-54

[0159] As shown in Route C, an SN2 displacement reaction between a secondary cyclic amine Compound N-51 and a tosylate Compound N-52 provides a linked bicyclic intermediate Compound N-53. The linkage between the two heterocycles is -CH2-. The BOC group in Compound N-53 is removed under acidic conditions to provide a secondary cyclic amine Compound N-54 ready to react with AB175-11.

[0160] Compound N-61 Compound N-62 Compound N-63 Compound N-64

[0161] As shown in Route D, an SN2 displacement reaction between a secondary cyclic amine Compound N-61 and a tosylate Compound N-62 provides a linked bicyclic intermediate Compound N-63. The linkage between the two heterocycles is -CH2-. The BOC group in Compound N-63 is removed under acidic conditions to provide a secondary cyclic amine Compound N-64 ready to react with AB175-11.

[0162] Compound N-71 Compound N-72 Compound N-73 Compound N-74

[0163] As shown in Route E, reductive amination between a secondary cyclic amine Compound N-71 and an aldehyde Compound N-72 provides a linked bicyclic intermediate Compound N-73. The linkage between the two heterocycles is -CH2-CH2-. The BOC group in Compound N-73 is removed under acidic conditions to provide a secondary cyclic amine Compound N-74 ready to react with AB175-11.

[0164] Compound N-81 Compound N-82 Compound N-83 Compound N-84

[0165] As shown in Route F, reductive amination between a secondary cyclic amine Compound N-81 and an aldehyde Compound N-82 provides a linked bicyclic intermediate Compound N-83. The linkage between the two heterocycles is -CH2-CH2-. The BOC group in Compound N-83 is removed under acidic conditions to provide a secondary cyclic amine Compound N-84 ready to react with AB175-11.

[0166] In another example, as shown in Scheme 3, a secondary amine Compound N-91 comprises two substituents Rxand RY. Rx is not limiting. RYis covalently linked to the secondary amine and is not limiting. The secondary amine in Compound N-91 can react with the tosylate AB175-11 to give Compounds N-92.

[0167] Scheme 3: Synthesis of Compound N-92Example 1: Synthesis of LUX106-6

[0168] Scheme 1 :

[0170] A mixture of LUX106-1 (7.87 g, 52.77 mmol) in 300 mL dry CH3CN was stirred under N2. TEA (10.7 g, 105.7mmol) was added, followed by Boc2O (11.52 g, 52.78 mmol) in 25ml CH3CN that was added dropwise at 0 ºC. The resulting mixture was allowed to warm up to room temperature gradually and stirred overnight. Then the mixture was concentrated, followed by adding 200 ml H2O and 200 ml ethyl acetate (“EA”). The aqueous phase was extracted with EA (200mL×2), and all the organic phases were combined and dried with Na2SO4. The combined organic phases were filtered, concentrated, and the residue was purified directly with silica gel column with MeOH / dicloromethane (“DCM”) to afford LUX106-2 (10.0 g) as a yellow liquid. LCMS (ESI): m / z [M+H-Boc]+150.1 found 150.0.

[0171] Step 2: LUX106-10

[0172] A mixture of LUX106-2 (7.70 g, 30.9 mmol) in 150 mL dry DCM was stirred under N2. TEA (6.30g, 62.25mmol) was added, followed by adding Ts2O (15.1g, 46.26mmol) in 43 mL DCM dropwise at 0 ºC. The resulting mixture was allowed to warm up to room temperature and stirred overnight. Then 200 ml H2O was added to the mixture. The aqueous phase was extracted with EA (200mL×3), and all the organic phases were combined, dried with Na2SO4, filtered, and concentrated. The crude was purified directly with silica gel column with EA / PE to afford LUX106-10 (12.1g) as a red liquid.1H NMR(400MHz, CDCl3) δ 7.82(d, J=7.6Hz, 2H), 7.36(d,J=7.6Hz, 2H), 4.98(s, 1H), 4.19(s, 2H), 3.71(s, 2H), 3.57-3.59(m, 4H), 3.52(t, J=4.8Hz, 2H), 3.30-3.31(m, 2H), 2.46(s, 3H), 1.45(s, 9H); LCMS (ESI): m / z [M+H-Boc]+304.2 found 303.9.

[0173] STEP 3: LUX106-5

[0174] A mixture of LUX106-10 (3.0g, 7.44 mmol) and methylamine 27~32% in methanol (30 mL) was stirred under N2. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated, followed by adding 100 mL saturated NaHCO3(aq) and 300 ml DCM added to the residue. The organic phase was washed with saturated NaHCO3 (aq) (100 mL×2), dried with Na2SO4, filtered, and concentrated. The crude was purified directly with silica gel column with MeOH / DCM / 0.5%NH3H2O to afford LUX106-5 (2.7g) as a colorless liquid.1H NMR(400MHz, CDCl3) δ 5.21(s, 1H) , 3.60-3.62(m, 6H), 3.55(t, J=5.2Hz, 2H), 3.32-3.35(s, 2H), 2.78(t, J=5.2Hz, 2H), 2.47(s, 3H), 1.46(s, 9H); LCMS (ESI): m / z [M+H]+263.2 found 263.0.

[0175] Step 4: LUX106-6A mixture of AB175-11 (800 mg, 0.904 mmol), LUX106-5 (1.18 g, 4.50 mmol) and K2CO3(375 mg, 2.71 mmol) in 25 mL CH3CN was stirred under N2. The resulting mixture was heat to 70 ºC and stirred overnight. The mixture was concentrated directly under vacuum. Thirty ml H2O and 30 ml DCM was added to the residue. The organic phase was washed with saturated H2O (30mL×2), and the organic phase was dried with Na2SO4, filtered, and concentrated. The crude was purified directly with silica gel column with MeOH / DCM to afford LUX106-6 (Compound A1) (120mg) as an off-white solid.1H NMR(400MHz, CDCl3) δ 5.49(s, 1H), 5.07(s, 1H), 4.94(s, 1H), 4.90(s, 1H), 4.80(s, 1H), 4.69(t, J=4.4Hz, 1H), 4.60(t, J=4.4Hz, 1H),4.25-4.38(m, 3H), 4.18(dd, J=4.4, 6.4Hz, 1H), 4.08-4.13(m, 1H), 3.94-4.04(m, 2H), 3.83- 3.90(m, 2H), 3.69-3.75(m, 1H), 3.50-3.66(m, 10H), 3.42(s, 3H), 3.28-3.31(m, 3H), 2.84-2.90(m, 2H), 2.65-2.78(m, 2H), 2.45-2.60(m, 4H), 2.35-2.41(m, 2H), 2.33(s, 3H), 2.17-2.30(m, 5H), 1.54-2.07(m, 19H), 1.43(s, 9H), 1.09(d, J=6.4Hz, 3H); LCMS (ESI): m / z [M+H]+975.5 found 974.8. Example 2: Synthesis of LUX106-7

[0176] Scheme 2:

[0178] A mixture of LUX106-1 (11.5 g, 77.1 mmol) in 360 mL dry CH3CN was stirred under N2. TEA (15.6 g, 154.2 mmol) was added, followed by Teoc-OSu (19.9 g, 77.1 mmol) in 100 mL CH3CN being added dropwise at 0 ºC. The resulting mixture was allowed to warm to room temperature and stirred for 5h. Then the mixture was concentrated, followed by adding 200 ml H2O and 200 ml EA. The aqueous phase was extracted with EA (200mL×2), and all the organic phases were combined, dried with Na2SO4, filtered and concentrated. The crude was purified directly with silica gel column with MeOH / DCM to afford LUX106-11 (20.3g) as a yellowliquid.1H NMR(400MHz, CDCl3) δ 5.29(s, 1H) ,4.17(t, J=7.6Hz, 2H), 3.76(s, 2H), 3.61- 3.66(m, 6H), 3.58(t, J=5.2Hz, 2H), 3.37-3.39(m, 2H), 2.60(s, 1H), 1.00(t, J=8.4Hz, 2H), 0.05(s, 9H); LCMS (ESI): m / z [M+Na]+316.1 found 315.9.

[0179] Step 2: LUX106-12

[0180] A mixture of LUX106-11 (20.3 g, 69.2 mmol) in 400 mL dry DCM was stirred under N2. TEA (14.1g, 138.5mmol) was added, followed by Ts2O (33.8 g, 104 mmol) in 110 ml DCM being added dropwise at 0 ºC. The resulting mixture was allowed to warm to room temperature and stirred for 5 h. Then 200ml H2O was added to the mixture. The aqueous phase was extracted with EA (100mL×3), and all the organic phases were combined, dried with Na2SO4, filtered, and concentrated. The crude was purified directly with silica gel column with EA / PE to afford LUX106-12 (30.1g) as a yellow liquid.1H NMR(400MHz, CDCl3) δ 7.81(d, J=8.4Hz, 2H), 7.35(d, J=8.0Hz, 2H), 5.09(s, 1H), 4.12-4.20(m, 4H), 3.70(t, J=4.8Hz, 2H), 3.55-3.61(m, 4H), 3.52(t, J=5.2Hz, 2H), 3.35(d, J=5.2Hz, 2H), 2.46(s, 3H), 0.99(t, J=8.4Hz, 2H), 0.05(s, 9H); LCMS (ESI): m / z [M+Na]+470.2 found 469.8.

[0181] Step 3, LUX106-14

[0182] A mixture of LUX106-12 (30.1 g, 75.9 mmol), N-Methylbenzylamine (13.8g, 114 mmol) and K2CO3(31.5 g, 228 mmol) in 300 mL CH3CN was stirred under N2. The resulting mixture was heat to 70ºC and stirred overnight. The mixture was filtered, and the filtrate was concentrated. Then 100 mL saturated NaHCO3 (aq) and 300 ml DCM was added to the residue. The organic phase was washed with saturated NaHCO3 (aq) (100mL×2) and the organic phase was dried with Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX106-14 (24.8 g) as a yellow liquid.1H NMR(400MHz, CDCl3) δ 7.23-7.33(m, 5H), 5.29(s, 1H) ,4.15(t, J=8.4Hz, 2H), 3.54- 3.64(m, 10H), 3.36-3.39(m, 2H), 2.64(t, J=5.6Hz, 2H), 2.28(s, 3H), 0.98(t, J=8.4Hz, 2H), 0.05(s, 9H); LCMS (ESI): m / z [M+H]+397.2 found 397.0.

[0183] Step 4: LUX106-13

[0184] A mixture of LUX106-14 (3.90 g, 9.84 mmol) and Pd(OH)2 / C (975 mg, 10%) in 78mL MeOH was stirred under N2. The resulting mixture was exchanged three times with H2and stirred overnight at rt. The mixture was filtered and the filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX106-13 (2.22 g) as a yellow liquid.1H NMR(400MHz, CDCl3) δ 5.40(s, 1H), 4.15(t, J=8.8Hz, 2H), 3.59-3.61(m, 6H), 3.55(t, J=4.8Hz, 2H), 3.35-3.38(m, 2H), 2.77(t, J=4.4Hz, 2H), 2.45(s, 3H), 0.98(t, J=8.4Hz, 2H), 0.03(s, 9H); LCMS (ESI): m / z [M+H]+307.2 found 307.0.

[0185] Step 5: LUX106-15

[0186] A mixture of AB175-11 (682 mg, 0.771mmol), LUX106-13 (1.18 g, 3.85 mmol) and diisopropylethyl amine (DIPEA) (300 mg, 2.31 mmol) in 21 mL CH3CN was stirred under N2. The resulting mixture was heat to 70 ºC and stirred overnight. The mixture was concentrated directly under vacuum. Then 10 ml water and 10 ml DCM was added to the residue. The organic phase was washed with saturated NaHCO3 (10mL×2), and the organic phase was dried with Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX106-15 (540mg) as a yellow liquid.1H NMR(400MHz, CDCl3) δ 5.69(s, 1H), 5.09(s, 1H), 4.97(s, 1H), 4.91(s, 1H), 4.81(s, 1H), 4.70(t, J=4.4Hz, 1H), 4.62(t, J=4.4Hz, 1H), 4.28-4.40(m, 3H), 4.10-4.21(m, 4H), 3.96-4.06(m, 2H), 3.79-3.91(m, 3H), 3.59-3.68(m, 8H), 3.54(t, J=4.8Hz, 2H), 3.44(s, 3H), 3.35-3.36(m, 2H), 3.31(d, J=2.8Hz, 1H), 2.17-2.91(m, 21H), 1.78-2.11(m, 8H), 1.69-1.75(m, 3H), 1.55-1.62(m,2H), 1.41-1.49(m, 3H), 1.35-1.39(m, 1H), 1.11(d, J=6.4Hz, 3H), 0.99(t, J=8.0Hz, 2H), 0.04(s, 8H); LCMS (ESI): m / z [M+H]+1019.6 found 1019.9.

[0187] Step 6: LUX106-7A mixture of LUX106-15 (494 mg, 0.485 mmol) and TBAF (2.91 ml, 1.0 M in THF) in 32 mL THF was stirred under N2. The resulting mixture was heat to 45 ºC and stirred for 2 h. The rection mixture was concentrated directly under vacuum. Then 10 ml water and 10 ml DCM were added to the residue. The organic phase was washed with saturated NaHCO3(10 mL×2) and the organic phase was dried with Na2SO4, which was concentrated to afford LUX106-7 (353 mg) as a yellow foamy solid.1H NMR(400MHz, CDCl3) δ 5.10(s, 1H), 4.99(s, 1H), 4.90(s, 1H), 4.80(s, 1H), 4.70(t, J=4.8Hz, 1H), 4.61(t, J=4.4Hz, 1H), 4.26-4.40(m, 3H), 4.18-4.20(m, 1H), 4.09-4.13(m, 1H), 3.96-4.05(m, 2H), 3.89-3.90(m, 2H), 3.78-3.82(m, 1H), 3.61-3.69(m, 7H), 3.57(t, J=5.2Hz, 2H), 3.43(s, 3H), 3.33(d, J=2.4Hz, 1H), 3.03-3.28(m, 6H), 2.96(t, J=4.8Hz, 2H), 2.85-2.90(m, 2H), 2.43-2.76(m, 6H), 2.16-2.34(m, 10H), 1.68-2.07(m, 8H), 1.55-1.60(m, 2H), 1.34-1.48(m, 5H), 1.10(d, J=6.4Hz, 3H); LCMS (ESI): m / z [M+H]+875.5 found 875.9. Example 3: Synthesis of LUX106-41

[0188] Scheme 3:

[0189] Step 1: LUX106-37

[0190] A mixture of LUX106-36 (30.0 g, 76.9 mmol) and NH4OAc(23.5 g, 304.8 mmol) in 300 ml dry DMF was stirred for 24 h at 25 ^C under N2. About 2000 mL H2O and 400 mL ethyl acetate (EA) was added to the mixture. The aqueous phase was extracted with EA (400mL×2). All the organic phases were combined and washed with saturated NaCl (400mL×4) and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated to afford crude intermediate (30.0 g) as a yellow liquid. A mixture of the crude intermediate (30.0 g) and triethyl amine (TEA) (19.4 g, 138.7 mmol) in 500 mL dry DCM was stirred at 20 ^C under N2. Then 4-nitrophenyl chloroformate (23.1 g, 114.9 mmol) was added dropwise. The resulting mixture was stirred for 22 h at 20 ^C. Then the mixture was concentrated, and the residue was purified directly with silica gel column with EA / PE to afford LUX106-37 (19.7 g) as an off- white solid.

[0191] Step 2: LUX106-45

[0192] A mixture of LUX106-37 (19.5 g, 38.0 mmol), CbzNHNH2 (18.9 g, 113.7 mmol) and DIPEA (14.7g, 113.7 mmol) in 293 mL THF was stirred for 18 h at 20 ^C under N2. The resulting mixture was concentrated, and the residue was partitioned between 300 mL H2O and 300 mL EA. The aqueous phase was further extracted with EA(300 mL×2), and all the organic phases were combined and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with EA / PE to afford LUX106-45 (10.6 g) as an off-white solid.

[0193] Step 3: LUX106-39

[0194] A mixture of LUX106-45 (5.0 g, 9.26 mmol), Pd / C(1.7 g, 10% on carbon) and AcOH (5.5 g, 91.6 mmol) in 150 mL MeOH was stirred under N2. The resulting mixture was exchanged three times with H2 and stirred for 2 h at 20 ^C. The mixture was filtered and the filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX106-39 (2.78 g) as an off-white solid.1H NMR (400MHz, CDCl3) δ 6.33 (s, 1H), 5.65 (d, J=8.0 Hz,1H), 5.42 (d, J=3.2 Hz,1H), 5.29 (t, J=10.0 Hz,1H), 5.07 (dd, J=3.6, 10.8 Hz,1H), 4.04-4.18 (m, 3H), 3.79 (bs, 2H), 2.15 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H).

[0195] Step 4: LUX106-40

[0196] A mixture of LUX106-6 (200 mg, 0.205 mmol), LUX106-39 (2.49 g, 6.13 mmol) and AcOH (61 mg, 1.02 mmol) in 4 mL EtOH was stirred for 24 h at 70 ^C under N2. The resulting mixture was concentrated, and the residue was partitioned between 30 mL H2O and 30 mL EA. The aqueous phase was separated and extracted with EA (30mL×2), and all the organic phases were combined and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM toafford LUX106-40 (135mg) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.43 (bs, 1H), 5.91 (d, J=8.0 Hz, 1H), 5.43 (d, J=2.8 Hz, 1H), 5.32-5.40 (m, 2H), 5.22 (t, J=8.8 Hz, 1H), 5.07 (dd, J=3.2, 10.4 Hz, 1H), 4.95 (s, 1H), 4.80-4.84 (m, 2H), 4.70-4.75 (m, 2H), 4.65 (t, J=4.4 Hz, 1H), 4.49-4.55 (m, 1H), 4.32-4.37 (m, 1H), 4.06-4.28 (m, 7H), 3.93-4.03 (m, 2H), 3.75-3.82 (m, 4H), 3.57-3.66 (m, 4H), 3.52 (t, J=5.2 Hz, 3H), 3.47 (d, J=3.2 Hz, 1H), 3.27-3.33 (m, 4H), 2.80-3.16 (m, 12H), 2.72 (s, 3H), 2.38-2.63 (m, 4H), 2.10-2.30 (m, 8H), 2.03 (s, 6H), 1.99 (s, 3H), 1.55-1.96 (m, 11H), 1.44 (s, 9H), 1.29-1.37 (m, 6H), 1.06 (d, J=6.4 Hz, 1H); LCMS (ESI): m / z [M / 2+H]+682.3 found 681.9.

[0197] Step 5: LUX106-41

[0198] A mixture of LUX106-40 (30 mg, 0.022 mmol) and MeONa in MeOH (0.0025 mL, 5.4M, 0.0135 mmol) in 5 mL dry MeOH was stirred for 3 h at 20 ^C under N2. The resulting mixture was purified directly by HPLC with a C18 column with CH3CN / 0.1% NH3H2O to afford LUX106-41 (3.1mg) as an off-white solid. LCMS (ESI): m / z [M + H]+1195.64 found 1195.7. Example 4: Synthesis of LUX116-20

[0199] Scheme 4:

[0201] A mixture of AB313-24 (20.0 g, 0.123 mol) in 200 mL MeOH was stirred under N2. TEA (59.6 mL, 0.429 mol) was added dropwise at 0-5 ^C, followed by adding CF3CO2Et (43.8 mL, 0.368 mmol) dropwise at 0-5 ^C. The resulting mixture was allowed to warm up to room temperature and stirred for 2 h. Then the mixture was concentrated, and the residue was diluted with 200 mL H2O. The pH of the mixture was adjusted to 4.0 with 1N HCl at 0-5 ^C, and 200 mL EA was added. The aqueous phase was extracted with EA (200mL×2), and all the organic phases were combined and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX115-13 (23.03 g) as a yellow liquid.1H NMR (400MHz, d6-DMSO) δ 12.56 (bs, 1H) , 9.55 (s, 1H), 4.02 (s, 2H), 3.50-3.59 (m, 6H), 3.35 (q, J=5.6Hz, 2H); LCMS (ESI): m / z [M + H]+260.0, found 260.2.

[0202] Step 2: LUX115-14

[0203] A mixture of LUX115-13 (28.3 g, 109.2 mmol) in 283 mL dry DMF was stirred under N2. K2CO3 (22.6 g, 163.5 mmol) was added at 0-5 ^C and stirred for 30 min, which followed by adding BnBr(20.5 g, 119.8 mmol) dropwise at 0-5 ^C. The resulting mixture was allowed to warm up to room temperature and stirred for 3 h. The mixture was filtered, and 1000 mL H2O and 300 mL methyl tert-butyl ether (MTBE) were added to the filtrate. The aqueous phase was extracted with MTBE (300 mL×3), and all the organic phases were combined and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with EA / PE to afford LUX115-14 (32.4 g) as a yellow liquid.1H NMR (400MHz, d6-DMSO) δ 9.47 (s, 1H), 7.32-7.41 (m, 5H), 5.16 (s, 2H), 4.20 (s, 2H), 3.60- 3.62 (m, 2H), 3.54-3.56 (m, 2H), 3.51 (t, J=5.6 Hz, 2H), 3.33-3.36 (m, 2H); LCMS (ESI): m / z [M + H]+350.1, found 350.1.

[0204] Step 3: LUX115-15

[0205] LUX115-14 (31.5 g, 0.090 mmol) in 315 mL DMF was stirred under N2, which followed by adding K2CO3(37.4 g, 270.7 mmol). The resulting mixture was stirred for 30 min at 0-5 ^C. MeI (166.5 g, 1.173 mol) was added and the resulting mixture was allowed to warm up to 20 ^C and stirred for 24 h. The mixture was filtered, and 1000 mL H2O and 300ml MTBE was added to the filtrate. The aqueous phase was extracted with MTBE (300mL×3), and all the organic phases were combined and dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with EA / PE to afford LUX115-15 (23.1 g) as a yellow liquid. LCMS (ESI): m / z [M + H]+364.1 found 364.1.

[0206] Step 4: LUX115-16

[0207] A mixture of LUX115-15 (23.1 g) and Pd / C (2.31g, 10%) in 460 mL MeOH was stirred under N2. The resulting mixture was exchanged three times with H2 and stirred for 2h at rt. The mixture was filtered, and the filtrate was concentrated to afford LUX115-16 (17.1 g) as a colorless liquid.1H NMR (400MHz, d6-DMSO) δ 12.78 (bs, 1H), 4.00 (s, 2H), 3.52-3.63 (m, 8H), 3.15 (d, J=1.2 Hz, 2H), 3.00 (s, 1H); LCMS (ESI): m / z [M + H]+274.1, found 274.2.

[0208] Step 5: LUX115-18

[0209] LUX115-16 (12.0 g, 43.9 mmol) in 120 mL DCM and 0.3 mL DMF was stirred under N2, followed by adding (COCl)2 (4.7 mL, 54.9 mmol) dropwise at 0-5 ^C. The resulting mixture was stirred for 2.5 h at rt. The mixture was concentrated and used at the next step without any purification. LUX115-5 (3.0 g, 14.6 mmol) in 300 mL DCM was stirred under N2, followed by adding a mixture of LUX115-17 in 36 mL DCM dropwise at 0-5 ^C and stirred for 20 h at rt. About 20 mL saturated NaHCO3(aq) was added dropwise to the mixture. The aqueous phase was extracted with DCM (20mL×2). All the organic phases were combined and washed with 20 mL brine. The organic phase was separated, dried with Na2SO4, filtered, and the filtrate was concentrated, and the residue was purified directly with silica gel column with EA / PE to afford LUX115-18 (2.85 g) as a yellow liquid.1H NMR (400MHz, d6-DMSO) δ 8.86-8.90 (m, 1H), 7.88 (d, J=8.0Hz, 1H), 7.70-7.73 (m, 1H), 7.62 (d, J=7.2Hz, 1H), 7.54-7.59 (m, 2H), 7.27-7.34 (m, 2H), 5.37 (s, 2H), 4.89 (s, 2H), 3.55-3.69 (m, 8H), 3.15 (d, J=1.2Hz, 2H), 3.00 (s, 1H); LCMS (ESI): m / z [M + H]+461.2, found 461.2

[0210] Step 6: LUX115-19

[0211] A mixture of LUX115-18 (2.55g, 5.54 mmol) and NaOH (665mg, 16.6 mmol) in 52 mL MeOH and 13 mL H2O was stirred for 2h at 50 ^C. The mixture was heated up to 50 ^C for 2 h. Then the mixture was cooled to rt and concentrated. The residue was partitioned between 20 mL H2O and 30 mL DCM. The aqueous phase was extracted with DCM (20 mL×2). All the organic phases were combined and washed with 20 mL saturated brine. The organic phase was separated, dried with Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX115-19 (1.51 g) as ayellow liquid.1H NMR(400 MHz, d6-DMSO) δ 8.88-8.91 (m, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.72- 7.74 (m, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.56-7.60 (m, 2H), 7.28-7.35 (m, 2H), 5.38 (s, 2H), 4.92 (s, 2H), 4.11(bs, 1H), 3.76-3.81(m, 2H), 3.65-3.67(m, 2H), 3.60(t, J=5.2 Hz, 2H), 2.81(t, J=5.6 Hz, 2H), 2.40(s, 3H); LCMS (ESI): m / z [M + H]+365.2 found 365.3.

[0212] Step 1: LUX115-20

[0213] A mixture of LUX115-19 (247 mg, 0.678 mmol), AB175-11 (120 mg, 0.136 mmol) and DIPEA (53 mg, 0.407 mmol) in 3.6 mL acetonitrile (“ACN”) was stirred for 24 h at 70 ºC. Then the mixture was concentrated, and residue was partitioned between 10 mL H2O and 15 mL DCM. The aqueous phase was extracted with DCM (10mL×2). All the organic phases were combined and washed with 10 mL saturated brine. The organic phase was separated, dried with Na2SO4, and filtered. The filtrate was concentrated and the residue was purified directly with silica gel column with MeOH / DCM to afford LUX115-20 (45 mg) as a white solid.1H NMR(400 MHz, CDCl3) δ 9.06 (d, J=8.0 Hz, 1H), 7.80-7.84 (m, 1H), 7.45-7.60 (m, 4H), 7.32- 7.37 (m, 2H), 5.37 (s, 1H), 5.18 (s, 2H), 5.10 (s, 1H), 4.97 (s, 2H), 4.87 (s, 1H), 4.80 (s, 1H), 4.69-4.73 (m, 1H), 4.60-4.63 (m, 1H), 4.28-4.38 (m, 3H), 4.18-4.22 (m, 1H), 3.81-4.15 (m, 11H), 3.59-3.67 (m, 2H), 3.41 (s, 3H), 3.29 (s, 2H), 2.85-2.93 (m, 3H), 2.67-2.74 (m, 2H), 2.45- 2.59 (m, 3H), 2.29-2.89 (m, 3H), 2.15-2.26 (m, 5H), 1.84-2.12 (m, 8H), 1.71-1.78 (m, 2H), 1.42- 1.50 (m, 2H), 1.28-1.35 (m, 8H), 1.07-1.13 (m, 3H), 0.88-0.92 (m, 1H); LCMS (ESI): m / z [M + H]+1077.5, found 1077.3.

[0214] Example 5: Synthesis of LUX126-1

[0215] Scheme 5:

[0216] Step 1: LUX126-2

[0217] A mixture of AB313-101 (2.0 g, 6.58 mmol) in 11 mL acetone was stirred at rt, followed by adding a mixture of CrO3(1.97 g, 19.73 mmol) in 1.8 mL H2SO4and 7.2 mL H2O dropwise at 0-5 ^C. The resulting mixture was stirred for 7 h at 0-5 ºC. Then 5.5 mL i-PrOH was added to the mixture, and stirring was continued for additional 30 min. The mixture was concentrated, and the residue was partitioned with 5.5mL EA and 5.5 mL water. The aqueous phase was separated, extracted with EA (5 mL×3). All the organic phases were combined, dried withNa2SO4, and filtered. The filtrate was concentrated, and the residue was purified directly with silica gel column with DCM / MeOH to afford LUX126-2 (1.47g) as a yellow liquid.1H NMR (400 MHz, CDCl3) δ 8.58 (bs, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.12-4.24 (m, 4H), 3.60-3.81 (m, 6H), 2.46 (s, 3H); LCMS (ESI): m / z [M + NH4+]+336.1, found 336.0.

[0218] Step 2: LUX126-2-SM-1

[0219] A mixture of LUX126-2 (930 mg, 2.92 mmol) in 9.3 mL DCM and 0.025 mL DMF was stirred under N2, followed by adding (COCl)2 (0.62 mL, 7.28 mmol) dropwise at 0-5 ºC. The resulting mixture was stirred for 2.5 h at rt and then was concentrated. The 1.14 g crude product was used at next step without any purification.

[0220] Step 3: LUX126-3

[0221] LUX115-5 (200 mg, 0.975 mmol) in 20 mL DCM was stirred under N2, followed by adding a mixture of the crude LUX126-2-SM-1 (1.14 g) and 2 mL DCM dropwise at 0-5 ºC. The resulting mixture was stirred for 20 h at 20-25 ^C. The mixture was cooled to 0-5 ºC, then 8 mL saturated aqueous NaHCO3 was added. The organic phase and the aqueous phase were separated. The aqueous phase was extracted with DCM (5 mL×2). All the organic phases were combined, washed with saturated aqueous NaHCO3(5 mL×2), dried with Na2SO4, and filtered, and the filtrate was concentrated. The residue was purified directly with silica gel column with EA / PE to afford LUX126-3 (181 mg) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=7.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 3H), 7.42-7.56 (m, 4H), 7.30-7.34 (m, 4H), 5.12 (s, 2H), 4.92 (s, 2H), 4.20 (t, J=4.2 Hz, 2H), 3.86-3.88 (m, 2H), 3.74-3.77 (m, 4H), 2.42 (s, 3H); LCMS (ESI): m / z [M + H]+506.1, found 506.0.

[0222] Step 4: LUX126-5

[0223] A mixture of LUX126-3 (180 mg, 0.356 mmol), LUC126-4 (108.7 mg, 1.782 mmol) and DIPEA (138 mg, 1.07 mmol) in 11 mL ACN was stirred under N2. The resulting mixture was heat up to 70 ºC and stirred for 7 h. The mixture was concentrated directly under vacuum. Then 8 mL H2O and 10 mL DCM were added to the residue. The aqueous phase was separated and extracted with DCM (5mL×2), and all the organic phases were combined, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified directly using HPCL with C18 column with CH3CN / 0.05% formic acid in water to afford LUX126-5 (115 mg) as a yellow solid. LCMS (ESI): m / z [M + H]+395.2, found 395.1.

[0224] Step 5: LUX124-SM-1

[0225] A mixture of AB175-10 (500 mg, 0.684 mmol) in 10 mL MeOH and 2.5 mL H2O was stirred, followed by adding NaIO4(292 mg, 1.37 mmol) at 0-5 ºC. The resulting mixture was stirred for 2.5 h at rt, then 5 mL saturated aqueous Na2S2O3 solution was added. The resulting mixture was stirred for 30 min. Then 10 mL DCM was added, and the aqueous phase was separated and extracted with DCM (10mL×3). All the organic phases were combined, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified directly with silica gel column with DCM / MeOH to afford LUX124-SM-1 (450 mg) as a white solid.1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 5.07 (s, 1H), 4.93 (s, 1H), 4.89 (s, 1H), 4.80 (s, 1H), 4.69 (t, J=4.0 Hz, 1H), 4.60 (t, J=4.0 Hz, 1H), 4.27-4.37 (m, 3H), 4.19 (t, J=4.2 Hz, 1H), 4.02-4.15 (m, 3H), 3.97 (t, J=10.4 Hz, 1H), 3.85-3.90 (m, 1H), 3.58-3.66 (m, 2H), 3.37 (s, 3H), 2.81-2.94 (m, 3H), 2.72 (dd, J=10.4, 16.4 Hz, 1H), 2.40-2.59 (m, 3H), 2.15-2.34 (m, 8H), 1.87-2.10 (m, 5H), 1.67-1.76 (m, 3H), 1.28-1.48 (m, 6H), 1.04-1.13 (m, 4H).

[0226] Step 6: LUX126-1

[0227] A mixture of LUX124-SM-1 (93.5 mg, 0.134 mmol) in 11.2 mL 1,2-dichloroethane (“DCE”) was stirred under N2, which followed by LUX126-5 (95 mg, 0.241 mmol) and acetic acid (16 mg, 0.268 mmol) was added at rt. The resulting mixture was stirred for 2.5 h at rt, then NaBH(OAc)3 (56.7 mg, 0.268 mmol) was added and the mixture was stirred for 2 h at rt. About 5 mL phosphate buffer (pH=7.0) was added and layers were separated. The aqueous phase was extracted with DCM (10mL×2). All the organic phases were combined, dried with Na2SO4, filtered, and the filtrate was concentrated. The residue was purified directly using HPLC with C18 column with CH3CN / 0.05% aqueous formic acid to afford LUX126-1 (37 mg) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.09 (d, J=7.6Hz, 1H), 7.82-7.87 (m, 1H), 7.55 (t, J=7.2 Hz, 2H), 7.49-7.51 (m, 1H), 7.43-7.58 (m, 1H), 7.31-7.35 (m, 2H), 5.16 (s, 2H), 5.09 (s, 1H), 4.98 (s, 2H), 4.96 (s, 1H), 4.91 (s, 1H), 4.81 (s, 1H), 4.71 (t, J=4.8 Hz, 1H), 4.62 (t, J=4.0 Hz, 1H), 4.27-4.38 (m, 3H), 4.20 (dd, J=4.4, 6.0 Hz, 1H), 4.08-4.15 (m, 1H), 4.04 (dd, J=4.4, 6.4 Hz, 1H), 3.90-3.99 (m, 3H), 3.81-3.87 (m, 1H), 3.76-3.80 (m, 2H), 3.61-3.71 (m, 7H), 3.43 (s, 3H), 3.23 (d, J=2.8 Hz, 1H), 2.78-2.93 (m, 7H), 2.72 (dd, J=10.4, 16.4 Hz, 1H), 2.40-2.57 (m, 3H), 2.16-2.34 (m, 8H), 1.82-1.99 (m, 5H), 1.55-1.76 (m, 5H), 1.29-1.49 (m, 6H), 1.05-1.14 (m, 4H); LCMS (ESI): m / z [M + H]+1077.5, found 1077.1 Example 6: Biological Assays

[0228] In vitro cell based assay for their anti-cancer activities:

[0229] Materials and Methods

[0230] The human prostate cancer cell lines LNCaP, MDA PCa2b, DU145, PC-3, and AsPC-1 were purchased from American Type Culture Collection (CRL1740, CRL2422, HTB81, CRL1435, and CRL1682), and maintained according to ATCC recommendations. Compound LUX106-6 (or LUX1) prepared above, Eribulin (mesylate; CAS: 441045-17-6) and Monomethyl Auristatin E (MMAE; CAS: 474645-27-7) were dissolved in DMSO, respectively, and freshly diluted in appropriate medium in each experiment.

[0231] Measurement of Cell Viability

[0232] Du-145 cells were seeded in 96 well plates and treated for 72-96 h with various concentrations of compounds. Cell viability was determined using the CellTiter- Glo®luminescent assay (CTG, Promega, Madison, WI, USA), according to manufacturer’s recommendation (CellTiter®-Glo Luminescent Cell Viability Assay, Technical Bulletin, TB 288; Promega). Luminescence for determination of cell viability (%) was measured using the Spectramax iD3 microplate reader. IC50 were calculated using GraphPad Prism version 5.00 (GraphPad Software, San Diego, CA, USA).

[0233] Cell viability results in DU145 for selected compounds according to CTG assay are shown in FIGs.1-9, respectively, and summarized in Table 2. FIG.1 shows cell viability results for two batches of LUX106-6. FIG.2 shows cell viability results for two batches of LUX106-6 and LUX106-8. FIG.3 shows cell viability results for two batches of LUX106-6 and LUX106- 16. FIG.4 shows cell viability results for two batches of LUX106-6 and LUX106-25. FIG.5 shows cell viability results for two batches of LUX106-6 and LUX106-41. FIG.6 shows cell viability results for two batches of LUX106-6 and LUX106-51. FIG.7 shows cell viability results for two batches of LUX106-6 and LUX106-58. FIG.8 shows cell viability results for two batches of LUX106-6 and LUX115-20. FIG.9 shows cell viability results for Eribulin and LUX126-1.

[0234] Table 2. Summary of Cell Viability Assay Results

[0235] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutionswill now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein: X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, *– NR11– CR2R3–, –CR2R3–NR11–CR2R3–, *–O–CR2R3–, or –CR2R3–O–CR2R3–; * denotes a connection to R1; R1is ; RG is a reactive group; L is a linker connecting X and RG; RAis –CR4R5R6; each R2, R3, R4, R5and R6is independently hydrogen, halogen, –U, or –G; or L and R4, together with atoms to which they are attached, form a ring, wherein the ring is optionally substituted with 1, 2, or 3 R9; –U is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C2- C6alkenyl, or C2-C6alkynyl; wherein each C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with 1, 2, or 3 R9and / or 1 or 2 –G; –G is independently C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; wherein each C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R11is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; andR9is independently halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4heteroalkyl, –C(O)H, –C(O)OH, –CN, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, –C(O)(C1-C4 alkyl), –C(O)O(C1-C4 alkyl), –C(O)NH2, –C(O)NH(C1-C4 alkyl), –C(O)N(C1-C4alkyl)2, –NH2, –NH(C1-C4alkyl), –N(C1-C4alkyl)2, –NH(C2-C4alkylene)-OH, –NH(C2-C4 alkylene)-O-(C1-C4 alkyl), –OH, –O(C1-C4 alkyl), –O(C1-C4 haloalkyl), –O(C2-C4 alkylene)-NH2, –O(C2-C4 alkylene)-NH-(C1-C4 alkyl), –O(C2-C4 alkylene)-N-(C1-C4alkyl)2, –O(C1-C4alkylene)-C(O)OH, –O(C1-C4alkylene)-C(O)O- (C1-C4alkyl), –O(C2-C4alkenyl), –O(C1-C4alkylene)-(C6-C10aryl), –O(C1-C4alkylene)- (5- to 10-membered heteroaryl), –O(C6-C10 aryl), –SH, S(O)2OH, –S(O)2(C1-C4 alkyl), – S(O)2NH2, –S(O)2NH(C1-C4alkyl), or –S(O)2N(C1-C4alkyl)2; or two R9, together with atoms to which they are attached, form a C3-C10cycloalkyl or a 3- to 10-membered heterocycloalkyl ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ia:wherein each R1to R6is as defined in claim 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ib:wherein each RA, R2, R3, RG, and L is as defined in claim 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ic:wherein each RG and L is as defined in claim 1; and wherein RDis hydrogen, halogen, –U, or – .

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Id:wherein each RG and L is as defined in claim 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula Ie:wherein each R4, R5, RG, and L is as defined in claim 1.

7. The compound of any one of claims 1-6, wherein:# denotes a connection to RG; each L1and L2is independently a bond, –O–, –NH–, C1-C6alkylene, C1-C6haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6alkylene, C1-C6haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; and each o and p is independently an integer of 1-6.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula II:wherein: RG is as defined in claim 1;heterocycle or heteroaryl; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl,alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; n is an integer of 0-4; each o and p is independently an integer of 1-6; and each Rais independently R9.

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IIa:wherein: R5and R6are as defined in claim 1; L1and L2are as defined in claim 8; each o and p is independently an integer of 1-6; X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; Y is CH or N; Z is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; each Rais independently R9; and n is an integer of 0-4.

10. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IIb:wherein: L1and L2are as defined in claim 9; each o and p is independently an integer of 1-6; Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

11. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IIc:wherein: L1and L2are as defined in claim 9; each o and p is independently an integer of 1-6; Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

12. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula IId:WSGR Docket No.65728-701.601wherein: L1and L2are as defined in claim 9; each o and p is independently an integer of 1-6; Y is –CH– or N; each Rais independently R9; and n is an integer of 0-4.

13. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, whereinheteroaryl.

14. Theclaim 8, wherein15. The compound of any one of claims 8-14, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 0.

16. The compound of any one of claims 8-14, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 1.

17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein Rais methyl, ethyl, trifluoromethyl, or halogen.

18. The compound of any one of claims 1-17, wherein: ,LG is a leaving group; RBis independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; RCis independently C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; R9is as defined in claim 1; each R12is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and q is an integer of 0-3.

19. The compound of claim 18, wherein LG is halide.

20. The compound of claim 18, wherein LG is nonaflate, triflate, fluorosulfonate, tosylate, mesylate, or besylate.

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is: ,,.

22. A compound of any one of Formulas III-VI:or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, *– NR11– CR2R3–, –CR2R3–NR11–CR2R3–, *–O–CR2R3–, or –CR2R3–O–CR2R3–; * denotes a connection to R1; R1is ; RG is a reactive group; L is a linker connecting X and RG; RAis –CR4R5R6; RNis –OH, –NH2, or –NH–C(O)OR20; each R2, R3, R4, R5and R6is independently hydrogen, halogen, –U, or –G; or L and R4, together with atoms to which they are attached, form a ring, wherein the ring is optionally substituted with 1, 2, or 3 R9; –U is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C2- C6 alkenyl, or C2-C6 alkynyl; wherein each C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with 1, 2, or 3 R9and / or 1 or 2 –G; –G is independently C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; wherein each C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R11is independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; R9is independently halogen, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4heteroalkyl, –C(O)H, –C(O)OH, –CN, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, –C(O)(C1-C4alkyl), –C(O)O(C1-C4alkyl), –C(O)NH2, –C(O)NH(C1-C4alkyl), –C(O)N(C1-C4alkyl)2, –NH2, –NH(C1-C4alkyl), –N(C1-C4alkyl)2, –NH(C2-C4alkylene)-OH, –NH(C2-C4 alkylene)-O-(C1-C4 alkyl), –OH, –O(C1-C4 alkyl), –O(C1-C4 haloalkyl), –O(C2-C4 alkylene)-NH2, –O(C2-C4 alkylene)-NH-(C1-C4 alkyl), –O(C2-C4 alkylene)-N-(C1-C4alkyl)2, –O(C1-C4alkylene)-C(O)OH, –O(C1-C4alkylene)-C(O)O- (C1-C4 alkyl), –O(C2-C4 alkenyl), –O(C1-C4 alkylene)-(C6-C10 aryl), –O(C1-C4 alkylene)- (5- to 10-membered heteroaryl), –O(C6-C10 aryl), –SH, S(O)2OH, –S(O)2(C1-C4 alkyl), – S(O)2NH2, –S(O)2NH(C1-C4alkyl), or –S(O)2N(C1-C4alkyl)2; or two R9, together withatoms to which they are attached, form a C3-C10cycloalkyl or a 3- to 10-membered heterocycloalkyl ring; R20is independently C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, or a monosaccharide, or a monosaccharide derivative; R22is –CR4R5R23; and R23is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl; wherein each C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1- C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with a hydroxy, or 1, 2, or 3 R9and / or 1 or 2 –G.

23. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to any one of Formulas IIIa-VIa:wherein each R1to R6, R22, and RNis as defined in claim 22.

24. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to any one of Formulas IIIb-VIb:wherein each RA, R2, R3, R22, RN, RG, and L is as defined in claim 22.

25. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to an one of Formulas IIIc-VIc:wherein each R22, RN, RG and L is as defined in claim 22; and wherein RDis hydrogen, halogen, –U, or –G.

26. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formulas IIId or Vd:wherein each RN, RG and L is as defined in claim 22.

27. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formulas IIIe or Ve:wherein each R4, R5, RN, RG, and L is as defined in claim 22.

28. The compound of any one of claims 22-27, wherein:# denotes a connection to RG; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10 aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6alkylene, C1-C6haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; and each o and p is independently an integer of 1-6.

29. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VII:wherein: RN, RG is as defined in claim 22;heterocycle or heteroaryl; each L1and L2is independently a bond, –O–, –NH–, C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6alkoxy–, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10cycloalkylene, 3- to 10- membered heterocycloalkylene, –C6-C10 aryl–, or 5- to 10-membered heteroarylene, wherein each C1-C6 alkylene, C1-C6 haloalkylene, –C1-C6 alkoxy–, C1-C6 heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, alkylamino, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, C3-C10 cycloalkylene, 3- to 10-membered heterocycloalkylene, –C6-C10 aryl–, and 5- to 10-membered heteroarylene is optionally substituted with 1, 2, or 3 R9; n is an integer of 0-4; each o and p is independently an integer of 1-6; and each Rais independently R9.

30. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIa:wherein: each of RN, R5and R6is as defined in claim 22; L1and L2are as defined in claim 29; each o and p is independently an integer of 1-6; X is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–; Y is CH or N; Z is a bond, –CH2–, –CH2–CH2–, –CR2R3–, – CR2R3–CR2R3–, –CR2=CR3–, –NR11– CR2R3–, –CR2R3–NR11–CR2R3–, –O–CR2R3–, or –CR2R3–O–CR2R3–;each Rais independently R9; and n is an integer of 0-4.

31. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIb:wherein: L1and L2are as defined in claim 29; RNis as defined in claim 22; each o and p is independently an integer of 1-6; Y is CH or N; each Rais independently R9; and n is an integer of 0-4.

32. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIIc:wherein: L1and L2are as defined in claim 29; RNis as defined in claim 22; each o and p is independently an integer of 1-6; Y is CH or N;each Rais independently R9; and n is an integer of 0-4.

33. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is according to Formula VIId:wherein: L1and L2are as defined in claim 29; RNis as defined in claim 22; each o and p is independently an integer of 1-6; Y is –CH– or N; each Rais independently R9; and n is an integer of 0-4.

34. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, whereinheteroaryl.

36. The compound of any one of claims 29-35, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 0.

37. The compound of any one of claims 29-35, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein n is 1.

38. The compound of claim 37, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein Rais methyl, ethyl, trifluoromethyl, or halogen.

39. The compound of any one of claims 22-38, wherein: ,LG is a leaving group; RBis independently hydrogen, C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; RCis independently C1-C6 alkyl, cycloalkyl-alkylene, C1-C6 haloalkyl, heteroalkyl- alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl- alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl;R9is as defined in claim 22; each R12is independently hydrogen, C1-C6alkyl, cycloalkyl-alkylene, C1-C6haloalkyl, heteroalkyl-alkylene, heteroaryl-alkylene, heterocycloalkyl-alkylene, aryl-alkylene, heteroaryl-alkylene, alkylamino-alkylene, alkylthio-alkylene, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; and q is an integer of 0-3.

40. The compound of claim 39, wherein LG is halide.

41. The compound of claim 39, wherein LG is nonaflate, triflate, fluorosulfonate, tosylate, mesylate, or besylate.

42. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein the compound is: ,,43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.

44. A method of treating a cancer in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or a pharmaceutical composition of claim 43.

45. A method of treating a cancer in a mammal suffering therefrom with a conjugate of a compound of any one of claims 1-42 linked with (i) a cell surface targeting agent, or (ii) a long acting reagent, comprising: administering to the mammal a therapeutically effective amount of (i) the conjugate of the compound of any one of claims 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, or (ii) a pharmaceutical composition comprising the conjugate of the compound of any one of claims 1-42, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier, wherein the cell surface targeting agent is a small molecule, a polypeptide, or an antibody, and wherein the long acting reagent comprising a polymer, human serum albumin (HSA), or a nanoparticle.

46. A conjugate comprising: (i) a compound of any one of claims 1-42 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof; and (ii) a cell surface targeting agent or a long acting reagent linked to the compound, wherein the cell surface targeting agent is a small molecule, a polypeptide, or an antibody, and wherein the long acting reagent comprising a polymer, human serum albumin (HSA), or a nanoparticle.

47. A pharmaceutical composition comprising a conjugate of claim 46, and a pharmaceutically acceptable carrier.

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