Carborane derivatives for therapeutic applications

Abstract

The present disclosure provides a compound having the structure of Formula (I): X-(Y)n-Z, wherein X is a drug comprising an anticancer agent; Y is a cleavable linker selected from esters, ethers, carbamates, amides, ketones, aldehydes, carboxylates, peroxides, anhydrides, amidines, hydrazones, imines, imides, azides, cyanates, nitriles, thiols, sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, and silyl ethers; and Z is a carborane isomer comprising ortho-, meta-, or para-carborane; or a pharmaceutically acceptable salt or solvate thereof. The disclosure also provides methods of treating cancer using the compound and pharmaceutical compositions comprising the compound and a pharmaceutically acceptable excipient.

Description

Docket No.: CAVE-01-PCT CARBORANE DERIVATIVES FOR THERAPEUTIC APPLICATIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application Serial No. 63 / 623,666 filed on January 22, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not Applicable. FIELD

[0003] The invention provides carborane based prodrug compounds, pharmaceutical compositions, and their use in the treatment of medical conditions, such as cancer. INTRODUCTION

[0004] Prodrugs are pharmacologically inactive compounds that can be converted within the body to active drug molecules. This approach is often employed to improve the pharmacokinetic and pharmacodynamic properties of therapeutic agents. By modifying the chemical structure of an active drug, prodrugs can enhance characteristics such as solubility, absorption, distribution, and metabolism, ultimately leading to improved efficacy and reduced side effects.

[0005] The development of prodrugs has become an important strategy in drug design and delivery, with estimates suggesting that up to 10% of marketed drugs can be classified as prodrugs. These compounds are typically designed to undergo enzymatic or chemical transformations in vivo, releasing the active drug at the desired site of action. This targeted approach can help overcome various barriers to drug efficacy, including poor oral bioavailability, limited tissue penetration, and rapid clearance from the body.

[0006] One area of particular interest in prodrug development is oncology, where the need for more effective and less toxic treatments remains a significant challenge. Cancer therapies often suffer from narrow therapeutic windows, where the dose required for efficacy is close to the dose that causes unacceptable toxicity. Prodrug strategies offer the potential toDocket No.: CAVE-01-PCT widen this therapeutic window by improving drug targeting and reducing systemic exposure to active compounds.

[0007] Despite the promise of prodrug approaches, several challenges persist in their development and application. These include ensuring efficient and selective activation of the prodrug, controlling the rate of drug release, and maintaining stability during formulation and storage. Additionally, the complexity of biological systems can lead to variability in prodrug activation between individuals, potentially affecting treatment outcomes.

[0008] As the field of drug delivery continues to advance, there is growing interest in novel molecular structures and chemical moieties that can be utilized in prodrug design. These innovations aim to provide greater control over drug release kinetics, improve targeting to specific tissues or cellular compartments, and enhance the overall therapeutic index of anticancer agents.

[0009] The ongoing search for improved anticancer therapies drives the exploration of new prodrug strategies that can address the limitations of current treatments while leveraging advances in our understanding of cancer biology and drug delivery technologies. SUMMARY

[0010] The present invention provides novel carborane-based prodrug compounds, pharmaceutical compositions comprising these compounds, and methods for their use in treating cancer.

[0011] In another aspect, there is provided a compound having the structure of Formula (I), or pharmaceutically accepted salt or solvate thereof: (I). is an ortho-, meta-, or para-carborane.

[0013] In another aspect, there is provided a pharmaceutical composition which includes a compound of Formula (I) and a pharmaceutically acceptable excipient.

[0014] In another aspect, there is provided a method of treating a subject withDocket No.: CAVE-01-PCT medical disorders. The method includes contacting a subject with an effective amount of a compound of Formula (I) thereby treating the medical disorder.

[0015] In another aspect, the compound of Formula I has the Formula (Ia) as set forth below and found in FIG.2:(Ia).

[0016] The structures of Formula (Ia) are carbaphostin isomers, including those isomers featured in Table 1: Table 1 Compound Derivative Type Name CAV-001 1-ortho-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 1-(1,2-Dicarba-closo-dodecaboran(12)-yl) ester CAV-002 1-meta-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 1-(1,7-Dicarba-closo-dodecaboran(12)-yl) ester CAV-003 9-ortho-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 9-(1,2-Dicarba-closo-dodecaboran(12)-yl) ester CAV-004 9-meta-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 9-(1,7-Dicarba-closo-dodecaboran(12)-yl) ester CAV-005 3-ortho-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 3-(1,2-Dicarba-closo-dodecaboran(12)-yl) ester CAV-006 2-meta-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 2-(1,7-Dicarba-closo-dodecaboran(12)-yl)Docket No.: CAVE-01-PCT ester CAV-007 2-para-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 2-(1,12-Dicarba-closo-dodecaboran(12)-yl) ester CAV-008 1-para-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, -(1,12-Dicarba-closo-dodecaboran(12)-yl) ester CAV-009 4-ortho-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 4-(1,2-Dicarba-closo-dodecaboran(12)-yl) ester CAV-010 8-ortho-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 8-(1,2-Dicarba-closo-dodecaboran(12)-yl) ester CAV-011 4-meta-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 4-(1,7-Dicarba-closo-dodecaboran(12)-yl) ester CAV-012 11-meta-derivative Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 11-(1,7-Dicarba-closo-dodecaboran(12)-yl) ester

[0017] In another aspect, there is provided a method of treating a subject with cancer. The method includes administering to a subject an effective amount of a compound of the disclosure.

[0018] In another aspect, the method of treating a subject with cancer further includes applying the subject with Boron Neutron Capture Therapy (BNCT) or Proton Boron Capture Therapy (PBCT), or a combination thereof. The method includes the steps of administering to the subject an effective amount of a compound of the disclosure; and followed by applying to the subject an effective amount of neutron or proton beam to the targeted tissues.

[0019] In some aspects, the invention provides a compound having the structure of Formula (I): X-(Y)n-Z, wherein X is a drug comprising an anticancer agent; Y is a cleavable linker selected from esters, ethers, carbamates, amides, ketones, aldehydes, carboxylates, peroxides, anhydrides, amidines, hydrazones, imines, imides, azides, cyanates, nitriles, thiols,Docket No.: CAVE-01-PCT sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, and silyl ethers; and Z is a carborane isomer comprising ortho-, meta-, or para-carborane; or a pharmaceutically acceptable salt or solvate thereof. In some cases, n may be an integer from 1 to 10.

[0020] In some implementations, the carborane isomer may be 1,2-dicarba-closo- dodecacarborane(12), 1,7-dicarba-closo-dodecacarborane(12), or 1,12-dicarba-closo- dodecacarborane(12). The cleavable linker may be an ester in some aspects of the invention. In some cases, the ester may be formed between a carboxylic acid group of the anticancer agent and a hydroxyl group of the carborane isomer.

[0021] The anticancer agent may be a tyrosine kinase inhibitor in some implementations. In some aspects, the tyrosine kinase inhibitor may be selected from imatinib, dasatinib, nilotinib, and bosutinib.

[0022] The invention also provides pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable excipient. In some cases, the pharmaceutically acceptable excipient may be selected from diluents, binders, lubricants, disintegrants, colorants, flavoring agents, and combinations thereof.

[0023] Methods of treating cancer in a subject are also provided, which may involve administering to the subject an effective amount of a compound of Formula (I). In some implementations, the method may further include applying Boron Neutron Capture Therapy (BNCT) or Proton Boron Capture Therapy (PBCT) to the subject after administering the compound.

[0024] The invention also encompasses methods of synthesizing compounds of Formula (I), which may include providing a carborane isomer, functionalizing the carborane isomer with a hydroxyl group, and reacting the hydroxyl-functionalized carborane with an activated form of the anticancer agent to form the cleavable linker. In some cases, the activated form of the anticancer agent may be an acid chloride.

[0025] Additionally, the invention provides kits comprising a compound of Formula (I) and instructions for administering the compound to a subject for treating cancer. In some implementations, the kit may further include diluents or solvents for reconstituting or diluting the compound, syringes, needles, or other delivery devices, alcohol swabs for sterilization, topical anesthetics for injection site preparation, and / or adhesive bandages or gauze pads..

[0026] The compounds, compositions, and methods of the present invention may provide improved therapeutic options for cancer treatment, potentially offering enhanced efficacy, reduced side effects, and improved patient outcomes compared to conventionalDocket No.: CAVE-01-PCT anticancer therapies.

[0027] These and other features, aspects and advantages of the present teachings will become better understood with reference to the following description, examples and appended claims. DRAWINGS

[0028] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0029] FIG.1 illustrates a schematic diagram of a carborane-based prodrug system, according to aspects of the present disclosure.

[0030] FIG.2 depicts a structural chemical formula of a carborane-based prodrug compound, according to an embodiment.

[0031] FIG.3 shows a comparison of pKa values for carborane isomers and organic compounds, according to aspects of the present disclosure.

[0032] FIG.4 illustrates a graph showing relationships between chemical structure and properties, according to an embodiment.

[0033] FIG.5 depicts the chemical development progression from AG 957 to Carbaphostin, according to aspects of the present disclosure.

[0034] FIG.6 shows a chemical reaction scheme for synthesizing carborane derivatives, according to an embodiment.

[0035] FIG.7 illustrates a chemical reaction scheme for forming an ester on a carborane cage, according to aspects of the present disclosure.

[0036] FIG.8 depicts a synthetic scheme for producing compound CAV-001, according to an embodiment.

[0037] FIG.9 shows a synthetic scheme for producing compound CAV-002, according to aspects of the present disclosure.

[0038] FIG.10 illustrates a synthetic scheme for preparing compound CAV-003, according to an embodiment.

[0039] FIG.11 depicts a synthetic scheme for producing compound CAV-004, according to aspects of the present disclosure.

[0040] FIG.12 shows a synthetic scheme for producing compound CAV-005, according to an embodiment.

[0041] FIG.13 illustrates a synthetic scheme for preparing compound CAV-006,Docket No.: CAVE-01-PCT according to aspects of the present disclosure.

[0042] FIG.14 depicts a synthetic scheme for producing compound CAV-007, according to an embodiment.

[0043] FIG.15 shows a synthetic scheme for preparing compound CAV-008, according to aspects of the present disclosure.

[0044] FIG.16 illustrates a bar graph comparing IC50 values of CAV-001 and adaphostin, according to an embodiment.

[0045] FIG.17 depicts a graph comparing IC50 values of CAV-002 and adaphostin, according to aspects of the present disclosure.

[0046] FIG.18 shows a bar graph comparing IC50 values of CAV-003 and adaphostin, according to an embodiment.

[0047] FIG.19 illustrates a bar graph comparing IC50 values of CAV-004 and adaphostin, according to aspects of the present disclosure.

[0048] FIG.20 depicts chromatographic traces showing LC-MS analysis results for CAV-001, according to an embodiment.

[0049] FIG.21 shows chromatographic traces of analytical data for a chemical compound, according to aspects of the present disclosure.

[0050] FIG.22 illustrates a proton nuclear magnetic resonance spectrum, according to an embodiment.

[0051] FIG.23 depicts a boron-11 NMR spectrum of CAV-002, according to aspects of the present disclosure.

[0052] FIG.24 shows chromatographic traces of analytical data for a chemical compound, according to an embodiment.

[0053] FIG.25 illustrates a proton nuclear magnetic resonance spectrum, according to aspects of the present disclosure.

[0054] FIG.26 depicts a boron-11 NMR spectrum, according to an embodiment.

[0055] FIG.27 shows chromatographic traces of analytical data for compound CAV-003, according to aspects of the present disclosure.

[0056] FIG.28 illustrates chromatographic traces showing boron-11 NMR analysis of CAV-003, according to an embodiment.

[0057] FIG.29 depicts a proton nuclear magnetic resonance spectrum, according to aspects of the present disclosure.

[0058] FIG.30 shows a boron-11 NMR spectrum, according to an embodiment.

[0059] FIG.31 illustrates chromatography traces showing analytical data for aDocket No.: CAVE-01-PCT compound, according to aspects of the present disclosure.

[0060] FIG.32 depicts chromatographic traces showing analytical data, according to an embodiment.

[0061] FIG.33 shows a proton nuclear magnetic resonance spectrum, according to aspects of the present disclosure.

[0062] FIG.34 illustrates a boron nuclear magnetic resonance spectrum, according to an embodiment.

[0063] FIG.35 depicts a graph showing compound half-lives in PBS at various pH levels, according to aspects of the present disclosure. DETAILED DESCRIPTION

[0064] Abbreviations and Definitions

[0065] To facilitate understanding of the invention, a number of terms and abbreviations as used herein are defined below as follows:

[0066] The term “carborane” refers to a class of boron compound of general formula [(CH)a(BH)mHb]cwhere c can be positive, negative or zero. The CH groups occupyother hydrogen atoms are either bridging or terminal. In terms of scope, carboranes can have as few as 5 and as many as 14 atoms in the cage framework. The majority have two cage carbon atoms. The corresponding C-alkyl and B-alkyl analogues are also known in a few cases.

[0067] The most common and chemically very robust, carboranes are those based on icosahedral [C2B10H12] clusters. The carbon and boron atoms can be arranged such that closely related isomers (ortho-, meta- and para-) are possible, which occupy approximately the same volume as a rotated phenyl ring.

[0068] Geometrical isomers of carboranes can exist because of the various locations of carbon within the cage. Isomers necessitate the use of the numerical prefixes in a compound's name. The closo-dicarbadecaborane can exist in three isomers: 1,2-, 1,7-, and 1,12-C2B10H12.

[0069] Where moieties are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical moieties that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0070] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbonDocket No.: CAVE-01-PCT radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4- pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0071] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by –CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, including those groups having 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0072] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0073] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and a heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O- CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)- CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, –CH=CH- N(CH3)-CH3, O-CH3, -O-CH2-CH3,and –CN. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and –CH2-S- CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andDocket No.: CAVE-01-PCT the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula –C(O)2R'- represents both –C(O)2R'- and –R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', - SR', and / or -SO2R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R''or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R''or the like.

[0074] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0075] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituent moieties for each of the above noted aryl and heteroaryl ring systems may be selected from the group of acceptable substituent moieties described below.

[0076] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingDocket No.: CAVE-01-PCT those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1- naphthyloxy)propyl, and the like).

[0077] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0078] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituent moieties for each type of radical are provided below.

[0079] Substituent moieties for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =O, =NR', =N-OR', -NR'R", -SR', - halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR- C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and –NO2 in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R', R", R"' and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1- 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and –CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0080] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficientDocket No.: CAVE-01-PCT amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0081] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0082] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0083] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.Docket No.: CAVE-01-PCT

[0084] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and / or isolate.

[0085] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0086] The term "treating" refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. For example, the methods of the invention successfully treat a patient’s delirium by decreasing the incidence of disturbances in consciousness or cognition.

[0087] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. It is understood that the claimed subject matter encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound provided herein, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms and how to determine antiproliferative activity using the standard tests described herein, or using other similar tests which are well known in the art.

[0088] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as high- performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purificationDocket No.: CAVE-01-PCT would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.

[0089] As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is used as is generally understood by those of skill in this art.

[0090] Compositions

[0091] In general, prodrugs have three different sections as shown below, with the caveat that these sections may overlap: Prodrug Mask-[Cleavable Linker]n-Active Molecule. This can also expressed as a simplified chemical formula: X-(Y)n-Z which may alternatively be referred to as Formula (I) where X is a drug comprising an anticancer agent, Y is a cleavable linker is selected from esters, ethers, carbamates, amides, ketones, aldehyde, carboxylates, peroxides, anhydrides, amidines, hydrozones, imines, imides, azides, cyanates, nitriles, thiols, sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, boronic acids, and silyl ethers, Z is a carborane isomer comprising ortho-, meta-, or para-carborane, and n is an integer from 1 to 10. An example of Formula (I) is provided in FIG.1 and as Formula (Ia) provided in FIG. 2.

[0092] In a first aspect, there is provided a compound having the structure of Formula (I), or pharmaceutically accepted salt or solvate thereof which is provided in FIG.1. With reference to Formula (I), carboranes are molecules which combine boron and carbon to create hybrid molecules. The carboranes of Formula (I) are of the 1,2-dicarba-closo- dodecacarborane(12), 1,7-dicarba-closo-dodecacarborane(12) and 1,12-dicarba-closo- dodecacarborane(12); more commonly known as ortho-, meta-, and para-carborane, based upon the relative positions of the carbon atoms, as demonstrated in the above referenced basic formula.

[0093] Basic schematic of carborane prodrug illustrating the three positions, ortho-, meta- and para- that may be occupied by the carbon atoms in dicarba-closo-carborane. These sp3-hybridized, icosahedral carboranes have a strong dipole moment that varies by isomer onDocket No.: CAVE-01-PCT the order of ortho->> meta->para-. This dipole moment leads to the molecule being electron withdrawing and electron donating, depending on the atom which is substituted. For example, on ortho-carborane position 1, which is a carbon atom, is strongly electron withdrawing. Conversely, position 9, which is a boron atom antipodal to the carbon atoms, is strongly electron donating. Judicious choice of carborane isomer is capable of varying the pKa of their carboxylic acid derivatives by more than 5 orders of magnitude as shown in Scheme 1 depicted in FIG.3. The strong dipole of carboranes facilitates strongly electron-withdrawing or electron-features with no steric difference.

[0094] This same dipole in the carboranes also leads to different hydrophobicities, ranging from para->>meta->ortho. This effect is drastic in small molecules, where just varying the isomer can result in a change of lipophilicities of nearly an order of magnitude. And all isomers are of identical steric size. Given these properties, it would be clear to someone in the art that the number of H-bond donor, H-bond acceptors and the lipophilicity of a molecule could be varied simply by the choice of carborane isomer; meaning three of Lipinski’s Rule of Five can be varied without any steric variance.

[0095] As shown in FIG.4, various carborane isomers can have significant effects on the LogP and IC50 values of an exemplary compound. “IC50” refers, in the customary sense, to the concentration of a drug required to achieve half maximal response. The dipole in carboranes once again shows up in the carborane’s ability to vary logP significantly in a molecule, leading to IC50 values that vary by more than 2 orders of magnitude.

[0096] As used herein, the term “Drug” refers to a moiety of the active molecule having activities to treat various diseases or medical disorders. In some embodiments, the drug moiety is an anticancer agent. Exemplary anticancer agents include but are not limited to: ABRAXANE; abiraterone; ace-11; aclarubicin; acivicin; acodazole hydrochloride; acronine; actinomycin;acylfulvene; adecypenol; adozelesin; adriamycin; aldesleukin; all trans-retinoic acid (ATRA); altretamine; ambamustine; ambomycin; ametantrone acetate; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; antarelix; anthramycin; aphidicolin glycinate; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; ARRY-162; ARRY-300; ARRY- 142266; AS703026; asparaginase; asperlin; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; azacitidine; AZD8330; azetepa; azotomycin; balanol; batimastat; BAY 11-7082; BAY 43-9006; BAY 869766; bendamustine; benzochlorins; benzodepa; benzoylstaurosporine; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bisnafideDocket No.: CAVE-01-PCT dimesylate; bistratene A; bisantrene hydrochloride; bleomycin; bleomycin sulfate; busulfan; bizelesin; breflate; bortezomib; brequinar sodium; bropirimine; budotitane; buthionine sulfoximine; bryostatin; cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; castanospermine; cecropin B; cedefingol; celecoxib; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; chlorambucil; Chlorofusin; cirolemycin; cisplatin; CI-1040; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; crisnatol mesylate; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cyclophosphamide; cytarabine; cytarabine ocfosfate; cytolytic factor; cytostatin; dacarbazine; dactinomycin; daunorubicin; daunorubicin hydrochloride; decarbazine; dacliximab; dasatinib; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; didemnin B; didox; diethylnorspermine; dihydro 5 azacytidine; dihydrotaxol; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; docetaxel; doxorubicin; doxorubicin hydrochloride; doxifluridine; droloxifene; droloxifene citrate; dromostanolone propionate; dronabinol; duazomycin; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; edatrexate; eflornithine hydrochloride; eflornithine; elemene; emitefur; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin; epirubicin hydrochloride; epristeride; erbulozole; eribulin;esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; exemestane; fadrozole; fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; floxuridine; fludarabine phosphate; fludarabine; fluorodaunorubicin hydrochloride; forfenimex; formestane; fluorouracil; floxouridine; flurocitabine; fosquidone; fostriecin sodium; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; geldanamycin; gossyphol; GDC-0973; GSK1120212 / trametinib; herceptin; hydroxyurea; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; ibrutinib; idarubicin; idarubicin hydrochloride; ifosfamide; canfosfamide; ilmofosine; iproplatin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imatinib (e.g., GLEEVEC); imiquimod; iobenguane; iododoxorubicin; ipomeanol; irinotecan; irinotecan hydrochloride; irsogladine; isobengazole; isohomohalicondrin B; itasetron; iimofosine; interleukin I1 (including recombinantDocket No.: CAVE-01-PCT interleukin IL-2; or rlL.sub.2); interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leuprorelin; levamisole; liarozole; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lanreotide acetate; lapatinib; letrozole; leucovorin; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; lenalidomide; lenvatinib; losoxantrone hydrochloride; LY294002; pomalidomide; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitonafide; mitoxantrone; mofarotene; molgramostim; mopidamol; mycaperoxide B; myriaporone; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nafarelin; nagrestip; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; nocodazole; nogalamycin; oblimersen (GENASENSE); octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; oxisuran; oxaloplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; porfiromycin; prednisone; prostaglandin J2; pyrazoloacridine; paclitaxel; PD035901; PD184352; PD318026; PD98059; peliomycin; pentamustine; peplomycin sulfate; PKC412; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; podophyllotoxin; polyphenol E; porfimer sodium; porfiromycin; prednimustine; procarbazine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; raltitrexed; ramosetron; retelliptine demethylated; rhizoxin; rituximab; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; riboprine; romidepsin; safingol; safingol hydrochloride; saintopin; sarcophytol A; sargramostim; semustine; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; sonermin; sorafenib; sunitinib; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; Spongistatin 2; Spongistatin 3; Spongistatin 4;Docket No.: CAVE-01-PCT Spongistatin 5; Spongistatin 6; Spongistatin 7; Spongistatin 8; and Spongistatin 9; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; suradista; suramin; swainsonine; SB239063; selumetinib / AZD6244; simtrazene; SP600125; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiroplatin; streptonigrin; streptozocin; sulofenur; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thymalfasin; thymopoietin receptor agonist; thymotrinan; tirapazamine; titanocene bichloride; topsentin; toremifene; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrphostins; talisomycin; TAK-733; taxotere; tegafur; teloxantrone hydrochloride; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trastuzumab; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitors; ubenimex; U0126; uracil mustard; uredepa; vapreotide; variolin B; velaresol; veramine; verteporfin; vinorelbine; vinxaltine; vitaxin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; wortmannin; XL518; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer; zinostatin; and zorubicin hydrochloride.

[0097] Other exemplary anti-cancer agents include Erbulozole (e.g., R-55104); Dolastatin 10 (e.g., DLS-10 and NSC-376128); Mivobulin isethionate (e.g., CI-980); NSC- 639829; Discodermolide (e.g., NVP-XX-A-296); ABT-751 (Abbott; e.g., E-7010); Altorhyrtin A; Altorhyrtin C); Cemadotin hydrochloride (e.g., LU-103793 and NSC-D- 669356); Epothilone A; Epothilone B; Epothilone C; Epothilone D; Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B; 21-hydroxyepothilone D; 26-fluoroepothilone; Auristatin PE (e.g., NSC-654663); Soblidotin (e.g., TZT-1027); LS-4559-P (Pharmacia; e.g., LS-4577); LS-4578 (Pharmacia; e.g., LS-477-P); LS-4477 (Pharmacia); LS-4559 (Pharmacia); RPR-112378 (Aventis); DZ- 3358 (Daiichi); FR-182877 (Fujisawa; e.g., WS-9265B); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); BSF-223651 (BASF; e.g., ILX-651 and LU-223651); SAH-49960 (Lilly / Novartis); SDZ-268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); Cryptophycin 52 (e.g., LY-355703); AC-7739 (Ajinomoto; e.g., AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto; e.g., AVE-8062; AVE-8062A; CS-39-L-Ser.HCl; andDocket No.: CAVE-01-PCT RPR-258062A); Vitilevuamide; Tubulysin A; Canadensol; CA-170 (Curis, Inc.); Centaureidin (e.g., NSC-106969); T-138067 (Tularik; e.g., T-67; TL-138067 and TI- 138067); COBRA-1 (Parker Hughes Institute; e.g., DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin A1 (e.g., BTO-956 and DIME); DDE-313 (Parker Hughes Institute); Fijianolide B; Laulimalide; SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute; e.g., SPIKET-P); 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine; e.g., MF-569); Narcosine (e.g.,NSC-5366); Nascapine; D-24851 (Asta Medica); A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine; e.g., MF-191); TMPN (Arizona State University); Vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol; lnanocine (e.g., NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tuiarik; e.g., T-900607); RPR- 115781 (Aventis); Eleutherobins (e.g., Desmethyleleutherobin; Desaetyleleutherobin; lsoeleutherobin A; and Z-Eleutherobin); Caribaeoside; Caribaeolin; Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); Taccalonolide A; TUB-245 (Aventis); A-259754 (Abbott); Diozostatin; (-)- Phenylahistin (e.g., NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica); Myoseverin B; D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate salt) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium; BPR-OY-007 (National Health Research Institutes); and SSR-250411 (Sanofi)); goserelin; leuprolide; triptolide; homoharringtonine; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA); erlotinib (TARCEVA); cetuximab (ERBITUX); lapatinib (TYKERB); panitumumab (VECTIBIX); vandetanib (CAPRELSA); afatinib / BIBW2992; CI-1033 / canertinib; neratinib / HKI-272; CP- 724714; TAK-285; AST-1306; ARRY334543; ARRY-380; AG-1478; acomitinib / PF299804; OSI-420 / desmethylerlotinib; AZD8931; AEE726; pelitinib / EKB-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5- azathioprine; 5-aza-2' deoxycytidine; 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG); 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; and BMS-599626.

[0098] In some embodiments, the cleavable linkers include but not limited to, esters, ethers, carbamates, amides, ketones, aldehyde, carboxylates, peroxides, anhydrides, amidines, hydrozones, imines, imides, azides, cyanates, nitriles, thiols, sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, boronic acids, silyl ethers etc.; each leading to unique chemical properties depending on theDocket No.: CAVE-01-PCT attachment point to the carborane.

[0099] In one embodiment of an ester prodrug, one could attach an ortho-carborane masking agent at the 1-position (a carbon molecule), which is electron withdrawing, to the parent molecule that would make the bond between the two moieties more stable at low pH while simultaneously making the ester easier to cleave the linker at high pH. Crucially, attaching the identical drug with an ester linker to the 9-position of the identical ortho- carborane would result in the inverse conditions; the prodrug would be less stable at a low pH and more stable at a high pH. Since these two molecules would be sterically invariant, one can use such carboranes as both a positive and negative control in a molecule with no change in the size or shape of the prodrug. This allows medicinal chemists much more granular and reliable information on how to modify the prodrug in a very fine, controlled manner. Such carborane-based prodrugs could be capable of targeting down to the organelle level, such as being stable in the cytoplasm, but cleaving to the active drug within the mitochondria, and / or vice versa. Most importantly, all of the envisioned isomers are sterically invariant. One skilled in the art can envision a variety of drugs that could use carboranes to improve pharmacodynamic and / or pharmacokinetic results; such as a doxorubicin, where tunable carboranes could be used to decrease cardiotoxicity while maintaining a wide therapeutic window.

[0100] In some embodiments, the carborane moiety may function as an inert molecule, or it could also be an active drug itself, providing two or more active drugs being released after the prodrug is cleaved within the body.

[0101] In some embodiments, the carborane cage can be used as a therapeutic as well once the prodrug is cleaved within the body. It functions either as a pharmacophore acting as an active drug, or through Boron Neutron Capture Therapy (BNCT) or Proton Boron Capture Therapy (PBCT), both binary cancer treatments, or a combination of each mechanism.

[0102] In some embodiments, BNCT is applied when boron-10 atoms are struck by slow moving neutrons to reach a meta-stable B-11 speciess, which then immediately splits into lithium and helium atoms with enough kinetic energy to destroy a cancerous cell, as well as a gamma photon.

[0103] In some embodiments, the carborane cage can be used as a therapeutic as well once the prodrug is cleaved within the body. It functions either as a pharmacophore acting as an active drug, or through proton boron capture therapy (PBCT), a binary cancer treatment, BNCT or a combination of all three.Docket No.: CAVE-01-PCT

[0104] In some embodiments, PBCT is applied when boron-11 atoms are struck by protons to reach a meta-stable12C species, which then splits into three alpha-particles with enough kinetic energy to destroy a cancerous cell.

[0105] In one embodiment, the carborane prodrug is used for BNCT, and / or as a pharmacophore, and carries a payload of an anticancer drug, allowing dual treatment of a cancer.

[0106] In some embodiments, the compound of Formula (I) has the structure of Formula (Ia) as follows, and as depicted in FIG.2 (wherein drug moiety is AG 957 and the linker is ester according to Formula (I)). In some embodiments of Formula (Ia), carborane prodrug illustrating the three positions, ortho-, meta- and para- that may be occupied by the carbon atoms in dicarba-closo-carborane. .

[0107] The progression of development of a carborane based prodrug for AG 957 is illustrated in FIG.5. AG 957 is a compound that was discovered in NCI screen to be active against several kinases, but was too polar to enter the cell. AG 957 was developed with an methyl ester instead of the free carboxylic acid, which allowed entry of the drug into the cell, but the t1 / 2 is still unacceptably low; just 3 mins in mice. Adaphostin was made to counter esterases with steric bulk, but t1 / 2was still only 42 mins, so the project was abandoned. The compounds of the invention provide different isomers of carbaphostin, which showed a significant increase in t1 / 2, with one isomer upping it to more than 150 minutes.

[0108] In some embodiments of the compounds of Formulae I and I(a) described above, the carborane moiety functions as permeability enhancing ester. A permeability enhancing ester is a chemical moiety that increases the cell permeability of the compound relative to the parent compounds. As known in the art, some active agents (e.g., drugs)Docket No.: CAVE-01-PCT exhibit poor permeability in the absence of facilitate transport by any of a variety of possible transporter proteins. Permeability enhancers in this context can act to increase drug absorption through either the paracellular or transcellular pathways. See e.g., Ouyang, H., et al., 2002, J. Med. Chem., 45:2857-2866; Lane, M.E. & Corrigan, O.I., 2006, J. Pharm. Pharmacol., 58:271-275.

[0109] Without wishing to be bound by any theory, it is believed that the lipophilicity of a permeability enhancer can play a major role in permeability enhancement. Accordingly, in some embodiments, the permeability enhancing ester has the structure of Formula (I) and Formula (Ia).

[0110] In some embodiments, carborane based compounds provided herein are more potent, less toxic and more selective than previously known parent candidates, such as AG 957 against cancer. The anticancer efficacy against cancer caused by the addition of a carborane group to the side chain of AG 957 is quite significant.

[0111] “IC50” refers, in the customary sense, to the concentration of a drug required to achieve half maximal response.

[0112] In some embodiments, a compound of Formula (Ia) having the structures of following carbaphostin isomers is found in Table 2. Table 2 Compound Derivative Type Structure CAV-001 1-ortho-derivative CAV-002 1-meta-derivativeDocket No.: CAVE-01-PCT CAV-003 9-ortho-derivativeCAV-004 9-meta-derivative CAV-005 3-ortho-derivativeCAV-006 2-meta-derivativeDocket No.: CAVE-01-PCT CAV-007 2-para-derivativeCAV-008 1-para-derivative CAV-009 4-ortho-CAV-010 8-ortho-derivativeDocket No.: CAVE-01-PCT CAV-011 4-meta-derivativeCAV-012 11-meta-derivative

[0113] It is understood that some compounds described herein can exist as stereoisomeric forms including e.g., R-, S- and racemic (RS-) forms. Unless expressly indicated otherwise, all stereoisomer forms are contemplated herein.

[0114] Exemplary Syntheses

[0115] In a more general sense, synthesis of carborane derivatives generally require knowledge of both organic and inorganic techniques. Such carborane prodrugs could be produced in FIG.6, using the production of an ester prodrug of 9-hydroxy-1, 7-dicarbacloso- meta-carborane. Nitration of the naked ortho-carborane followed by reduction to the hydroxyl is known in the literature (Zakharkin, L. I.; Kalinin, V. N.; Podvisotskaya, L. S. Zh. Obshch. Khim.1966, 36, 1779 [Russian; p.1786], however, this reaction fails in practice for meta-carborane. Also failing was the reaction with PIFA ((Bis(trifluoroacetoxy)iodo)benzene. However, bromination followed by using Pd cross- coupling conditions produces 9-hydroxy-1,2-dicarbacloso-meta-carborane in very good yield (Dziedzic, R. M., Saleh, L. M. A., Axtell J. C., Martin, J. L., Stevens, S. L., Royappa, A. T., Rheingold, A. L., Spokoyny. J. Am Chem. Soc.2016, Jul 27; 138(29); 9081-4 ). But once again, when this reaction was tried under identical conditions using ortho-carborane, it failed. This emphasizes the difficulty of carborane chemistry; chemistry works for one isomer oftenDocket No.: CAVE-01-PCT does not work on another. In the case of Pd-catalyzed reactions, as shown in Scheme 4, choice of halogen and Lewis acid for the halogenation step can lead to quantitative yields or zero yields depending on the conditions and carborane isomer employed. Therefore, proper choice of reagents and reaction pathways are crucial to ensuring success. Subsequent esterification with an acid chloride or similar species will yield the final ester prodrug, shown in FIG.7. One skilled in the art can easily see a multitude of potential applications and pathways for these prodrugs. Additional schemes and experimental details for the synthesis of carborane based prodrug isomers are provided in the Examples.

[0116] Methods of Use

[0117] The compounds provided herein are useful, inter alia, in treating various diseases. Examples below describe the synthesis of specific compounds of the invention.

[0118] In another aspect, the invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. In other aspects, novel methods for synthesis, analysis, separation, isolation, purification, characterization, and testing of the compounds of this invention are provided.

[0119] In another aspect, a method of treating cancer with carborane based prodrugs is provided. The method includes contacting a compound of Formula I or I(a) or embodiment thereof with a cell.

[0120] In another aspect, there is provided a method of treating cancer. The method includes administrating a subject with an effective amount of a compound of Formulae (I) or I(a). The method may further include the step of applying BNCT to the subject, therefore treating cancer.

[0121] Methods of Treating Disease

[0122] In another aspect, a method of treating a subject with diseases is provided. The method includes administering to a subject in need thereof an effective amount of a compound of Formula I or I(a) or embodiments thereof. Diseases contemplated in the practice of the methods disclosed herein include but not limited to cancers.

[0123] Pharmaceutical Compositions

[0124] In another aspect, the present invention provides pharmaceutical compositions. The pharmaceutical composition includes a pharmaceutically acceptable excipient and a compound of the present invention (e.g. Formula I or embodiments thereof)).Docket No.: CAVE-01-PCT

[0125] The pharmaceutical compositions described herein are typically used to treat a disorder or condition using known methods of d pharmaceutical anticancer therapies.

[0126] In an exemplary embodiment, the pharmaceutical composition includes from 1 ug to 2000 mg of a compound disclosed herein, e.g., 1 ug to 1 mg, 1 mg to 10 mg, 1 mg to 100 mg, 1 mg to 1000mg, 1 mg to 1500 mg, or even 1 mg to 2000 mg.

[0127] Formulations

[0128] The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compounds of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. The compounds of the present invention can also be administered by in intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol.75:107-111, 1995). Thus, the pharmaceutical compositions described herein may be adapted for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet. Moreover, the present invention provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and either a compound of the present invention, or a pharmaceutically acceptable salt of a compound of the present invention.

[0129] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of REMINGTON'S PHARMACEUTICAL SCIENCES, Maack Publishing Co, Easton PA ("Remington’s").

[0130] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with theDocket No.: CAVE-01-PCT carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0131] The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0132] Suitable solid excipients are carbohydrate or protein fillers include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl- cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0133] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain compounds of Formulae I or II mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0134] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.Docket No.: CAVE-01-PCT

[0135] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0136] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0137] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0138] Oil suspensions can be formulated by suspending a compound in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gumDocket No.: CAVE-01-PCT acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono- oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0139] The compounds can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0140] The compounds can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug - containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.

[0141] The compounds can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use

[0142] In another embodiment, the compounds are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compound dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pHDocket No.: CAVE-01-PCT adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compound in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally- acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0143] In another embodiment, the compound can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compound into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293- 306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0144] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0145] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0146] Compounds of the invention may be metabolized by cells and then converted to the active drugs.

[0147] Effective Dosages

[0148] Pharmaceutical compositions provided herein include compositions whereinDocket No.: CAVE-01-PCT the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result.

[0149] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health- related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein.

[0150] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing viral activity as measured, for example, using the methods described.

[0151] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring cancer inhibition and adjusting the dosage upwards or downwards, as described above.

[0152] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. In one embodiment of the invention, the dosage range is 0.001% to 10% w / v. In another embodiment, the dosage range is 0.1% to 5% w / v.

[0153] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.Docket No.: CAVE-01-PCT

[0154] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0155] Toxicity

[0156] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and ED50(the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p.l, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.

[0157] Methods of Synthesis

[0158] The carborane-based prodrug compounds of the present invention may be synthesized using various synthetic routes and techniques. In some aspects, the general synthetic approach may involve the following key steps: (1) preparation or modification of the carborane cage structure, (2) functionalization of the carborane with a suitable reactive group, and (3) coupling of the functionalized carborane with the anticancer agent through a cleavable linker.

[0159] In some implementations, the synthesis may begin with commercially available carborane isomers such as ortho-, meta-, or para-carborane. These starting materials may be subjected to various reactions to introduce functional groups at specific positions on the carborane cage. For example, as illustrated in FIG.6, bromination of a carborane starting material may be achieved using Br2 in the presence of AlCl3 as a catalyst. The resultingDocket No.: CAVE-01-PCT brominated intermediate may then undergo a palladium-catalyzed transformation using reagents such as SPhos Pd G2, SPhos, K3PO4, and H2O to yield a hydroxylated carborane product.

[0160] In some cases, the hydroxylation of carborane cages may be accomplished through alternative methods. For instance, as shown in FIG.8, treatment of ortho-carborane with n-BuLi followed by B(OCH3)3 and subsequent oxidation with H2O2 may yield a hydroxylated intermediate. Similar approaches may be applied to meta- and para-carborane isomers, as demonstrated in FIG.9 and FIG.15, respectively.

[0161] The hydroxylated carborane intermediates may serve as key precursors for further functionalization. In some aspects, these intermediates may undergo esterification reactions with activated forms of the anticancer agents to form the desired prodrug compounds. FIG.7 illustrates a general esterification reaction where a hydroxylated carborane derivative reacts with an acid chloride (R-C(=O)Cl) to form an ester linkage.

[0162] In some implementations, the synthesis of specific carbaphostin isomers may involve multiple steps, as exemplified in FIG.8 through FIG.15. These synthetic routes may include esterification of the hydroxylated carborane with 4-nitrobenzoyl chloride, followed by reduction of the nitro group to an amine. The resulting amine intermediate may then undergo reductive amination with 2,5-dihydroxybenzaldehyde to yield the final carbaphostin product.

[0163] The synthesis of compounds with different carborane isomers and attachment points may require tailored approaches. For example, FIG.10 outlines the synthesis of CAV-003, a 9-ortho-derivative carborane compound, which involves initial treatment of ortho-carborane with HNO3 followed by Zn / SnCl2 to produce a hydroxylated intermediate at the 9-position.

[0164] In some cases, the synthesis may involve the formation of nido-carborane salt intermediates, as shown in FIG.12 and FIG.13 for the preparation of CAV-005 and CAV- 006, respectively. These intermediates may be further functionalized through a series of reactions to introduce the desired substituents at specific positions on the carborane cage.

[0165] The final coupling step to form the ester linkage between the functionalized carborane and the anticancer agent may be achieved using various conditions. In some implementations, the reaction may be carried out in the presence of coupling agents such as DMAP and pyridine in dichloromethane solvent, as illustrated in several synthetic schemes (e.g., FIG.8, FIG.9, FIG.10).

[0166] In some aspects, the synthesis may involve one-pot reactions for the finalDocket No.: CAVE-01-PCT steps, combining reduction and reductive amination in a single reaction vessel. This approach may be advantageous for improving overall yield and simplifying the purification process.

[0167] The synthesized compounds may be purified using standard techniques such as column chromatography, recrystallization, or preparative HPLC. In some cases, the final products may be converted to pharmaceutically acceptable salts or solvates through additional processing steps.

[0168] The methods described herein may be adapted and optimized for large-scale production of the carborane-based prodrug compounds. In some implementations, alternative reagents, solvents, or reaction conditions may be employed to improve yield, reduce costs, or enhance the environmental sustainability of the synthetic process.

[0169] Kits

[0170] The present invention provides kits comprising carborane-based prodrug compounds and components for their administration in cancer treatment. These kits may be designed for various applications, including research, clinical trials, and therapeutic use.

[0171] In some aspects, a basic kit may include: a) A compound according to Formula (I): X-(Y)n-Z, wherein X is a drug comprising an anticancer agent; Y is a cleavable linker; and Z is a carborane isomer comprising ortho-, meta-, or para-carborane; or a pharmaceutically acceptable salt or solvate thereof. b) Instructions for administering the compound to a subject for treating cancer.

[0172] The compound may be provided in various forms, such as a lyophilized powder, a solution, or a suspension. In some implementations, the kit may include multiple doses of the compound, each dose individually packaged in a sealed container or vial.

[0173] The instructions may include information on dosage, route of administration, potential side effects, and contraindications. In some cases, the instructions may be provided in printed form, as a digital file on a storage device, or accessible via a web link.

[0174] In some aspects, the kit may further include additional components to facilitate the administration of the compound. These components may include: 1. Diluents or solvents for reconstituting or diluting the compound 2. Syringes, needles, or other delivery devices 3. Alcohol swabs for sterilization 4. Topical anesthetics for injection site preparation 5. Adhesive bandages or gauze padsDocket No.: CAVE-01-PCT

[0175] Examples

[0176] The examples below are meant to illustrate certain embodiments of the invention, and not to limit the scope of the invention.

[0177] General. All reagents were of commercial quality and used without further purification unless indicated otherwise. Chromatographic purification was done using the flash method with silica gel 60 (EMD Chemicals, Inc., 230–400 mesh).1H NMR spectra were recorded on Varian HG spectrophotometers operating at 400 MHz and are reported in units of parts per million (ppm) relative to internal tetramethylsilane at 0.00 ppm.

[0178] Example 1. Exemplary Synthesis of CAV-001

[0179] Synthesis of CAV-001 is provided in Scheme 5 in FIG.8. For the synthesis of the carborane alcohol, 1-OH-o-CB, i, a literature procedure was followed (see Ohta, K., Goto, T., Yamazaki, Hiroto, Pichierri, F., Endo, Y., Inorg. Chem.2007, 46, 3966-3970.). The commercially available ortho-carborane was deprotonated with n-BuLi and quenched with trimethylborate. This was subsequently quenched with hydroperoxide and acetic acid. The decomposition of the peroxide was very exothermic and the temperature rose to reflux. After neutralization, work-up and column chromatography the desired i was obtained in 25% yield. Most likely the decomposition of the peroxide was too harsh, leading to a loss in yield.

[0180] With the obtained i the synthesis of CAV-001 was started. Reaction of i with 4-nitro benzoyl chloride afforded the ester compound, ii. Reduction with Pd / C under a hydrogen atmosphere gave the free aniline iii. Reductive amination with the desired aldehyde was less straightforward. The desired target was formed but side-products as well. The target CAV-001, iv, was isolated by column chromatography but still contained some oxidized product. The quinone moiety is difficult to prevent from oxidizing, but it can be purified by a subsequent chromatography column. The LC-MS and NMR data for CAV-001 are shown in FIGs.20-23.

[0181] Example 2. Exemplary Synthesis of CAV-002

[0182] Synthesis of CAV-002 is provided in Scheme 6 in FIG.9. For the synthesis of 1-OH-m-CB, i, a literature procedure was followed (see Ohta, K., Goto, T., Yamazaki, Hiroto, Pichierri, F., Endo, Y., Inorg. Chem.2007, 46, 3966-3970.). The commercially available meta-carborane was deprotonated with n-BuLi and quenched with trimethylborate.Docket No.: CAVE-01-PCT This was subsequently quenched with hydroperoxide and acetic acid. After workup i was obtained in 84% yield.

[0183] Approximately 850 mg was available of i and this was acylated with p-nitrobenzoyl chloride. The esterified product, ii, was obtained in 95% yield and did not require purification by column chromatography. Thereafter a one-pot reduction-reductive amination was attempted. To our delight this reaction worked very well. Initially the nitro group of the ester, ii, was reduced to the corresponding amine, iii, with palladium on carbon and hydrogen. Upon completion aldehyde and acetic acid were added to the reaction mixture, resulting in product CAV-002 in 93% yield (total reaction time ~2 h). The LC-MS and NMR data for CAV-002 are shown in FIGs.24-26.

[0184] Example 3. Exemplary Synthesis of CAV-003

[0185] Synthesis of CAV-003 is provided in Scheme 7 in FIG.10. The synthesis of 9-OH-o-CB, i, was completed on a 2 grams scale. Treatment of ortho-carborane with HNO3yielded a mixture of both the nitrate and the alcohol. However, this mixture was treated with Tin / HCl which converts the nitrate into the hydroxyl, i. Column chromatography afforded 2.1 g of the alcohol.

[0186] The i was treated with the 4-nitrobenzoyl chloride in the presence of 4- DMAP and pyridine as solvent. This afforded compound the esterified compound, ii. After column chromatography 2.0 g of pure compound ester was obtained. Reduction with Pd / C under a hydrogen atmosphere afforded the intermediate amine, iii, which was directly treated with the aldehyde in situ and reduced to the target compound CAV-003. Column chromatography afforded 2.0 g of CAV-003 in a good NMR purity. The LC-MS and NMR data for CAV-003 are shown in FIGs.27-30.

[0187] Example 4. Exemplary Synthesis of CAV-004

[0188] Synthesis of CAV-004 is provided in Scheme 8 in FIG.11.9-Bromo-meta- caborane (i) was synthesized from meta-carborane using Br2 with catalytic AlCl3, and was obtained in quantitative yield. Next, the bromide was converted to the corresponding hydroxyl (9-OH-m-CB, ii) employing a palladium catalyzed reaction. This reaction furnished 9-OH product in 85% yield (literature reported 56% yield). Acylation with p-nitrobenzoyl chloride gave the ester, iii, in 96% yield (1.5 g available) and did not require purification by column chromatography.

[0189] The one-pot reductive amination began with the nitro compound reduced toDocket No.: CAVE-01-PCT the amine followed by addition of the aldehyde to produce the imine which converts in situ to the target compound CAV-004. The initial purification of target CAV-004 resulted in 1.8 g of product (90%, EtOAc / heptane eluent), but unfortunately the product was not pure enough according to1H NMR. The product was then repurified by silica column chromatography again (using Et2O / heptane eluent) and resulted in 1.4 g (70% yield) pure product. The LC- MS and NMR data for CAV-004 are shown in FIGs.31-34.

[0190] Example 5. Exemplary Synthesis of CAV-005

[0191] Synthesis of CAV-005 is provided in Scheme 9 in FIG.12. First, commercially available ortho-carborane is treated with KOH in refluxing EtOH overnight to yield the nido-carborane salt, (i). This leaves an “open face” on the carborane ready for substitution. Removal of the bridging hydrogen with n-BuLi and treatment with BBr3caps the open face, leaving a free Br at the 3-position ideal for metal-catalyzed cross-coupling reactions, as illustrated with compound ii below. The bromine derivative is treated identically to the bromo-derivative of CAV-004, forming the hydroxylated speciess (iii) which when reacted with the acid acid chloride, results in the ester compound (iv).

[0192] Reduction of the corresponding nitro group to the free aniline under palladium on carbon with hydrogen conditions can be immediately followed by addition of the aldehyde to the reaction mixture. In this manner, the imine is formed and immediately reduced to the final product, CAV-005, in a one pot reductive amination similar to CAV-002, CAV-003 and CAV-004.

[0193] Example 6. Exemplary Synthesis of CAV-006

[0194] Synthesis of CAV-006 is provided in Scheme 10 in FIG.13. In a nearly identical synthesis to CAV-005, commercially available meta-carborane is first treated with KOH in refluxing EtOH. This again produces the nido- salt of meta-carborane (i). Capping this speciess by removal of the bridging hydrogen atom and treatment with BBr3results in a species capped with a Br at the 2-position (ii). Subsequent metal cross coupling would result in the production of the corresponding alcohol (iii). Coupling with the alcohol yields the ester (iv). Reduction of the nitro group on the ester produces the intermediate aniline species. To this reaction mixture is the aldehyde with which to form the imine. The imine is then reduced in the same pot, resulting in target CAV-006.Docket No.: CAVE-01-PCT

[0195] Example 7. Exemplary Synthesis of CAV-007

[0196] Synthesis of CAV-007 is provided in Scheme 11 in FIG.14. Synthesis of CAV-007 is nearly identical to the synthesis of CAV-004. First, commercially available para-carborane is treated with BBr3with catalytic amounts of AlCl3present. The resulting bromide (i) is converted via metal catalyzed cross coupling to yield the alcohol (ii). This free alcohol is then coupled to the acid chloride, forming the key ester bond (iii) in the process. One pot reduction to the aniline derivative, production of the imine derivative after introduction to the aldehyde to the reaction pot and then reduction leads to the target compound, CAV-007.

[0197] Example 8. Exemplary Synthesis of CAV-008

[0198] Synthesis of CAV-008 is provided in Scheme 12. The synthesis of CAV-008 is nearly identical to the synthesis of CAV-001 or CAV-002. For the synthesis of i, a literature procedure can be followed (see Ohta, K., Goto, T., Yamazaki, Hiroto, Pichierri, F., Endo, Y., Inorg. Chem.2007, 46, 3966-3970.). The commercially available para-carborane was deprotonated with n-BuLi and quenched with trimethylborate. This was subsequently quenched with hydroperoxide and acetic acid.

[0199] This alcohol was acylated with p-nitrobenzoyl chloride. The esterified product (ii) was then obtained and hereafter a one-pot reduction-reductive amination is employed for the reductions of both the nitro and imine functional groups formed in the next steps. Upon completion aldehyde and acetic acid were added to the reaction mixture, resulting in product CAV-008.

[0200] Example 9. Anticancer activity

[0201] Compounds of the invention were tested for anticancer activity in cancer cell lines as described below. CAV-001, CAV-002, CAV-003, CAV-004 and Adaphostin were tested against a Panel of 102 Cancer Cell Lines as shown in Table 3. Table 3. Cell lines used for the tested Compounds Cell Line ATCC # Tissue Disease 5637 HTB-9 Bladder / Urinary Bladder carcinoma Tract 769-P CRL-1933 Kidney Renal cell carcinomaDocket No.: CAVE-01-PCT 786-O CRL-1932 Kidney Renal cell carcinoma A-172 CRL-1620 CNS / Brain Glioblastoma A-204 HTB-82 Soft Tissue Embryonal rhabdomyosarcoma A-375 CRL-1619 Skin Amelanotic melanoma A-388 CRL-7905 Skin Skin squamous cell carcinoma A-427 HTB-53 Lung Lung adenocarcinoma A-498 HTB-44 Kidney Renal cell carcinoma A-549 CCL-185 Lung Lung adenocarcinoma A-704 HTB-45 Kidney Renal cell carcinoma ACHN CRL-1611 Kidney Papillary renal cell carcinoma AN3-CA HTB-111 Uterus Endometrial adenocarcinoma AsPC-1 CRL-1682 Pancreas Pancreatic ductal adenocarcinoma AU565 CRL-2351 Breast Breast adenocarcinoma BT-20 HTB-19 Breast Invasive breast carcinoma of no special type BT-549 HTB-122 Breast Invasive breast carcinoma of no special type BxPC-3 CRL-1687 Pancreas Pancreatic ductal adenocarcinoma C-33 A HTB-31 Cervix Cervical squamous cell carcinoma, not otherwise specified CAL-27 CRL-2095 Head and Neck Tongue squamous cell carcinoma CCF- CRL-1718 CNS / Brain Astrocytoma STTG1 CCRF- CCL-119 Lymphoid Childhood T acute lymphoblastic CEM leukemia COLO 205 CCL-222 Bowel Colon adenocarcinoma COLO 829 CRL-1974 Skin Cutaneous melanoma Daoy HTB-186 CNS / Brain Medulloblastoma DB CRL-2289 Lymphoid Diffuse large B-cell lymphoma germinal center B-cell type DLD-1 CCL-221 Bowel Colon adenocarcinoma DoTc2 CRL-7920 Cervix Cervical carcinoma 4510Docket No.: CAVE-01-PCT DU145 HTB-81 Prostate Prostate carcinoma DU4475 HTB-123 Breast Breast carcinoma ES-2 CRL-1978 Ovary / Fallopian Ovarian clear cell adenocarcinoma Tube FaDu HTB-43 Head and Neck Hypopharyngeal squamous cell carcinoma G-361 CRL-1424 Skin Melanoma HCT 116 CCL-247 Bowel Colon carcinoma HCT 15 CCL-225 Bowel Colon adenocarcinoma HL-60 CCL-240 Myeloid Adult acute myeloid leukemia Hs 578T HTB-126 Breast Invasive breast carcinoma of no special type Hs 746.T HTB-135 Esophagus / Stomach Gastric adenocarcinoma Hs 766T HTB-134 Pancreas Pancreatic adenocarcinoma HT CRL-2260 Lymphoid Diffuse large B-cell lymphoma germinal center B-cell type HT-1080 CCL-121 Soft Tissue Fibrosarcoma HuTu 80 HTB-40 Bowel Duodenal adenocarcinoma J82 HTB-1 Bladder / Urinary Bladder carcinoma Tract JAR HTB-144 Uterus Gestational choriocarcinoma Jurkat E6.1 TIB-152 Lymphoid Childhood T acute lymphoblastic leukemia K-562 CCL-243 Myeloid Blast phase chronic myelogenous leukemia, BCR-ABL1 positive KATO III HTB-103 Esophagus / Stomach Gastric signet ring cell adenocarcinoma KG-1 CCL-246 Myeloid Adult acute myeloid leukemia KLE CRL-1622 Uterus Endometrial adenocarcinoma Ku812 CRL-2099 Myeloid Chronic myelogenous leukemia, BCR- ABL1 positive LNCaP CRL-1740 Prostate Prostate carcinoma clone FGC LoVo CCL-229 Bowel Colon adenocarcinomaDocket No.: CAVE-01-PCT LS174T CL-188 Bowel Colon adenocarcinoma LS411N CRL-2159 Bowel Cecum adenocarcinoma MCF-7 HTB-22 Breast Invasive breast carcinoma of no special type MeWo HTB-65 Skin Cutaneous melanoma MG-63 CRL-1427 Bone Osteosarcoma MIA PaCa- CRL-1420 Pancreas Pancreatic ductal adenocarcinoma 2 4 CRL-1582 Lymphoid Adult T acute lymphoblastic leukemia NCC-IT CRL-2073 Testis Testicular embryonal carcinoma NCI-H460 HTB-177 Lung Lung large cell carcinoma NCI-H661 HTB-183 Lung Lung large cell carcinoma NCI-H82 HTB-175 Lung Lung small cell carcinoma OVCAR-3 HTB-161 Ovary / Fallopian High grade ovarian serous Tube adenocarcinoma PA-1 CRL-1572 Ovary / Fallopian Ovarian mixed germ cell tumor Tube PC-3 CRL-1435 Prostate Prostate carcinoma PFSK-1 CRL-2060 CNS / Brain Primitive neuroectodermal tumor RD CCL-136 Soft Tissue Embryonal rhabdomyosarcoma Rh30 CRL-2061 Soft Tissue Alveolar rhabdomyosarcoma RKO CRL-2577 Bowel Colon carcinoma RL CRL-2261 Lymphoid Diffuse large B-cell lymphoma RL95-2 CRL-1671 Uterus Endometrial adenosquamous carcinoma RPMI- HTB-66 Skin Melanoma 7951 RS4;11 CRL-1873 Lymphoid Adult B acute lymphoblastic leukemia RT-4 HTB-2 Bladder / Urinary Bladder carcinoma Tract SHP-77 CRL-2195 Lung Lung small cell carcinoma SK-N-AS CRL-2137 Peripheral Nervous Neuroblastoma System SK-N-FI CRL-2142 Peripheral Nervous NeuroblastomaDocket No.: CAVE-01-PCT System SNU-5 CRL-5973 Esophagus / Stomach Gastric adenocarcinoma SNU-C2B CCL-250 Bowel Cecum adenocarcinoma SR CRL-2262 Lymphoid Anaplastic large cell lymphoma, ALK- positive SU-DHL-1 CRL-2955 Lymphoid Anaplastic large cell lymphoma, ALK- positive SU-DHL-6 CRL-2959 Lymphoid Diffuse large B-cell lymphoma germinal center B-cell type SUP-T1 ACC140 Lymphoid Childhood T lymphoblastic lymphoma SW48 CCL-231 Bowel Colon adenocarcinoma SW480 CCL-228 Bowel Colon adenocarcinoma SW620 CCL-227 Bowel Colon adenocarcinoma SW626 HTB-78 Bowel Colon adenocarcinoma SW837 CCL-235 Bowel Rectal adenocarcinoma SW872 HTB-92 Soft Tissue Liposarcoma SW900 HTB-59 Lung Lung squamous cell carcinoma SW948 CCL-237 Bowel Colon adenocarcinoma SW982 HTB-93 Soft Tissue Biphasic synovial sarcoma T24 HTB-4 Bladder / Urinary Bladder carcinoma Tract T98G CRL-1690 CNS / Brain Glioblastoma TCCSUP HTB-5 Bladder / Urinary Bladder carcinoma Tract THP-1 TIB-202 Myeloid Childhood acute monocytic leukemia TT CRL-1803 Thyroid Hereditary thyroid gland medullary carcinoma U-118MG HTB-15 CNS / Brain Astrocytoma U-87MG HTB-14 CNS / Brain Glioblastoma ATCC U2OS HTB-96 Bone Osteosarcoma VA-ES-BJ CRL-2138 Soft Tissue Epithelioid sarcomaDocket No.: CAVE-01-PCT

[0202] Experimental Methods

[0203] Cell preparation. All cell lines have been licensed from the American Type Culture Collection (ATCC) Manassas, Virginia (US). Master and working cell banks (MCB and WCB) were prepared by subculturing in ATCC-recommended media and freezing according to ATCC recommended protocols (www.atcc.org). Cell line stocks for the assays were prepared from the WCB. The MCB, WCBs and assay stocks were prepared within respectively 3, 6 and 10 passages of the ATCC vial.

[0204] Compound preparation. Solid powders of reference compounds were stored as indicated by supplier. Compounds were weighed on a calibrated balance and dissolved in 100 % DMSO. DMSO samples were stored at room temperature. At the day of the experiment, the compound stock was diluted in 3.16 fold steps in 100 % DMSO to obtain a 9-point dilution series. This was further diluted 31.6 times in 20mM sterile Hepes buffer pH 7.4. A volume of 5 μl was transferred to the cells to generate the test concentration range in duplicate. The final DMSO concentration during incubation was 0.4 % in all wells. If a compound showed very potent activity, the testing range was expanded to ensure a full dose- response curve could be measured in duplicate. If a compound can only be dissolved in an aqueous solution, the recommended buffer is used instead of 100 % DMSO.

[0205] Cell proliferation assay. Cells were diluted in the corresponding ATCC recommended medium and dispensed in a 384-well plate, depending on the cell line used, at a density of 100 - 6400 cells per well in 45 μl medium. For each used cell line the optimal cell density is used. The margins of the plate were filled with phosphate-buffered saline. Plated cells were incubated in a humidified atmosphere of 5 % CO2 at 37 ºC. After 24 hours, 5 μl of compound dilution was added and plates were further incubated. At t=end, 24 μl of ATPlite 1Step™ (PerkinElmer) solution was added to each well, and subsequently shaken for 2 minutes. After 10 minutes of incubation in the dark, the luminescence was recorded on an Envision multimode reader (PerkinElmer).

[0206] Controls

[0207] t = 0 signal. On a parallel plate, 45 μl cells were dispensed and incubated in a humidified atmosphere of 5 % CO2 at 37 ºC. After 24 hours 5 μl DMSO-containing Hepes buffer and 25 μl ATPlite 1Step™ solution were mixed, and luminescence measured after 10 minutes incubation (= luminescencet=0).

[0208] Reference compound. The IC50of the reference compound doxorubicin is measured on a separate plate. The IC50 is trended. If the IC50 is out of specification (0.32 -Docket No.: CAVE-01-PCT 3.16 times deviating from historic average) the assay is invalidated.

[0209] Cell growth control. The cellular doubling times of all cell lines are calculated from the t = 0 hours and t = end growth signals of the untreated cells. If the doubling time is out of specification (0.5 – 2.0 times deviating from historic average) the assay is invalidated.

[0210] Maximum signals. For each cell line, the maximum luminescence was recorded after incubation until t= end without compound in the presence of 0.4% DMSO (= luminescenceuntreated,t=end).

[0211] Data Analysis

[0212] The purpose of testing the synthesized compounds was to show equivalence to adaphostin; we wished to show that the substitution of the carborane for the adamantane on the prodrug did not change its potency or MOA. For this test, we first screened adaphostin against the 102 cancer cell lines shown above. We then screened CAV-001, CAV-002, CAV- 003 and CAV-004 against the same cell lines.

[0213] All IC50 data were then converted to nanomolar (nM) concentration for all data points. Then, we took the log10 of the data points. We then subtracted the log of the IC50 of adaphostin from the log of the respective experimental compounds for each individual cell type, and then dividing by 102 to give an average difference from adaphostin as shown in this equation: (^(Log(IC50 CAV-00X)-Log(IC50 Adaphostin))) / 102. Given this equation, compounds which are more potent than adaphostin will have a negative number and compounds which are less potent than adaphostin will have a positive number. Most importantly, a compound that is matched to adaphostin will have an average approaching zero, as the IC50 of the compound approaches the IC50 of adaphostin, subtracting their logs will approach zero.

[0214] Table 4. Delta of the mean and median IC50 values for each compound (CAV-001, CAV-002, CAV-003 and CAV-004) of adaphostin in 102 cell line cancer screen. Delta from Adaphostin Compound Average Median CAV-001 1.36 1.37 CAV-002 0.0764 0.0779 CAV-003 0.61 0.605 CAV-004 0.353 0.357Docket No.: CAVE-01-PCT

[0215] As shown in Table 3 above, compound CAV-002 is nearly identical to adaphostin in this test. To further flush out this data, the values for the delta to adaphostin can be plotted for each compound. In these plots, values to the right of zero (positive numbers) indicate that a compound was less potent than adaphostin and values to the left of zero (negative numbers) indicate that a compound is more potent than adaphostin.

[0216] As shown in Tables 4-7 in FIGS.16-19, it becomes apparent that CAV-002 (Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 1-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester)) is very closely matched to adaphostin. One can assume that this similarity in potency while using whole cells is a strong indication that the mechanism of action is also extremely similar (or identical) to the comparator compound, adaphostin.

[0217] Example 10. Compound Stability in Phosphate Buffered Saline (PBS)

[0218] The compounds of the invention (CAV-001, CAV-002, CAV-003 and CAV- 004) and Adaphostin were incubated with Phosphate Buffered Saline (PBS) at the conditions stated below, and the samples are analyzed using UPLC / HR-MS to evaluate in vitro stability.

[0219] Conditions

[0220] Sample type: PBS at pH 1.2 , 4.5, 7.4, 8.4 and 10.4

[0221] Time points:0, 30, 60, 120, 240 min

[0222] Concentration: 1 µM;

[0223] Replicates: 2;

[0224] Incubation volume: 500 µl;

[0225] Sampling volume: 50 µl;

[0226] Spiking solvent: 50% DMSO (spiking 1 / 100 to incubation);

[0227] Quenching solvent: 2-fold volume of 75% ACN.

[0228] Study compounds:

[0229] Adaphostin

[0230] CMPD1

[0231] CMPD2

[0232] CMPD3

[0233] CMPD4Docket No.: CAVE-01-PCT

[0234] Details of Procedure:

[0235] Incubations: The study compound is incubated with the buffer as specified above. The incubations are quenched using cold acetonitrile and stored at -20°C until thawed, centrifuged and analysed. Stock solutions are prepared using 50% DMSO, and spiked 1 / 100 into the incubation (final DMSO content 0.5%).

[0236] Analysis of the samples: The samples are analysed by UPLC / PDA with high resolution mass spectrometry (QE-Orbitrap-MS on data dependent MS / MS mode) to monitor substrate depletion. The same analytical method will be optimised for chromatographic (peak shape, retention) and mass spectrometric (ionisation) performance. Disappearance is based on LC / MS peak areas (0 min = 100%) without calibration curve.

[0237] Results:

[0238] As shown in FIG.16, the balanced solution was found with CAV-002. This molecule has an increase in half-life of nearly 50% (18.35 vs 12.88) vs Adaphostin. Importantly, this difference, based on cancer-cell screening, demonstrates how a fairly large change in half-life can still lead to similar

[0239] Example 11. Metabolic Stability

[0240] Metabolic stability for the compounds of the invention were tested in human blood.

[0241] The compounds (Adaphostin, CAV-001, CAV-002, CAV-003 and CAV- 004) are incubated with whole blood, and collected samples are analyzed by UPLC / HR-MS to measure stability of the compounds.

[0242] Outcomes: Metabolic stability in whole blood (half-life)

[0243] Compound requirement: 1 − 3 mg, or 50 µl of 10 mM DMSO stock.

[0244] In vitro system sample type: fresh whole blood (Li-Hep anticoagulant);

[0245] Species: human (human mixed gender);

[0246] Time points: 0, 30, 60, 120, 240, 480 min;

[0247] Concentration: 1 µM;

[0248] Replicates: 2

[0249] Incubation volume: 500 µl;

[0250] Sampling volume: 50 µl;

[0251] Spiking solvent: 50% DMSO (1 / 100 to incubation);

[0252] Quenching solvent: 2-fold volume of 100% ACN;

[0253] Control: propanthelin bromide (1 µM);Docket No.: CAVE-01-PCT

[0254] Study compounds: Adaphostin, CAV-001, CAV-002, CAV-003, and CAV- 004.

[0255] Description of the process:

[0256] Incubations: The study compounds are incubated with fresh whole blood at 37°C as specified above. The incubations are quenched using a 2-fold volume of cold acetonitrile and stored at -20°C until thawed on ice, centrifuged and analyzed.

[0257] Analysis of the samples: The samples are analyzed by UPLC / PDA with high resolution mass spectrometry (QE-Orbitrap-MS on data dependent MS / MS mode) to monitor disappearance of the compound. The analytical method is optimized by using the parent compounds for optimum chromatographic properties (peak shape and retention) and mass spectrometric ionization. Disappearance is based on relative LC / MS peak areas, marking 0 min as 100%. Table 5. Half-life of adaphostin and carborane based prodrug compounds in whole human blood Compound Half-Life Adaphostin 51.59 CAV-001 Not Found CAV-002 76.11 CAV-003 108.02 CAV-004 151.53

[0258] As shown in Table 5, the performance of adaphostin and the synthesized carbophostin compounds in whole human blood mirrors what was seen in the stability of the compounds at physiological pH. In this case, adaphostin was found to have a half-life of 51.59 min which is very close to the literature numbers of 42 min. CAV-001 was not found in the solution at all, which is possibly due to having an extremely short half-life, which would match with the data at physiological pH in PBS buffer. The test was repeated and again, CAV-001 was the only compound that was not found.

[0259] Meanwhile, CAV-002 has a half-life of 76.11 minutes. This increase of approximately 50% over adaphostin is nearly identical to the 50% increase in the half-life of CAV-002 over adaphostin in the buffered PBS experiment above.

[0260] CAV-003 and CAV-004 again have very long half-lives, which could be expected with how strongly electron donating the carborane cage is to the ester bond. ThisDocket No.: CAVE-01-PCT added stability of the drug prevents it from being unmasked when the prodrug carborane is cleaved. One could see that an increase in half-life over adaphostin is beneficial, but an excessive half-life (as determined by effectiveness of the drug) could lead to an impotent drug, unable to be released from its prodrug.

[0261] As shown in the data for the compounds stability in Phosphate Buffered Saline and metabolic stability in human blood, the most effective molecule (CAV-002) is one of the optimums. It is neither the most electron-withdrawing nor the most electron-donating carborane which gave the best results. Furthermore, we can attest these different outcomes to purely electronic differences, as all of the carboranes have an identical size.

[0262] The property of differing electronics (and a large ammount of isomers) expressed by the carboranes is able to be very fine tuned. Each distinct boron and carbon have different electronic properties, allowing each isomer to provide multiple possible solutions by giving the medicinal chemist another tool in their toolbox.

[0263] Finally, the data from the chemical stability tests and the human blood stability tests show that while increasing the half-life of the parent molecule, adaphostin, there is a limit on how much longer of a half-life is beneficial. The compounds where the ester bond was formed on a boron molecule (CAV-003 and CAV-004) both showed the longest half-life, but this led to a significant decrease in potency when screened against cancer cells. Presumably, this is from the stability of the prodrug, which does not allow the free (and active) drug to form in the mitochondria, where adaphostin is cleaved. Similarly, the compound with the shortest half-life, CAV-001, also performed poorly, presumably from cleaving prior to entrance into the cell and thereby preventing the now very polar molecule from entering the cell.

[0264] Example 12. Boron Neutron Capture Therapy (BNCT)

[0265] Boron neutron capture therapy (BNCT) is a technology based on boron nuclear reactions. After being irradiated by neutrons, l0B becomes unstable 11B, which continues to decay its energy and radiates particles (4He) and 7Li recoil particles, releasing a large amount of energy and accompanied by a small amount of gamma rays during the reaction. The BNCT treatment process requires selective boron accumulation of nonradioactive drugs in tumor cells, followed by the irradiation of local tissue with neutron beams, causing the release of large quantities of high-energy particles with nuclear fission to selectively kill the tumor cells in a narrow range. The radiation radius of the reaction limits its scope of action, and tumor cells can be rapidly and selectively killed once boronDocket No.: CAVE-01-PCT is ingested without damaging the surrounding normal tissue. BNCT has been studied in a variety of diseases, including glioblastoma multiforme (GBM), primary and recurrent head and neck cancer, lung cancer, liver cancer, and extramammary Paget’s disease. Therefore, BNCT has very promising development value and application prospects. In fact, BNCT has been evaluated as an alternative treatment for a variety of cancers, including GBM, melanoma, and head and neck cancer in multiple phases I and II clinical trials. However, challenges of BNCT include, such as cell selectivity of boron delivery agents, delivery mode, and irradiation depth of neutron beam and reactor, all of which involve the intersection of multiple technologies. (See, S Wang, et al, “Boron Neutron Capture Therapy: Current Status and Challenges’, Front. Oncol., 31 March 2022, Volume 12, Article 788770, which is incorporated herein by reference.)

[0266] In one embodiment, the carborane based prodrug of the invention is used for BNCT, and / or as a pharmacophore, and carries a payload of an anticancer drug, allowing dual treatment of a cancer. The prodrug may be used for BNCT where a proton beam is used to activate the boron (11B) in the cancer cells, resulting in the production of three alpha particles promoting cytotoxicity. In this way, the carborane based prodrugs of the invention are both act like a conventional drug and a BNCT sensitizing agent.

[0267] BNCT of a binary cancer treatment is designed when boron-10 atoms are struck by slow moving neutrons (between 0.5 keV and 30 keV) to reach a meta-stable B-11 species, which then immediately splits into lithium and helium atoms with enough kinetic energy to destroy a cancerous cell. Simultaneously, a gamma particle is also released. Because the distance that the cytotoxic speciess (7Li and4He) travels is limited to approximately one cell length, selective delivery of the boron to cancerous cells can result in very precise chemotherapies.

[0268] While the concept of BNCT was first theorized in the 1930s and used on patients since the 1950s, the field suffers greatly from a lack of drugs that can selectively deliver boron to the cancerous cells while sparing the surrounding tissue. Both compounds approved for study in humans, BPA (borophenylalanine) and BSH (sodium borocaptate) were developed more than 50 years ago and provided a low tumor:healthy tissue ratio for boron concentration in the tissue. The invention provides a series of compounds that are carborane based prodrugs to address the issue. The exemplary compounds of the invention are based upon a kinase inhibitor that was being developed for several different cancers, but did not have a long enough half-life. The compounds of the invention provide optimized half-life and enhanced efficacy for the cancer treatment. In addition, the compounds provide betterDocket No.: CAVE-01-PCT selectivity for the BNCT treatment.

[0269] In a simple process, the patient would be dosed with the carborane- containing prodrug intravenously. After a given amount of time to allow clearance of the boron-containing component from the blood, the patient would then be transported into a room containing an accelerator (neutron or proton). The accelerator would then be aimed at the targeted cancerous tissue and the beam applied. After proper dosage of the beam, the patient would return to their day-to-day life, and the cancerous tissue would be monitored for response to the treatment. If needed, the treatment could be fractionated into several installments, allowing for very precise control over both the dosage given but also of any side effects.

[0270] Other Embodiments

[0271] The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

[0272] References Cited

[0273] All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

Claims

Docket No.: CAVE-01-PCT CLAIMS What is claimed is:

1. A compound having the structure of Formula (I):(I) wherein Drug comprising an anticancer agent; Cleavable Linker is selected from esters, ethers, carbamates, amides, ketones, aldehyde, carboxylates, peroxides, anhydrides, amidines, hydrozones, imines, imides, azides, cyanates, nitriles, thiols, sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, boronic acids, and silyl ethers; and Carborane is an isomer comprising ortho-, meta-, or para-carborane, or pharmaceutically accepted salt or solvate thereof.

2. The compound of claim 1, herein the carborane is 1,2-dicarba-closo- dodecacarborane(12).

3. The compound of claim 1, wherein the carborane is 1,7-dicarba-closo- dodecacarborane(12).

4. The compound of claim 1, wherein the carborane is 1,12-dicarba-closo-Docket No.: CAVE-01-PCT dodecacarborane(12).

5. The compound of claim 1, with structure of Formula (Ia):the structure comprises a carbophostin isomer.

6. The compound of Claim 5, wherein the carbaphostin isomer is selected from the group consisting of: , ,Docket No.: CAVE-01-PCT , , , ,Docket No.: CAVE-01-PCT , , , ,Docket No.: CAVE-01-PCTselected from the group consisting of: Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 1-(1,2-Dicarba-closo- dodecaboran(12)-yl) ester), Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 1-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 9-(1,2-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 9-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 3-(1,2-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 2-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 2-(1,12-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, -(1,12-Dicarba-closo-Docket No.: CAVE-01-PCT dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 4-(1,2-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 8-(1,2-Dicarba-closo- dodecaboran(12)-yl) ester, Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 4-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester, and Benzoic acid, 4-[[(2,5-dihydroxyphenyl)-methyl]- amino]-, 11-(1,7-Dicarba-closo- dodecaboran(12)-yl) ester.

8. A pharmaceutical composition comprising a compound of any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. A method of inhibiting cancer from a cell comprising contacting the cell with an effective amount of a compound of one of claims 1 to 8 thereby inhibiting said cancer.

10. A method of treating a subject with cancer comprising administering to the subject in need thereof an effective amount of a compound of one of claims 1 to 8.

11. The method of Claim 10, further comprising applying the subject with Boron Neutron Capture Therapy (BNCT) or Proton Boron Capture Therapy (PBCT), or a combination thereof.

12. The method of Claim 11, comprising the steps of: administering to the subject an effective amount of a compound of one of claims 1 to 8; and applying to the subject an effective amount of neutron or proton beam to a targeted tissue.

13. A compound having the structure of Formula (I): X-(Y)n-Z wherein: X is a drug comprising an anticancer agent; Y is a cleavable linker selected from the group consisting of esters, ethers, carbamates, amides, ketones, aldehydes, carboxylates, peroxides, anhydrides, amidines, hydrazones, imines, imides, azides, cyanates, nitriles, thiols, sulfides, sulfoxides, sulfones, thiocyanates, thials, thioesters, phosphonic acids, phosphodiesters, boronic acids, and silyl ethers; Z is a carborane isomer selected from the group consisting of ortho-carborane, meta- carborane, and para-carborane; andDocket No.: CAVE-01-PCT n is an integer from 1 to 10; or a pharmaceutically acceptable salt or solvate thereof.

14. The compound according to claim 13, wherein the carborane isomer is 1,2- dicarba-closo-dodecacarborane(12).

15. The compound according to claim 13, wherein the carborane isomer is 1,7- dicarba-closo-dodecacarborane(12).

16. The compound according to claim 13, wherein the carborane isomer is 1,12- dicarba-closo-dodecacarborane(12).

17. The compound according to any one of claims 13 to 16, wherein the cleavable linker is an ester.

18. The compound according to claim 17, wherein the ester is formed between a carboxylic acid group of the anticancer agent and a hydroxyl group of the carborane isomer.

19. The compound according to any one of claims 13 to 18, wherein the anticancer agent is a tyrosine kinase inhibitor.

20. The compound according to claim 19, wherein the tyrosine kinase inhibitor is selected from the group consisting of imatinib, dasatinib, nilotinib, and bosutinib.

21. A pharmaceutical composition comprising a compound according to any one of claims 13 to 20 and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition according to claim 21, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, lubricants, disintegrants, colorants, flavoring agents, and combinations thereof.

23. Use of a compound according to any one of claims 13 to 22 for the manufacture of a medicament for treating cancer.

24. A compound according to any one of claims 13 to22 for use in treating cancer.

25. The compound for use according to claim 24, wherein the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, lung cancer, colorectal cancer, prostate cancer, and melanoma.

26. A method of synthesizing a compound according to any one of claims 13 to 21, comprising: a) providing a carborane isomer; b) functionalizing the carborane isomer with a hydroxyl group; c) reacting the hydroxyl-functionalized carborane with an activated form of the anticancer agent to form the cleavable linker.

27. The method according to claim 21, wherein the activated form of theDocket No.: CAVE-01-PCT anticancer agent is an acid chloride.

28. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 13 to 21.

29. The method according to claim 28, further comprising applying Boron Neutron Capture Therapy (BNCT) to the subject after administering the compound.

30. The method according to claim 28 or 29, further comprising applying Proton Boron Capture Therapy (PBCT) to the subject after administering the compound.

31. A kit comprising: a) a compound according to any one of claims 13 to 22; and b) instructions for administering the compound to a subject for treating cancer.

32. The kit according to claim 31, further comprising at least one of diluents or solvents for reconstituting or diluting the compound, syringes, needles, or other delivery devices, alcohol swabs for sterilization, topical anesthetics for injection site preparation, and adhesive bandages or gauze pads.

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