Targeted camptothecin derivatives for cancer treatment

Abstract

This invention relates to compounds and methods for treating cancer. In various embodiments, the compound includes a heptamethine carbocyanine dye (HMCD) component, a camptothecin derivative component, and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component. In various embodiments, the method includes administering a therapeutically effective amount of the compound to a subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject.

Description

TARGETED CAMPTOTHECIN DERIVATIVES FOR CANCER TREATMENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. provisional patent application No. 63 / 635,978, filed April 18, 2024, the entirety of which is hereby incorporated by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant No. CA256419 awarded by the National Institutes of Health, and Grant Nos. W81XWH-22-1-0551 and W81XWH-22-1-0553 awarded by the Department of Defense. The government has certain rights in the invention.FIELD OF THE INVENTION

[0003] This invention relates to compounds for treating cancer.BACKGROUND

[0004] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0005] Irinotecan is a major component of the FOLFIRINOX regimen used for treating pancreatic ductal adenocarcinoma (PDAC) and other cancers. Although, irinotecan is very effective in killing the cancer cells through inhibiting Topoisomerase 1, it is very toxic and only a small percentage of patients can tolerate it because of its high toxicity. Therefore, there is an ongoing need for improvements in the art. The embodiments of the present invention address that need.SUMMARY OF THE INVENTION

[0006] In various embodiments, the present invention provides a compound, comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component;and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

[0007] In some embodiments, the linker moiety (L) is bonded to the HMCD component via an amide or ester bond; and the linker moiety (L) is bonded to the camptothecin derivative component via an ester, ether, carbamate, or thiocarbamate bond.

[0008] In some embodiments, the linker moiety (L) is selected from the group consisting of:-O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r-NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, - NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and -NH-(CH2)r-NHCSO-, where r is an integer 2-8.

[0009] In some embodiments, the compound of the present invention has a structure of Formula (I):Formula (I)X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, arylsulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; n is 4; m is 4; andL is selected from the group consisting of: -O-(CH2)r-COO-, -0-(CH2)r-0-, -0-(CH2)r- NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and - NH-(CH2)r-NHCS0-, where r is an integer 2-8.

[0010] In some embodiments, the compound of the present invention has a structure of Formula (II):Formula (II)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, arylsulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; n is 4; and m is 4.

[0011] In some embodiments, the compound of the present invention has a structure of Formula (III):Formula (III)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); n is 4; and m is 4.

[0012] In various embodiments, the present invention provides a compound having a structure of Formula (IV):Formula (IV)wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3; each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R8is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR18, and co-acyl-lysine, wherein R18is selected from the group consisting of hydrogen and alkyl;D' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluorob orate, and a pharmaceutically acceptable anion; p is 4; and q is 4.

[0013] In various embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention.

[0014] In various embodiments, the present invention provides a method for treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of the present invention to the subject. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0015] In various embodiments, the present invention provides a method for detecting and treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of the present invention to the subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0017] FIG. 1 depicts in accordance with various embodiments of the invention, SN38 and DZ-SN-38 performs better than Irinotecan in decreasing the survival of MIA PaCa-2 cells. *p<0.05 vs. control. #p<0.05 vs. the same dose of irinotecan.

[0018] FIG. 2 depicts in accordance with various embodiments of the invention, Combination of low dose of AP-001 and DZ-SN38 induces an additive effect in decreasing survival of pancreatic cancer BxPC-3 cells. *p<0.05 vs. control. #p<0.05 vs. the same dose of irinotecan or DZ-SN38 alone.

[0019] FIG. 3A - FIG. 3C depict in accordance with various embodiments of the invention, DZ-SN38 performs better than irinotecan in decreasing survival of PDAC cells measure by MTT assay. *p<0.05 vs. control; #p<0.05 vs. same dose of irinotecan.

[0020] FIG. 4 depicts in accordance with various embodiments of the invention, Infrared DZ-SN38 is retained in PDAC cells for up to 2 weeks but not in normal cells. MIA PaCa-2 cells were treated with DZ-SN38 (IpM) for 1 hour, then media changed, and infra-red fluorescence measured at different times.

[0021] FIG. 5A - FIG. 5E depict in accordance with various embodiments of the invention, DZ-SN38 decreases mitochondria bioenergetics in PDAC cells. MIAPaCa-2 cells were treated with the drugs for 2 hours before the seahorse assay. *p<0.05 vs. control; #p<0.05 vs. irinotecan.

[0022] FIG. 6A - FIG. 6B depict in accordance with various embodiments of the invention, Irinotecan resistant (IR) PDAC cells MIA PaCa-2 and BxPC3 are sensitive to DZ- SN38. Survival measured by MTT assay after treatment for 48 hours. *p<0.05 vs. control.DESCRIPTION OF THE INVENTION

[0023] All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical, and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0024] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Other features and advantages of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below. For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here.

[0025] Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The definitions and terminology used herein are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims.

[0026] As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, systems, articles of manufacture, apparatus, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). Although the open- ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of’ or “consisting essentially of.”

[0027] Unless stated otherwise, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment of the application (especially in the context of claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0028] “Optional" or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0029] In some embodiments, the numbers expressing quantities of reagents, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0030] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasonsof convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0031] As used herein the term “electron donating group” is well-known in the art and generally refers to a functional group or atom that pushes electron density away from itself, towards other portions of the molecule, e.g., through resonance and / or inductive effects. Nonlimiting examples of electron-donating groups include ORC, NRcRd, alkyl groups, wherein Rcand Rdare each independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclyl, or optionally substituted heterocyclyl.

[0032] As used herein the term “electron withdrawing group” is well-known in the art and generally refers to a functional group or atom that pulls electron density towards itself, away from other portions of the molecule, e.g., through resonance and / or inductive effects. Non-limiting examples of electron-withdrawing groups include NO2, F, Cl, Br, I, CF3, CN, CO2Ra, C(=O)NRaRb, C(=O)Ra, SO2Ra, SO2ORa, SO2NRaRb, PO3RaRb, or NO, wherein Raand Rbare each independently H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cyclyl, or optionally substituted heterocyclyl.

[0033] As used herein, the term “alkyl” means a straight or branched, saturated aliphatic group having a chain of carbon atoms. Cx alkyl and Cx-Cyalkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, Ci-Cealkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and the like). Alkyl represented along with another group (e.g., as in arylalkyl) means a straight or branched, saturated alkyl divalent group having the number of atoms indicated or when no atoms are indicated means a bond, e.g., (Ce-Cio)aryl(Co- C3)alkyl includes phenyl, benzyl, phenethyl, 1 -phenylethyl 3 -phenylpropyl, and the like. The backbone of the alkyl can be optionally inserted with one or more heteroatoms, such as N, O, or S.

[0034] In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. The term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkylmoieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.

[0035] Unless the number of carbons is otherwise specified, “lower alkyl” as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0036] Non-limiting examples of substituents of a substituted alkyl can include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), - CF3, -CN and the like.

[0037] As used herein, the term “alkenyl” refers to unsaturated straight-chain, branched- chain or cyclic hydrocarbon group having at least one carbon-carbon double bond. Cx alkenyl and Cx-Cyalkenyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C2-Cealkenyl includes alkenyls that have a chain of between 2 and 6 carbons and at least one double bond, e.g., vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- methylallyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, and the like). Alkenyl represented along with another group (e.g., as in arylalkenyl) means a straight or branched, alkenyl divalent group having the number of atoms indicated. The backbone of the alkenyl can be optionally inserted with one or more heteroatoms, such as N, O, or S.

[0038] As used herein, the term “alkynyl” refers to unsaturated hydrocarbon groups having at least one carbon-carbon triple bond. Cx alkynyl and Cx-Cyalkynyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C2-Cealkynyl includes alkynyls that have a chain of between 2 and 6 carbons and at least one triple bond, e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, isopentynyl, 1,3-hexa-diyn-yl, n-hexynyl, 3- pentynyl, l-hexen-3-ynyl and the like. Alkynyl represented along with another group (e.g., as in arylalkynyl) means a straight or branched, alkynyl divalent group having the number of atoms indicated. The backbone of the alkynyl can be optionally inserted with one or more heteroatoms, such as N, O, or S.

[0039] The terms “alkylene,” “alkenylene,” and “alkynylene” refer to divalent alkyl, alkelyne, and alkynylene” groups. Prefixes Cx and Cx-Cyare typically used where X and Y indicate the number of carbon atoms in the chain. For example, Ci-Cealkylene includes methylene, ( — CH2 — ), ethylene ( — CH2CH2 — ), trimethylene ( — CH2CH2CH2 — ), tetramethylene ( —CH2CH2CH2CH2 — ), 2-methyltetramethylene ( — CH2CH(CH3)CH2CH2 — ), pentamethylene ( — CH2CH2CH2CH2CH2— ) and the like).

[0040] As used herein, the term “alkylidene” means a straight or branched unsaturated, aliphatic, divalent group having a general formula =CRaRb. Non-limiting examples of Ra and Rb are each independently hydrogen, alkyl, substituted alkyl, alkenyl, or substituted alkenyl. Cx alkylidene and Cx-Cyalkylidene are typically used where X and Y indicate the number of carbon atoms in the chain. For example, C2-Cealkylidene includes methylidene (=CH2), ethylidene (=CHCH3), isopropylidene (=C(CH3)2), propylidene (=CHCH2CH3), allylidene (=CH — CH=CH2), and the like).

[0041] The term “heteroalkyl”, as used herein, refers to straight or branched chain, or cyclic carbon-containing groups, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0042] As used herein, the term “halogen” or “halo” refers to an atom selected from fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term “halogen radioisotope” or “halo radioisotope” refers to a radionuclide of an atom selected from fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0043] In some embodiments, “iodo” refers to the iodine atom (I) when it is used in the context of a halo functional group or halogen functional group or as a halo substituent or halogen substituent.

[0044] In some embodiments, “bromo” refers to the bromine atom (Br) when it is used in the context of a halo functional group or halogen functional group or as a halo substituent or halogen substituent.

[0045] In some embodiments, “chloro” refers to the chlorine atom (Cl) when it is used in the context of a halo functional group or halogen functional group or as a halo substituent or halogen substituent.

[0046] In some embodiments, “fluoro” refers to the fluorine atom (F) when it is used in the context of a halo functional group or halogen functional group or as a halo substituent or halogen substituent.

[0047] A “halogen-substituted moiety” or “halo-substituted moiety”, as an isolated group or part of a larger group, means an aliphatic, alicyclic, or aromatic moiety, as described herein, substituted by one or more “halo” atoms, as such terms are defined in this application. For example, halo- substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and thelike (e.g. halosubstituted (Ci-C3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl (-CF3), 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).

[0048] The term “aryl” refers to monocyclic, bicyclic, or tricyclic fused aromatic ring system. Cx aryl and Cx-Cyaryl are typically used where X and Y indicate the number of carbon atoms in the ring system. For example, C6-C12 aryl includes aryls that have 6 to 12 carbon atoms in the ring system. Exemplary aryl groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzyl, phenyl, naphthyl, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl, and the like. In some embodiments, 1, 2, 3, or 4 hydrogen atoms of each ring can be substituted by a substituent.

[0049] The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered fused bicyclic, or 11-14 membered fused tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively. Cx heteroaryl and Cx-Cyheteroaryl are typically used where X and Y indicate the number of carbon atoms in the ring system. For example, C4-C9 heteroaryl includes heteroaryls that have 4 to 9 carbon atoms in the ring system. Heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzofb] thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- b]pyridine, thieno[2, 3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyrimidine, imidazo[l,2-c]pyrimidine, imidazo[l,5-a]pyrimidine, imidazo[l,5- c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3cj pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2- b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo [2,3-b]pyrazine, pyrazolo[l,5-a]pyridine, pyrrolo[l,2-b]pyridazine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2- a]pyrimidine, pyrrolo[l,2-a]pyrazine, triazofl, 5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothi azene, phenoxazine, l,2-dihydropyrrolo[3,2,l-hi]indole, indolizine, pyrido[l,2-a]indole, 2(lH)-pyridinone, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thi enothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl and xanthenyl. Some exemplary heteroaryl groups include, but are not limited to, pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, pyridazinyl, pyrazinyl, quinolinyl, indolyl, thiazolyl, naphthyridinyl, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, andthe like. In some embodiments, 1, 2, 3, or 4 hydrogen atoms of each ring may be substituted by a substituent.

[0050] The term “cyclyl” or “cycloalkyl” refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and, for example, 3 to 6 carbons. Cxcyclyl and Cx-Cycycyl are typically used where X and Y indicate the number of carbon atoms in the ring system. For example, Cs-Cs cyclyl includes cyclyls that have 3 to 8 carbon atoms in the ring system. The cycloalkyl group additionally can be optionally substituted, e.g., with 1, 2, 3, or 4 substituents. Cs-Ciocyclyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, adamantan-l-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2- oxobicyclo [2.2.1 ]hept-l-yl, and the like.

[0051] Aryl and heteroaryls can be optionally substituted with one or more substituents at one or more positions, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

[0052] The term “heterocyclyl” refers to a nonaromatic 4-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Cxheterocyclyl and Cx-Cyheterocyclyl are typically used where X and Y indicate the number of carbon atoms in the ring system. For example, C4-C9 heterocyclyl includes heterocyclyls that have 4-9 carbon atoms in the ring system. In some embodiments, 1, 2 or 3 hydrogen atoms of each ring can be substituted by a substituent. Exemplary heterocyclyl groups include, but are not limited to piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyland the like.

[0053] The terms “bicyclic” and “tricyclic” refer to fused, bridged, or joined by single bond polycyclic ring assemblies.

[0054] The term “cyclylalkylene” means a divalent aryl, heteroaryl, cyclyl, or heterocyclyl.

[0055] As used herein, the term “fused ring” refers to a ring that is bonded to another ring to form a compound having a bicyclic structure when the ring atoms that are common to both rings are directly bound to each other. Non-exclusive examples of common fused rings includedecalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like. Compounds having fused ring systems can be saturated, partially saturated, cyclyl, heterocyclyl, aromatics, heteroaromatics, and the like.

[0056] As used herein, the term “carbonyl” means the group — C(O) — . It is noted that the carbonyl group can be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, ketones, and the like.

[0057] The term “carboxy” means the group — C(O)O — . It is noted that compounds described herein containing carboxy moieties can include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. The term "carboxyl" means -COOH.

[0058] The term “cyano” means the group — CN.

[0059] The term, “heteroatom” refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, sulfur and halogens. A “heteroatom moiety” includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include — N=, — NRN— , — N+(O )=, — O — , — S — or — S(O)2— , — OS(O)2 — , and — SS — , wherein RNis H or a further substituent.

[0060] The term “hydroxy” means the group — OH.

[0061] The term “imine derivative” means a derivative comprising the moiety — C(NR) — , wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

[0062] The term “nitro” means the group — NO2.

[0063] An “oxaaliphatic,” “oxaalicyclic”, or “oxaaromatic” mean an aliphatic, alicyclic, or aromatic, as defined herein, except where one or more oxygen atoms ( — O — ) are positioned between carbon atoms of the aliphatic, alicyclic, or aromatic respectively.

[0064] An “oxoaliphatic,” “oxoalicyclic”, or “oxoaromatic” means an aliphatic, alicyclic, or aromatic, as defined herein, substituted with a carbonyl group. The carbonyl group can be an aldehyde, ketone, ester, amide, acid, or acid halide.

[0065] As used herein, the term “aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring can be such that the ring atoms are only carbon atoms (e.g., aryl) or can include carbon and non-carbon atoms (e.g., heteroaryl).

[0066] As used herein, the term “substituted” refers to independent replacement of one or more (typically 1, 2, 3, 4, or 5) of the hydrogen atoms on the substituted moiety with substituents independently selected from the group of substituents listed below in the definition for “substituents” or otherwise specified. In general, a non-hydrogen substituent can be anysubstituent that can be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, acyl, acylamino, acyloxy, aldehyde, alicyclic, aliphatic, alkanesulfonamido, alkanesulfonyl, alkaryl, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylcarbanoyl, alkylene, alkylidene, alkylthios, alkynyl, amide, amido, amino, aminoalkyl, aralkyl, aralkylsulfonamido, arenesulfonamido, arenesulfonyl, aromatic, aryl, arylamino, aryl carb anoyl, aryloxy, azido, carbamoyl, carbonyl, carbonyls including ketones, carboxy, carboxylates, CF3, cyano (CN), cycloalkyl, cycloalkylene, ester, ether, haloalkyl, halogen, halogen, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, imino, iminoketone, ketone, mercapto, nitro, oxaalkyl, oxo, oxoalkyl, phosphoryl (including phosphonate and phosphinate), silyl groups, sulfonamido, sulfonyl (including sulfate, sulfamoyl and sulfonate), thiols, and ureido moieties, each of which may optionally also be substituted or unsubstituted. In some cases, two substituents, together with the carbon(s) to which they are attached to, can form a ring.

[0067] Substituents may be protected as necessary and any of the protecting groups commonly used in the art may be employed. Non-limiting examples of protecting groups may be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 3rd Ed. (New York: Wiley, 1999).

[0068] The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen atom attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy can be represented by -O-aryl or O- heteroaryl, wherein aryl and heteroaryl are as defined below. The alkoxy and aroxy groups can be substituted as described above for alkyl.

[0069] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0070] The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur atom attached thereto. In preferred embodiments, the “alkylthio” moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term “alkylthio” also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. “Arylthio” refers to aryl or heteroaryl groups.

[0071] The term “sulfinyl” means the group — SO — . It is noted that the sulfinyl group can be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfmamides, sulfinyl esters, sulfoxides, and the like.

[0072] The term “sulfonyl” means the group — SO2 — . It is noted that the sulfonyl group can be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids (-SO3H), sulfonamides, sulfonate esters, sulfones, and the like.

[0073] The term “thiocarbonyl” means the group — C(S) — . It is noted that the thiocarbonyl group can be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, thioketones, and the like.

[0074] As used herein, the term “amino” means -NH2. The term “alkylamino” means a nitrogen moiety having at least one straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl groups attached to the nitrogen. For example, representative amino groups include — NH2, — NHCH3, — N(CH3)2, — NH(Ci-Cioalkyl), — N(Ci-Cioalkyl)2, and the like. The term “alkylamino” includes “alkenylamino,” “alkynylamino,” “cyclylamino,” and “heterocyclylamino.” The term “arylamino” means a nitrogen moiety having at least one aryl group attached to the nitrogen. For example — NHaryl, and — N(aryl)2. The term “heteroarylamino” means a nitrogen moiety having at least one heteroaryl group attached to the nitrogen. For example — NHheteroaryl, and — N(heteroaryl)2. Optionally, two substituents together with the nitrogen can also form a ring. Unless indicated otherwise, the compounds described herein containing amino moieties can include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like.

[0075] The term “aminoalkyl” means an alkyl, alkenyl, and alkynyl as defined above, except where one or more substituted or unsubstituted nitrogen atoms ( — N — ) are positioned between carbon atoms of the alkyl, alkenyl, or alkynyl . For example, an (C2-C6) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.

[0076] The term “alkoxyalkoxy” means -O-(alkyl)-O-(alkyl), such as -OCH2CH2OCH3, and the like.

[0077] The term “alkoxy carbonyl" means -C(O)O-(alkyl), such as -C(=O)OCH3, - C(=O)OCH2CH3, and the like.

[0078] The term “alkoxyalkyl” means -(alkyl)-O-(alkyl), such as — CH2OCH3, - CH2OCH2CH3, and the like.

[0079] The term “aryloxy” means -O-(aryl), such as -O-phenyl, -O-pyridinyl, and the like.

[0080] The term “arylalkyl" means -(alkyl)-(aryl), such as benzyl (i.e., -CFkphenyl), - CH2-pyrindinyl, and the like.

[0081] The term “arylalkyloxy” means -O-(alkyl)-(aryl), such as -O-benzyl, -O-CH2- pyridinyl, and the like.

[0082] The term “cycloalkyloxy” means -O-(cycloalkyl), such as -O-cyclohexyl, and the like.

[0083] The term “cycloalkylalkyloxy” means -O-(alkyl)-(cycloalkyl, such as -OCThcyclohexyl, and the like.

[0084] The term “aminoalkoxy” means -O-(alkyl)-NH2, such as -OCH2NH2, -OCH2CH2NH2, and the like.

[0085] The term “mono- or di-alkylamino” means -NH(alkyl) or -N(alkyl)(alkyl), respectively, such as -NHCH3, -N(CHs)2, and the like.

[0086] The term "mono- or di-alkylaminoalkoxy” means -O-(alkyl)-NH(alkyl) or -O- (alkyl)-N(alkyl)(alkyl), respectively, such as -OCH2NHCH3, -OCH2CH2N(CH3)2, and the like.

[0087] The term “arylamino" means -NH(aryl), such as -NH-phenyl, -NH-pyridinyl, and the like.

[0088] The term “arylalkylamino” means -NH-(alkyl)-(aryl), such as -NH-benzyl, - NHCTb-pyridinyl, and the like.

[0089] The term “alkylamino” means -NH(alkyl), such as -NHCH3, -NHCH2CH3, and the like.

[0090] The term “cycloalkylamino” means -NH-(cycloalkyl), such as -NH-cyclohexyl, and the like.

[0091] The term “cycloalkylalkylamino” -NH-(alkyl)-(cycloalkyl), such as -NHCH2- cyclohexyl, and the like.

[0092] It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a Ci alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a Ci alkyl comprises methyl (i.e., — CH3) as well as — CRaRbRc where Ra, Rb, and Rccan each independently be hydrogen or any other substituent where the atom alpha to the carbon is a heteroatom or cyano. Hence, CF3, CH2OH and CH2CN are all Ci alkyls.

[0093] Unless otherwise stated, structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a13C- or14C-enriched carbon are within the scope of the invention.

[0094] In various embodiments, compounds of the present invention as disclosed herein may be synthesized using any synthetic method available to one of skill in the art. Non-limiting examples of synthetic methods used to prepare various embodiments of compounds of the present invention are disclosed in the Examples section herein.

[0095] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” when used in reference to a symptom, disease, disorder, or disease condition, refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to reverse, alleviate, ameliorate, inhibit, lessen, slow down or stop the progression or severity of a symptom, disease condition, disease, or disorder. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a disease condition, disease, or disorder. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a symptom, disease, disorder, disease condition is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in the absence of treatment. Also, “treatment” may mean to pursue or obtain beneficial results, or lower the chances of the individual developing the disease condition, disease, or disorder even if the treatment is ultimately unsuccessful. Those in need of treatment include those already with the symptom, disease condition, disease, or disorder as well as those prone to have the symptom, disease condition, disease, or disorder, or those in whom the symptom, disease condition, disease, or disorder is to be prevented. Treatment also includes a decrease in mortality or an increase in the lifespan of a subject as compared to one not receiving the treatment.

[0096] The term “preventative treatment” means maintaining or improving a healthy state or non-diseased state of a healthy subject or subject that does not have a symptom, disease, disorder, or disease condition. The term “preventative treatment” also means to prevent or to slow the appearance of symptoms associated with a disease condition, disease, or disorder. The term “preventative treatment” also means to prevent or slow a subject from obtaining a symptom, disease condition, disease, or disorder.

[0097] Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. The term "treatment" of a disease condition, disease, or disorder also includes providing relief from the symptoms or side-effects of the disease, disorder, or disease condition (including palliative treatment). Those in need of treatment include those already with the disease condition, disease, or disorder as wellas those prone to have the disease condition, disease, or disorder or those in whom the disease condition, disease, or disorder is to be prevented.

[0098] “Beneficial results” or “desired results” may include, but are in no way limited to, lessening or alleviating the severity of the symptom, disease, disorder, or disease condition; preventing the symptom, disease, disorder, or disease condition from worsening; curing the symptom, disease, disorder, or disease condition; preventing the symptom, disease, disorder, or disease condition from developing; lowering the chances of a patient developing the symptom, disease, disorder, or disease condition; decreasing morbidity and mortality; and prolonging a patient’s life or life expectancy. As non-limiting examples, “beneficial results” or “desired results” may be alleviation of one or more symptom(s); diminishment of extent of the deficit; stabilized (i.e., not worsening) state of a symptom, disease, disorder, or disease condition; delay or slowing of a symptom, disease, disorder, or disease condition; and amelioration or palliation of symptoms associated with a disease, disorder, or disease condition.

[0099] As used herein, the term “administering,” refers to the placement of a compound or an agent (e.g., a compound, a composition, a drug, combination of drugs, combination of compounds, therapeutic agent, pharmaceutical composition, compound of the present invention, compound of Formula (I), compound of Formula (II), compound of Formula (III), compound of Formula (IV), DZ-1-10-HCPT, DZ-1-SN38, AP-001, existing therapy, etc.) or a treatment as disclosed herein into a subject by a method or route which results in at least partial localization of the compound, composition, drug, combination of drugs, therapeutic agent, pharmaceutical composition, compound of the present invention, compound of Formula (I), compound of Formula (II), compound of Formula (III), compound of Formula (IV), DZ-1-10-HCPT, DZ-1-SN38, AP- 001, existing therapy, or treatment at a desired site.

[0100] “Route of administration” may refer to any administration pathway known in the art, including but not limited to aerosol, nasal, via inhalation, oral, anal, intra-anal, peri-anal, transmucosal, transdermal, parenteral, enteral, topical or local. “Parenteral” refers to a route of administration that is generally associated with injection, including intracranial, intraventricular, intrathecal, epidural, intradural, intraorbital, infusion, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravascular, intravenous, intraarterial, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders. Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres orlipid vesicles or polymer vesicles allowing controlled release. Via the topical route, the pharmaceutical compositions can be in the form of aerosol, lotion, cream, gel, ointment, suspensions, solutions or emulsions. In accordance with the present invention, “administering” can be self-administering. For example, it is considered as “administering” that a subject consumes a compound, a composition, a drug, combination of drugs, combination of compounds, therapeutic agent, pharmaceutical composition, compound of the present invention, compound of Formula (I), compound of Formula (II), compound of Formula (III), compound of Formula (IV), DZ-1-10-HCPT, DZ-1-SN38, AP-001, or existing therapy, as disclosed herein.

[0101] As used herein, an “effective amount” is that amount effective to bring about the physiological change desired in the subject or sample to which a compound or agent (e.g., a compound, a composition, a drug, combination of drugs, combination of compounds, therapeutic agent, pharmaceutical composition, compound of the present invention, compound of Formula (I), compound of Formula (II), compound of Formula (III), compound of Formula (IV), DZ-1-10- HCPT, DZ-1-SN38, AP-001, or existing therapy) is administered. The term “therapeutically effective amount” as used herein, means that amount of a compound or agent (e.g., a compound, a composition, a drug, combination of drugs, combination of compounds, therapeutic agent, pharmaceutical composition, compound of the present invention, compound of Formula (I), compound of Formula (II), compound of Formula (III), compound of Formula (IV), DZ-1-10- HCPT, DZ-1-SN38, AP-001, or existing therapy), alone or in combination, or in combination with another compound or agent according to an embodiment of the invention, that elicits the biological or medicinal response in a subject or sample that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease, disorder, or disease condition being treated. For example, if the drug is a therapeutic agent, an effective amount of the drug is that amount sufficient to treat a pathological condition (e.g., a disease, disorder, or disease condition) in the subject or sample to which the drug is administered. For example, in the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; kill existing cancer cells; and / or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the therapeutic agent may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0102] “Diagnostic” means identifying the presence or nature of a symptom, diseasecondition, disease, or disorder and includes identifying patients who are at risk of developing a specific disease condition, disease, or disorder. Diagnostic methods differ in their sensitivity and specificity. The “sensitivity” of a diagnostic assay is the percentage of diseased individuals who test positive (percent of “true positives”). Diseased individuals not detected by the assay are “false negatives.” Subjects who are not diseased and who test negative in the assay, are termed “true negatives.” The “specificity” of a diagnostic assay is 1 minus the false positive rate, where the “false positive” rate is defined as the proportion of those without the disease who test positive. While a particular diagnostic method may not provide a definitive diagnosis of a disease condition, disease, or disorder it suffices if the method provides a positive indication that aids in diagnosis.

[0103] The terms “detection”, “detecting” and the like, may be used in the context of detecting a compound of the present invention bound to or in contact with a tissue (e.g., a tissue, a cell, a cancerous tissue, cancer tissue, cancer cell, tumor, tumor cell, or tumor tissue). In some embodiments, the terms “detection”, “detecting” and the like, may be used in the context of detecting a disease condition, detecting a disease, or detecting a disorder (e.g. when positive assay results are obtained).

[0104] The term “diagnosis,” or “dx,” refers to the identification of the nature and cause of a certain phenomenon. As used herein, a diagnosis typically refers to a medical diagnosis, which is the process of determining which disease, disorder, or disease condition explains a symptoms and signs. A diagnostic procedure, often a diagnostic test or assay, can be used to provide a diagnosis.

[0105] The term “prognosis,” or “px,” as used herein refers to predicting the likely outcome of a current standing. For example, a prognosis can include the expected duration and course of a symptom, disease, disorder, or disease condition, such as progressive decline or expected recovery.

[0106] The term “theranosis,” or “tx” as used herein refers to a diagnosis or prognosis used in the context of a medical treatment. For example, theranostics can include diagnostic testing used for selecting appropriate and optimal therapies (or the inverse) based on the context of genetic content or other molecular or cellular analysis. Theranostics includes pharmacogenomics, personalized and precision medicine.

[0107] As used herein, a “subject” means a human or animal. For example, the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, and canine species, e.g.,dog, fox, wolf. The terms, “patient”, “individual” and “subject” are used interchangeably herein. In an embodiment, the subject is mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. In addition, the methods described herein can be used to treat domesticated animals and / or pets. In some embodiments, the subject is a human.

[0108] The terms “subject”, “patient” or “individual” generally refer to a human, although the methods of the invention are not limited to humans, and should be useful in other animals (e.g. birds, reptiles, amphibians, mammals), particularly in mammals, since albumin is homologous among species.

[0109] “Mammal,” as used herein, refers to any member of the class Mammalia, including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domesticated mammals, such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be included within the scope of this term.

[0110] A subject can be one who has been previously diagnosed with or identified as suffering from or having a disease, disorder, or disease condition in need of treatment or one or more complications related to the disease, disorder, or disease condition, and optionally, have already undergone treatment for the disease, disorder, or disease condition, or the one or more complications related to the disease, disorder, or disease condition. Alternatively, a subject can also be one who has not been previously diagnosed as having a disease, disorder, or disease condition, or one or more complications related to the disease, disorder, or disease condition. For example, a subject can be one who exhibits one or more risk factors for a disease, disorder, or disease condition or one or more complications related to the disease, disorder, or disease condition, or a subject who does not exhibit risk factors. For example, a subject can be one who exhibits one or more symptoms for a disease, disorder, or disease condition, or one or more complications related to the disease, disorder, or disease condition, or a subject who does not exhibit symptoms. A “subject in need” of diagnosis or treatment for a particular disease, disorder, or disease condition, can be a subject suspected of having that disease, disorder, disease condition, diagnosed as having that disease, disorder, or disease condition, already treated or being treated for that disease, disorder, or disease condition, not treated for that disease, disorder, or disease condition, or at risk of developing that disease, disorder, or disease condition.

[0111] In some embodiments, the subject is at risk of developing cancer. In some embodiments, the subject has cancer. In some embodiments, the subject has been diagnosed with cancer. In some embodiments, the subject is at risk of developing cancer. In some embodiments, the subject is at risk of developing cancer. In some embodiments, the subject has been treated for cancer. In some embodiments, the subject is being treated for cancer. In some embodiments, the subject is a cancer patient. In some embodiments, the subject is a cancer patient that is undergoing and / or being treated with chemotherapy.

[0112] In some embodiments, the subject is selected from the group consisting of a subject suspected of having cancer, a subject that has cancer, a subject diagnosed with cancer, a subject that is at risk of developing cancer, a subject that has been treated for cancer, and a subject that is being treated for cancer.

[0113] By “at risk of’ is intended to mean at increased risk of, compared to a normal subject, or compared to a control group, e.g. a patient population, or a reference. Thus a subject carrying a particular marker may have an increased risk for a specific symptom, disease condition, disease, or disorder, and be identified as needing further testing. “Increased risk” or “elevated risk” means any statistically significant increase in the probability, e.g., that the subject has the symptom, disease, disorder, or disease condition. In some embodiments, the risk is increased by at least 10% over the control group or reference with which the comparison is being made. In some embodiments, the risk is increased by at least 20% over the control group or reference with which the comparison is being made. In some embodiments, the risk is increased by at least 50% over the control group or reference with which the comparison is being made.

[0114] In some embodiments, the reference is selected from: (i) a control subject or a sample from the control subject, wherein the control subject does not have the disease, disorder, or disease condition; (ii) a control subject or a sample from the control subject, wherein the control subject has the disease, disorder, or disease condition; (iii) the subject or a sample from the subject that was obtained from the subject at an earlier point in time; (iv) a healthy subject or a sample from the healthy subject; an (v) the subject or a sample from the subject after the subject was treated for the disease, disorder, or disease condition.

[0115] The term “statistically significant” or “significantly” refers to statistical evidence that there is a difference. It is defined as the probability of making a decision to reject the null hypothesis when the null hypothesis is actually true. The decision is often made using the p-value.

[0116] “Sample” is used herein in its broadest sense. The term “biological sample” as used herein denotes a sample taken or isolated from a biological organism. A sample or biological sample may comprise a bodily fluid including blood, serum, plasma, tears, aqueous and vitreoushumor, spinal fluid; a soluble fraction of a cell or tissue preparation, or media in which cells were grown; or membrane isolated or extracted from a cell or tissue; polypeptides, or peptides in solution or bound to a substrate; a cell; a tissue; a tissue print; a fingerprint, skin or hair; fragments and derivatives thereof. Non-limiting examples of samples or biological samples include cheek swab; mucus; whole blood, blood, serum; plasma; urine; saliva; semen; lymph; fecal extract; sputum; other body fluid or biofluid; cell sample; and tissue sample etc. The term also includes a mixture of the above-mentioned samples or biological samples. The term “sample” also includes untreated or pretreated (or pre-processed) biological samples. In some embodiments, a sample or biological sample can comprise one or more cells from the subject. In some embodiments, a sample or biological sample can comprise one or more tissue samples from the subject. In some embodiments, a sample or biological sample is a tissue or tissue sample. In some embodiments, a sample or biological sample can be a tumor cell sample, e.g. the sample can comprise cancerous cells, cells from a tumor, and / or a tumor biopsy.

[0117] In some embodiments, a sample can comprise one or more cells from the subject. In some embodiments, the sample can comprise one or more tissues from the subject. In some embodiments, a sample is a cell or cell sample. In some embodiments, a sample is a tissue or tissue sample. In some embodiments, the sample is a tumor, tumor tissue, or tumor cell. In some embodiments, the sample is a cancer cell or cancer tissue. In some embodiments, a sample can be a tumor cell sample, e.g. the sample can comprise cancerous cells, cancer cells, cells from a tumor, and / or a tumor biopsy. In some embodiments, the tissue is a cancer tissue. In some embodiments, the tissue is a tumor tissue. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a tumor cell.

[0118] Non-limiting examples of samples or biological samples include, cheek swab; mucus; whole blood, blood, serum; plasma; blood products, urine; saliva; semen; lymph; fecal extract; sputum; other body fluid or biofluid; cell sample; tissue sample; tissue extract; tissue biopsy etc.

[0119] In some embodiments, samples or biological samples comprise blood products, including whole blood, blood, plasma and / or serum. In some embodiments, samples or biological samples comprise derivatives of blood products, including whole blood, blood, plasma and / or serum. In some embodiments, the sample is a biological sample. In some embodiments, the sample is whole blood. In some embodiments, the sample is blood. In some embodiments, the sample is plasma. In some embodiments, the sample is serum.

[0120] In some embodiments, the sample is a tissue sample. In some embodiments, the sample is a tissue extract. In some embodiments the sample is a biopsy sample. In some embodiments the sample is a biopsy specimen.

[0121] The terms “body fluid” or “bodily fluids” are liquids originating from inside the bodies of organisms. Bodily fluids include amniotic fluid, aqueous humour, vitreous humour, bile, whole blood, blood (e.g., serum, plasma), breast milk, cerebrospinal fluid, cerumen (earwax), chyle, chyme, endolymph and perilymph, exudates, feces, female ejaculate, gastric acid, gastric juice, lymph, mucus (e.g., nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum (skin oil), serous fluid, semen, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretion, and vomit. Extracellular bodily fluids include intravascular fluid (blood plasma), interstitial fluids, lymphatic fluid and transcellular fluid. Immunoglobulin G (IgG), the most abundant antibody subclass, may be found in all body fluids. “Biological sample” also includes a mixture of the above-mentioned body fluids. “Biological samples” may be untreated or pretreated (or pre-processed) biological samples.

[0122] Sample collection procedures and devices known in the art are suitable for use with various embodiment of the present invention. Examples of sample collection procedures and devices include but are not limited to: phlebotomy tubes (e.g., a vacutainer blood / specimen collection device for collection and / or storage of the blood / specimen), dried blood spots, Microvette CB300 Capillary Collection Device (Sarstedt), HemaXis blood collection devices (microfluidic technology, Hemaxis), Volumetric Absorptive Microsampling ( such as CE-IVD Mitra microsampling device for accurate dried blood sampling (Neoteryx), HemaSpot™-HF Blood Collection Device. Additional sample collection procedures and devices include but are not limited to: a tissue sample collection device; standard collection / storage device (e.g., a collection / storage device for collection and / or storage of a sample (e.g., blood, plasma, serum, urine, etc.); a dried blood spot sampling device. In some embodiments, the Volumetric Absorptive Microsampling (VAMS™) samples can be stored and mailed, and an assay can be performed remotely.

[0123] The term “threshold” as used herein refers to the magnitude or intensity that must be exceeded for a certain reaction, phenomenon, result, or condition to occur or be considered relevant. The relevance can depend on context, e.g., it may refer to a positive, reactive or statistically significant relevance.

[0124] The term “disease” refers to an abnormal condition affecting the body of an organism. For example, the disease or abnormal condition may result from a pathophysiological response to external or internal factors.

[0125] The term “disorder” refers to a functional abnormality or disturbance. For example, a disorder may be a disruption of the disease to the normal or regular functions in the body or a part of the body.

[0126] The term “disease condition” refers to an abnormal state of health that interferes with the usual activities of feeling or wellbeing.

[0127] The term “normal condition” or “healthy condition” refers to a normal state of health.

[0128] The term “healthy state” or “normal state” means that the state of the subject (e.g., biological state or health state, etc.) is not abnormal or does not comprise a disease, disorder, or disease condition.

[0129] A “healthy subject” or “normal subject” is a subject that does not have a disease, disorder, or disease condition.

[0130] The term “unhealthy subject” or “abnormal subject” is a subject that does have a disease, disorder, or disease condition.

[0131] “Diseases”, “disorders” and “disease conditions,” as used herein may include cancer, but are in no way limited to any form of a cancer.

[0132] In various embodiments, the disease is at least one cancer. In various embodiments, the disorder is at least one cancer. In various embodiments, the disease condition is at least one cancer.

[0133] Examples of cancer include but are not limited to breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; cervical cancers such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; acute myeloid leukemia (AML), preferably acute promyleocytic leukemia in peripheral blood; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinickeratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi’s sarcoma; Ewing sarcoma; central nervous system cancers such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme (GBM)), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas; oral cavity and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and nonseminomas; and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; head cancer; neck cancer; throat cancer; and thymus cancer, such as to thymomas, thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors. Also, the methods can be used to treat viral-induced cancers. The major virusmalignancy systems include hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia / lymphoma; and human papilloma virus (HPV) and cervical cancer. In some embodiments, the cancer is metastasized. In some embodiments, the cancer is glioma. In some embodiments, the glioma is selected from the group consisting of astrocytoma, anaplastic astrocytoma, glioblastoma multiforme (GBM), oligodendroglioma and combinations thereof.

[0134] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0135] “Therapeutic agents” as used herein refers to agents or compounds that are used to, for example, treat, inhibit, prevent, mitigate the effects of, reduce the severity of, reduce the likelihood of developing, slow the progression of a disease, disorder, condition, medical condition, or disease condition. Diseases targeted by the therapeutic agents include but are not limited to cancer. In some embodiments, the diseases targeted by the therapeutic agents include but are not limited to cancer. In some embodiments, the therapeutic agent comprises at least one compound of the present invention, at least one compound of Formula (I), at least one compound of Formula (II), at least one compound of Formula (III), at least one compound of Formula (IV), DZ-1-10- HCPT, DZ-1-SN38, or AP-001.

[0136] A “pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound described herein that is utilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound. The pharmaceutically acceptable salt form can also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body. An example of a pharmacokinetic property that can be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can critically affect bioavailability, the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized. One of skill in the art will appreciate that an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid absorption of the compound.

[0137] Pharmaceutically acceptable salts include those derived from inorganic acids such as sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. See, for example, Berge et al., “Pharmaceutical Salts”, J. Pharm. Set. 66: 1-19 (1977), the content of which is herein incorporated by reference in its entirety. Exemplary salts also include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, succinate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. Suitable acids which are capable of forming salts with the compounds of the disclosure include inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, 2- naphthalenesulfonic acid, 3 -phenylpropionic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, 4,4’-mefhylenebis(3-hydroxy-2-ene-l-carboxylic acid), acetic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid,muconic acid , naphthalene sulfonic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p- chlorobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, tertiary butylacetic acid, trifluoroacetic acid, trimethylacetic acid, and the like. Suitable bases capable of forming salts with the compounds of the disclosure include inorganic bases such as sodium hydroxide, ammonium hydroxide, sodium carbonate, calcium hydroxide, potassium hydroxide and the like; and organic bases such as mono-, di- and tri-alkyl and aryl amines (e.g., triethylamine, diisopropyl amine, methyl amine, dimethyl amine, N-methylglucamine, pyridine, picoline, di cyclohexylamine, N,N’- dibezylethylenediamine, and the like), and optionally substituted ethanol-amines (e.g., ethanolamine, diethanolamine, trierhanolamine and the like).

[0138] In various embodiments, the pharmaceutical compositions according to the invention can contain any pharmaceutically acceptable excipient. “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of excipients include but are not limited to starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, wetting agents, emulsifiers, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, antioxidants, plasticizers, gelling agents, thickeners, hardeners, setting agents, suspending agents, surfactants, humectants, carriers, stabilizers, and combinations thereof.

[0139] In various embodiments, the pharmaceutical compositions according to the invention can contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0140] Irinotecan is a major component of the FOLFIRINOX regimen used for treating pancreatic ductal adenocarcinoma (PDAC) and other cancers. Although, irinotecan is veryeffective in killing the cancer cells through inhibiting Topoisomerase 1, it is very toxic and only a small percentage of patients can tolerate it because of its high toxicity. We have developed a novel drug using the active part of irinotecan to make a specific cancer cell targeted therapy. The drug is a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (HMCD) we call DZ chemically conjugated to SN38, the active part of irinotecan. DZ-SN38 conjugate was synthesized and tested for mechanism and efficacy in cells and animal models of PDAC.

[0141] The targeting of DZ-SN38 specifically to PDAC cells was measured by determining the NIR fluorescence in cells and tissues in animals. Mitochondrial bioenergetics and functions were measured by Seahorse and flow cytometry, respectively. Apoptosis was assessed by DNA fragmentation and An / PI staining. The effect of DZ-SN38 on tumor growth, and metastasis was tested in the syngeneic mice with PDAC.

[0142] In animal models of PDAC, NIR fluorescence showed specific localization of DZ- SN38 to tumors but not to normal cells and tissues. DZ-SN38 was retained in cancer cells for up to two weeks while its retention in normal cells did not exceed few hours. DZ-SN38 was more potent than irinotecan or SN38 on decreasing survival and inducing apoptosis in human and mouse PDAC cells. Compared to irinotecan, DZ-SN38 had greater potency for killing PDAC cells. Furthermore, DZ-SN38 was able to kill cancer cells resistant to irinotecan. Normal cells were killed by irinotecan, but greater doses of DZ-SN38 were needed to induce normal cell death. Mechanistically, DZ-SN38 inhibited topoisomerase 1 as effectively as irinotecan but had a unique anti-cancer effect by significantly decreasing mitochondria bioenergetics, decreasing ATP production, and increasing ROS production. DZ-SN38 was significantly more effective in inhibiting tumor growth and metastasis in our animal models.

[0143] DZ-SN38 is a unique cancer-targeting therapeutic that overcomes the toxicity of irinotecan and outperforms it in in vitro and in vivo models of pancreatic cancer.

[0144] By using the near-infrared (NIR) organic heptamethine carboyanine dye (HMCD) which we call DZ for tumor targeting, we synthesized DZ conjugates with the Irinotecan (also known as CPT-11) active metabolite SN-38 (a CPT-11 derivative) for targeted drug delivery.

[0145] In addition, we also found that DZ-SN38 performs significantly better than Irinotecan in killing the cancer cells and that it has an additive effect when combined with AP-001 (also known as Metavert).

[0146] Effect of the new conjugates on pancreatic cancer cell survival

[0147] Pancreatic cancer cells were treated with different doses of Irinotecan or DZ-SN38. We found that DZ-SN38 performed better than Irinotecan in decreasing cancer cell survival. DZ- SN38 significantly decreased cell survival in MIA PaCa-2 pancreatic cancer cells (FIG. 1)compared to the levels induced by Irinotecan. Importantly, we found that combination of low doses of AP-001 and DZ-SN38 induced an additive effect on decreasing cancer cells survival (FIG. 2).

[0148] In various embodiments, the present invention pertains to conjugates of a heptamethine carbocyanine dye (DZ-1) with derivatives of camptothecin, for example, 10- hydroxycamptothecin (10-HCPT) and 7-ethyl-10-hydroxycamptothecin (SN-38), including DZ- 1-10-HCPT and DZ-1-SN38, for use in targeted therapy of cancer, for example, for use in targeted therapy for pancreatic ductal adenocarcinoma (PDAC). The conjugates feature a linker moiety that attaches to DZ-1 via an ester or amide bond, and to the camptothecin derivative through an ester, ether, carbamate, or thiocarbamate bond. These conjugates demonstrate significant anti- PDAC cell activity in vitro. The compounds offer several advantages, including specific targeting of tumors, efficacy against therapy -resistant cancer cells, and potential to cross the blood-brain barrier.

[0149] Our data indicate that DZ-SN38 performs better than irinotecan in killing PDAC MIA PaCa-2 (FIG. 3A), BxPC3 (FIG. 3B) and PANC-1 cells (FIG. 3C). Published data shows that irinotecan is released from cancer cells within hours. Our data indicate that DZ-SN38 (used at low doses not to kill cells) is retained in PDAC cells for up to 2 weeks, but not detected in normal cells after 48 hours (FIG. 4). Cells were treated for 1 hour to allow accumulation of the drug in cells and then media was changed.

[0150] Next, we tested the effect of the drugs on mitochondrial bioenergetics knowing that DZ conjugates affect mitochondria functions. We found that DZ-SN38 significantly decreases mitochondrial bioenergetics in MIA PaCa-2 cells compared to Irinotecan and SN38 suggesting a novel mechanism of affecting cancer cell survival (FIG. 5A - FIG. 5E). Treatment for 2 hours with IpM of DZ-SN38 induced a significant decrease in oxygen consumption rate (FIG. 5A), extracellular acidification rate (FIG. 5B), basal and maximal respiration (FIG. 5C, FIG. 5D), and spare respiratory capacity (FIG. 5E) indicating a significant impairment in mitochondria function.

[0151] We have developed irinotecan-resistant (IR) PDAC cells. MIA PaCa-2 IR and BxPC3 IR are PDAC cells resistant to irinotecan (FIG. 6A); however, when DZ-SN38 was added to these cells, they showed a significant decrease in cell survival indicating that DZ-SN38 overcomes the mechanism of resistance developed against irinotecan (FIG. 6B).

[0152] Various embodiments of the present invention provide a compound, comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component. In some embodiments, the linker moiety (L) is bonded to the HMCD component viaan amide or ester bond; and the linker moiety (L) is bonded to the camptothecin derivative component via an ester, ether, carbamate, or thiocarbamate bond. In some embodiments, the linker moiety (L) is selected from the group consisting of: -O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r- NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and - NH-(CH2)r-NHCS0-, where r is an integer 2-8.

[0153] In various embodiments, the present invention provides a compound having a structure of Formula (I):Formula (I)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluorob orate, and a pharmaceutically acceptable anion; n is 4;m is 4; andL is selected from the group consisting of: -O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r- NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and - NH-(CH2)r-NHCS0-, where r is an integer 2-8.

[0154] In various embodiments, the present invention provides a compound having a structure of Formula (II):wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluorob orate, and a pharmaceutically acceptable anion; n is 4; and m is 4.

[0155] In various embodiments, the present invention provides a compound having a structure of Formula (III):Formula (III)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); n is 4; and m is 4.

[0156] In various embodiments, the present invention provides compound having a structure of Formula (IV):wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3; each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R8is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR18, and co-acyl-lysine, wherein R18is selected from the group consisting of hydrogen and alkyl;D' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; p is 4; and q is 4.

[0157] In some embodiments, the compound of Formula (I) is a compound comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

[0158] In some embodiments, the compound of Formula (II) is a compound comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

[0159] In some embodiments, the compound of Formula (III) is a compound comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

[0160] In some embodiments, the compound of Formula (I) is a compound of Formula(II). In some embodiments, the compound of Formula (II) is a compound of Formula (I).

[0161] In some embodiments, the compound of Formula (I) is a compound of Formula(III). In some embodiments, the compound of Formula (III) is a compound of Formula (I).

[0162] In some embodiments, the compound of Formula (III) is a compound of Formula (II). In some embodiments, the compound of Formula (II) is a compound of Formula (III).

[0163] In some embodiments, A' is present. In some embodiments, A' is not present. In some embodiments, A' is absent.

[0164] In some embodiments, D' is present. In some embodiments, D' is not present. In some embodiments, D' is absent.

[0165] In some embodiments, AP-001 has the structureHIn some embodiments, AP-001 is known as Metavert.

[0168] In some embodiments, the terms DZ-1-SN38 and DZ-SN38 have the same meaning and are used interchangeably.

[0169] Additional embodiments include those listed below:

[0170] Embodiment 1. A compound, comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

[0171] Embodiment 2. The compound of embodiment 1, wherein the linker moiety (L) is bonded to the HMCD component via an amide or ester bond; and the linker moiety (L) is bonded to the camptothecin derivative component via an ester, ether, carbamate, or thiocarbamate bond.

[0172] Embodiment 3. The compound of embodiment 1, wherein the linker moiety (L) is selected from the group consisting of: -O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r-NHCOO-, -O- (CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and -NH-(CH2)r- NHCSO-, where r is an integer 2-8.

[0173] Embodiment 4. The compound of any one of embodiments 1-3, wherein the compound has a structure of Formula (I):Formula (I)X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion;n is 4; m is 4; andL is selected from the group consisting of: -O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r- NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and - NH-(CH2)r-NHCS0-, where r is an integer 2-8.

[0174] Embodiment 5. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0175] Embodiment 6. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0176] Embodiment 7. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0177] Embodiment 8. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0178] Embodiment 9. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0179] Embodiment 10. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0180] Embodiment 11. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0181] Embodiment 12. The compound of any one of embodiments 1-4, wherein the compound is:wherein R1is H or CH2CH3.

[0182] Embodiment 13. The compound of any one of embodiments 1-4, wherein the compound has a structure of Formula (II):Formula (II)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGyl carb oxy late, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; n is 4; and m is 4.

[0183] Embodiment 14. The compound of embodiment 13, wherein the compound has a structure of Formula (III):Formula (III)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); n is 4; and m is 4.

[0184] Embodiment 15. The compound of embodiment 13 or embodiment 14, wherein the compound is:wherein R1is H or CH2CH3.

[0185] Embodiment 16. The compound of any one of embodiments 13-15, wherein the compound is:

[0186] Embodiment 17. The compound of any one of embodiments 13-15, wherein the compound is:

[0187] Embodiment 18. A pharmaceutical composition comprising the compound of any one of embodiments 1-17.

[0188] Embodiment 19. The pharmaceutical composition of embodiment 18, further comprising at least one pharmaceutically acceptable carrier.

[0189] Embodiment 20. The pharmaceutical composition of embodiment 18, further comprising at least one pharmaceutically acceptable excipient.

[0190] Embodiment 21. A method for treating cancer in a subject, the method comprising: administering a therapeutically effective amount of the compound of any one of embodiments 1- 17 to the subject.

[0191] Embodiment 22. The method of embodiment 21, wherein the cancer is pancreatic cancer.

[0192] Embodiment 23. The method of embodiment 21, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0193] Embodiment 24. The method of any one of embodiments 21-23, further comprising administering a therapeutically effective amount of at least one other compound to theH subject, wherein the at least one other compound is

[0194] Embodiment 25. The method of embodiment 24, wherein the compound of any one of embodiments 1-17 and the at least one other compound are administered sequentially.

[0195] Embodiment 26. The method of embodiment 24, wherein the compound of any one of embodiments 1-17 and the at least one other compound are administered simultaneously.

[0196] Embodiment 27. A method for detecting and treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of any one of embodiments 1-17 to the subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject.

[0197] Embodiment 28. The method of embodiment 27, wherein the cancer is pancreatic cancer.

[0198] Embodiment 29. The method of embodiment 27, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0199] Embodiment 30. A compound having a structure of Formula (IV):wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3; each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R8is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR18, and co-acyl-lysine, wherein R18is selected from the group consisting of hydrogen and alkyl;D' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; p is 4; and q is 4.

[0200] Embodiment 31. The compound of embodiment 30, wherein the compound is:wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3 each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);p is 4; and q is 4.

[0201] Embodiment 32. The compound of embodiment 30 or embodiment 31, wherein the compound is:wherein,R5is H or CH2CH3.

[0202] Embodiment 33. The compound of any one of embodiments 30-32, wherein the compound is:

[0203] Embodiment 34. The compound of any one of embodiments 30-32, wherein the compound is:

[0204] Embodiment 35. A pharmaceutical composition comprising the compound of any one of embodiments 30-34.

[0205] Embodiment 36. The pharmaceutical composition of embodiment 35, further comprising at least one pharmaceutically acceptable carrier.

[0206] Embodiment 37. The pharmaceutical composition of embodiment 35, further comprising at least one pharmaceutically acceptable excipient.

[0207] Embodiment 38. Amethod for treating cancer in a subject, the method comprising: administering a therapeutically effective amount of the compound of any one of embodiments 30- 34 to the subject.

[0208] Embodiment 39. The method of embodiment 38, wherein the cancer is pancreatic cancer.

[0209] Embodiment 40. The method of embodiment 38, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

[0210] Embodiment 41. The method of any one of embodiments 38-40, further comprising administering a therapeutically effective amount of at least one other compound to the subject,H wherein the at least one other compound is

[0211] Embodiment 42. The method of embodiment 41, wherein the compound of any one of embodiments 30-34 and the at least one other compound are administered sequentially.

[0212] Embodiment 43. The method of embodiment 41, wherein the compound of any one of embodiments 30-34 and the at least one other compound are administered simultaneously.

[0213] Embodiment 44. A method for detecting and treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of any one of embodiments 30-34 to the subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject.

[0214] Embodiment 45. The method of embodiment 44, wherein the cancer is pancreatic cancer.

[0215] Embodiment 46. The method of embodiment 44, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).EXAMPLES

[0216] The invention is further illustrated by the following examples which are intended to be purely exemplary of the invention, and which should not be construed as limiting the invention in any way. The following examples are illustrative only, and are not intended to limit, in any manner, any of the aspects described herein. The following examples are provided to betterillustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.

[0217] Chemicals and Instruments

[0218] SN38 and 10-Hydroxycamptothecin (another CPT-11 derivative) were purchased from Medkoo Biosciences, Inc (Morrisville, NC). All other chemicals and reagents were purchased from Sigma-Aldrich (St. Louis, MO) or Fisher Scientific (Waltham, MA). Deionized water (18.2 MQ-cm) for solutions was obtained from the Milli-Q Direct Ultrapure Water System (Merck Millipore, Billerica, Massachusetts). Purification of the newly synthesized compounds was conducted on a preparative High-performance liquid chromatography (HPLC) system consisting of an Agilent system equipped with a PDA detector using either Agilent C18 preparative column (120 A, 250x30 mm) and / or an Apollo C18 semi-preparative column (5 pm, 250x 10 mm) (Grace Davison Discovery Sciences). Two mobile phases were used for HPLC: Solvent A (0.1% TFAin water) and Solvent B (0.1% TFAin 80% aqueous acetonitrile). The mobile phase gradient varied according to the characteristics of the compound, and eluents were monitored at dual wavelengths 254 and 780 nm (a flow rate of 12 mL / min for the preparative column and 3 mL / min for the semi-preparative column). For analytical HPLC, Agilent Cl 8 reverse phase column (2.7p, 4.6mm ID x 50mm) was used at a flow rate of 1 mL min. Electrospray ionization (ESI) mass spectrometry analysis of new compounds was performed using a Thermo Fisher TSQ Fortis Triple Quadrupole system (Thermo Fisher Scientific, Waltham, MA).

[0219] Example 1Synthesis and CharacterizationScheme 1.Reagents and conditions: (i) THF, EtsN, 3h at rt; (ii)l. CH2CI2, N-Boc-l,3-propanediamine, EtiN; 2. 20% TFA in CH2CI2, 2h at rt; (iii) DMF, EDC, HOBt, Compound 4, 3h at rt. a: DZ-10-HCPT; b: DZ-SN38.

[0220] 4-Nitrophenyl camptothecin-10-yl carbonate (3a): To a solution of 10- hydroxycamptothecin (10-HCPT) la (500 mg, 1.35 mmol) in anhydrous Tetrahydrofuran (THF) (100 mL) at 0 °C was added tri ethylamine (2 mL, 13.8 mmol) followed by 4-nitrophenyl chloroformate 2 (830 mg, 4.1 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvents were then removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (200-400 mesh, EtOAc) to afford compound 3a (421 mg, 59%). Mass spectrum (ESI) m / z 530.19 [M+H]+.

[0221] 4-Nitrophenyl 7-Ethyl camptothecin- 10-yl carbonate (3b): To a solution of 7- Ethyl-10-hydroxycamptothecin (SN38) lb (500 mg, 1.27 mmol) in anhydrous THF (100 mL) at 0 °C was added triethylamine (2 mL, 13.8 mmol) followed by 4-nitrophenyl chloroformate 2 (770 mg, 3.8 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvents were then removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (200-400 mesh, EtOAc) to afford compound 3b (432mg, 61%). Mass spectrum (ESI) m / z 558.22 [M+H]+.

[0222] Camptothecin-10-yl(3-aminopropyl)carbamate (4a). Compound 3a (300 mg, 0.57 mmol) and N-Boc- 1,3 -propanediamine (118 mg, 0.68 mmol) were dissolved in dry CH2CI2 (15 ml). Triethylamine (160pL, 1.15mmol) was added. The resulting mixture was stirred for 3 h at rt, and the solvent was removed under reduced pressure. The resulting crude product was purified by silica column chromatography elution with ethyl acetate. The major band was collected, and the solvents are removed under reduced pressure. The product was dissolved in20%TFA CH2CI2 solution and the mixture was stirred at rt for 2h to afford compound 4a (129mg, 49%). Mass spectrum (ESI) m / z 465.29 [M+H]+.

[0223] 7-Ethyl camptothecin-10-yl(3-aminopropyl)carbamate (4b). Compound 3b (180 mg, 0.32 mmol) and N-Boc-l,3-propanediamine (68 mg, 0.39 mmol) were dissolved in dry CH2CI2 (10 ml). Triethylamine (90pL, 0.65 mmol) was added. The resulting mixture was stirred for 3 h at rt, and the solvent was removed under reduced pressure. The resulting crude product was purified by silica column chromatography elution with ethyl acetate. The major band was collected, and the solvents were removed under reduced pressure. The product was dissolved in 20%TFA CH2CI2 solution and the mixture was stirred at rt for 2h to afford compound 4b (91 mg, 58%). Mass spectrum (ESI) m / z 493.31 [M+H]+.

[0224] DZ-1-10-HCPT 6a. The mixture of DZ-1 5 (150 mg, 0.21 mmol), l-ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride (61 mg, 0.32 mmol), and l-hydroxy-7- azabenzotri azole (34 mg, 0.25 mmol) were dissolved in 10.0 mL CH2CI2 solution. The mixture was stirred for 15 min, then compound 4a (98 mg, 0.21 mmol) was added and stirred for additional 3 hours at rt. The solvent was removed under reduced pressure, and the product was purified by C18-RP silica chromatography elution with methanol -water to afford desired product 6a as a dark green solid (94mg, 39%). Mass spectrum (ESI) m / z 1151.55 [M+H]+.

[0225] DZ-1-SN38 6b. The mixture of DZ-1 5 (126 mg, 0.18 mmol), l-ethyl-3-(3- dimethyllaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol), and l-hydroxy-7- azabenzotri azole (29 mg, 0.25 mmol) were dissolved in 10.0 mL CH2CI2 solution. The mixture was stirred for 15 min, then compound 4b (89 mg, 0.18 mmol) was added and stirred for 3 hours at rt. The solvent was removed under reduced pressure. The product was purified by Cl 8-RP silica chromatography elution with methanol -water to afford the desired product 6b as a dark green solid (97mg, 46%). Mass spectrum (ESI) m / z 1179.51 [M+H]+.

[0226] Example 2

[0227] Pancreatic cancer cells were treated with different doses of Irinotecan or DZ-SN38.We found that DZ-SN38 performed better than Irinotecan in decreasing cancer cell survival. DZ- SN38 significantly decreased cell survival in MIA PaCa-2 pancreatic cancer cells (FIG. 1) compared to the levels induced by Irinotecan.

[0228] Example 3

[0229] Importantly, we found that combination of low doses of AP-001 and DZ-SN38 induced an additive effect on decreasing cancer cells survival (FIG. 2).

[0230] The various methods and techniques described above provide a number of ways to carry out the application. Of course, it is to be understood that not necessarily all objectives oradvantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features.

[0231] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature, or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

[0232] Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses and modifications and equivalents thereof.

[0233] Preferred embodiments of this application are described herein, including the best mode known to the inventors for carrying out the application. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

[0234] All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and / or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting affect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and / orthe use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and / or the use of the term in the present document shall prevail.

[0235] It is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

[0236] Various embodiments of the invention are described above in the Detailed Description. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and / or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

[0237] The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention is not limited to the particular embodiments disclosed for carrying out the invention.

[0238] While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention.

Claims

CLAIMSWhat is claimed is:

1. A compound, comprising: a heptamethine carbocyanine dye (HMCD) component; a camptothecin derivative component; and a linker moiety (L) connecting the HMCD component and the camptothecin derivative component.

2. The compound of claim 1, wherein the linker moiety (L) is bonded to the HMCD component via an amide or ester bond; and the linker moiety (L) is bonded to the camptothecin derivative component via an ester, ether, carbamate, or thiocarbamate bond.

3. The compound of claim 1, wherein the linker moiety (L) is selected from the group consisting of:-O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r-NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, - NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and -NH-(CH2)r-NHCSO-, where r is an integer 2-8.

4. The compound of any one of claims 1-3, wherein the compound has a structure of Formula (I):Formula (I)X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3;each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; n is 4; m is 4; andL is selected from the group consisting of: -O-(CH2)r-COO-, -O-(CH2)r-O-, -O-(CH2)r- NHCOO-, -O-(CH2)r-NHCSO-, -NH-(CH2)r-COO-, -NH-(CH2)r-O-, -NH-(CH2)r-NHCOO-, and -NH-(CH2)r-NHCS0-, where r is an integer 2-8.

5. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

6. The compound of any one of claims 1-4, wherein the compound is:

7. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

8. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

9. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

10. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

11. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

12. The compound of any one of claims 1-4, wherein the compound is:wherein R1is H or CH2CH3.

13. The compound of any one of claims 1-4, wherein the compound has a structure of Formula (II):Formula (II)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R4is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR13, and co-acyl-lysine, wherein R13is selected from the group consisting of hydrogen and alkyl;A' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, arylsulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; n is 4; and m is 4.

14. The compound of claim 13, wherein the compound has a structure of Formula (III):Formula (III)wherein:X is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR9, NHR10, 4-S-Ph-NHR11, w-iminoacyl-NHR12, and w-aminoacyl- lysine, wherein R9, R10, R11, and R12are each independently selected from the group consisting of hydrogen and alkyl;R1is H or CH2CH3; each R2is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R3is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); n is 4; and m is 4.

15. The compound of claim 13 or claim 14, wherein the compound is:wherein R1is H or CH2CH3.

16. The compound of any one of claims 13-15, wherein the compound is:

17. The compound of any one of claims 13-15, wherein the compound is:

18. A pharmaceutical composition comprising the compound of any one of claims 1-17.

19. The pharmaceutical composition of claim 18, further comprising at least one pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 18, further comprising at least one pharmaceutically acceptable excipient.

21. A method for treating cancer in a subject, the method comprising: administering a therapeutically effective amount of the compound of any one of claims 1-17 to the subject.

22. The method of claim 21, wherein the cancer is pancreatic cancer.

23. The method of claim 21, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

24. The method of any one of claims 21-23, further comprising administering a therapeutically effective amount of at least one other compound to the subject, wherein the at least one other compound25. The method of claim 24, wherein the compound of any one of claims 1-17 and the at least one other compound are administered sequentially.

26. The method of claim 24, wherein the compound of any one of claims 1-17 and the at least one other compound are administered simultaneously.

27. A method for detecting and treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of any one of claims 1- 17 to the subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject.

28. The method of claim 27, wherein the cancer is pancreatic cancer.

29. The method of claim 27, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

30. A compound having a structure of Formula (IV):Formula (IV)wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3; each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG);R8is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkyl sulfonato, alkylcarboxy, alkylcarboxyl, alkylamino, co-alkylaminium, co-alkynyl, PEGyl, PEGylcarboxylate, co-PEGylaminium, co-acyl-NHR18, and co-acyl-lysine, wherein R18is selected from the group consisting of hydrogen and alkyl;D' is an optional counter ion selected from the group consisting of iodide, bromide, chloride, aryl sulfonato, alkyl sulfonato, tetrafluoroborate, and a pharmaceutically acceptable anion; p is 4; and q is 4.

31. The compound of claim 30, wherein the compound is:wherein:Y is selected from the group consisting of hydrogen, halogen, CN, Me, OH, 4-O-Ph- CH2CH2COOH, 4-O-Ph-NHR14, NHR15, 4-S-Ph-NHR16, w-iminoacyl-NHR17, and w-aminoacyl- lysine, wherein R14, R15, R16, and R17are each independently selected from the group consisting of hydrogen and alkyl;R5is H or CH2CH3 each R6is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); each R7is independently selected from the group consisting of hydrogen, sulfonato, an electron withdrawing group (EWG), and an electron donating group (EDG); p is 4; and q is 4.

32. The compound of claim 30 or claim 31, wherein the compound is:wherein,R5is H or CH2CH3.

33. The compound of any one of claims 30-32, wherein the compound is:

35. A pharmaceutical composition comprising the compound of any one of claims 30-34.

36. The pharmaceutical composition of claim 35, further comprising at least one pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 35, further comprising at least one pharmaceutically acceptable excipient.

38. A method for treating cancer in a subject, the method comprising: administering a therapeutically effective amount of the compound of any one of claims 30-34 to the subject.

39. The method of claim 38, wherein the cancer is pancreatic cancer.

40. The method of claim 38, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

41. The method of any one of claims 38-40, further comprising administering a therapeutically effective amount of at least one other compound to the subject, wherein the at least one other compound42. The method of claim 41, wherein the compound of any one of claims 30-34 and the at least one other compound are administered sequentially.

43. The method of claim 41, wherein the compound of any one of claims 30-34 and the at least one other compound are administered simultaneously.

44. A method for detecting and treating cancer in a subject, the method comprising: administering a therapeutically effective amount of a compound of any one of claims 30-34 to the subject, thereby contacting a tissue of the subject with the compound such that the compound binds to the tissue; detecting the compound bound to the tissue, wherein the presence of the compound bound to the tissue is indicative of the cancer in the subject; and delivering the compound to the tissue thereby treating the cancer in the subject.

45. The method of claim 44, wherein the cancer is pancreatic cancer.

46. The method of claim 44, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

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