Polymers with steroids or vitamins

Abstract

Conjugates of vitamins or steroids are disclosed. The compounds may have the following structure (I) or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, L1, L2, L3, L4, L5, L6, M1, M2, p, q, m and n are as defined herein. The compounds of structure (I) have a variety of uses, including as therapeutic agents for various therapeutic methods. # imgabs0 #

Description

[0001] background

[0002] field

[0003] Embodiments of the present disclosure generally relate to polymeric biologically active compounds having steroids or vitamins, and methods of making the same.

[0004] Description of Related Technology

[0005] Unlike chemotherapy, targeted drug conjugates deliver drugs to target cells with little or no off-target activity. Typically, targeted drug conjugates include targeting molecules connected to a bioactive payload or drug. By combining unique targeting capabilities with the therapeutic effectiveness of a bioactive drug (or part), the conjugate can deliver the drug only to the intended target and minimize potential side effects. Antibody-drug conjugates (ADC, antibody-drug conjugates) are a class of targeted drug conjugates with special significance for the treatment of various diseases. Although ADCs for cancer treatment are becoming more and more popular, other uses of ADCs are still in their infancy.

[0006] Therefore, there is a need in the art to develop effective, targeted drug conjugates with high therapeutic index that are not limited to oncology and methods for their preparation. The present disclosure satisfies this need and provides further related advantages.

[0007] Brief Overview

[0008] In one embodiment, a compound having the following structure (I) or a stereoisomer, tautomer or salt thereof is provided:

[0009]

[0010] Where R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 、M 1 、M 2 , p, q, m and n are as defined herein. The compounds of structure (I) are useful in a variety of applications, including use as therapeutic agents in various therapeutic methods.

[0011] In another embodiment, a composition is provided comprising a compound of structure (I) and a pharmaceutically acceptable carrier.

[0012] In yet another embodiment, a method of treating a disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M 2 Independently, it is a biologically active moiety that is effective in treating the disease.

[0013] These and other aspects of the disclosure will become apparent upon reference to the following detailed description.

[0014] Detailed Description

[0015] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will appreciate that the present disclosure can be practiced without these details.

[0016] Throughout this specification and claims, unless the context requires otherwise, the word "comprise" and variations such as, "comprises" and "comprising", should be interpreted in the open and inclusive sense, ie, "including but not limited to".

[0017] References in this specification to "one embodiment" or "an embodiment" mean that the particular features, structures, or characteristics described in conjunction with that embodiment are included in at least one embodiment of the present disclosure. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] "Amino" means a -NH2 group.

[0019] "Carboxy" means a -CO2H group.

[0020] "Cyano" means a -CN group.

[0021] "Formyl" means a -C(=O)H group.

[0022] "Hydroxy" or "hydroxyl" means an -OH group.

[0023] "Imino" means a =NH group.

[0024] "Nitro" means a -NO2 group.

[0025] "Oxo" refers to a =0 substituent.

[0026] "Mercapto" means a -SH group.

[0027] "Thio" refers to a =S group.

[0028] "Alkyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms (C1-C 12 Alkyl groups are optionally substituted, unless otherwise specifically stated in the specification, or alkyl groups are optionally substituted, and are linked to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted.

[0029] "Alkylene" or "alkylene chain" means a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to the residue, which consists only of carbon and hydrogen, contains no unsaturation, and has 1-12 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule and to the residue by a single bond. The points of connection of the alkylene chain to the rest of the molecule and to the residue can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, alkylene is optionally substituted.

[0030] "Alkenylene" or "alkenylene chain" means a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to the residue, which consists only of carbon and hydrogen, contains at least one carbon-carbon double bond and has 2-12 carbon atoms, for example, vinylene, propenylene, n-butenylene, etc. The alkenylene chain is connected to the rest of the molecule and to the residue by a double bond or a single bond. The connection point of the alkenylene chain to the rest of the molecule and to the residue can be through one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, alkenylene is optionally substituted.

[0031] "Alkynylidene" or "alkynylene chain" means a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a residue, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond and having 2-12 carbon atoms, for example, ethynylene, propynylene, n-butynylene, etc. The alkynylene chain is connected to the rest of the molecule and to the residue by a double bond or a single bond. The connection point of the alkynylene chain to the rest of the molecule and to the residue can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, alkynylene is optionally substituted.

[0032] "Alkyl ether" means any alkyl group as defined above, wherein at least one carbon-carbon bond is replaced by a carbon-oxygen bond. The carbon-oxygen bond may be on the terminal end (as in an alkoxy group), or the carbon-oxygen bond may be internal (i.e., COC). Alkyl ethers include at least one carbon-oxygen bond, but may include more than one. For example, polyethylene glycol (PEG) is included within the meaning of alkyl ethers. Unless otherwise specifically stated in the specification, an alkyl ether group is optionally substituted. For example, in certain embodiments, an alkyl ether is replaced by an alcohol or -OP (=R a )(R b )R c Substitution, where R a , R b and R c Each of which is as defined for the compound of structure (I).

[0033] "Alkoxy" is represented by -OR a A group in which R a is an alkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0034] "Alkoxy alkyl ether" expression -OR a R b A group in which R a is an alkylene group as defined above containing 1 to 12 carbon atoms, and R b is an alkyl ether group as defined herein. Unless stated otherwise specifically in the specification, an alkoxyalkyl ether group is optionally substituted, for example by an alcohol or -OP(=R a )(R b )R c Substitution, where R a , R b and R c Each of which is as defined for the compound of structure (I).

[0035] "Heteroalkyl" means an alkyl group as defined above that contains at least one heteroatom (e.g., N, O, P, or S) within the alkyl group or at the end of the alkyl group. In certain embodiments, the heteroatom is within the alkyl group (i.e., the heteroalkyl group contains at least one carbon-[heteroatom] x -carbon bond, wherein x is 1, 2 or 3). In other embodiments, the heteroatom is at the end of the alkyl group and is thus used to connect the alkyl group to the rest of the molecule (e.g., M1-HA), wherein M1 is part of the molecule, H is a heteroatom and A is an alkyl group). Unless otherwise specifically stated in the specification, heteroalkyl groups are optionally substituted. Exemplary heteroalkyl groups include oxyethylene (e.g., polyoxyethylene), optionally including a phosphorus-oxygen bond, such as a phosphodiester bond.

[0036] "Heteroalkoxy" is represented by -OR a A group in which R a is a heteroalkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a heteroalkoxy group is optionally substituted.

[0037] "Heteroalkylene" means an alkylene group as defined above that contains at least one heteroatom (e.g., Si, N, O, P, or S) within the alkylene chain or at the terminus of the alkylene chain. In certain embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene group contains at least one carbon-[heteroatom]-carbon bond where x is 1, 2, or 3). In other embodiments, the heteroatom is at the terminus of the alkylene group and thus serves to connect the alkylene group to the rest of the molecule (e.g., M 1 -HAM 2 , where M 1 and M 2 is part of a molecule, H is a heteroatom and A is an alkylene group). Unless otherwise specifically stated in the specification, heteroalkylene groups are optionally substituted. Exemplary heteroalkylene groups include oxyethylene (e.g., polyoxyethylene) and the "C", "HEG" and "PEG" linking groups explained below:

[0038]

[0039] "PEG 1K Linker"

[0040] Multimers of the above C-linkers, HEG linkers and / or PEG 1K linkers are included in different embodiments of heteroalkylene linkers. In certain embodiments of the PEG 1K linker, n ranges from 19 to 25, for example, n is 19, 20, 21, 22, 23, 24 or 25. The multimer may include, for example, the following structure:

[0041]

[0042] wherein x is an integer of 0 or greater, for example, x ranges from 0 to 100 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0043] "Linker" means a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus and combinations thereof, which connects a part of a molecule to another part of the same molecule or to different molecules, parts or solid supports (e.g., microparticles). A linker can connect molecules via covalent bonds or other means, such as ionic bonds or hydrogen bonds. In certain embodiments, the linker is a heteroatom linker (e.g., comprising 1-10 Si, N, O, P or S atoms), a sub-assorted alkyl (e.g., comprising 1-10 Si, N, O, P or S atoms and an alkylene chain) or an alkylene linker (e.g., comprising 1-12 carbon atoms). In certain embodiments, the sub-assorted alkyl linker comprises the following structure:

[0044]

[0045] in:

[0046] x 9 and x 10 Each is independently an integer greater than 0. In certain embodiments, the heteroatom linker is -O-, -S-, or -OP(=O)O - In certain embodiments, the heteroalkylene linker comprises -OP(=O)O - -O-. In certain embodiments, the heteroalkylene linker comprises at least one SS bond.

[0047] "Physiologically cleavable linker" means a molecular connection that can be split or separated in a specified manner in the presence of an in vivo or in vitro environment of an organism or cell system, thereby producing two or more separated molecules. Typically, the physiological conditions that induce such a cutting or cleavage event can include a temperature in the range of about 20 to 40 ° C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), a pH of about 5 to 8, a glucose concentration of about 1 to 20 mM, an atmospheric oxygen concentration, and the Earth's gravity. In certain embodiments, physiological conditions include enzymatic conditions (i.e., enzymes activated by cathepsin). Key cleavage or cleavage can be homolytic or heterolytic.

[0048] "Heteroalkenylene" is a heteroalkylene as defined above containing at least one carbon-carbon double bond. Unless stated otherwise specifically in the specification, a heteroalkenylene group is optionally substituted.

[0049] "Heteroalkynylene" is a heteroalkylene group containing at least one carbon-carbon triple bond. Unless stated otherwise specifically in the specification, a heteroalkynylene group is optionally substituted.

[0050] "Heteroatom" in reference to "heteroatom linkers" means a linker group consisting of one or more heteroatoms. Exemplary heteroatom linkers include single atoms and multiple heteroatoms selected from O, N, P, and S, such as linkers and multimers having the formula -P(O-)(=O)O- or -OP(O-)(=O)O-, and combinations thereof.

[0051] "Phosphate" means -OP(=O)(R a )R b Group, where R a It is OH, O - OR c ; and R b It is OH, O - , OR c , thiophosphate / ester group or other phosphate / ester group, wherein R c is a counterion (e.g., Na + wait).

[0052] "Phosphoalkyl" means -OP(=O)(R a )R b Group, where R a It is OH, O - OR c ; and R b is -O alkyl, where R c is a counterion (e.g., Na + Unless otherwise specifically stated in the specification, the phosphoalkyl group is optionally substituted. For example, in certain embodiments, the -Oalkyl portion of the phosphoalkyl group is optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c One or more substitutions in which R a , R b and R c Each of which is as defined for the compound of structure (I).

[0053] "Phosphate alkyl ether" means -OP(=O)(R a )R b Group, where R a It is OH, O - OR c ; and R b is -O alkyl ether, where R c is a counterion (e.g., Na +Unless otherwise specifically stated in the specification, the phosphate alkyl ether group is optionally substituted. For example, in certain embodiments, the -O alkyl ether portion of the phosphate alkyl ether group is optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphate alkyl, thiophosphate alkyl, phosphate alkyl ether, thiophosphate alkyl ether, or -OP (=R a )(R b )R c One or more substitutions in which R a , R b and R c Each of which is as defined for the compound of structure (I).

[0054] "Phosphorothioate" means -OP(=R a )(R b )R c Group, where R a O or S, R b It is OH, O - , S - , OR d or SR d ; and R c OH, SH, O - , S - , OR d , SR d , phosphate / ester group or other thiophosphate / ester group, wherein R d is a counterion (e.g., Na + etc.) and the conditions are: i) R a is S; ii) R b YesS - or SR d iii) R c It is SH, S - or SR d ; or iv) a combination of i), ii) and / or iii).

[0055] "Phosphorothioate alkyl" means -OP(=R a )(R b )R c Group, where R a O or S, R b It is OH, O - , S - , OR d or SR d ; and R c is -O alkyl, where R d is a counterion (e.g., Na + etc.) and the conditions are: i) Ra is S; ii) R b YesS - or SR d or iii) R a is S and R b YesS - or SR d Unless otherwise specifically stated in the specification, the thiophosphoroalkyl group is optionally substituted. For example, in certain embodiments, the -Oalkyl portion of the thiophosphoroalkyl group is optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, thiophosphoroalkyl ether, or -OP(=R a )(R b )R c One or more substitutions in which R a , R b and R c Each of which is as defined for the compound of structure (I).

[0056] "Thiophosphorothioate alkyl ether" means -OP(=R a )(R b )R c Group, where R a O or S, R b It is OH, O - , S - , OR d or SR d ; and R c is -O alkyl ether, where R d is a counterion (e.g., Na + etc.) and the conditions are: i) R a is S; ii) R b YesS - or SR d or iii) R a is S and R b YesS - or SR d Unless otherwise specifically stated in the specification, the thiophosphorothioic acid alkyl ether group is optionally substituted. For example, in certain embodiments, the -O alkyl ether portion of the thiophosphorothioic acid alkyl group is optionally substituted with a hydroxyl, an amino, a sulfhydryl, a phosphate, a thiophosphate, a phosphate alkyl, a thiophosphorothioic acid alkyl, a phosphate alkyl ether, a thiophosphorothioic acid alkyl ether, or an -OP(=R a )(R b )R c One or more substitutions in which R a , R b and R cEach of which is as defined for the compound of structure (I).

[0057] "Carbocycle" means a stable 3-18-membered aromatic or non-aromatic ring containing 3-18 carbon atoms. Unless otherwise specifically stated in the specification, the carbocycle can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused or bridged ring system, and can be partially or completely saturated. Non-aromatic carbocyclyl residues include cycloalkyl, while aromatic carbocyclyl residues include aryl. Unless otherwise specifically stated in the specification, the carbocyclic group is optionally substituted.

[0058] "Cycloalkyl" means a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which may include a fused or bridged ring system, having 3-15 carbon atoms, preferably 3-10 carbon atoms, and which is saturated or unsaturated and connected to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, etc. Unless otherwise specifically stated in the specification, cycloalkyls are optionally substituted.

[0059] "Aryl" means a ring system containing at least one carbocyclic aromatic ring. In certain embodiments, an aryl group contains 6-18 carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl groups include, but are not limited to, aceanthrene, acenaphthylene, acephenanthrene, anthracene, azulene, benzene, Aryl groups derived from fluoranthene, fluorene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, phenalene, phenanthrene, septauene, pyrene and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0060] "Heterocycle" means a stable 3-18 membered aromatic or non-aromatic ring containing 1-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, the heterocycle can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycle can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocycle can be partially or fully saturated. Examples of aromatic heterocycles are listed below in the definition of heteroaryl (i.e., heteroaryl is a subset of heterocycle). Examples of non-aromatic heterocycles include, but are not limited to, dioxolane, thienyl [1,3] dithiohexyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trioxane, trithiohexane, triazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, heterocyclic groups are optionally substituted.

[0061] "Heteroaryl" means a 5-14 membered ring system containing 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. For the purposes of certain embodiments of the present disclosure, heteroaryl residues can be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl residues can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzo benzopyranyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, benzoxazolinyl, benzimidazolesulfinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl , indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinetrienyl, oxazolyl, oxacyclopropyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinone, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridone, pyrazinyl, pyrimidinyl, pyrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thienyl). Unless otherwise specifically stated in the specification, heteroaryl is optionally substituted.

[0062] The suffix "-ene" indicates a specific structural feature (e.g., alkyl, aryl, heteroalkyl, heteroaryl) that is attached to the rest of the molecule by a single bond and to the residue by a single bond. In other words, the suffix "-ene" indicates a linker having the structural features of the moiety to which it is attached. The points of attachment of the "-ene" chain to the rest of the molecule and the residue can be through one atom or any two atoms within the chain. For example, heteroarylene refers to a linker comprising a heteroaryl moiety as defined herein.

[0063] "Fused" means a ring system comprising at least two rings, wherein the two rings share at least one common ring atom, e.g., two common ring atoms. When the fused ring is a heterocyclyl ring or a heteroaryl ring, the common ring atoms may be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tetracyclic, etc.

[0064] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkyl ether, phosphate alkyl, phosphate alkyl ether, thiophosphoroalkyl, thiophosphoroalkyl ether, carbocyclic, cycloalkyl, aryl, heterocyclic and / or heteroaryl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all of the hydrogen atoms) is replaced by a bond to a non-hydrogen atom, such as, but not limited to, a halogen atom such as F, Cl, Br and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other heteroatoms in various other groups. "Substitution" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double bond or a triple bond) with a heteroatom, such as oxygen in oxo groups, carbonyl groups, carboxyl groups and ester groups; and nitrogen in groups such as imines, oximes, hydrazones and nitriles. For example, "substitution" includes any of the above groups in which one or more hydrogen atoms are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g S02R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、-SO2R g 、-OSO2R g 、-SO2OR g , =NSO2R g and -SO2NR g R h"Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NR g R h In the foregoing, R g and R h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substitution" further refers to any of the above groups, wherein one or more hydrogen atoms are replaced by a bond with the following groups: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. In addition, each of the aforementioned substituents may also be optionally substituted by one or more of the above substituents.

[0065] "Conjugation" refers to the overlap of one p-orbital with another p-orbital across an intervening sigma bond. Conjugation can occur in cyclic or acyclic compounds. "Degree of conjugation" refers to the overlap of at least one p-orbital with another p-orbital across an intervening sigma bond. For example, 1,3-butadiene has one degree of conjugation, while benzene and other aromatic compounds typically have multiple degrees of conjugation. Fluorescent and colored compounds typically contain at least one degree of conjugation.

[0066] "Fluorescent" refers to a molecule that absorbs light of a particular frequency and emits light of a different frequency. Fluorescence is well known to those of ordinary skill in the art.

[0067] "Colored" refers to molecules that absorb light within the colored spectrum (ie, red, yellow, blue, etc.).

[0068] The term "biomolecule" refers to any of a variety of biological materials, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers, and mixtures thereof. More specifically, the term is intended to include, but is not limited to, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens and toxins, as well as bacteria, viruses, blood cells and tissue cells. As further described herein, visually detectable biomolecules of the present disclosure (e.g., compounds having structure (I) of a biomolecule attached thereto) are prepared by contacting the biomolecule with a compound having a reactive group that can attach the biomolecule to the compound via any available atom or functional group (such as an amino, hydroxyl, carboxyl or sulfhydryl group on the biomolecule).

[0069] A "reactive group" is a moiety that can react with a second reactive group (e.g., a "complementary reactive group") to form one or more covalent bonds, such as by displacement, oxidation, reduction, addition, or cycloaddition reactions. Exemplary reactive groups are provided in Table 1, and include, for example, nucleophiles, electrophiles, dienes, dienophiles, aldehydes, oximes, hydrazones, alkynes, amines, azides, acyl azides, acyl halides, nitriles, nitrones, sulfhydryls, disulfides, sulfonyl halides, isothiocyanates, imidoesters, activated esters, ketones, α,β-unsaturated carbonyls, olefins, maleimides, α-haloamides, epoxides, aziridines, tetrazines, tetrazoles, phosphines, biotin, thiirane, etc.

[0070] "Bioconjugate" or "bioconjugate" and related variants refer to a chemical reaction strategy that forms a stable covalent bond between two molecules. The term "bioconjugate" is usually used when one of the molecules is a biological molecule (e.g., an antibody), but can be used to describe the formation of a covalent bond with a non-biological molecule (e.g., a polymer resin). The product or compound resulting from such a reaction strategy is a "conjugate," "bioconjugate," or grammatical equivalents.

[0071] The terms "visible" and "visually detectable" are used herein to refer to substances that can be observed by visual inspection without prior illumination or chemical or enzymatic activation. Such visually detectable substances absorb and emit light in the spectral region ranging from about 300 to about 900 nm. Preferably, such substances have an intense color, preferably having a wavelength of at least about 40,000 nm. -1 cm -1 The molar extinction coefficient is preferably at least about 50,000 M -1 cm -1 , more preferably at least about 60,000 M -1 cm -1 , and even more preferably at least about 70,000 M -1 cm-1 , and most preferably at least about 80,000 M -1 cm -1 . The compounds of the present disclosure can be detected by visual observation, or by optical-based detection devices, including but not limited to absorption spectrophotometers, transmission optical microscopes, digital cameras and scanners. Visually detectable substances are not limited to those that emit and / or absorb light in the visible spectrum. Substances that emit and / or absorb light in the ultraviolet (UV) region (about 10nm to about 400nm), infrared (IR) region (about 700nm to about 1mm) and substances that emit and / or absorb light in other electromagnetic spectrum regions are also included in the scope of "visually detectable" substances.

[0072] For the purpose of the embodiments of the present disclosure, the term "light-stable visual dye" means a chemical moiety that is visually detectable as defined above and does not significantly change or decompose after exposure to light. Preferably, the light-stable visual dye does not show significant discoloration or decomposition after being exposed to light for at least 1 hour. More preferably, the visual dye is stable after being exposed to light for at least 12 hours, more preferably at least 24 hours, more preferably at least 1 week, and most preferably at least 1 month. Non-limiting examples of light-stable visual dyes suitable for compounds and methods of the present disclosure include azo dyes, thioindigo dyes, quinacridone pigments, dioxazines, phthalocyanines, perinones, diketopyrrolopyrroles, quinophthalones, and trueycarbonium.

[0073] As used herein, the term "perylene derivative" is intended to include any substituted perylene that is visually detectable. However, the term is not intended to include perylene itself. The terms "anthracene derivative," "naphthalene derivative," and "pyrene derivative" are used similarly. In certain preferred embodiments, the derivative (e.g., perylene, pyrene, anthracene, or naphthalene derivative) is an imide, diimide, or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene.

[0074] Visually detectable molecules of various embodiments of the present disclosure can be used in a variety of analytical applications, such as biochemical applications and biomedical applications, where it is necessary to determine the presence, location or amount of a specific analyte (e.g., a biomolecule). Therefore, in another aspect, the present disclosure provides a method for visually detecting a biomolecule, comprising: (a) providing a biological system with a visually detectable biomolecule comprising a compound of structure (I) attached to the biomolecule; and (b) detecting the biomolecule by its visual performance. For the purposes of the present disclosure, the phrase "detecting the biomolecule by its visual performance" means observing the biomolecule with the naked eye or with the aid of an optical detection device, including but not limited to an absorption spectrophotometer, a transmission optical microscope, a digital camera and a scanner, without illumination or chemical or enzymatic activation. A densitometer can be used to quantify the amount of visually detectable biomolecules present. For example, by measuring the relative optical density, the relative amount of biomolecules in two samples can be determined. If the stoichiometry of the dye molecule for each biomolecule is known and the extinction coefficient of the dye molecule is known, the absolute concentration of the biomolecule can also be determined from the measured value of the optical density. As used herein, the term "biological system" is used to refer to any solution or mixture containing one or more biomolecules in addition to visually detectable biomolecules. Non-limiting examples of such biological systems include cells, cell extracts, tissue samples, electrophoresis gels, assay mixtures, and hybridization reaction mixtures.

[0075] "Solid support" or "solid resin" means any solid matrix known in the art for solid support of molecules, for example, "microparticles" means any of a number of small particles that can be used to attach to the compounds of the present disclosure, including but not limited to glass beads, magnetic beads, polymer beads, non-polymer beads, etc. In certain embodiments, the microparticles comprise polystyrene beads. In certain embodiments, the solid support or solid resin is controlled pore glass or macroporous polystyrene.

[0076] "Solid support residue" refers to a functional group that remains attached to a molecule when the molecule is cleaved from the solid support. Solid support residues are known in the art and can be readily deduced based on the structure of the solid support and the groups to which the molecule is attached.

[0077] "Targeting moiety" is a part that selectively binds or associates with a specific target (such as an analyte molecule). "Selectively" binding or association means that, relative to other targets, the targeting moiety preferentially associates or binds to the desired target. In certain embodiments, the compounds disclosed herein include a connection with a targeting moiety, the purpose of which is to selectively bind or associate the compound with the target analyte (that is, the target of the targeting moiety), thereby allowing the detection of the analyte. Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, etc. The targeting moiety is such a part (such as an antibody): it selectively binds or associates to a target feature on or in a cell, such as a target feature on a cell membrane or other cell structure, thereby allowing the detection of a cell of interest. In certain embodiments, small molecules that selectively bind or associate to a desired analyte are also considered as targeting moieties. Those skilled in the art will understand other analytes and corresponding targeting moieties that will be useful in various embodiments.

[0078] "Base pairing moiety" means a heterocyclic moiety that is capable of hybridizing to a complementary heterocyclic moiety through hydrogen bonding (e.g., Watson-Crick base pairing). Base pairing moieties include natural bases and unnatural bases. Non-limiting examples of base pairing moieties are RNA and DNA bases such as adenosine, guanosine, thymidine, cytosine, and uridine and their analogs.

[0079] The embodiments of the disclosure disclosed herein are also intended to encompass all compounds that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I.

[0080] Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described hereinafter and in the examples which follow, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used.

[0081] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0082] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl may or may not be substituted, and that the description includes substituted alkyl and unsubstituted alkyl.

[0083] "Salt" includes both acid and base addition salts.

[0084] "Acid addition salts" refer to salts prepared with inorganic acids (such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, salts formed by gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0085] "Base addition salt" refers to those salts prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, dibenzylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0086] Crystallization can produce solvates of the compounds described herein. Embodiments of the present disclosure include all solvates of the compounds described. The term "solvate" as used herein means an aggregate of one or more molecules of a compound of the present disclosure and one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Therefore, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of the present disclosure can be true solvates, while in other cases, the compounds of the present disclosure can retain only exogenous water or another solvent or a mixture of water plus some exogenous solvent.

[0087] Embodiments of the compounds of the present disclosure (e.g., compounds of Structure I) or salts, tautomers or solvates thereof may contain one or more stereocenters and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Embodiments of the present disclosure are intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0088] "Stereoisomers" refers to compounds made up of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0089] "Tautomer" means that a proton is transferred from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the described compounds. One of ordinary skill in the art can easily deduce the various tautomeric forms of a compound.

[0090] "Steroid" means an organic compound with biological activity arranged in four fused rings. The core structure of steroids comprises three six-membered cyclohexane rings (i.e., rings A, B, and C) and a five-membered cyclopentane ring. Steroids vary according to the functional groups attached to the core structure and the oxidation state of the ring. For example, the 3-position on the A ring of steroids can be a hydroxyl group (e.g., cholesterol, bile acid, lanosterol, and β-sitosterol) or a carbonyl (-C=O) group (e.g., testosterone, dexamethasone, progesterone, and medrogestrel). The example of steroids used in certain embodiments includes cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

[0091] "Vitamin" refers to a group of organic compounds that are essential for normal growth and nutrition and need to be taken in small amounts from the diet because the body cannot synthesize them. Such compounds include vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, and K. Vitamin E is a fat-soluble compound that includes four tocopherols and four tocotrienols. The core structure of vitamin E contains 3,4-dihydro 2H-1 benzopyran. The difference in chemical structure between tocotrienols and tocopherols is that tocotrienols have unsaturated isoprenoid side chains with three carbon-carbon double bonds located outside the 3,4-dihydro 2H-1 benzopyran core structure, while tocopherols have saturated isoprenoid side chains. Both tocotrienols and tocopherol have four structural isomers, including α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.

[0092] "Amino acid side chain" or "side chain" refers to a substituent attached to the α-carbon, β-carbon, or γ-carbon of an amino acid. The amino acid side chain may be a side chain associated with a natural or unnatural amino acid.

[0093] "Amino acid sequence" or "peptide sequence" refers to the primary structure of amino acid residues connected along the main chain formed by peptide bonds. The sequence is usually expressed from the N-terminal end to the C-terminal end. Where indicated, embodiments of the present invention include compounds comprising a specific amino acid sequence. Where appropriate, amino acid sequences are indicated by 3-letter or 1-letter abbreviations.

[0094] "Letter code", "1-letter code", or "3-letter code" refers to an indication or abbreviation of an amino acid or amino acid residue in an amino acid sequence. A general list of 1 and 3-letter codes and their corresponding amino acids is as follows:

[0095] Amino Acids 3-letter code 1-Letter code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamate Glu E Glutamine Gln Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V Selenocysteine Sec U Pyrrolysine Pyl O

[0096] "Beta sheet", "β-sheet", "β pleated sheet" or "β-pleated sheet" refers to the secondary structure of an amino acid sequence formed by intramolecular folding. The amino acid chains are linked laterally by hydrogen bonding to form pleated sheets that are usually twisted. The amino acid chains that form this secondary structure are usually 3 to 10 amino acid residues in length. The amino acid sequences to which the present invention relates include amino acid residues that have a propensity to form a beta sheet, wherein the beta sheet portion is indicated. These residues include, but are not limited to, glycine, methionine, serine, valine, tyrosine, phenylalanine, tryptophan, threonine and isoleucine.

[0097] "Alpha helix" or "α-helix" refers to the secondary structure of an amino acid chain formed by intramolecular folding. A helical conformation is formed in which the main chain NH group provides hydrogen bonds to the main chain C=O group of the amino acid four residues before. The amino acid side chain sequence affects the formation of the alpha helical structure. The amino acid sequence to which the present invention relates includes residues with a tendency to form a helix, wherein the alpha helical portion is indicated. These residues include, but are not limited to, glycine, methionine, alanine, arginine, histidine, leucine, glutamate, glutamic acid, phenylalanine, valine, tyrosine and lysine.

[0098] The chemical naming schemes and structure diagrams used herein are a modification of the IUPAC nomenclature system using the ACD / Name version 9.07 software program and / or the ChemDraw Ultra version 11.0 software naming program (CambridgeSoft). Common names familiar to those of ordinary skill in the art are also used.

[0099] Compound

[0100] As noted above, in one embodiment of the present disclosure, compounds are provided that can be used as covalent linkers between biologically active moieties (such as steroids and / or vitamins) and targeting moieties. 1 is independently at each occurrence a moiety comprising a fluorescent or colored dye; M 2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 is a steroid or a vitamin. In certain embodiments, M 2 is a steroid or vitamin (e.g., cholesterol, tocopherol, etc.) and M 1 It is a fluorescent dye (eg, fluorescein, etc.).

[0101] The embodiments disclosed herein provide a number of advantages, including the ability to control the bioactive moiety M attached to the polymer backbone and any subsequent targeting moiety. 2 The number and type of biologically active moieties, the spacing between adjacent biologically active moieties on the polymer backbone (e.g., the number of biologically active moieties M 2 The distance between the polymer backbone and the biologically active moiety (e.g., the length of the linker outside the polymer backbone) and the spacing between the polymer backbone and the biologically active moiety (e.g., the length of the linker outside the polymer backbone).

[0102] The biologically active moiety can be connected to the polymer backbone by a physiologically cleavable or non-cleavable linker. The procedure described in the present disclosure provides the ability to selectively install a physiologically cleavable and / or non-cleavable linker. This allows the synthesis of compounds with physiologically cleavable and non-cleavable linkers and one or more biologically active moieties. In this regard, the biologically active moiety can be cut successively according to physiological conditions. In addition, compounds with fluorescent moieties and multiple biologically active moieties connected by physiologically cleavable and / or non-cleavable linkers can be synthesized.

[0103] Certain embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties, and dye moieties (e.g., chromophores or fluorophores) that can be used for simultaneous targeting, treatment, and detection. The ease of coupling polymer-drug constructs to targeting agents (e.g., antibodies, antibody fragments, proteins, or other clinically interesting agents) provides utility for a variety of applications of interest (e.g., surface chemistry, assay development, etc.). Thus, in certain embodiments, M 1 is a fluorophore (eg, FITC, 5-FAM, 6-FAM, etc.) or a colored moiety.

[0104] The compounds of certain embodiments also provide other desirable properties, including enhanced permeability and retention effects. In addition to providing the necessary solubility properties, the chemical characteristics of the embodiments of the compounds of the present invention can be adjusted to regulate the ability of the compounds to penetrate diseased cells / tissues and remain inside them. These characteristics allow for effective delivery of bioactive agents by increasing penetration and increasing efficacy by enhancing retention.

[0105] Therefore, it should be understood that any embodiment of the compound of structure (I) as described above can be independently combined with other embodiments to form embodiments of the present disclosure not specifically set forth above. It should be understood that in this specification, the combination of substituents and / or variables of the described formulas is permitted only when such contributions lead to stable compounds.

[0106] Therefore, one embodiment provides a compound having the following structure (I):

[0107]

[0108] or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

[0109] R 1 and R 2 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c, Q or its protected form, L′;

[0110] R a is O or S;

[0111] R b OH, SH, O - , S - , OR d or SR d ;

[0112] R c OH, SH, O - , S - , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether;

[0113] R d is the counter ion;

[0114] R 3 is independently at each occurrence H, alkyl or alkoxy;

[0115] R 4 is, independently at each occurrence, OH, SH, O - , S - , OR d or SR d ;

[0116] R 5 is independently at each occurrence oxo or thio;

[0117] L 1 , L 2 , L 5 and L 6 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker;

[0118] L 3 is independently at each occurrence an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker;

[0119] L 4 is a connectome independently at each occurrence;

[0120] M 1 independently at each occurrence is a moiety comprising a fluorescent or colored dye;

[0121] M 2is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin;

[0122] Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety;

[0123] L' is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to another compound of structure (I); and

[0124] m is independently an integer of 1 or greater at each occurrence;

[0125] p is an integer of 0 or greater at each occurrence;

[0126] q is an integer of 1 or greater at each occurrence; and

[0127] n is an integer of 1 or greater.

[0128] The various linkers and substituents (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 、M 1 、M 2 R and Q) are optionally substituted with one or more substituents. For example, in certain embodiments, the optional substituent is selected to optimize the water solubility or other properties of the compound of structure (I). In certain embodiments, each chromophore, alkyl, alkoxy, alkyl ether, sub-heteroaryl, heteroalkyl, alkylene, alkenylene, alkynylene, sub-heteroalkyl, sub-heteroalkenyl, sub-heteroalkynyl, alkoxyalkyl ether, phosphate alkyl, thiophosphate alkyl, phosphate alkyl ether and thiophosphate alkyl ether in the compound of structure (I) are optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate / ester, thiophosphate / ester, phosphate alkyl, thiophosphate alkyl, phosphate alkyl ether and thiophosphate alkyl ether. In certain embodiments, the optional substituent is -OP(=R a)(R b )R c , where R a , R b and R c As defined for the compounds of structure (I).

[0129] In certain embodiments, L 3 In certain embodiments, at least one occurrence of L is heteroalkylene. 3 Each occurrence of is heteroalkylene. In certain embodiments, L 3 In certain more specific embodiments, at least one occurrence of L comprises an oxyalkylene group. 3 In certain more specific embodiments, the oxyethylene is polyoxyethylene. In certain embodiments, L 3 Has the following structure at each occurrence:

[0130]

[0131] in:

[0132] z is an integer from 1 to 100; and * indicates a bond to an adjacent phosphorus atom.

[0133] In certain embodiments, z is an integer from 3 to 8. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6. In certain embodiments, z is 7. In certain embodiments, z is 8.

[0134] In certain other embodiments, z is an integer from 22 to 26. In certain embodiments, z is 22. In certain embodiments, z is 23. In certain embodiments, z is 24. In certain embodiments, z is 25. In certain embodiments, z is 26.

[0135] In certain other embodiments, z ranges from 19 to 28. In certain embodiments, the average z is 23. In certain embodiments, the average z is 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0136] In other embodiments, L 3 In certain more specific embodiments, at least one occurrence of L is an alkylene linker (e.g., methylene). 3 At each occurrence is an alkylene linker (eg, methylene).

[0137] In certain embodiments, At least one occurrence in a compound of structure (I) comprises one of the following structures:

[0138]

[0139] wherein z is an integer from 1 to 100. In certain embodiments, z is an integer from 3 to 8. In certain other embodiments, z is an integer from 22 to 26. In certain other embodiments, z ranges from 19 to 28.

[0140] In certain embodiments, at each occurrence, in a compound of structure (I) Contains one of the following structures:

[0141]

[0142] wherein z is an integer from 1 to 100. In certain embodiments, z is an integer from 3 to 8. In certain other embodiments, z is an integer from 22 to 26. In certain other embodiments, z ranges from 19 to 28.

[0143] Certain embodiments provide compounds having the following structure (IA):

[0144]

[0145] or a stereoisomer, a salt or a tautomer thereof.

[0146] In certain embodiments, L 1 , L 2 , L 5 and L 6 is independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker at each occurrence. 1 , L 2 and L 6 In each occurrence, L is independently alkylene. 1 , L 2 and L 6 L is independently C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene at each occurrence. In certain more specific embodiments, L 1 , L 2 and L 6 The alkylene linker is a C1 alkyl linker. In certain more specific embodiments, L 1 , L 2 and L 6 The alkylene linker is a C2 alkyl linker. In certain more specific embodiments, L 1 , L 2 and L 6The alkylene linker is a C3 alkyl linker. In certain more specific embodiments, L 1 , L 2 and L 6 The alkylene linker is a C4 alkyl linker. In certain more specific embodiments, L 1 , L 2 and L 6 The alkylene linker is a C5 alkyl linker. In certain more specific embodiments, L 1 , L 2 and L 6 The alkylene linker is a C6 alkyl linker.

[0147] In certain specific embodiments, L 5 The alkylene linker is a C1 alkyl linker. In certain specific embodiments, L 5 The alkylene linker is a C2 alkyl linker. In certain specific embodiments, L 5 The alkylene linker is a C3 alkyl linker. In certain specific embodiments, L 5 The alkylene linker is a C4 alkyl linker. In certain specific embodiments, L 5 The alkylene linker is a C5 alkyl linker. In certain specific embodiments, L 5 The alkylene linker of is a C6 alkyl linker. In other embodiments, L 5 In certain other embodiments, at least one occurrence of L is a direct bond. 5 Each occurrence of is a direct key.

[0148] Certain embodiments provide compounds having the following structure (IB):

[0149]

[0150] or a stereoisomer, a salt or a tautomer thereof,

[0151] in:

[0152] y 1 ,y 2 and 6 is independently at each occurrence an integer from 1 to 6; and

[0153] y 5 is independently an integer from 0 to 6 at each occurrence.

[0154] In certain embodiments, y 5 is the integer 0 at each occurrence (i.e., L 5 is a direct bond). In certain embodiments, y 5is the integer 1 at each occurrence. In certain embodiments, y 5 is the integer 2 at each occurrence. In certain embodiments, y 5 is the integer 3 at each occurrence. In certain embodiments, y 5 is the integer 4 at each occurrence. In certain embodiments, y 5 is the integer 5 at each occurrence. In certain embodiments, y 5 In each occurrence it is the integer 6.

[0155] In certain embodiments, y 1 ,y 2 and 6 is the integer 1 at each occurrence. In certain embodiments, y 1 ,y 2 and 6 is the integer 2 at each occurrence. In certain embodiments, y 1 ,y 2 and 6 is the integer 3 at each occurrence. In certain embodiments, y 1 ,y 2 and 6 is the integer 4 at each occurrence. In certain embodiments, y 1 ,y 2 and 6 is the integer 5 at each occurrence. In certain embodiments, y 1 ,y 2 and 6 In each occurrence it is the integer 6.

[0156] In certain specific embodiments, y 1 is the integer 0 at each occurrence; and y 2 and 3 is 1 at each occurrence. In certain other embodiments, y 1 is the integer 1 at every occurrence; and y 2 and 3 It is 1 at each occurrence.

[0157] Certain embodiments provide compounds having structure (II):

[0158]

[0159] or a stereoisomer, a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0160] M 1 independently at each occurrence is a moiety comprising a fluorescent dye;

[0161] M2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin;

[0162] L 4 is a connectome independently at each occurrence;

[0163] L 1 , L 2 , L 3 and L 5 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker;

[0164] R 21 is independently at each occurrence a natural or unnatural amino acid side chain;

[0165] R 1 and R 2 Each is independently H, OH, SH, -NH2, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or its protected form, L′;

[0166] R a is O or S;

[0167] R b OH, SH, O-, S-, OR d or SR d ;

[0168] R c OH, SH, O-, S-, OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether;

[0169] R d is the counter ion;

[0170] Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety;

[0171] L′ is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to another compound of structure (II);

[0172] m is independently an integer of 0 or greater at each occurrence;

[0173] p is independently an integer of 0 or greater at each occurrence;

[0174] v is independently an integer of 1 or greater at each occurrence; and

[0175] n is an integer of 1 or greater.

[0176] The compound of structure (II) has a peptide-based backbone. The various linkers and substituents (e.g., M 1 、M 2 ,Q,R 1 , R 2 , R 21 , L 1 , L 2 , L 3 , L 4 and L') are optionally substituted with one or more substituents. For example, in certain embodiments, the optional substituents are selected to optimize the water solubility, permeability, retention or other properties of the compounds of structure (II). In certain embodiments, each alkyl, alkoxy, alkyl ether, heteroalkyl, alkylamino, alkylcarbonyl or alkoxycarbonyl in the compounds of structure (II) is optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate / ester, thiophosphate / ester, phosphate alkyl, thiophosphate alkyl, phosphate alkyl ether and thiophosphate alkyl ether. In certain embodiments, the optional substituent is -OP(=R a )(R b )R c , where R a O or S, R b OH, SH, O - , S - , OR d or SR d , R c OH, SH, O - , S - , OR d , SR d, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether or thiophosphoroalkyl ether, and R d is a counterion. In certain embodiments, substituents are selected to increase cell or tissue penetration. In related embodiments, substituents are selected to increase cell or tissue retention.

[0177] In certain embodiments, at least one R 21 is a neutral amino acid side chain. In certain embodiments, at least one R 21 is a charged amino acid side chain. 21 is independently H, alkyl, -CH2CO2 at each occurrence - 、-CH2CH2CO2 - 、-CH2CH2CH2CH2NH3 + 、-CH2CH2CH2NHC(=NH2 + )NH2 or imidazolyl.

[0178] In a more specific embodiment, R is selected 21 , L 5 and m such that Has (G) 10 , (GDGDGDGDGD) or (GKGKGKGKGK).

[0179] In another embodiment, R 21 , L 5 and m such that Having an amino acid sequence capable of forming an α-helix or β-sheet secondary structure. In some of those embodiments, the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

[0180] In certain embodiments, L 5 or L 2 or both are present for at least one occurrence. In a more specific embodiment, when present, L 5 or L 2 or both are heteroalkylene linkers. In some of those embodiments, the heteroalkylene linker comprises a functional group capable of maintaining a positive or negative charge in an aqueous solution at a pH range of 3 to 11. In more specific embodiments, L 5 or L 2 or at least one occurrence of both has the following structure:

[0181]

[0182] In certain embodiments, L 5 or L 2 or at least one occurrence of both has the following structure:

[0183]

[0184] In certain embodiments, L 1 and L 3 is independently absent or is a heteroalkylene linker. In a more specific embodiment, the heteroalkylene linker is a peptidyl linker.

[0185] Certain embodiments provide compounds having structure (III):

[0186]

[0187] or a stereoisomer, a pharmaceutically acceptable salt or a tautomer thereof, wherein:

[0188] M 1 independently at each occurrence is a moiety comprising a fluorescent dye;

[0189] M 2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin;

[0190] L 4 is a connectome independently at each occurrence;

[0191] L 1 , L 2 and L 3 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker;

[0192] L 5 is independently at each occurrence an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker comprising one or more charged moieties, with the proviso that at least one of the charged moieties is not phosphate;

[0193] R 3 is independently at each occurrence H, alkyl or alkoxy;

[0194] R 1 and R 2 are independently -H, -OH, -SH, alkyl, alkoxy, alkyl ether, heteroalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, -OP(=R a )(R b)R c , Q or its protected form or L′;

[0195] R a is O or S;

[0196] R b OH, SH, O - , S - , OR d or SR d ;

[0197] R c OH, SH, O - , S - , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether;

[0198] R d is the counter ion;

[0199] Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety;

[0200] L′ is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a solid support or a solid support residue, a linker comprising a covalent bond to a solid support or a solid support residue, or a linker comprising a covalent bond to another compound of structure (III);

[0201] p is independently an integer of 0 or greater at each occurrence;

[0202] v is independently an integer of 1 or greater at each occurrence; and

[0203] n is an integer of 1 or greater.

[0204] Various linkers and substituents (e.g., M 1 、M 2 ,Q,R 1 , R 2 , R 3 , L 1 , L 2 , L 5and L') are optionally substituted with one or more substituents. For example, in certain embodiments, the optional substituent is selected to optimize the water solubility, permeability, retention or other properties of the compound of structure (III). In certain embodiments, each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linker or alkyl, alkoxy, alkyl ether, heteroalkyl, alkylamino, alkylcarbonyl or alkoxycarbonyl in the compound of structure (III) is optionally substituted with one or more substituents selected from hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate / ester, thiophosphate / ester, phosphate alkyl, thiophosphate alkyl, phosphate alkyl ether and thiophosphate alkyl ether. In certain embodiments, the optional substituent is -OP(=R a )(R b )R c , where R a O or S, R b OH, SH, O - , S - , OR d or SR d , R c OH, SH, O - , S - , OR d , SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether or thiophosphoroalkyl ether, and R d It is a counterion. In certain embodiments, a substituent is selected to increase cell or tissue penetration. In a related embodiment, a substituent is selected to increase cell or tissue retention. In certain embodiments, the alkyl, alkoxy, alkyl ether, assorted alkyl, alkylamino, alkylcarbonyl and alkoxycarbonyl are optionally substituted by hydroxyl, amino, sulfydryl, phosphate, thiophosphate, phosphate alkyl, thiophosphorothioate alkyl, phosphate alkyl ether or thiophosphorothioate alkyl ether or a combination thereof.

[0205] In certain embodiments, the charged moiety is positively charged. In more specific embodiments, the charged moiety comprises a protonated amine or quaternary amine functional group. In more specific embodiments, the charged moiety independently has one of the following structures:

[0206]

[0207] in:

[0208] R at each occurrence is independently H or C1-C6 alkyl.

[0209] In other embodiments, the charged moiety is negatively charged. In certain embodiments, the charged moiety comprises a carboxylic acid, phosphate / ester, or sulfate functional group. In certain embodiments, the charged moiety has the following structure:

[0210]

[0211] In certain embodiments, the charged moieties comprise a combination of positively charged moieties and negatively charged moieties.

[0212] In certain embodiments, the charged moiety is pendant from the backbone of the compound (e.g., attached to a linker via an alkylene or heteroalkylene linker). In certain embodiments, the charged moiety is part of the backbone of the compound (e.g., part of a continuous chain of a linker).

[0213] In certain embodiments, L 5 Contains one of the following structures:

[0214]

[0215]

[0216] in:

[0217] R at each occurrence is independently H or C1-C6 alkyl;

[0218] x is an integer from 0 to 6; and

[0219] m is an integer of 1 or greater, provided that m is selected such that the compound comprises at least two charged moieties.

[0220] Connector L 4 Can be used as M 1 and M 2 For example, in certain embodiments, a synthetic precursor of a compound of structure (I), (II), or (III) is prepared and M is coupled to the precursor using any number of coupling methods known in the art. 1 and M 2 In further embodiments, L 4 At least one occurrence of comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano group, a nitro group, or a combination thereof. In other embodiments, the functional group comprises an amide or an ester. In more specific embodiments, L 4 At least one occurrence of contains one of the following structures:

[0221]

[0222]

[0223] In further embodiments, L 4 Each occurrence of comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano group, a nitro group, or a combination thereof. In other embodiments, the functional group comprises an amide. In more specific embodiments, L 4 Each occurrence of contains one of the following structures:

[0224]

[0225] In certain embodiments, R 3 At least one occurrence of is H. In certain embodiments, R 3 In certain embodiments, at least one occurrence of is alkyl. 3 At least one occurrence of is alkoxy. 3 Every occurrence of is H.

[0226] In certain embodiments, R 5 At least one occurrence of is oxo (=O). In certain embodiments, R 5 At least one occurrence of is thio (=S). In certain embodiments, R 5 Each occurrence of is oxo (=O).

[0227] In certain embodiments, R 4 At least one occurrence of is OH. In certain embodiments, R 4 At least one occurrence of is SH. In certain embodiments, R 4 At least one occurrence of is O - In certain embodiments, R 4 At least one occurrence of S - In certain embodiments, R 4 Every occurrence of is O - .

[0228] In various other embodiments, R 1 and R 2 Each is independently OH or -OP (= R a )(R b )R c In certain different embodiments, R 1 or R 2 is OH or -OP (=R a )(R b )Rc , and R 1 or R 2 The other one of them is Q or a linker comprising a covalent bond to Q.

[0229] In further various embodiments of any of the aforementioned compounds of structures (I), (II) or (III), R 1 and R 2 Each is independently -OP(=R a )(R b )R c In some of these embodiments, R c It’s OL′.

[0230] In other embodiments, R 1 and R 2 Each is independently -OP(=R a )(R b )OL′, and L′ is an alkylene or heteroalkylene linker to: Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or other compound of structure (I), (II), or (III).

[0231] The linker L' can be any linker suitable for connecting Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or other compound of structure (I), (II) or (III) to a compound of structure (I), (II) or (III). Advantageously, certain embodiments include using a selected L' portion to increase or optimize the water solubility of the compound. In certain embodiments, L' is a heteroalkylene portion. In certain other specific embodiments, L' comprises an oxyalkylene or phosphodiester portion or a combination thereof.

[0232] In certain other embodiments, R 2 is L'. For example, in certain embodiments, L' is a linker to a targeting moiety. In another embodiment, in certain embodiments, R 2 is -NH2. In other embodiments, R 2 or R 1 One is L' and L' is a linker comprising a covalent bond to a solid support. In certain embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0233] In certain specific embodiments, L' is a linker to a targeting moiety, the linker comprising an oxyalkylene or phosphodiester moiety or a combination thereof. In other embodiments, L' has one of the following structures:

[0234]

[0235] in:

[0236] x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently an integer from 1 to 10;

[0237] R b is H, electron pair or counter ion;

[0238] L" is a targeting moiety or a linkage to a targeting moiety.

[0239] In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 1. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 2. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 3. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 4. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 5. In certain embodiments, x1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 6. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 7. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 8. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently the integer 9. In certain embodiments, x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 is independently the integer 10.

[0240] In certain embodiments, R b is H. In certain embodiments, R b is a counterion. For example, in certain embodiments, R b Yes + In certain embodiments, R b It's K + .

[0241] In certain embodiments, L" is a targeting moiety. In certain other embodiments, L" is linked to a targeting moiety. For example, the targeting moiety is an antibody. In another embodiment, the targeting moiety is a cell surface receptor antagonist. In certain more specific embodiments, the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate / ester or a MET inhibitor. In other embodiments, the targeting moiety is a monoclonal antibody. For example, in certain embodiments, the monoclonal antibody is abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, bencitumomab, belotosumab, rantumomab, brocitumomab, brosuolumab, canakinumab, calicizumab, becerolizumab, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, efrenuzumab, eloumab, remanezumab, ganezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, ilizumab , icamizumab, lanarizumab, logivirizumab, mepolizumab, natalizumab, octosacizumab, ocrelizumab, omalizumab, patizumab, ranibizumab, rexilumab, reslizumab, Rmab, rovizumab, rulizumab, salizumab, securinumab, tirazumab, thiomab, tocilizumab, ustekinumab, vedolizumab, alirocumab, actosumab, aducanumab, afacilizumab, afelimumab, aniluzumab, anrulitumab (IMA-638), asekizumab, atumab, baculumab Pituzumab, BCD-100, betilimumab, besozumab, bicizumab, bimalumab, bigelimumab, portelizumab, brezumab, busoluzumab, bercocilizumab, brasilicumab, brianuzumab, brionizumab, bucitumumab, calutuzumab, caprotuximab, cilizumab, clazakizumab, climuximab, concecizumab, coveximab, CR6261, crezetuzumab, lizanlizumab, crotedutumab, detuximab, mafodotin, delotuzumab biotin, dezamizumab, delivuzumab, domalozumab Antibody, dustuzumab, emetichol, ebumab, efalizumab, ifengucumab, edilutumab, elenuzumab, enokizumab, epinephrine, erlizumab, edeluzumab, evezumab, ivoflavone, efavirenzumab, efavirenzumab, efezolizumab, efavirenzumab, efavirenzumab, fasutuzumab, faramotuzumab, farasizumab, fasutuzumab, panvelizumab, fezanuzumab, flanuzumab, votuzumab, fontuzumab, fulavirenzumab, flocumab, forlanumab, gavirimumab, gevolizumab, kinselumab, gomiliximab, gonelizumab, ilimumab,Inlasoumab, Inomucizumab, Iomab-B, Keliximab, Lampazumab, Lanlozumab, Laveximab, Lerezumab, Renvimab, Ledetumumab, Lelizumab, Liverumumab, Ligozumab, Lodicuzumab, Pelulizumab, Matasizumab, Mavrilimumab, Metitumumab, Migizumab, Motavizumab, Muromonab CD3, Nebacumab, Nemolizumab, NEOD001, Nicevir Antibody, odumumab, olendalizumab, ololituzumab, OMS721, opinumab, otezumab, oxetinezumab, otilizumab, oselumab, ozaneluzumab, olizumab, paxilumab, pabacumab, pacolizumab, patizumab, PDR001, pelaqualizumab, pexelizumab, pralulumab, lozalizumab, ponecizumab, perveximab, prenizumab, priliximab, PRO 140, quilizumab, levuzumab, ramucizumab, ranevizumab, lavagalimab, ravulizumab, refelizumab, rigavirumab, relalizumab, linusumab, risankizumab, roledutumab, romozumab, longlizumab, SA237, satelizumab, sevirumab, SHP647, sifalimumab, sintuzumab, cilizumab, sirukumab, solanizumab, sonecilizumab, spartalizumab, setamizumab, thiosomab, sutofumab, sutolizumab, suvetumab, sutosumab, Taduzumab, taclizumab, tantovetumab, tanezumab, tefizumab, atemotuzumab, teneciximab, telizumab, tetumumab, tezelumab, tibrilizumab, tocilizumab, trorocirumab, trogolucumab, tuvirizumab, urolulumab, urolizumab, varisucomab, vepamumab, vesentuzumab, visilizumab, wolbalizumab, atozumab, trastuzumab, gemtuzumab, brentuximab, worse tuzumab, lovatuzumab, cantuzumab, bivacuzumab or ecamizumab or vadatuximab.

[0242] In other more specific embodiments of any of the aforementioned compounds of structures (I), (II) or (III), R 1 or R 2 Has one of the following structures:

[0243]

[0244]

[0245] Where R a is H or a solid support.

[0246] In certain specific embodiments, R 2 Has one of the following structures:

[0247]

[0248] Certain embodiments of compounds of structures (I), (II) or (III) may be prepared according to solid phase synthesis methods similar to those known in the art for preparing oligonucleotides. Thus, in certain embodiments, L' is a linkage to a solid support, a solid support residue, or a nucleoside. Solid supports containing activated deoxythymidine (dT) groups are readily available and, in certain embodiments, can be used as a starting material for preparing compounds of structures (I), (II) or (III). Thus, in certain specific embodiments, R 1 Has the following structure:

[0249]

[0250] Those skilled in the art will appreciate that including the above dT group is only for ease of synthesis and economic efficiency, and is not essential. Other solid supports may be used and may result in different nucleosides or solid support residues being present on L', or nucleosides or solid support residues may be removed or modified after synthesis.

[0251] In certain embodiments, the analyte molecule is a nucleic acid, an amino acid or a polymer thereof. In certain embodiments, the analyte molecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer or a prion. In certain embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In certain other embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0252] In yet other embodiments, Q is independently a moiety comprising a reactive group at each occurrence that is capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q is independently a moiety comprising a reactive group at each occurrence that is capable of forming a covalent bond with a complementary reactive group Q'. For example, in certain embodiments, Q' is present on another compound of structure (I), (II), or (III) (e.g., in R 1 or R 2 Position), and Q and Q' comprise complementary reactive groups, such that the reaction of a compound of structure (I), (II) or (III) with another compound of structure (I), (II) or (III) produces a covalently bound dimer of a compound of structure (I), (II) or (III). Multimeric compounds of structure (I), (II) or (III) can also be prepared in a similar manner, and are included within the scope of embodiments of the present disclosure.

[0253] The type of Q group and the connectivity of the Q group to the rest of the compound of structure (I), (II) or (III) are not limited, provided that Q comprises a moiety with appropriate reactivity for forming the desired bond.

[0254] In certain embodiments, Q is a moiety that is not susceptible to hydrolysis under aqueous conditions but is sufficiently reactive to form a bond with an analyte molecule or a corresponding group on a solid support (eg, an amine, azide, or alkyne).

[0255] Certain embodiments of compounds of structure (I), (II) or (III) contain Q groups commonly used in the field of bioconjugation. For example, in certain embodiments, Q contains a nucleophilic reactive group, an electrophilic reactive group or a cycloaddition reactive group. In certain more specific embodiments, Q contains a sulfhydryl, a disulfide, an activated ester, an isothiocyanate, an azide, an alkyne, an alkene, a diene, a dienophile, an acyl halide, a sulfonyl halide, a phosphine, an α-haloamide, a biotin, an amino or a maleimide functional group. In certain embodiments, the activated ester is an N-succinimidyl ester, an imidoester or a polyfluorophenyl ester. In other embodiments, the alkyne is an alkyl azide or an acyl azide.

[0256] The Q group can be conveniently provided in a protected form to increase storage stability or other desired properties, and then the protecting group is removed at an appropriate time to conjugate with, for example, a targeting moiety or an analyte. Therefore, the Q group includes a "protected form" of a reactive group, including any reactive group described in Table 1 above and below. A "protected form" of Q represents a portion that has a lower reactivity relative to Q under predetermined reaction conditions, but that is preferably not degrading other portions of the compound of structure (I), (II) or (III) or not reacting with them and can be converted to Q. Depending on the specific Q and the desired end use and storage conditions, a person skilled in the art can deduce the appropriate protected form of Q. For example, when Q is SH, the protected form of Q includes a disulfide, which can be reduced to reveal the SH moiety using known techniques and reagents.

[0257] Exemplary Q moieties are provided in Table I below.

[0258] Table 1. Exemplary Q fractions

[0259]

[0260]

[0261]

[0262] It should be noted that in certain embodiments, where Q is SH, the SH moiety will tend to form a disulfide bond with another sulfhydryl group (e.g., on another compound of structure (I), (II) or (III)). Thus, some embodiments include compounds of structure (I), (II) or (III) in the form of a disulfide dimer, the disulfide bond being derived from the SH Q group.

[0263] In other embodiments, the Q portion is conveniently masked (e.g., protected) as a disulfide portion, which can then be reduced to provide an activated Q portion for binding to a desired analyte molecule or targeting moiety. For example, the Q portion can be masked as a disulfide having the following structure:

[0264]

[0265] Wherein R is an optionally substituted alkyl. For example, in certain embodiments, Q is provided as a disulfide moiety having the following structure:

[0266]

[0267] wherein n is an integer from 1 to 10.

[0268] In certain embodiments, M 1 is independently a moiety comprising four or more aryl or heteroaryl rings or combinations thereof at one or more occurrences. 1 In one or more occurrences, M is independently fluorescent or colored. 1 In one or more occurrences, M is fluorescent. 1 In one or more occurrences, M independently comprises a fused polycyclic aryl or heteroaryl moiety comprising at least 4 fused rings. 1 is independently selected at each occurrence from the group consisting of phenyl, (difluorophenyl-difluorobora-diaza-indacenyl)phenyl, quaterphenyl, bibenzothiazole, terbenzothiazole, binaphthyl, bianthracenyl, squaraine, squarylium, 9,10-ethynylanthracene, and ternaphthyl moieties. In certain other embodiments, M 1 is independently selected at each occurrence from the group consisting of: p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthene, Rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof. In certain other embodiments, M 1is independently selected at each occurrence from the group consisting of: coumarin dyes, resorufin dyes, dipyrromethene boron difluoride dyes, ruthenium bipyridine dyes, thiazole orange dyes, polymethines, and N-aryl-1,8-naphthalimide dyes. In addition, in certain other embodiments, M 1 Independently selected at each occurrence are: coumarin dyes, boro-dipyrromethene, rhodamine, cyanine, pyrene, perylene, perylene monoimide, 6-carboxyfluorescein (6-FAM), 5-carboxyfluorescein (5-FAM), 6-fluorescein isothiocyanate (6-FITC), 5-fluorescein isothiocyanate (5-FITC), and derivatives thereof.

[0269] In certain other embodiments, M 1 Each occurrence independently has one of the following structures:

[0270]

[0271]

[0272] In certain embodiments, M 1 Each occurrence independently has one of the following structures:

[0273]

[0274] In certain specific embodiments, M 1 At least one occurrence of has the following structure:

[0275]

[0276] In certain more specific embodiments, M 1 Each occurrence of has the following structure:

[0277]

[0278] In certain embodiments, -L 4 -M 1 At least one occurrence of has one of the following structures:

[0279]

[0280] In certain more specific embodiments, -L 4 -M 1 Each occurrence of has one of the following structures:

[0281]

[0282] In certain embodiments, M 2 is the same at each occurrence; however, it is important to note that M2 Each occurrence of M does not need to be the same 2 , and certain embodiments include compounds wherein M 2 is not the same at each occurrence. For example, in certain embodiments, each M 2 are not the same, and choose different M 2 In some other embodiments, each M 2 It is a different M 2 Part and at least one M 2 It's a steroid or a vitamin.

[0283] In certain embodiments, M 2 At least one occurrence of M 2 is a steroid, which is a biologically active organic compound having four rings arranged in a specific molecular configuration as shown below. For example, in certain embodiments, M 2 At least one occurrence of is cholesterol, Cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone or beclomethasone. In certain more specific embodiments, M 2 At least one occurrence of has one of the following structures:

[0284]

[0285] in:

[0286] R 11 is H or halogen;

[0287] R 12 and R 13 is independently OH, H, alkyl, substituted alkyl or heteroalkyl;

[0288] R 14 is H, halogen, OH or alkyl;

[0289] R 15 is H or OH;

[0290] R 16 , R 17 and R 18 is H, alkyl or substituted alkyl; and

[0291] Represents a carbon-carbon single or double bond.

[0292] In certain embodiments, M 2 At least one occurrence of has one of the following structures:

[0293]

[0294]

[0295] Furthermore, in certain embodiments, M 2 At least one occurrence of is a vitamin. For example, in certain embodiments, M 2 At least one occurrence of is vitamin E. In certain more specific embodiments, M 2 At least one occurrence of is tocopherol. In certain embodiments, M 2 At least one occurrence of is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol or delta-tocotrienol.

[0296] In certain embodiments, M 2 At least one occurrence of has the following structure:

[0297]

[0298] in

[0299] R 19 and R 20 are independently H or CH3; and

[0300] Represents a carbon-carbon single or double bond.

[0301] In certain specific embodiments, M 2 At least one occurrence of has one of the following structures:

[0302]

[0303]

[0304] In certain embodiments, the compound is a compound selected from Table 2. The compounds in Table 2 were prepared according to the procedures described in the Examples.

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] Among them, M 2 Has one of the following structures:

[0322]

[0323]

[0324] In certain embodiments, the compounds of structures (II) and (III) are selected from Table 3. The compounds in Table 3 were prepared according to the procedures described in the Examples.

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] As used in Table 3 and throughout this application, where M 2 Has one of the following structures:

[0337]

[0338]

[0339] Fluorescence intensity or effectiveness against arthritis can also be adjusted by selecting different n values. In certain embodiments, n is an integer of 1 or greater. In certain embodiments, n is an integer of 1 to 100. In other embodiments, n is an integer of 1 to 10. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

[0340] Fluorescence or effectiveness against arthritis can also be adjusted by selecting the value of m. The value of m can control the adjacent M 1 and M 2 In certain embodiments, m is an integer of 0 or greater. In certain embodiments, m is an integer of 0 to 100. In certain embodiments, m is an integer of 0 to 10. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. In certain specific embodiments, m is 1 or 2. In certain specific embodiments, m is 1, 2, 3, 4 or 5. The value of m depends on M 1 or M 2 Hydrophobicity. 1 or M 2 More spacer units may be required, which would increase the value of m. In this regard, the less hydrophobic M 1 or M 2 Fewer spacer units may be required, which would lower the value of m.

[0341] The fluorescence intensity can be adjusted by the amount of fluorescent dye moieties attached to the polymer backbone. The value of p can control the brightness of the compound. In certain embodiments, p is an integer of 0 or greater at each occurrence. In certain more specific embodiments, p is 0 to 10. In certain embodiments, p is 0 to 5. For example, in certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain other embodiments, p is 0, 1, 2, 3 or 4. In certain other embodiments, p is 1.

[0342] The effectiveness against arthritis can also be adjusted by selecting the value of q. In certain embodiments, q is an integer of 1 or greater at each occurrence. In certain more specific embodiments, q is from 1 to 10. In certain embodiments, q is from 1 to 6. For example, in certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5. In certain embodiments, q is 6. In certain other embodiments, q is 1, 2, 3, 4, 5 or 6.

[0343] In certain embodiments of Structure (II) or (III), v is an integer of 1 or greater. For example, in certain embodiments, v is an integer of 1 to 100. In addition, in certain embodiments, v is an integer of 1 to 10. In certain embodiments, v is 1. In certain embodiments, v is 2. In certain embodiments, v is 3. In certain embodiments, v is 4. In certain embodiments, v is 5. In certain embodiments, v is 6. In certain embodiments, v is 7. In certain embodiments, v is 8. In certain embodiments, v is 9. In certain embodiments, v is 10.

[0344] The values ​​of n, p, q, and m are closely related to provide the ability to control fluorescence and effectiveness against arthritis. In certain embodiments, n is 1; p is 1; q is 5; and m is 1 or 2. In certain other embodiments, n is 1; p is 1; q is 4; and m is 1 or 2.

[0345] Pharmaceutical composition

[0346] One embodiment provides a composition comprising a compound according to any of the embodiments disclosed herein (eg, a compound of structure (I), (II) or (III)) and a pharmaceutically acceptable carrier.

[0347] Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the compounds of structure (I), (II) or (III) and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In more embodiments, the pharmaceutical composition comprises a compound of structure (I), (II) or (III) and an additional therapeutic agent (e.g., an anticancer agent). Non-limiting examples of such therapeutic agents are described below.

[0348] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0349] In certain embodiments, the compound of structure (I), (II) or (III) is applied locally rather than systemically, for example, via direct injection of the compound into an organ, usually in a depot preparation or a sustained release preparation. In a specific embodiment, the long-acting preparation is applied by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In addition, in other embodiments, in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody, the drug is delivered. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compound of structure (I), (II) or (III) is provided in the form of a rapid release preparation, in the form of an extended release preparation, or in the form of an intermediate release preparation. In other embodiments, the compound of structure (I), (II) or (III) is applied locally.

[0350] The compounds of structure (I), (II) or (III) are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01-1000 mg, 0.5-100 mg, 1-50 mg / day and 5-40 mg / day are examples of dosages used in certain embodiments. An exemplary dosage is 10-30 mg / day. The exact dosage will depend on the route of administration, the form of the compound being administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0351] In certain embodiments, a compound of structure (I), (II) or (III) is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, to rapidly introduce the agent. However, other routes may also be used as appropriate. A single dose of a compound of structure (I), (II) or (III) may also be used to treat acute conditions.

[0352] In certain embodiments, the compound of structure (I), (II) or (III) is administered in multiple doses. In certain embodiments, administration is about once, twice, three times, four times, five times, six times or more than six times a day. In other embodiments, administration is about once a month, once every two weeks, once a week or once every other day. In another embodiment, the compound of structure (I), (II) or (III) and another medicament are administered together about once a day to about six times a day. In another embodiment, the administration of the compound of structure (I), (II) or (III) and the medicament continues for less than about 7 days. In another embodiment, administration continues for more than about 6, 10, 14, 28 days, two months, six months or one year. In some cases, continuous administration can be achieved and maintained as long as necessary.

[0353] Administration of a compound of structure (I), (II) or (III) may continue as long as desired. In certain embodiments, a compound of structure (I) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In certain embodiments, a compound of structure (I), (II) or (III) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In certain embodiments, a compound of structure (I), (II) or (III) is administered on a continuous basis for a long period of time, for example, to treat a chronic effect.

[0354] In certain embodiments, the compound of structure (I), (II) or (III) is administered in a dose. It is known in the art that due to the inter-subject variability of compound pharmacokinetics, individualization of the dosing regimen is necessary for optimal treatment. In view of the disclosure of the present invention, the dosage of the compound of the present disclosure can be found by routine experimentation.

[0355] In certain embodiments, the compound of structure (I), (II) or (III) is formulated into a pharmaceutical composition. In specific embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate processing of the active compound into a pharmaceutically acceptable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers and excipients are suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0356] Provided herein are pharmaceutical compositions comprising a compound of structure (I), (II) or (III) and a pharmaceutically acceptable diluent, excipient or carrier. In certain embodiments, the described compounds are administered as pharmaceutical compositions, wherein the compound of structure (I), (II) or (III) is mixed with other active ingredients, such as in combination therapy. Contemplated herein are all combinations of active substances described in the following combination therapy sections and throughout the present disclosure. In specific embodiments, the pharmaceutical composition comprises one or more compounds of structure (I), (II) or (III).

[0357] As used herein, a pharmaceutical composition refers to a mixture of a compound of structure (I), (II) or (III) and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. In certain embodiments, the pharmaceutical composition promotes the administration of the compound to an organism. In certain embodiments of the treatment or use methods provided herein, a therapeutically effective amount of a compound of structure (I), (II) or (III) provided herein is administered in a pharmaceutical composition to a mammal suffering from a disease, disorder or medical condition to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies according to the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. A compound of structure (I), (II) or (III) is used alone or in combination with one or more therapeutic agents (as components of a mixture).

[0358] In one embodiment, one or more compounds of structure (I), (II) or (III) are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer such as Hank's solution, Ringer's solution or a physiological saline buffer. In other embodiments, one or more compounds of structure (I), (II) or (III) are formulated for transmucosal administration. In specific embodiments, the transmucosal formulation includes a penetrant suitable for the barrier to be penetrated. In other embodiments in which the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0359] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms, which include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0360] In certain embodiments, a pharmaceutical preparation for oral use is obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if necessary) to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In a specific embodiment, a disintegrant is optionally added. Disintegrants include, by way of example only, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0361] In one embodiment, one or more suitable coatings are provided to dosage forms (such as dragee cores and tablets). In a specific embodiment, concentrated sugar solution is used for coated dosage forms. Sugar solution optionally contains other components, such as only as an example, gum arabic, talcum powder, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Dye and / or pigment are also optionally added to the coating for identification purposes. In addition, dye and / or pigment are optionally used to characterize the different combinations of active compound dosage.

[0362] In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). In a specific embodiment, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optional stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0363] In other embodiments, a therapeutically effective amount of at least one compound described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for rapid push or continuous infusion. In specific embodiments, the formulation for injection is present in a unit dosage form (e.g., in an ampoule) or in a multiple dose container. A preservative is optionally added to the injection formulation. In other embodiments, the pharmaceutical composition is formulated into a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains a preparatant, such as a suspending agent, a stabilizer, and / or a dispersant. In specific embodiments, the pharmaceutical formulation for parenteral administration includes an aqueous solution of the active compound in a water-soluble form. In another embodiment, a suspension of the active compound (e.g., a compound of structure (I), (II), or (III)) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension contains a suitable stabilizer or increases the solubility of the compound to allow the preparation of a highly concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form for preparation with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0364] In other embodiments, the compound of structure (I), (II) or (III) is administered topically. The compounds described herein are formulated into a variety of compositions for topical administration, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0365] In other embodiments, the compound of structure (I), (II) or (III) is formulated for transdermal administration. In a specific embodiment, the transdermal preparation adopts a transdermal delivery device and a transdermal delivery patch, and can be a lipophilic emulsion or a buffered aqueous solution, dissolved and / or dispersed in a polymer or an adhesive. In different embodiments, such patches are constructed for continuous, pulsating (pulsatile) or on-demand delivery of pharmaceutical agents. In other embodiments, the transdermal delivery of the compound of structure (I), (II) or (III) is completed by means of an iontophoresis patch etc. In certain embodiments, a transdermal patch provides the controlled delivery of the compound of structure (I), (II) or (III). In a specific embodiment, the absorption rate is slowed down by using a rate-controlled membrane or by trapping the compound in a polymer matrix or a gel. In an alternative embodiment, an absorption enhancer is used to increase absorption. An absorption enhancer or a carrier includes an absorbable pharmaceutically acceptable solvent that helps to penetrate the skin. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with a carrier, an optional rate controlling barrier (to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time), and means for securing the device to the skin.

[0366] In other embodiments, the compound of structure (I), (II) or (III) is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of any compound of structure (I), (II) or (III) are conveniently delivered in an aerosol spray presentation form from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In a specific embodiment, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a quantitative amount. In certain embodiments, capsules and cartridges of gelatin formulated for use in an inhaler or insufflator (such as, by way of example only) contain a powder mixture of the compound and a suitable powder base (such as lactose or starch).

[0367] In still other embodiments, the compounds of structure (I), (II) or (III) are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In suppository forms of the compositions, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally is combined with melted cocoa butter.

[0368] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. Suitable formulations depend on the route of administration selected. Any pharmaceutically acceptable techniques, carriers and excipients are optionally used as appropriate. Pharmaceutical compositions comprising compounds of structure (I), (II) or (III) are prepared in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, embedding or compression processes.

[0369] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of structure (I), (II) or (III) (described herein as an active ingredient). The active ingredient is in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also referred to as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. In addition, the compounds described herein encompass unsolvated forms and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally includes other drugs or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0370] Methods for preparing compositions comprising compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solids, semisolids, or liquids. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein are in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like.

[0371] In certain embodiments, pharmaceutical compositions comprising at least one compound of structure (I), (II) or (III) are illustratively in liquid form, wherein the agent is present in a solution, a suspension, or both. Typically, when the composition is administered as a solution or a suspension, a first portion of the agent is present in a solution, and a second portion of the agent is suspended in a liquid matrix in particulate form. In certain embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0372] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers (e.g., hydroxypropyl methylcellulose) and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain mucoadhesive polymers, for example selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0373] Useful pharmaceutical compositions also optionally include solubilizing agents that contribute to the dissolution of compounds of structure (I), (II) or (III). The term "solubilizing agent" generally includes agents that result in the formation of micellar solutions or true solutions of the agents. Certain acceptable nonionic surfactants, such as polysorbate 80, can be used as solubilizing agents, and ophthalmologically acceptable glycols, polyglycols (e.g., polyethylene glycol 400) and glycol ethers can also be used as solubilizing agents.

[0374] In addition, useful pharmaceutical compositions optionally include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0375] In addition, useful compositions optionally include one or more salts in an amount required to bring the osmolality of the composition to an acceptable range. Such salts include salts having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0376] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyl trimethylammonium bromide and cetylpyridinium chloride.

[0377] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example, octoxynol 10, octoxynol 40.

[0378] Still other useful compositions include one or more antioxidants to enhance chemical stability where desired. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0379] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case a preservative is typically included in the composition.

[0380] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful in this article. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In other embodiments, sustained release systems are used to deliver compounds as described herein, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents. Various sustained releases are useful in this article. In certain embodiments, sustained release capsules release compounds for several weeks until more than 100 days. According to the chemical properties and biological stability of the therapeutic reagent, additional strategies for protein stability are adopted.

[0381] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0382] In certain embodiments, the concentration of one or more compounds provided in the pharmaceutical composition is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.39%, 0.30%, 0.31%, 0.32%, 0.33%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.39%, 0.30%, 0.31%, 0.3 ... 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0383] In certain embodiments, the concentration of one or more compounds is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0. 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0384] In certain embodiments, the concentration of one or more compounds is between about 0.0001% and about 50%, about 0.001% and about 40%, about 0.01% and about 30%, about 0.02% and about 29%, about 0.03% and about 28%, about 0.04% and about 27%, about 0.05% and about 26%, about 0.06% and about 25%, about 0.07% and about 24%, about 0.08% and about 26%. about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v range.

[0385] In certain embodiments, the concentration of one or more compounds is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0386] In certain embodiments, the amount of one or more compounds is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0. 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0387] In certain embodiments, the amount of one or more compounds exceeds 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.007 5g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0 .035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0 .085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g ,0.5g,0.55g,0.6g,,0.65g,0.7g,0.75g,0.8g,0.85g,0.9g,0.95g,1g,1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g.

[0388] In certain embodiments, the amount of one or more compounds ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0389] Treatment

[0390] Certain compounds of the present disclosure can be used to treat diseases (i.e., compounds of structure (I), (II) or (III)). Those compounds disclosed herein provide a targeted approach for drug delivery strategies. Thus, one embodiment provides a method of treating a disease (or its symptoms), the method comprising administering a therapeutically effective amount of a compound of structure (I), (II) or (III) to a mammal (e.g., a human) in need thereof.

[0391] For example, in certain embodiments, the present disclosure provides a method of treating an autoimmune disease such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, childhood Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathies, psoriasis, or osteoarthritis.

[0392] Other therapeutic agents that can be combined with the compounds of the present disclosure can be found in "The Pharmacological Basis of Therapeutics" by Goodman and Gilman (10th Edition, ed. by Hardman, Limbird and Gilman) or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0393] Depending on the condition being treated, the compounds of structures (I), (II) or (III) described herein may be used in combination with the agents disclosed herein or other suitable agents. Thus, in certain embodiments, one or more compounds of the present disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. Such combined administration may include simultaneous administration in the same dosage form, simultaneous administration in separate dosage forms, and separate administration of the two agents. That is, the compounds described herein and any of the above-mentioned agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the above-mentioned agents may be administered simultaneously, wherein the two agents are present in separate preparations. In another alternative, the compounds of the present disclosure may be administered immediately following any of the above-mentioned agents, or vice versa. In certain embodiments of the separate administration scheme, the compounds of the present disclosure and any of the above-mentioned agents are administered a few minutes apart, or a few hours apart, or a few days apart.

[0394] The examples and preparations provided below further illustrate and illustrate the compounds of the present disclosure and methods for preparing such compounds. It should be understood that the scope of the present disclosure is not limited in any way to the scope of the following examples and preparations. In the following examples and throughout the entire specification and claims, unless otherwise indicated, molecules and moieties with a single stereocenter exist as racemic mixtures. Unless otherwise indicated, those molecules and moieties with two or more stereocenters exist as racemic mixtures of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0395] Representative DNA synthesis cycle

[0396]

[0397] Oligomerization is usually started by removing protecting groups (e.g., dimethoxytrityl, DMTr) to expose free-OH (hydroxyl) groups (step 1, detritylation). In the subsequent coupling step, a phosphoramidite monomer is introduced, which reacts with free OH groups to form a new covalent bond with phosphorus, with the loss of a diisopropylamine group (step 2, coupling). The phosphite triester obtained is oxidized (e.g., with I2 and pyridine) to a more stable phosphate (step 3, oxidation), and an end-capping step makes any remaining free OH groups unreactive (step 4, end-capping). The new product phosphate oligomer contains the OH group protected by DMTr, which can be deprotected to restart the synthesis cycle so that another phosphoramidite monomer can be attached to the oligomer.

[0398] Customization occurs in step 2 by selecting the phosphoramidite monomer. The properties of L (i.e., the linker group) and M (i.e., the chemotherapeutic agent) in the above scheme are selected so as to synthesize the desired compound of structure (I), (III), or (IV). M may optionally be absent to include the desired spacing between the M moieties. One of ordinary skill in the art can select a variety of monomer types to obtain compounds of the present disclosure containing a variety of therapeutic agents and / or other moieties (e.g., fluorophores or chromophores) and the linker group is simultaneously variable.

[0399] Several steroid phosphoramidites and vitamin phosphoramidites are commercially available and can be used in the above DNA synthesis cycle. These include cholesterol phosphoramidites and tocopherol / tocotrienol phosphoramidites as shown below:

[0400] Example

[0401] General approach

[0402] Mass spectrometry analysis was performed on a Waters / Micromass Quattro micro MS / MS system (in MS-only mode) using MassLynx 4.1 acquisition software. The mobile phase for dye LC / MS was 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. Phosphoramidites and precursor molecules were also analyzed using a Waters Acquity UHPLC system with a 2.1 mm × 50 mm Acquity BEH-C 18 The column was used with an acetonitrile / water mobile phase gradient. The MS / MS was performed on a Waters / Micromass Quattro micro MS / MS system (in MS-only mode). Onium cation infusion enhanced ionization yielded molecular weights of monomeric intermediates. Excitation and emission curve experiments were recorded on a Cary Eclipse spectrophotometer.

[0403] Unless otherwise stated, all reactions were performed in oven-dried glassware under a nitrogen atmosphere. Commercially available DNA synthesis reagents were purchased from Glen Research (Sterling, VA). Anhydrous pyridine, toluene, dichloromethane, diisopropylethylamine, triethylamine, acetic acid, pyridine, and THF were purchased from Aldrich. All other chemicals were purchased from Aldrich or TCI and used as received without additional purification.

[0404] Example 1

[0405] Synthesis of Compound I-1

[0406] Stock solution preparation

[0407] Prepare borate buffer at 250 mM, pH 10

[0408] Prepare fluorescein-NHS solution at 350 mM (300 mg in 1.35 mL of 25:75 DMSO:acetonitrile)

[0409] Solid phase synthesis

[0410] Compound I-1 was prepared on a DNA synthesizer using standard DNA synthesis techniques (i.e., DMT protected 2-cyanoethyl phosphoramidite) on a solid support. The polymer was removed from the solid support using ammonium hydroxide and lyophilized to a paste. A 250 mg aliquot was reconstituted in water. A small aliquot was taken and a serial dilution was prepared in 100 mM NaCO3 (pH 9) to determine the concentration (A 263ε=10,000). The final stock concentration was found to be 14.5 mM.

[0411] Dye coupling reaction

[0412] Water (1.110 μL), borate buffer (1.800 μL), Compound I-1 polymer solution (466 μL), acetonitrile (137.5 μL), triethylamine (313 μL) and fluorescein-NHS solution (675 μL) were placed in a 50 mL centrifuge tube equipped with a magnetic stirring bar. The test tube was wrapped in aluminum foil and the mixture was stirred at room temperature overnight.

[0413] Size Exclusion Filtration

[0414] Add 1mL water to Amicon Ultra-15 centrifugal filter (Millipore UFC900324, molecular weight cutoff value = 3000). The crude product (4.5mL) produced by the dye coupling reaction is added to the filter. The reaction vessel is rinsed 2 times with 4mL of 100mM NaOH, and the rinse is transferred to the filter. The filter is centrifuged at maximum speed (3220g, rotating drum, 30 minutes). The filtrate is removed, and the retentate is treated with another 10mL of 100mM NaOH. The filter is centrifuged as before. The filtrate is removed again, and the third 10mL 100mM NaOH aliquot is added to the retentate. The device is centrifuged as before, and the filtrate is removed. The fourth 10mL 100mM NaOH aliquot is added to the retentate, and centrifuged as before. Remove the filtrate and add 10mL water to the filter. The mixture is centrifuged as before. The retentate was removed, the filtration vessel was washed with water and the rinses were added to final volume (3.5 mL).The desired product was confirmed by LC-MS and the concentration was determined using absorbance.

[0415] Example 2

[0416] Activation of Compound I-1 and Antibody Conjugation

[0417]

[0418] Maleimide functionalized compound I-1 was prepared according to the method described in Example 1. In parallel, UCHT-1 antibody was treated with bismaleimidoethane ("BMOE") to reduce disulfide bonds. The reduced antibody was reacted with compound I-1 at a polymer to antibody molar ratio of 5:1. The reaction produced a final product having a polymer to antibody ratio of 1:1 as detected by size exclusion chromatography. In certain embodiments, anti-CD33, anti-CD70 or anti-CD123 can be used with bismaleimidoethane ("BMOE") to reduce disulfide bonds.

[0419] Example 3

[0420] General synthesis of peptide backbones by solid phase synthesis

[0421]

[0422] The above reaction scheme illustrates an exemplary method for preparing intermediates that can be used to prepare compounds of structure (II), wherein PG is a suitable protecting group, X is a functional unit that can build a peptide chain, the shaded circle is a suitable solid support, and "BAM" is a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding site, provided that at least one occurrence of M is not a fluorescent dye.

[0423] Small porous beads are first treated with functional units, which are bound to the surface of the porous beads. Peptide chains are established on the functional unit sites and remain covalently bonded to the beads until they are cleaved. Once attached, the peptide chains are immobilized on the solid phase and retained during the filtration process, where liquid reagents and byproducts of synthesis are washed away.

[0424] The general cycle of solid phase synthesis is one of repeated cycles of deprotection-washing-coupling-washing. The free N-terminal amine of the peptide attached to the solid support is coupled with an N-protected amino acid group (e.g., with Fmoc or Boc). The newly introduced amino acid unit is deprotected to expose a new N-terminal amine, which further reacts with another amino acid. The process is repeated, and the peptide chain is extended.

[0425] When the peptide chain has contained all the desired amino acids and monomer units, it is cleaved from the beads. The peptide chain can be cleaved from the beads using a cleavage agent such as anhydrous hydrogen fluoride or trifluoroacetic acid. The peptide chain is then collected, purified and characterized.

[0426] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet, including U.S. Provisional Patent Application No. 63 / 409,000 filed on September 22, 2022, are incorporated herein by reference in their entirety to the extent not inconsistent with this specification. Aspects of the embodiments may be modified, if necessary, to employ concepts of different patents, applications, and publications to provide other embodiments.

[0427] From the foregoing it will be appreciated that although specific embodiments of the present disclosure have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure is limited only by the appended claims.

Claims

1. A compound having the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 1 and R 2 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or its protected form, L′; R a is O or S; R b OH, SH, O - , S - , OR d or SR d ; R c OH, SH, O - , S - , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether; R d is the counter ion; R 3 is independently at each occurrence H, alkyl or alkoxy; R 4 is, independently at each occurrence, OH, SH, O - , S - , OR d or SR d ; R 5 is independently at each occurrence oxo or thio; L 1 , L 2 , L 5 and L 6 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker; L 3 is independently at each occurrence an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is a connectome independently at each occurrence; M 1 independently at each occurrence is a moiety comprising a fluorescent or colored dye; M 2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin; Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L' is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to another compound of structure (I); and m is independently an integer of 1 or greater at each occurrence; p is an integer of 0 or greater at each occurrence; q is an integer of 1 or greater at each occurrence; and n is an integer of 1 or greater.

2. The compound of claim 1, wherein L 3 At least one occurrence of is heteroalkylene.

3. The compound of claim 1-2, wherein L 3 Each occurrence of is heteroalkylene.

4. The compound of claim 3, wherein the heteroalkylene group comprises an oxyalkylene group.

5. The compound of claim 4, wherein the heteroalkylene group comprises an oxyethylene group. The compound of claim 5 , wherein the oxyethylene group is a polyoxyethylene group.

7. The compound of any one of claims 1 to 6, wherein L 3 Has the following structure at each occurrence: in: z is an integer from 1 to 100; and *Indicates bonds to neighboring phosphorus atoms.

8. The compound of claim 7, wherein z is an integer from 3 to 8.

9. The compound of claim 7, wherein z is an integer from 22 to 26.

10. The compound of claim 7 having the following structure (IA): or a stereoisomer, a salt or a tautomer thereof.

11. The compound of any one of claims 1 to 10, wherein L 1 At least one occurrence of is alkylene.

12. The compound of any one of claims 1 to 11, wherein L 1 Each occurrence of is an alkylene group.

13. The compound of any one of claims 1 to 12, wherein L 2 At least one occurrence of is alkylene.

14. The compound of any one of claims 1 to 13, wherein L 2 Each occurrence of is an alkylene group.

15. The compound of any one of claims 1 to 14, wherein L 5 At least one occurrence of is a direct key.

16. The compound of any one of claims 1 to 15, wherein L 5 Each occurrence of is a direct key.

17. The compound of any one of claims 1 to 16, wherein L 6 At least one occurrence of is alkylene.

18. The compound of any one of claims 1 to 17, wherein L 6 Each occurrence of is an alkylene group.

19. The compound of any one of claims 1-18, having the following structure (IB): or a stereoisomer, a salt or a tautomer thereof, where y 1 ,y 2 and 6 is independently an integer from 1 to 6 at each occurrence; and y 5 is independently an integer from 0 to 6 at each occurrence.

20. A compound having the following structure (II): or a stereoisomer, a pharmaceutically acceptable salt or a tautomer thereof, wherein: M 1 independently at each occurrence is a moiety comprising a fluorescent dye; M 2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin; L 1 , L 2 , L 3 and L 5 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker; L 4 is a connectome independently at each occurrence; R 21 is independently at each occurrence a natural or unnatural amino acid side chain; R 1 and R 2 Each is independently H, OH, SH, -NH2, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or its protected form, L′; R a is O or S; R b OH, SH, O-, S-, OR d or SR d ; R c OH, SH, O-, S-, OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether; R d is the counter ion; Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L′ is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to another compound of structure (II); m is independently an integer of 0 or greater at each occurrence; p is independently an integer of 0 or greater at each occurrence; v is independently an integer of 1 or greater at each occurrence; and n is an integer of 1 or greater.

21. The compound of claim 20, wherein at least one R 21 It is a neutral amino acid side chain.

22. The compound of any one of claims 20 or 21, wherein at least one R 21 Amino acid side chains are charged.

23. The compound of any one of claims 20-22, wherein R 21 is independently H, alkyl, -CH2CO2 at each occurrence - 、-CH2CH2CO2 - 、-CH2CH2CH2CH2NH3 + 、-CH2CH2CH2NHC(=NH2 + )NH2 or imidazolyl.

24. The compound of any one of claims 20-23, wherein R 21 , L 5 and m such that Has (G) 10 , (GDGDGDGDGD) or (GKGKGKGKGK).

25. The compound of claim 24, wherein R 21 , L 5 and m such that It has an amino acid sequence that can form an α-helix or β-sheet secondary structure.

26. The compound of claim 25, wherein the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

27. The compound of any one of claims 20-26, wherein L 5 or L 2 Or both exist for at least one occurrence.

28. The compound according to claim 27, wherein When present, L 5 or L 2 or both are heteroalkylene linkers.

29. The compound of claim 28, wherein the heteroalkylene linker comprises a functional group capable of maintaining a positive or negative charge in an aqueous solution at a pH range of 3 to 11.

30. The compound of claim 29, wherein L 5 or L 2 or at least one occurrence of both has the following structure:

31. The compound of claim 29, wherein L 5 or L 2 or at least one occurrence of both has the following structure:

32. The compound of any one of claims 20-31, wherein L 1 and L 3 is independently absent or is a heteroalkylene linker.

33. The compound of claim 32, wherein the heteroalkylene linker is a peptidyl linker.

34. A compound having the following structure (III): or a stereoisomer, a pharmaceutically acceptable salt or a tautomer thereof, wherein: M 1 independently at each occurrence is a moiety comprising a fluorescent dye; M 2 is independently at each occurrence a moiety comprising a biologically active moiety, provided that M 2 at least one occurrence of a steroid or vitamin; L 4 is a connectome independently at each occurrence; L 1 , L 2 and L 3 is independently at each occurrence a direct bond or is independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker; L 5 is independently at each occurrence an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker comprising one or more charged moieties, with the proviso that at least one of the charged moieties is not phosphate; R 3 is independently at each occurrence H, alkyl or alkoxy; R 1 and R 2 are independently -H, -OH, -SH, alkyl, alkoxy, alkyl ether, heteroalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, -OP(=R a )(R b )R c , Q or its protected form or L′; R a is O or S; R b OH, SH, O - , S - , OR d or SR d ; R c OH, SH, O - , S - , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphate alkyl, thiophosphoroalkyl, phosphate alkyl ether, or thiophosphoroalkyl ether; R d is the counter ion; Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L′ is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a solid support or a solid support residue, a linker comprising a covalent bond to a solid support or a solid support residue, or a linker comprising a covalent bond to another compound of structure (III); p is independently an integer of 0 or greater at each occurrence; v is independently an integer of 1 or greater at each occurrence; and n is an integer of 1 or greater.

35. The compound of claim 34, wherein the charged moiety is positively charged.

36. The compound of claim 35, wherein the charged moieties independently have one of the following structures: in: R at each occurrence is independently H or C1-C6 alkyl.

37. The compound of claim 34, wherein the charged moiety is negatively charged.

38. The compound of claim 37, wherein the charged moiety has the structure:

39. The compound of any one of claims 34-38, wherein L 5 Contains one of the following structures: in: R at each occurrence is independently H or C1-C6 alkyl; x is an integer from 0 to 6; and m is an integer of 1 or greater.

40. The compound of any one of claims 1-39, wherein L 4 At least one occurrence of comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano group, a nitro group, or a combination thereof.

41. The compound of claim 40, wherein L 4 Contains amide or ester functionality.

42. The compound of any one of claims 1-41, wherein L 4 At least one occurrence of contains one of the following structures:

43. The compound of any one of claims 1-42, wherein L 4 Each occurrence of comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano group, a nitro group, or a combination thereof.

44. The compound of any one of claims 1-43, wherein L 4 Each occurrence of contains one of the following structures:

45. The compound of any one of claims 1-44, wherein R 3 At least one occurrence of is H.

46. ​​The compound of any one of claims 1-45, wherein R 3 Every occurrence of is H.

47. The compound of any one of claims 1-46, wherein R 5 At each occurrence is oxo.

48. The compound of any one of claims 1-47, wherein R 4 O in each occurrence - .

49. The compound of any one of claims 1-48, wherein R 1 and R 2 Each is independently OH or -OP (= R a )(R b )R c .

50. The compound of any one of claims 1-49, wherein R 1 or R 2 One of them is OH or -OP (=R a )(R b )R c , and R 1 or R 2 The other one of them is Q or a linker comprising a covalent bond to Q.

51. The compound of any one of claims 1-50, wherein R 1 and R 2 Each is independently -OP(=R a )(R b )R c .

52. The compound of any one of claims 1-51, wherein R 2 or R 1 One is L' and L' is a linker comprising a covalent bond to the solid support.

53. The compound of any one of claims 1-52, wherein L' is a linker to a targeting moiety.

54. The compound of any one of claims 1-53, wherein L' is a linker to a targeting moiety, the linker comprising an oxyalkylene or phosphodiester moiety or a combination thereof.

55. The compound of any one of claims 1-54, wherein L' has one of the following structures: in: x 1 、x 2 、x 3 、x 4 、x 5 、x 6 、x 7 and x 8 are independently an integer from 1 to 10; R b is H, an electron pair, or a counterion; and L" is a targeting moiety or a linkage to a targeting moiety.

56. The compound of any one of claims 1-55, wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

57. The compound of claim 56, wherein the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate or a MET inhibitor.

58. The compound of claims 1-57, wherein the targeting moiety is a monoclonal antibody.

59. The compound of claim 58, wherein the monoclonal antibody is abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benrazumab, belotosumab, rantumomab, brocitumomab, brosuolumab, canakinumab, calasinumab, becerolizumab, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, eprezumab, eloumab, remanezumab, ganezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, ilizumab, ecamizumab, ranarizumab, logivumab, mepolizumab, natalizumab, ocrelizumab , omalizumab, patuzumab, ranibizumab, ranibizumab, reslizumab, Rmab, rovizumab, rulizumab, salilumab, securumab, tirazumab, thiomab, tocilizumab, ustekinumab, vedolizumab, alirocumab, actosumab, aducanumab, afacumumab, afelimomab, aniluomab, anrulumab (IMA-638), asekizumab, atumumab, bapilumab, BCD-100, bertilimumab, besozumab, bicizumab, bimalumab, bigelizumab, portelumab, brevilumab, busoluzumab, bercocilizumab, brasilizumab, brianuzumab, brionizumab, bucitumumab, caprokusumab, caprouximab Antibody, cilizumab, clazakizumab, cleximab, concecizumab, coveximab, CR6261, crezumab, lizanlizumab, clotuzumab, detuximab, mafodotin, delotuzumab biotin, dezamizumab, delivuzumab, domarozumab, dustuzumab, emtansimab, ebazumab, efalizumab, ifenguzumab, edirumab, elenuzumab, enokizumab, eprenazumab, erlizumab, edilizumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, efezumab, Flocilizumab, forlanumab, gantuzumab, gavilimumab, gevolizumab, kinselumab, gomiliximab, gonelizumab, iliumumab, inlasutumab, inomucomab, Iomab-B, keliximab, lambazumab, lanlozumab, laviximab, lerezumab, renvimab, ledetumumab, lelizumab, livimab, ligozumab, lodicuzumab, pelulizumab, matasizumab, mavrilimumab, metilimumab, migizumab, movilimumab, muromonab CD3, nebacumab, nemolizumab, NEOD001, niecevir, odumumab, orendalizumab, ololituzumab, OMS721, opinumab, otesuzumab,Oxetizumab, otilizumab, oseltuzumab, ozaneluzumab, olizumab, paxilumab, pabacumab, pacolizumab, patezumab, PDR001, pelaqualizumab, pexelizumab, pralulumab, lozalizumab, ponecizumab, perveximab, prenizumab, priliximab, PRO 140, quilizumab, levuzumab, ramucizumab, ranevizumab, lavagalimab, ravulizumab, refelizumab, rigavirumab, relalizumab, linusumab, risankizumab, roledutumab, romozumab, longlizumab, SA237, satelizumab, sevirumab, SHP647, sifalimumab, sintuzumab, cilizumab, sirukumab, solanizumab, sonecilizumab, spartalizumab, setamizumab, thiosomab, sutofumab, sutolizumab, suvetumab, sutosumab, Taduzumab, taclizumab, tantovetumab, tanezumab, tefizumab, atemotuzumab, teneciximab, telizumab, tetumumab, tezelumab, tibrilizumab, tocilizumab, trorocirumab, trogolucumab, tuvirizumab, urolulumab, urolizumab, varisucomab, vepamumab, vesentuzumab, visilizumab, wolbalizumab, atozumab, trastuzumab, gemtuzumab, brentuximab, worse tuzumab, lovatuzumab, cantuzumab, bivacuzumab or ecamizumab or vadatuximab.

60. The compound of any one of claims 1-59, wherein R 1 or R 2 Has one of the following structures: Where R a is H or a solid support.

61. The compound of any one of claims 1-60, wherein R 2 Has one of the following structures:

62. The compound of any one of claims 1-61, wherein R 1 Has the following structure:

63. The compound of any one of claims 1-62, wherein M 1 and R in one or more occurrences is independently a moiety comprising four or more aryl or heteroaryl rings or combinations thereof.

64. The compound of any one of claims 1-63, wherein M 1 and wherein one or more occurrences independently comprise a fused polycyclic aryl or heteroaryl moiety comprising at least 4 fused rings.

65. The compound of any one of claims 1-64, wherein M 1 is independently selected at each occurrence from the group consisting of phenyl, (difluorophenyl-difluorobora-diaza-indacenyl)phenyl, quaterphenyl, bibenzothiazole, terbenzothiazole, binaphthyl, bianthracenyl, squaryl, squarylium, 9,10-ethynylanthracene, and ternaphthyl moieties.

66. The compound of any one of claims 1-65, wherein M 1 is independently selected at each occurrence from the group consisting of: p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthene, Rubrene, coronene, cyanine, perylene imide, perylene amide, and their derivatives.

67. The compound of any one of claims 1-66, wherein M 1 is independently selected at each occurrence from the group consisting of: coumarin dyes, resorufin dyes, dipyrromethene boron difluoride dyes, ruthenium bipyridyl dyes, thiazole orange dyes, polymethines, and N-aryl-1,8-naphthalimide dyes.

68. The compound of any one of claims 1-67, wherein M 1 Independently selected at each occurrence are: coumarin dyes, boro-dipyrromethene, rhodamine, cyanine, pyrene, perylene, perylene monoimide, 6-carboxyfluorescein (6-FAM), 5-carboxyfluorescein (5-FAM), 6-fluorescein isothiocyanate (6-FITC), 5-fluorescein isothiocyanate (5-FITC), and derivatives thereof.

69. The compound of any one of claims 1-68, wherein M 1 Each occurrence independently has one of the following structures:

70. The compound of any one of claims 1-69, wherein M 1 At least one occurrence of has the following structure:

71. The compound of any one of claims 1-70, wherein M 1 Each occurrence of has the following structure:

72. The compound of any one of claims 1-71, wherein -L 4 -M 1 At least one occurrence of has one of the following structures:

73. The compound of any one of claims 1-72, wherein -L 4 -M 1 Each occurrence of has one of the following structures:

74. The compound of any one of claims 1-73, wherein M 2 At least one occurrence of was on steroids.

75. The compound of claim 74, wherein M 2 At least one occurrence of cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

76. The compound of any one of claims 74-75, wherein M 2 At least one occurrence of has one of the following structures: in: R 11 is H or halogen; R 12 and R 13 is independently OH, H, alkyl, substituted alkyl, or heteroalkyl; R 14 is H, halogen, OH or alkyl; R 15 is H or OH; R 16 , R 17 and R 18 is H, alkyl or substituted alkyl; and Represents a carbon-carbon single or double bond.

77. The compound of any one of claims 1-76, wherein M 2 At least one occurrence of has one of the following structures:

78. The compound of claim 77, wherein M 2 At least one occurrence of has the following structure:

79. The compound of claim 78, wherein M 2 Each occurrence of has the following structure:

80. The compound of claim 79, wherein -L 4 -M 2 At least one occurrence of has one of the following structures:

81. The compound of claim 80, wherein -L 4 -M 2 Each occurrence of has one of the following structures:

82. The compound of any one of claims 1-73, wherein M 2 At least one occurrence of vitamins.

83. The compound of claim 82, wherein M 2 At least one occurrence was vitamin E.

84. The compound of claim 83, wherein M 2 At least one occurrence of is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol or delta-tocotrienol.

85. The compound of any one of claims 82-84, wherein M 2 At least one occurrence of has the following structure: in: R 19 and R 20 are independently H or CH3; and Represents a carbon-carbon single or double bond.

86. The compound of any one of claims 82-85, wherein M 2 At least one occurrence of has one of the following structures:

87. The compound of claim 86, wherein M 2 At least one occurrence of has the following structure:

88. The compound of claim 87, wherein M 2 Each occurrence of has the following structure:

89. The compound of claim 86, wherein -L 4 -M 2 At least one occurrence of has one of the following structures:

90. The compound of claim 89, wherein -L 4 -M 2 Each occurrence of has one of the following structures:

91. The compound of any one of claims 1-90, wherein M 2 Has one of the following structures:

92. The compound of any one of claims 1-91, wherein Q has the structure: Or -NH2.

93. The compound of any one of claims 1-92, wherein m is 0 to 10.

94. The compound of any one of claims 1-93, wherein m is 1, 2, 3, 4 or 5.

95. The compound of any one of claims 1-94, wherein m is 1 or 2.

96. The compound of any one of claims 1-95, wherein n is 1, 2, 3 or 4.

97. The compound of any one of claims 1-96, wherein n is 1 or 2.

98. The compound of any one of claims 1-97, wherein p is 0, 1, 2, 3 or 4.

99. The compound of any one of claims 1-98, wherein p is 0.

100. The compound of any one of claims 1-99, wherein p is 1.

101. The compound of any one of claims 1-80, wherein q is 1, 2, 3, 4, 5 or 6.

102. The compound of any one of claims 1-101, wherein q is 1.

103. The compound of any one of claims 1-102, wherein q is 4.

104. The compound of any one of claims 1-103, wherein q is 5.

105. The compound of any one of claims 20-104, wherein v is an integer from 1 to 100.

106. The compound of any one of claims 20-105, wherein v is an integer from 1 to 10.

107. The compound of any one of claims 1-104, wherein y 1 ,y 2 and 6 is the integer 1 at each occurrence, and y 5 The integer 0 at each occurrence.

108. The compound of any one of claims 1-104, wherein y 1 ,y 2 ,y 5 and 6 The integer 1 at each occurrence.

109. The compound of any one of claims 1-104, wherein n is 1; p is 1; q is 5; and m is 1 or 2.

110. The compound of any one of claims 1-104, wherein n is 1; p is 1; q is 4; and m is 1 or 2.

111. The compound of any one of claims 1-110, wherein the compound has one of the structures of Tables 2-3 or a salt or tautomer thereof.

112. A pharmaceutical composition comprising a compound according to any one of claims 1-111, and a pharmaceutically acceptable carrier, diluent or excipient.

113. A method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-111 or a pharmaceutical composition of claim 112.

114. The method of claim 113, wherein the disease or disorder is an autoimmune disease.

115. The method of claim 113 or 114, wherein the autoimmune disease comprises rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, childhood Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathies, psoriasis, and osteoarthritis.

Images