Degradable hyaluronic acid hydrogel

Abstract

The present invention relates to conjugates comprising crosslinked hyaluronic acid having multiple drug moieties covalently and reversibly conjugated thereto, the hyaluronic acid exhibiting a particular degree of modification and including degradable crosslinker moieties, and to their use as pharmaceuticals and in the diagnosis, prevention, and treatment of disease. [Selection diagram] None

Description

Technical Field

[0001] The present invention relates to conjugates comprising cross-linked hyaluronic acid in which a plurality of drug moieties are covalently and reversibly conjugated, wherein the hyaluronic acid exhibits a certain degree of modification and contains a degradable cross-linking agent moiety. The present invention also relates to their use as medicaments, as well as their use in the diagnosis, prevention and treatment of diseases.

Background Art

[0002] A hydrogel is a three-dimensional hydrophilic or amphiphilic polymer network that can incorporate a large amount of water. These networks are composed of various polymers and are insoluble due to the presence of covalent chemical and / or physical cross-links.

[0003] Hydrogels can be used for many applications, for example, for the sustained release of drug molecules. Such drug molecules can be non-covalently embedded in the hydrogel or covalently and reversibly bound. Hyaluronic acid, an anionic non-sulfated glycosaminoglycan, is a useful polymer for such hydrogels because hyaluronic acid occurs naturally in connective, epithelial and nerve tissues and is therefore well tolerated in the human body. Due to the widespread presence of hyaluronidase, hyaluronic acid is also biodegradable.

[0004] Depending on the drug conjugated to the hydrogel and the desired dosing frequency, a high or low amount of drug loading is required, and such fine-tuning can sometimes be difficult to achieve. Derivatization of hyaluronic acid can prevent its degradability by hyaluronidase, and for this reason the presence of degradable bonds is desirable.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Accordingly, there is a need for a degradable hyaluronic acid-based hydrogel that enables both high and low levels of covalent drug loading.

[0006] It is an object of the present invention to overcome this drawback at least in part.

Means for Solving the Problem

[0007] This object is a conjugate comprising crosslinked hyaluronic acid chains to which a plurality of drug moieties are covalently and reversibly conjugated, and the following:

[0008]

Chemical Formula

[0009] Within the scope of the present invention, the terms are used with the following meanings.

[0010] As used herein, the terms "chain" or "hyaluronic acid chain" are used synonymously, and the dashed line without a label refers to a straight chain of disaccharide units connected so as to indicate the bonding point to the adjacent unit of the dashed line labeled with #. The dashed line without a label of the first unit of such a straight chain indicates a bond to hydrogen, and the dashed line labeled with # of the last unit of such a straight chain indicates a bond to hydroxyl.

[0011] As used herein, the phrase "direct connection" between two specific atoms refers to the shortest portion connecting the two specific atoms, and the "shortest portion" is measured by the number of atoms between these two specific atoms.

[0012] As used herein, the term "spacer" refers to a portion to which at least two other portions are connected to each other.

[0013] As used herein, the term "crosslinker" refers to a portion, for example, a spacer portion that connects at least two hyaluronic acid chains. When at least two hyaluronic acid chains are connected by a crosslinker portion, such hyaluronic acid chains are "crosslinked".

[0014] As used herein, the term "water-insoluble" refers to a compound that may have less than 1 g of the amount that dissolves in 1 liter of water at 20 °C to form a homogeneous solution. Thus, the term "water-soluble" refers to a compound that may have 1 g or more of the amount that dissolves in 1 liter of water at 20 °C to form a homogeneous solution.

[0015] As used herein, the term "sustained release" refers to the property of a compound, such as a conjugate of the present invention, that releases a drug, for example one or more antibiotics, with a release half-life of at least one day.

[0016] The term "drug" as used herein refers to a substance used in the treatment, cure, prevention or diagnosis of a disease or otherwise used to enhance physical or mental health. When a drug is conjugated to another moiety, the moiety derived from the drug of the resulting product is referred to as the "drug moiety".

[0017] As used herein, the term "π-electron pair donating heterocyclic aromatic N-containing moiety" refers to a moiety that gives rise to a drug D-H after cleavage of the linkage of -D and -L 1 - and the -D of the drug moiety and the corresponding D-H likewise contain at least one, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, heterocyclic aromatic nitrogen atoms that donate a π-electron pair to the aromatic π-system. Examples of chemical structures containing such heterocyclic aromatics that donate a π-electron pair to the aromatic π-system include, but are not limited to, pyrrole, pyrazole, imidazole, isoindazole, indole, indazole, purine, tetrazole, triazole and carbazole. For example, in the following imidazole ring, the heterocyclic aromatic nitrogen that donates a π-electron pair to the aromatic π-system is marked with "#".

[0018]

Chemical formula

[0019] A π-electron donating heterocyclic aromatic nitrogen atom donates only one electron (i.e., not a pair of π-electrons) to the aromatic π-system, and does not include, for example, the nitrogen marked with "§" in the imidazole ring structure described above. The drug D-H may exist in one or more tautomeric forms, for example, with at least one hydrogen atom moving between at least two heterocyclic aromatic nitrogen atoms. In all such cases, the linker moiety binds covalently and reversibly to a heterocyclic aromatic nitrogen that donates a pair of π-electrons to the aromatic π-system.

[0020] As used herein, the term "prodrug" refers to a biologically active moiety reversibly and covalently connected to a specified protecting group via a reversible prodrug linker moiety, which is a linker moiety that includes a reversible linkage to the biologically active moiety, and the specified protecting group modifies or eliminates undesirable properties of the parent molecule. This also includes enhancing desirable properties and suppressing undesirable properties of the drug. The specified non-toxic protecting group may also be referred to as a "carrier". The prodrug releases the reversibly and covalently bound biologically active moiety in the form of its corresponding drug. In other words, the prodrug is a conjugate that includes a drug moiety covalently and reversibly conjugated to a carrier moiety via a reversible prodrug linker moiety, and the covalent and reversible conjugation of the carrier to the reversible prodrug linker moiety is either direct or through a spacer. Such a conjugate preferably releases the previously conjugated drug moiety in the form of the free drug, in which case the reversible linker or reversible prodrug linker is a linker that leaves no trace. The conjugate of the present invention is a prodrug.

[0021] As used herein, the term "free form" of a drug means the unmodified pharmacologically active form of the drug.

[0022] As used herein, the terms "reversible", "reversibly", "degradable" or "degradably" refer to a bond that is cleaved under physiological conditions, which are aqueous buffers at pH 7.4 and 37°C, and the half-life ranges from 12 hours to 3 months, such as from 1 day to 10 weeks, from 2 days to 2 months or from 2 days to 1 month. The cleavage is preferably non-enzymatic. Thus, the term "stable" with respect to the attachment of a first moiety to a second moiety means that the linkage connecting the first and second moieties exhibits a half-life of more than 3 months under physiological conditions.

[0023] As used herein, the term "reagent" means a chemical compound containing at least one functional group that reacts with a functional group of another chemical compound or drug. It is understood that a drug containing a functional group is also a reagent.

[0024] As used herein, the term "moiety" means a part of a molecule that lacks one or more atoms compared to the corresponding reagent. For example, when a reagent of the formula "H-X-H" reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure "H-X-" or "-X-", where each "-" represents a bond to another moiety. Thus, the drug moiety is released as a drug from the reversible linkage.

[0025] When the chemical structure of a group of atoms is provided and this group of atoms attaches to or interrupts two moieties, it is understood that the sequence or chemical structure can attach to the two moieties in either direction unless specifically stated otherwise. For example, the "-C(O)N(R 1 )-" moiety can attach to two moieties or interrupt one moiety as either "-C(O)N(R 1 )-" or "-N(R 1 )C(O)-". Similarly, the following:

[0026]

Chemical formula

[0027]

Chem.

[0028]

Chem.

[0029] As used herein, the term "activator" refers to, for example, N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-(-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), [ethylcyano(hydroxyimino)acetate-O 2Tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), N-[(5-chloro-3-oxide-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate (HDMC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium tetrafluoroborate (TATU), 2-(1-oxy-pyridin-2-yl)-1,1,3,3-tetramethylisothiouronium tetrafluoroborate (TOTT), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 2-propanephosphonic anhydride (T3P), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium salt (DMTMM), bis-trichloromethyl carbonate (BTC), 1,1'-carbonyldiimidazole (CDI) and dicyclohexylcarbodiimide (DIC).

[0030] As used herein, "additive" refers to, for example, hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), ethyl 2-cyano-2-(hydroximino)acetate, carboxylic acid derivatives (e.g., those of formula (y-3')), 4,6-dimethoxy-1,3,5-triazin-2-ol, N-hydroxysuccinimide, 1-hydroxy-2,5-dioxopyrrolidine-3-sulfonic acid, 4-nitrophenol, 2,4-dinitrophenol and mono-, di-, tri-, tetra-, penta-fluorophenol (flurophenol) (e.g., those of formula (y'-10)), selected from the group consisting of.

[0031] As used herein, the term "substituted" means that one or more -H atoms of a molecule or moiety are replaced by a different atom or group of atoms called a "substituent".

[0032] As used herein, the term "substituent" in certain embodiments refers to halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 )(S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )(C(O)R x1a , -N(R x1 )(S(O)2R x1a , -N(R x1 )(S(O)R x1a , -N(R x1 )(C(O)OR x1a , -N(R x1 )(C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1~50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, and -T 0 , C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are each independently optionally substituted with one or more -R x2 s, and C 1~50 alkyl, C 2~50Alkenyl and C 2~50 Alkynyl is interrupted, optionally, by one or more groups selected from the group consisting of -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 ), -, -S(O)2N(R x3 ), -, -S(O)N(R x3 ), -, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a ), -, -S-, -N(R x3 ), -, -OC(OR x3 )(R x3a ), -, -N(R x3 )C(O)N(R x3a ), - and -OC(O)N(R x3 ), and is optionally substituted with one or more -R -, -R x1 -, -R x1a -, -R x1b is independently selected from the group consisting of -H, -T 0 , C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl, and -T 0 , C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are optionally substituted with one or more -R x2 that are the same or different, and C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 ), -, -S(O)2N(R x3 ), -, -S(O)N(R x3 ), -; -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a ), -, -S-, -N(R x3 ), -, -OC(OR x3 )(R x3a ), -, -N(R x3 )C(O)N(R x3a ), - and -OC(O)N(R x3)-selected from the group consisting of one or more groups optionally interrupted by, each T 0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each T 0 is independently optionally substituted with one or more -R x2 wherein, each -R x2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COOR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 , -S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1~6 alkyl is independently selected from the group consisting of, C 1~6 alkyl is optionally substituted with one or more halogen which are the same or different, each -R x3 , -R x3a , -Rx4 ,-R x4a ,-R x4b is independently selected from the group consisting of -H and C 1~6 alkyl, and C 1~6 alkyl is optionally substituted with one or more halogens which are the same or different.

[0033] In certain embodiments, up to 6 -H atoms in the optionally substituted molecule are independently replaced by substituents, for example, 5 -H atoms are independently replaced by substituents, 4 -H atoms are independently replaced by substituents, 3 -H atoms are independently replaced by substituents, 2 -H atoms are independently replaced by substituents or 1 -H atom is replaced by a substituent.

[0034] As used herein, the term "hydrogel" means a hydrophilic or amphiphilic polymer network composed of a homopolymer or copolymer, and is insoluble due to the presence of hydrophobic interactions, hydrogen bonds, ionic interactions and / or covalent chemical cross - links. The cross - links provide the network structure and physical integrity. It is understood that the conjugate of the present invention is a hydrogel.

[0035] As used herein, the term "about" when combined with a numerical value is used to indicate a range from the numerical value plus or minus up to 25% of the numerical value (including this numerical value), more preferably up to 20% of the numerical value (including this numerical value), and most preferably up to 10% of the numerical value (including this numerical value). For example, the phrase "about 200" is used to mean a range from 200 + / - 25% (including this value), i.e., a range from 150 to 250 (including these values), preferably a range from 200 + / - 20% (including this value), i.e., a range from 160 to 240 (including these values), and even more preferably a range from 200 + / - 10% (including this value), i.e., a range from 180 to 220 (including these values). A percentage presented as "about 50%" does not mean "50% + / - 25%", i.e., does not mean a range from 25 to 75% (including these values), but rather "about 50%" is understood to mean a range from 37.5 to 62.5% (including these values), i.e., plus or minus 25% of the numerical value of 50.

[0036] As used herein, the term "polymer" means a molecule containing repeating structural units, i.e., monomers, connected by chemical bonds in linear, cyclic, branched, cross-linked or dendrimeric form, or combinations thereof, and can be synthetic, biologically derived, or a combination of both. The monomers may be the same, in which case the polymer is a homopolymer, or different, in which case the polymer is a heteropolymer. Heteropolymers are sometimes referred to as "copolymers" and include, for example, alternating copolymers in which different types of monomers are arranged alternately, periodic copolymers in which different types of monomers are arranged in a repeating sequence, statistical copolymers in which different types of monomers are arranged randomly, block copolymers in which blocks of different homopolymers consisting of only one type of monomer are covalently linked, and gradient copolymers in which the composition of different monomers changes gradually along the polymer chain. It is understood that a polymer can also contain one or more other moieties, such as one or more functional groups. Similarly, peptides or proteins are understood to be polymers even if the side chains of the individual amino acid residues are different. It is understood that covalently cross-linked polymers, such as hydrogels, cannot provide a meaningful molecular weight range.

[0037] As used herein, the term "polymeric" refers to a reagent or moiety that contains one or more polymers or polymer moieties. The polymeric reagent or moiety may optionally also contain one or more other moieties, which in certain embodiments are the following: - C 1~50 alkyl, C 2~50 alkenyl, C 2~50 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and - The following:

[0038]

Chemical formula

[0039] It is understood by those skilled in the art that not all of the polymerization products obtained by the polymerization reaction have the same molecular weight, but rather exhibit a molecular weight distribution. Thus, the molecular weight range, molecular weight, range of number of monomers, and number of monomers in the polymer, as used herein, refer to the number average molecular weight and average number of monomers, i.e., the arithmetic mean of the molecular weights of the polymer or polymer moiety and the arithmetic mean of the number of monomers in the polymer or polymer moiety.

[0040] Thus, in a polymer moiety containing "x" monomer units, any integer presented by "x" corresponds thereby to the arithmetic mean (arithmetic average) of the number of monomers. Any range of integers presented by "x" provides a range of integers that are the arithmetic average of the number of monomers. An integer of "x" presented as "about x" means that the arithmetic average of the number of monomers is in the range of x + / - 25%, preferably x + / - 20%, more preferably x + / - 10%.

[0041] As used herein, the term "number average molecular weight" means the ordinary arithmetic mean of the molecular weights of the individual polymers.

[0042] As used herein, the term "hyaluronic acid-based" in relation to a moiety or reagent means that the moiety or reagent contains hyaluronic acid. Such hyaluronic acid-based moieties or reagents contain at least 10% (w / w) hyaluronic acid, such as at least 20% (w / w) hyaluronic acid, such as at least 30% (w / w) hyaluronic acid, such as at least 40% (w / w) hyaluronic acid, such as at least 50% (w / w) hyaluronic acid, such as at least 60% (w / w) hyaluronic acid, such as at least 70% (w / w) hyaluronic acid, such as at least 80% (w / w) hyaluronic acid, such as at least 90% (w / w) hyaluronic acid, or such as at least 95% (w / w) hyaluronic acid. The remaining weight percentage of the hyaluronic acid-based moiety or reagent is that of other moieties, such as the following: - C 1~50 alkyl, C 2~50 alkenyl, C 2~50 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and - the following:

[0043]

Chemical formula

[0044] The term "interrupted" means that a moiety is inserted between two carbon atoms or, if the insertion is at the end of the moiety, between a carbon atom and a hydrogen atom.

[0045] As used herein, the term "C 1~4 alkyl" means a straight or branched chain alkyl moiety having from 1 to 4 carbon atoms, alone or in combination. When present at the end of a molecule, straight or branched chain C 1~4 Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. When two moieties of a molecule are linked by C 1~4 alkyl, examples of such C 1~4 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-. Each hydrogen on a C 1~4 alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, C 1~4 alkyl may be interrupted by one or more moieties as defined below.

[0046] As used herein, the term "C 1~6 alkyl" means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, alone or in combination. When present at the end of a molecule, straight and branched chain C 1~6 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. When two moieties of a molecule are linked by a C 1~6 alkyl group, examples of such C 1~6 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)- and -C(CH3)2-. C 1~6Each hydrogen atom in the carbon may optionally be replaced by the substituents defined above. Optionally C 1~6 The alkyl may be interrupted by one or more moieties defined below.

[0047] Accordingly, the term "C 1~10 alkyl", "C 1~20 alkyl" or "C 1~50 alkyl" each means an alkyl chain having 1 to 10, 1 to 20 or 1 to 50 carbon atoms, and C 1~10 C 1~20 or C 1~50 Each hydrogen atom in the carbon may optionally be replaced by the substituents defined above. Optionally C 1~10 or C 1~50 The alkyl may be interrupted by one or more moieties defined below.

[0048] As used herein, the term "C 2~6 alkenyl" alone or in combination means a straight or branched chain hydrocarbon moiety containing at least one carbon-carbon double bond having 2 to 6 carbon atoms. When present at the end of the molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3 and -CH=CH-CH=CH2. When two parts of the molecule are linked by a C 2~6 alkenyl group, an example of such C 2~6 alkenyl is -CH=CH-. Each hydrogen atom in the C 2~6 alkenyl moiety may optionally be replaced by the substituents defined above. Optionally C 2~6 The alkenyl may be interrupted by one or more moieties defined below.

[0049] Accordingly, the terms "C 2~10 alkenyl", "C 2~20 alkenyl" or "C 2~50"Alkenyl", alone or in combination, means a linear or branched hydrocarbon moiety having at least one carbon-carbon double bond and having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. C 2~10 Alkenyl, C 2~20 Alkenyl or C 2~50 Each hydrogen atom of the alkenyl group may optionally be replaced with a substituent as defined above. Optionally C 2~10 Alkenyl, C 2~20 Alkenyl or C 2~50 Alkenyl may be interrupted by one or more moieties as defined below.

[0050] As used herein, the term "C 2~6 "Alkynyl", alone or in combination, means a linear or branched hydrocarbon moiety having at least one carbon-carbon triple bond and having 2 to 6 carbon atoms. When present at the end of a molecule, examples are -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two moieties of a molecule are linked by an alkynyl group, an example is -C≡C-. C 2~6 Each hydrogen atom of the alkynyl group may optionally be replaced with a substituent as defined above. Optionally, one or more double bonds may occur. Optionally C 2~6 Alkynyl may be interrupted by one or more moieties as defined below.

[0051] Thus, as used herein, the terms "C 2~10 "Alkynyl", "C 2~20 "Alkynyl", and "C 2~50 "Alkynyl", alone or in combination, mean a linear or branched hydrocarbon moiety having at least one carbon-carbon triple bond and having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. C 2~10 Alkynyl, C 2~20 Alkynyl or C 2~50 Each hydrogen atom of the alkynyl group may optionally be replaced with a substituent as defined above. Optionally, one or more double bonds may occur. Optionally C 2~10Alkynyl, C 2~20 Alkynyl or C 2~50 Alkynyl may be interrupted by one or more moieties as defined below.

[0052] As described above, C 1~4 Alkyl, C 1~6 Alkyl, C 1~10 Alkyl, C 1~20 Alkyl, C 1~50 Alkyl, C 2~6 Alkenyl, C 2~10 Alkenyl, C 2~20 Alkenyl, C 2~50 Alkenyl, C 2~6 Alkynyl, C 2~10 Alkynyl, C 2~20 Alkenyl or C 2~50 Alkynyl is as follows:

[0053] [Chemical formula] [wherein, The dashed line indicates a bond to the remainder of the moiety or reagent, -R and -R a are independently selected from the group consisting of -H and C 1~6 alkyl] may be optionally interrupted by one or more moieties preferably selected from the group consisting of

[0054] As used herein, the term "C 3~10 Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. Each hydrogen atom at C 3~10 Cycloalkyl carbon may be replaced by a substituent as defined above. The term "C 3~10 Cycloalkyl" also includes bridged bicyclics such as norbornane or norbornene.

[0055] The term "8- to 30-membered carbopolycyclic" or "8- to 30-membered carbopolycycle" means a polycyclic moiety having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom and may contain up to the maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings). Preferably, 8- to 30-membered carbopolycyclic means a cyclic moiety of 2, 3, 4 or 5 rings, more preferably 2, 3 or 4 rings.

[0056] As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" means a ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that may contain up to the maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), where at least 1 to 4 of the ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (-S(O)-, -S(O)2-), oxygen and nitrogen (=N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be replaced by a substituent.

[0057] As used herein, the term "8- to 11-membered heterobicyclic" or "8- to 11-membered heterobicycle" means a bicyclic heterocyclic moiety having 8 to 11 ring atoms, where at least 1 ring atom is shared by both rings, may contain up to the maximum number of double bonds (aromatic or non-aromatic rings that are fully saturated, partially saturated, or unsaturated), and at least 1 to 6 ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples of 8- to 11-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom in an 8- to 11-membered heterobicyclic or 8- to 11-membered heterobicyclic carbon may be replaced by a substituent.

[0058] Similarly, the term "8- to 30-membered heteropolycyclic" or "8- to 30-membered heteropolycycle" means a heterocyclic moiety having more than two rings, preferably 3, 4 or 5 rings, having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom and may contain up to the maximum number of double bonds (aromatic or non-aromatic rings, fully saturated, partially saturated or unsaturated), with at least 1 to 10 ring atoms replaced by heteroatoms selected from the group consisting of sulfur (-S(O)-, -S(O)2-), oxygen and nitrogen (=N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom.

[0059] Portion of the following structure

[0060]

Chemical formula

[0061]

Chemical formula

[0062] Portion of the following structure

[0063]

Chemical formula

[0064]

Chem.

[0065] The part of the following structure

[0066]

Chem.

[0067]

Chem.

[0068]

Chem.

[0069] The part of the following structure

[0070]

Chem.

[0071]

Chemical formula

[0072] In the phrase "π-electron donating heteroaromatic N", "N" is understood to refer to nitrogen.

[0073] The phrases "electron donating heteroaromatic N + containing moiety" and "-D + to the N + bond" and "N + " are understood to refer to a positively charged nitrogen atom.

[0074] As used herein, "halogen" means fluoro, chloro, bromo, or iodo. In certain embodiments, the halogen is fluoro or chloro.

[0075] As used herein, the term "alkali metal ion" refers to Na + , K + , Li + , Rb + and Cs + . In certain embodiments, "alkali metal ion" refers to Na + , K + and Li + .

[0076] As used herein, the term "alkaline earth metal ion" refers to Mg 2+ , Ca 2+ , Sr 2+ and Ba 2+ . In certain embodiments, the alkaline earth metal ion is Mg 2+ or Ca 2+ .

[0077] As used herein, the term "functional group" means a group of atoms that can react with other groups of atoms. Exemplary functional groups are carboxylic acid, primary amine, secondary amine, tertiary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamide, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane and aziridine.

[0078] When the conjugate of the present invention contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically utilized salts. Thus, the conjugate of the present invention containing an acidic group can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt or an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts of ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids, or quaternary ammonium, such as tetrabutylammonium and cetyltrimethylammonium salts. The conjugate of the present invention containing one or more basic groups, i.e., groups that can be protonated, can exist in the form of addition salts with inorganic or organic acids or can be used according to the present invention in the form of such addition salts. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, trifluoroacetic acid, and other acids known to those skilled in the art. Those skilled in the art also know further methods for converting basic groups to cations, such as alkylation of amine groups, to yield positively charged ammonium groups and appropriate counterions for the salts. When the conjugate of the present invention contains both acidic and basic groups simultaneously, the present invention also includes inner salts or betaines (zwitterions) in addition to the described salt forms. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these prodrugs with organic or inorganic acids or bases in a solvent or dispersion, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the conjugate of the present invention that are not directly suitable for use in medicine due to low physiological compatibility but can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts.

[0079] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient, preferably one that has received approval by a regulatory authority, such as EMA (Europe) and / or FDA (US) for use in animals, preferably for use in humans, and / or by the regulatory authority of any other country.

[0080] As used herein, the term "excipient" refers to a diluent, adjuvant or vehicle with which a therapeutic agent, such as a drug or prodrug, is administered. Such pharmaceutical excipients may be sterile liquids, such as water, or oils of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred excipients when the pharmaceutical composition is administered intravenously. Saline solutions, as well as aqueous dextrose and glycerol solutions, are preferably used as liquid excipients for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, non-fat dry milk, glycerol, propylene, glycol, hyaluronic acid, propylene glycol, water, ethanol, etc. The pharmaceutical composition may, if desired, contain trace amounts of wetting agents or emulsifiers, pH buffers, etc., such as acetate (acetate), succinate (succinate), Tris, carbonate (carbonate), phosphate (phosphate), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or detergents, such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or amino acids, such as glycine, lysine or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The pharmaceutical composition can be formulated as a suppository using traditional binders and excipients, such as triglycerides. Oral formulations can contain standard excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions contain a therapeutically effective amount of a drug or drug moiety together with an appropriate amount of excipient to provide a form suitable for proper administration to a patient. The formulation should be suitable for the mode of administration.

[0081] As used herein, the term "peptide" refers to a chain of at least 2 to 50 amino acid monomer moieties, which may also be referred to as "amino acid residues" when linked by peptide (amide) linkages. The amino acid monomers may be selected from the group consisting of proteinogenic and non-proteinogenic amino acids and may be D- or L-amino acids. The term "peptide" also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides, and depsipeptides, and encompasses peptidomimetic chains having up to 50 monomer moieties.

[0082] As used herein, the term "protein" refers to a chain of more than 50 amino acid monomer moieties, which may also be referred to as "amino acid residues" when linked by peptide linkages, and preferably up to 12,000 amino acid monomers are linked by peptide linkages, such as up to 10,000 amino acid monomer moieties, up to 8,000 amino acid monomer moieties, up to 5,000 amino acid monomer moieties, or up to 2,000 amino acid monomer moieties.

[0083] As used herein, the term "oligonucleotide" refers to a nucleic acid polymer of up to 100 bases and can be both DNA and RNA. This term also includes aptamers and morpholinos.

[0084] As used herein, the term "small molecule drug" refers to a drug that is an organic compound having a molecular weight of 1 kDa or less, for example up to 900 kDa.

[0085] As used herein, the term "antibiotic" refers to an antimicrobial drug for the treatment or prevention of bacterial infections, which kills bacteria or inhibits bacterial growth. This term also refers to drugs having antiprotozoal and antifungal activity.

[0086] As used herein, the term "biofilm" refers to a plurality of bacteria embedded in an extracellular matrix composed of extracellular polymeric substances, such as polysaccharides, proteins, and DNA, selected from the group consisting of a plurality of microorganisms, such as bacteria, archaea, protozoa, fungi, and algae, wherein the extracellular matrix may contain materials from the surrounding environment, such as blood components. Biofilms may form on living and non-living surfaces and may contain more than one type of microorganism. During the aging process of biofilms, individual cells not only form tight bonds with the surface, but the extracellular matrix also provides a protective environment that limits the access of antibiotics to the microorganisms, making it increasingly difficult to eradicate biofilms.

[0087] As used herein, the term "pattern recognition receptor agonist" ("PRRA") refers to a molecule that binds to and activates one or more immune cell-related receptors that recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), resulting in immune cell activation and / or a pathogen- or damage-induced inflammatory response. PRRs are typically expressed by cells of the innate immune system, such as monocytes, macrophages, dendritic cells (DCs), neutrophils, and epithelial cells, as well as by cells of the adaptive immune system.

[0088] As used herein, the term "tyrosine kinase inhibitor" or "TKI" refers to a molecule that binds to and inhibits one or more cell-associated receptor or non-receptor tyrosine kinases that are activated via polypeptide growth factors, cytokines, hormones, or phosphorylation and are involved in cell signaling, cell development, cell proliferation, cell maturation, cell metabolism, angiogenesis, and in certain cases tumor formation. Tyrosine kinases are ubiquitously expressed by almost all cells. TKIs inhibit tyrosine kinase activation by a number of mechanisms, such as competing with or allosterically antagonizing the binding of adenosine triphosphate (ATP) to the tyrosine kinase ATP-binding site, or inhibiting the enzymatic phosphorylation of said binding site or inhibiting the enzymatic kinase activity. In the case of receptor tyrosine kinases (RTKs), receptor TKIs can bind to one or more RTKs and inhibit RTK activation as described above or antagonize the activation of ligand interaction, and thus can prevent receptor tyrosine kinase activation.

[0089] As used herein, the terms "anti-CTLA4 drug" and "anti-CTLA4 moiety" refer to a drug or moiety, respectively, that binds to CTLA4 and can block its interaction with its ligands B7.1 and B7.2 (CD80 and CD86). In certain embodiments, such anti-CTLA4 drugs or anti-CTLA4 moieties can be selected from the group consisting of antibodies, antibody fragments, affibodies, affilins, affimers, affitins, alphamabs, alphabodies, anticalins, avimers, DARPins, Fynomer®, Kunitz domain peptides, monobodies, nanoCLAMPs, cyclic peptides, small molecules, and nanobodies.

[0090] As used herein, the term "VEGF antagonist" refers to a molecule capable of binding to VEGF, reducing the expression level of VEGF, or neutralizing, blocking, inhibiting, suppressing, reducing or interfering with the biological activity of VEGF, including but not limited to binding of VEGF to one or more VEGF receptors, VEGF signaling, and VEGF-mediated angiogenesis and epithelial cell survival or proliferation. For example, a molecule capable of neutralizing, blocking, inhibiting, suppressing, reducing or interfering with the biological activity of VEGF can exert its effect by binding to one or more VEGF receptors (VEGFRs) (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptor (mbVEGFR) or soluble VEGF receptor (sVEGFR)). Included as VEGF antagonists useful in the methods of the present invention are polypeptides that specifically bind to VEGF, anti-VEGF antibodies and antigen-binding fragments thereof, receptor molecules and derivatives that specifically bind to VEGF and thereby block binding to one or more receptors, fusion proteins (e.g., VEGF-Trap (Regeneron)), and VEGF121-gelonin (Peregrine). VEGF antagonists include antagonist variants of VEGF polypeptides, antisense nucleic acid base oligomers that are complementary to at least fragments of nucleic acid molecules encoding VEGF polypeptides, small RNAs that are complementary to at least fragments of nucleic acid molecules encoding VEGF polypeptides, ribozymes that target VEGF, peptibodies against VEGF, and VEGF aptamers. VEGF antagonists also include polypeptides that bind to VEGFR, anti-VEGFR antibodies and antigen-binding fragments thereof, derivatives that bind to VEGFR and thereby block, inhibit, suppress, reduce or interfere with the biological activity of VEGF (e.g., VEGF signaling), or fusion proteins. VEGF antagonists also include non-peptide small molecules that bind to VEGF or VEGFR and can block, inhibit, suppress, reduce or interfere with the biological activity of VEGF. Thus, the term "VEGF activity" specifically includes the VEGF-mediated biological activity of VEGF.In certain embodiments, the VEGF antagonist reduces or inhibits the expression level or biological activity of VEGF by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the VEGF inhibited by the VEGF-specific antagonist is VEGF(8-109), VEGF(1-109) or VEGF165. As used herein, "VEGF antagonist" includes anti-VEGFR2 antibodies and related molecules (e.g., ramucirumab, tanibirumab, aflibercept), anti-VEGFR1 antibodies and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye, EYLEA®) and ziv-aflibercept (VEGF Trap, ZALTRAP®), bispecific VEGF antibodies (e.g., MP-0250, vanucizumab (VEGF-ANG2) and the bispecific antibodies disclosed in US2001 / 0236388), bispecific antibodies comprising a combination of two of the anti-VEGF, anti-VEGFR1 and anti-VEGFR2 arms, anti-VEGF antibodies (e.g., bevacizumab, sevastizumab and ranibizumab), and non-peptide small molecule VEGF antagonists (e.g., pazopanib, axitinib, vandetanib, stivarga, cabozantinib, lenvatinib, nintedanib, orantinib, teratinib, dovitinib, cediranib, motesanib, sulfatinib, apatinib, foretinib, famitinib and tivozanib), but is not limited thereto. Additional VEGF antagonists are described below.

[0091] Generally, the term "comprise" or "comprising" also encompasses "consist of" or "consisting of".

[0092] The first Z 3 Carbon atoms marked with * in the moiety and the second Z 3The presence of at least one cleavable bond during the direct connection to the carbon atom marked with an asterisk in the moiety ensures that after all such cleavable bonds present in the conjugate of the present invention are cleaved, the hyaluronic acid chains present in the conjugate are no longer cross-linked, which enables the clearance of the hyaluronic acid network.

[0093] When the cleavable bond is located in a ring structure present in the direct connection between the carbon atom marked with an asterisk in the first Z 3 moiety and the carbon atom marked with an asterisk in the second Z 3 moiety, such a cleavable bond is not sufficient to allow complete cleavage. Therefore, one or more additional cleavable bonds are understood to be present in the direct connection between the carbon atom marked with an asterisk in the first Z 3 moiety and the carbon atom marked with an asterisk in the second Z 3 moiety.

[0094] The phrase "the dashed line marked with § indicates the connection points of at least two Z 3 units via the -CL- moiety" is understood to refer to the following structure:

[0095]

Chemical formula

[0096] The phrase "-X 0E - and / or -X 0F - together with a part of -SP- or -SP- forms one or more ring structures selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclic, and adamantyl" is understood to refer to structures such as those shown below:

[0097]

Chemical formula

[0098] This also applies to other variable elements.

[0099] If all the hyaluronic acid chains of the conjugate of the present invention are connected to only one Z 3 unit of a different hyaluronic acid chain and contain only one Z 3 unit, it is understood that a three-dimensional cross-linked hydrogel cannot be formed. However, when the first Z 3 unit is connected to more than one Z 3 unit of a different chain, i.e., when -CL- is branched, such a first Z 3 unit can cross-link with two or more other Z 3 units of two or more different hyaluronic acid chains. Therefore, the number of Z 3 units per hyaluronic acid required for the cross-linked hyaluronic acid hydrogel is determined according to the degree of branching of -CL-. In certain embodiments, at least 30% of all the hyaluronic acid chains present in the conjugate are connected to at least two other hyaluronic acid chains. It is understood that it is sufficient for the remaining hyaluronic acid chains to be connected to only one other hyaluronic acid chain.

[0100] Z 1 moiety is an unmodified disaccharide of hyaluronic acid, the Z 2 moiety is a disaccharide unit reversibly conjugated to the drug moiety, and Z3 It is understood that the moiety is a disaccharide unit crosslinked via the CL moiety.

[0101] The conjugate of the present invention is as follows:

[0102]

Chemical formula

[0103] Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 and Z 10 The units of, for example, Z 4 represent units where at least the ends of -CL- are not conjugated with the Z 3 units. Depending on the order in which the elements of the conjugate of the present invention are assembled, different such partially reacted or unreacted units may exist. It is understood that the presence of such parts cannot be avoided. In certain embodiments, Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 and Z 10 The total of the units of is 25% or less, for example 10% or less, for example 15% or less, or for example 10% or less of the total number of the Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 and Z 10 units in the conjugate.

[0104] In certain embodiments, the variable element of Z 4 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19. In certain embodiments, the variable element of Z 4 is a positive integer in the range of 20 to 200.

[0105] In certain embodiments, the b of Z 4 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19. In certain embodiments, the b of Z 4 is a positive integer in the range of 20 to 200.

[0106] Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 and Z 10 In addition to the units of, the conjugate may also include units that are the result of cleavage of a reversible bond between -D and -L 1 or cleavage of one or more labile bonds present in a direct connection between any two carbon atoms marked with *, connected by a -CL- moiety, i.e., units resulting from the degradation of the conjugate. It is further understood that

[0107] In certain embodiments, each chain present in the conjugate of the invention comprises at least 20 units, such as, for example, 20 to 2500 units, 25 to 2200 units, 50 to 2000 units, 75 to 100 units, 75 to 100 units, 80 to 560 units, 100 to 250 units, 200 to 800 units, 20 to 1000, 60 to 1000, 60 to 400 or 200 to 600 units.

[0108] In certain embodiments, the -CL- moieties present in the conjugate of the invention have different structures. In certain embodiments, the -CL- moieties present in the conjugate of the invention have the same structure.

[0109] Generally, any moiety that connects at least two other moieties is suitable for use as a -CL- moiety and may also be referred to as a "crosslinking agent moiety".

[0110] At least two Zs connected via a -CL- moiety 3 units may be located on the same hyaluronic acid chain or on different hyaluronic acid chains.

[0111] The -CL- moiety can be linear or branched. In certain embodiments, -CL- is linear. In certain embodiments, -CL- is branched.

[0112] In certain embodiments, -CL- connects two Z 3 units. In certain embodiments, -CL- connects three Z 3 units. In certain embodiments, -CL- connects four Z 3 units. In certain embodiments, -CL- connects five Z 3 units. In certain embodiments, -CL- connects six Z 3 units. In certain embodiments, -CL- connects seven Z 3 units. In certain embodiments, -CL- connects eight Z 3 units. In certain embodiments, -CL- connects nine Z 3 units.

[0113] When -CL- connects two Z 3 units, -CL- can be linear or branched. When -CL- connects more than two Z 3 units, -CL- is branched.

[0114] The branched -CL- moiety contains at least one branch point from which at least three branches extend, which may also be referred to as "arms". Such branch points are as follows:

[0115]

Chemical formula

[0116] In certain embodiments, -R B is selected from the group consisting of -H, methyl and ethyl.

[0117] The branched -CL- moiety can contain multiple branch points, e.g., 1, 2, 3, 4, 5, 6, 7 or more branch points, which may be the same or different.

[0118] When the -CL- moiety connects three Z 3 units, such a -CL- moiety contains at least one branch point from which at least three arms extend.

[0119] When the -CL- moiety connects four Z 3 units, such a -CL- moiety can contain at least one branch point from which four arms extend. However, alternative shapes are also possible, e.g., at least two branch points from which at least three arms extend each. Connected Z3 The greater the number of units, the greater the number of possible shapes.

[0120] In a first embodiment, at least 70%, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90% or such as at least 95% of the number of hyaluronic acid chains in the conjugate of the present invention has at least one Z 2 moiety and at least one Z 3 moiety. In such an embodiment, Z 2 and Z 3 units can be found in substantially all of the hyaluronic acid chains present in the conjugate of the present invention.

[0121] Thus, the conjugate of this first embodiment comprises crosslinked hyaluronic acid chains to which a plurality of drug moieties are covalently and reversibly conjugated, and the conjugate is as follows:

[0122] [Chemical formula] [wherein, The unlabeled dashed line indicates a bonding point to an adjacent unit marked with # or to hydrogen, The dashed line marked with # indicates a bonding point to an adjacent unit marked with an unlabeled dashed line or to a hydroxyl group, The dashed line marked with § indicates a connection point of at least two Z 3 units via a -CL- moiety, -D, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -SP-, -CL-, -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E -, -X 0F -, -R a1 and -R a2 are used as defined above] comprises a plurality of connecting units selected from the group consisting of All Z units present in the conjugate 1 may be the same or different, All Z units present in the conjugate 2 may be the same or different, All Z units present in the conjugate 3 may be the same or different, Z 1 The number of units ranges from 1% to 98% of the total number of units present in the conjugate, Z 2 The number of units ranges from 1% to 98% of the total number of units present in the conjugate, provided that at least one Z 2 unit is present in the conjugate, Z 3 The number of units ranges from 1% to 97% of the total number of units present in the conjugate, provided that at least one Z 3 unit is present in each chain, At least 70% of all hyaluronic acid chains contain at least one Z 2 moiety and at least one Z 3 moiety.

[0123] The conjugate of this first embodiment may also contain units selected from the group consisting of Z 4 Z 5 Z 6 Z 7 Z 8 Z 9 and Z 10 as described above.

[0124] In the conjugate of this first embodiment, the number of Z 2 units ranges from 1 to 70% of all units present in the conjugate, for example, 2 to 15%, 2 to 10%, 16 to 39, 40 to 65% or 50 to 60% of all units present in the conjugate.

[0125] In the conjugate of this first embodiment, Z 3The number of units is in the range of 1 to 30% of all units present in the conjugate, for example, 2 to 5%, 5 to 20%, 10 to 18% or 14 to 18% of all units present in the conjugate.

[0126] In the conjugate of this first embodiment, Z 1 The number of units is in the range of 10 to 97% of all units present in the conjugate, for example 20 to 40% of all units present in the conjugate, for example 25 to 35%, for example 41 to 95%, for example 45 to 90%, for example 50 to 70%.

[0127] Each degradable bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety may be different, or all such degradable bonds present in the conjugate may be identical.

[0128] Each direct connection between two carbon atoms marked with * and connected by the -CL- moiety can have the same or different numbers of degradable bonds.

[0129] In certain embodiments, the number of degradable bonds present in the conjugate of the invention between all combinations of two carbon atoms marked with * and connected by the -CL- moiety is the same, and all such degradable bonds have the same structure.

[0130] In the first embodiment, at least one labile bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety can be selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond. Carbamate and amide are not themselves reversible, and in this context, it is understood that the adjacent groups render these bonds reversible. In certain embodiments, there is one labile bond selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety. In certain embodiments, there are two labile bonds selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety, and these labile bonds may be the same or different. In certain embodiments, there are three labile bonds selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety, and these labile bonds may be the same or different. In certain embodiments, there are four labile bonds selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety, and these labile bonds may be the same or different. In certain embodiments, there are five labile bonds selected from the group consisting of ester, carbonate, sulfate, phosphate bond, carbamate and amide bond in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety, and these labile bonds may be the same or different.In certain embodiments, there are six labile bonds selected from the group consisting of ester, carbonate, sulfate, phosphate, carbamate, and amide bonds in the direct connection between any two carbon atoms marked with * that are connected by the -CL- moiety, and these labile bonds may be the same or different. More than two Zs. 3 When units are connected by -CL-, there are more than two carbons marked with * that are connected, and thus it is understood that there are more than one shortest connections to at least one labile bond present. Each shortest connection may have the same or different numbers of labile bonds.

[0131] In certain embodiments, at least one labile bond, such as 1, 2, 3, 4, 5, 6 labile bonds, is located within -CL-.

[0132] In certain embodiments, at least one labile bond present in the direct connection between any two carbon atoms marked with * that are connected by the -CL- moiety is one ester bond. In other embodiments, at least one labile bond is two ester bonds. In other embodiments, at least one labile bond is three ester bonds. In other embodiments, at least one labile bond is four ester bonds. In other embodiments, at least one labile bond is five ester bonds. In other embodiments, at least one labile bond is six ester bonds.

[0133] In certain embodiments, at least one cleavable bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety is one carbonate bond. In other embodiments, at least one cleavable bond is two carbonate bonds. In other embodiments, at least one cleavable bond is three carbonate bonds. In other embodiments, at least one cleavable bond is four carbonate bonds. In other embodiments, at least one cleavable bond is five carbonate bonds. In other embodiments, at least one cleavable bond is six carbonate bonds.

[0134] In certain embodiments, at least one cleavable bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety is one phosphate bond. In other embodiments, at least one cleavable bond is two phosphate bonds. In other embodiments, at least one cleavable bond is three phosphate bonds. In other embodiments, at least one cleavable bond is four phosphate bonds. In other embodiments, at least one cleavable bond is five phosphate bonds. In other embodiments, at least one cleavable bond is six phosphate bonds.

[0135] In certain embodiments, at least one cleavable bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety is one sulfate bond. In other embodiments, at least one cleavable bond is two sulfate bonds. In other embodiments, at least one cleavable bond is three sulfate bonds. In other embodiments, at least one cleavable bond is four sulfate bonds. In other embodiments, at least one cleavable bond is five sulfate bonds. In other embodiments, at least one cleavable bond is six sulfate bonds.

[0136] In certain embodiments, at least one labile bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety is one carbamate bond. In other embodiments, at least one labile bond is two carbamate bonds. In other embodiments, at least one labile bond is three carbamate bonds. In other embodiments, at least one labile bond is four carbamate bonds. In other embodiments, at least one labile bond is five carbamate bonds. In other embodiments, at least one labile bond is six carbamate bonds.

[0137] In certain embodiments, at least one labile bond present in the direct connection between any two carbon atoms marked with * and connected by the -CL- moiety is one amide bond. In other embodiments, at least one labile bond is two amide bonds. In other embodiments, at least one labile bond is three amide bonds. In other embodiments, at least one labile bond is four amide bonds. In other embodiments, at least one labile bond is five amide bonds. In other embodiments, at least one labile bond is six amide bonds.

[0138] Highly derivatized disaccharide units of hyaluronic acid, i.e., Z 1 It has been found that a number of units less than 80% of all the units present in the conjugate interfere with the degradation of the hydrogel by a certain hyaluronidase. This has the effect of reducing the occurrence of degradation by hyaluronidase and the effect of making the chemical cleavage of the labile bond more relevant. This makes the degradation of the conjugate more predictable. The level of an enzyme, such as hyaluronidase, exhibits inter-patient variability and can vary between different administration sites, while chemical cleavage depends mainly on the more stable parameters of temperature and pH, and thus chemical cleavage is more likely to be more predictable.

[0139] In some embodiments, -CL- is C alkyl optionally interrupted by one or more atoms or groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R c1 )-, -S(O)2-, -S(O)-, -S-, -N(R c1 )-, -OC(OR c1 )(R c1a )- and -OC(O)N(R c1 )-, and 1~50 -T- is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclic, 3~10 and -R and -R c1 are each independently selected from the group consisting of -H and C c1a alkyl. 1~6

[0140] In certain embodiments, such -CL- moieties include at least one (e.g., 1, 2, 3, 4, 5, or 6) cleavable bond, such as a cleavable bond selected from the group consisting of ester, carbonate, sulfate, phosphate, carbamate, and amide bonds.

[0141] In certain embodiments, -CL- is of formula (A)

[0142]

Chemical formula

[0143]

Chemical formula

[0144]

Chem.

[0145]

Chem.

[0146]

Chem.

[0147]

Chem.

[0148]

Chem.

[0149] [Chemical formula] (In the formula, the dashed line marked with an asterisk indicates a bond to -O-, and the unmarked dashed line indicates a bond to -(C=O)-) and is -D 1 -, -D 2 -, -D 3 -, -D 4 -, -D 5 -, -D 6 - and -D 7 - are the same or different and are each independently selected from the group consisting of -O-, -NR 11 -, -N + R 12 R 12a -, -S-, -(S=O)-, -(S(O)2), -C(O)-, -P(O)R 13 and -CR 14 R 14a - is selected from the group; -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 3a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 6a , -R 7 , -R 7a , -R 8 , -R 8a , -R 9 , -R 9a , -R 10 , -R 10a , -R 11 , -R 12 , -R 12a , -R 13 , -R 14 and -R 14a are the same or different and are each independently selected from the group consisting of -H and C 1~6 alkyl, Optionally, for -R 1 / -R 1a , -R2 / -R 2a 、 -R 3 / -R 3a 、 -R 4 / -R 4a 、 -R 1 / -R 2 、 -R 3 / -R 4 、 -R 1a / -R 2a 、 -R 3a / -R 4a 、 -R 12 / -R 12a and -R 14 / -R 14a One or more of them form a chemical bond, or together with the atoms to which they are attached form a C 3~8 cycloalkyl, or form ring A, or together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl or an 8- to 11-membered heterobicyclic or adamantyl, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl and tetralinyl, r1, r2, r5, r6, r13, r14, r15 and r16 are independently 0 or 1, r3, r4, r7, r8, r9, r10, r11, r12 are independently 0, 1, 2, 3 or 4, r17, r18, r19, r20, r21 and r22 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, s1, s2, s4, s5 are independently 1, 2, 3, 4, 5 or 6, s3 ranges from 1 to 200, preferably from 1 to 100, more preferably from 1 to 50] is a part of.

[0150] In certain embodiments, r1 of formula (A) is 0. In certain embodiments, r1 of formula (A) is 1. In certain embodiments, r2 of formula (A) is 0. In certain embodiments, r2 of formula (A) is 1. In certain embodiments, r5 of formula (A) is 0. In certain embodiments, r5 of formula (A) is 1. In certain embodiments, r6 of formula (A) is 0. In certain embodiments, r6 of formula (A) is 1. In certain embodiments, r13 of formula (A) is 0. In certain embodiments, r13 of formula (A) is 1. In certain embodiments, r14 of formula (A) is 0. In certain embodiments, r14 of formula (A) is 1. In certain embodiments, r15 of formula (A) is 0. In certain embodiments, r15 of formula (A) is 1. In certain embodiments, r16 of formula (A) is 0. In certain embodiments, r16 of formula (A) is 1.

[0151] In certain embodiments, r3 of formula (A) is 0. In certain embodiments, r3 of formula (A) is 1. In certain embodiments, r3 of formula (A) is 2. In certain embodiments, r3 of formula (A) is 3. In certain embodiments, r3 of formula (A) is 4. In certain embodiments, r4 of formula (A) is 0. In certain embodiments, r4 of formula (A) is 1. In certain embodiments, r4 of formula (A) is 2. In certain embodiments, r4 of formula (A) is 3. In certain embodiments, r4 of formula (A) is 4. In certain embodiments, both r3 of formula (A) and r4 of formula (A) are 0.

[0152] In certain embodiments, r7 of formula (A) is 0. In certain embodiments, r7 of formula (A) is 1. In certain embodiments, r7 of formula (A) is 2. In certain embodiments, r7 of formula (A) is 3. In certain embodiments, r7 of formula (A) is 4. In certain embodiments, r8 of formula (A) is 0. In certain embodiments, r8 of formula (A) is 1. In certain embodiments, r8 of formula (A) is 2. In certain embodiments, r8 of formula (A) is 3. In certain embodiments, r8 of formula (A) is 4. In certain embodiments, r9 of formula (A) is 0. In certain embodiments, r9 of formula (A) is 1. In certain embodiments, r9 of formula (A) is 2. In certain embodiments, r9 of formula (A) is 3. In certain embodiments, r9 of formula (A) is 4. In certain embodiments, r10 of formula (A) is 0. In certain embodiments, r10 of formula (A) is 1. In certain embodiments, r10 of formula (A) is 2. In certain embodiments, r10 of formula (A) is 3. In certain embodiments, r10 of formula (A) is 4. In certain embodiments, r11 of formula (A) is 0. In certain embodiments, r11 of formula (A) is 1. In certain embodiments, r11 of formula (A) is 2. In certain embodiments, r11 of formula (A) is 3. In certain embodiments, r11 of formula (A) is 4. In certain embodiments, r12 of formula (A) is 0. In certain embodiments, r12 of formula (A) is 1. In certain embodiments, r12 of formula (A) is 2. In certain embodiments, r12 of formula (A) is 3. In certain embodiments, r12 of formula (A) is 4.

[0153] In certain embodiments, r17 of formula (A) is 1. In certain embodiments, r17 of formula (A) is 2. In certain embodiments, r17 of formula (A) is 3. In certain embodiments, r18 of formula (A) is 1. In certain embodiments, r18 of formula (A) is 2. In certain embodiments, r18 of formula (A) is 3. In certain embodiments, r19 of formula (A) is 1. In certain embodiments, r19 of formula (A) is 2. In certain embodiments, r19 of formula (A) is 3. In certain embodiments, r20 of formula (A) is 1. In certain embodiments, r20 of formula (A) is 2. In certain embodiments, r20 of formula (A) is 3. In certain embodiments, r21 of formula (A) is 1. In certain embodiments, r21 of formula (A) is 2. In certain embodiments, r21 of formula (A) is 3. In certain embodiments, r22 of formula (A) is 1. In certain embodiments, r22 of formula (A) is 2. In certain embodiments, r22 of formula (A) is 3.

[0154] In certain embodiments, s1 of formula (A) is 1. In certain embodiments, s1 of formula (A) is 2. In certain embodiments, s1 of formula (A) is 3. In certain embodiments, s2 of formula (A) is 1. In certain embodiments, s2 of formula (A) is 2. In certain embodiments, s2 of formula (A) is 3. In certain embodiments, s4 of formula (A) is 1. In certain embodiments, s4 of formula (A) is 2. In certain embodiments, s4 of formula (A) is 3.

[0155] In certain embodiments, s3 of formula (A) ranges from 1 to 100. In certain embodiments, s3 of formula (A) ranges from 1 to 75. In certain embodiments, s3 of formula (A) ranges from 2 to 50. In certain embodiments, s3 of formula (A) ranges from 2 to 40. In certain embodiments, s3 of formula (A) ranges from 3 to 30. In certain embodiments, s3 of formula (A) ranges from 3 to 20. In certain embodiments, s3 of formula (A) ranges from 3 to 10. In certain embodiments, s3 of formula (A) is about 2. In certain embodiments, s3 of formula (A) is about 3. In certain embodiments, s3 of formula (A) is about 4. In certain embodiments, s3 of formula (A) is about 5. In certain embodiments, s3 of formula (A) is about 6. In certain embodiments, s3 of formula (A) is about 7. In certain embodiments, s3 of formula (A) is about 8. In certain embodiments, s3 of formula (A) is about 9. In certain embodiments, s3 of formula (A) is about 10. In certain embodiments, s3 of formula (A) is 2. In certain embodiments, s3 of formula (A) is 3. In certain embodiments, s3 of formula (A) is 4. In certain embodiments, s3 of formula (A) is 5. In certain embodiments, s3 of formula (A) is 6. In certain embodiments, s3 of formula (A) is 7. In certain embodiments, s3 of formula (A) is 8. In certain embodiments, s3 of formula (A) is 9. In certain embodiments, s3 of formula (A) is 10. In certain embodiments, s3 of formula (A) is 20. In certain embodiments, s3 of formula (A) is 25.

[0156] In certain embodiments, -R of formula (A) 1 is -H. In certain embodiments, -R of formula (A) 1 is methyl. In certain embodiments, -R of formula (A) 1 is ethyl. In certain embodiments, -R of formula (A) 1ais -H. In certain embodiments, -R of formula (A) 1a is methyl. In certain embodiments, -R of formula (A) 1a is ethyl. In certain embodiments, -R of formula (A) 2 is -H. In certain embodiments, -R of formula (A) 2 is methyl. In certain embodiments, -R of formula (A) 2 is ethyl. In certain embodiments, -R of formula (A) 2a is -H. In certain embodiments, -R of formula (A) 2a is methyl. In certain embodiments, -R of formula (A) 2a is ethyl. In certain embodiments, -R of formula (A) 3 is -H. In certain embodiments, -R of formula (A) 3 is methyl. In certain embodiments, -R of formula (A) 3 is ethyl. In certain embodiments, -R of formula (A) 3a is -H. In certain embodiments, -R of formula (A) 3a is methyl. In certain embodiments, -R of formula (A) 3a is ethyl. In certain embodiments, -R of formula (A) 4 is -H. In certain embodiments, -R of formula (A) 4 is methyl. In certain embodiments, -R of formula (A) 4 is methyl. In certain embodiments, -R of formula (A) 4a is -H. In certain embodiments, -R of formula (A) 4a is methyl. In certain embodiments, -R of formula (A) 4a is ethyl. In certain embodiments, -R of formula (A) 5 is -H. In certain embodiments, -R of formula (A) 5 is methyl. In certain embodiments, -R of formula (A) 5 is ethyl. In certain embodiments, -R of formula (A) 5ais -H. In certain embodiments, -R of formula (A) 5a is methyl. In certain embodiments, -R of formula (A) 5a is ethyl. In certain embodiments, -R of formula (A) 6 is -H. In certain embodiments, -R of formula (A) 6 is methyl. In certain embodiments, -R of formula (A) 6 is ethyl. In certain embodiments, -R of formula (A) 6a is -H. In certain embodiments, -R of formula (A) 6a is methyl. In certain embodiments, -R of formula (A) 6a is ethyl. In certain embodiments, -R of formula (A) 7 is -H. In certain embodiments, -R of formula (A) 7 is methyl. In certain embodiments, -R of formula (A) 7 is ethyl. In certain embodiments, -R of formula (A) 8 is -H. In certain embodiments, -R of formula (A) 8 is methyl. In certain embodiments, -R of formula (A) 8 is ethyl. In certain embodiments, -R of formula (A) 8a is -H. In certain embodiments, -R of formula (A) 8a is methyl. In certain embodiments, -R of formula (A) 8a is ethyl. In certain embodiments, -R of formula (A) 9 is -H. In certain embodiments, -R of formula (A) 9 is methyl. In certain embodiments, -R of formula (A) 9 is ethyl. In certain embodiments, -R of formula (A) 9a is -H. In certain embodiments, -R of formula (A) 9a is methyl. In certain embodiments, -R of formula (A) 9a is ethyl. In certain embodiments, -R of formula (A) 9ais -H. In certain embodiments, -R of formula (A) 9a is methyl. In certain embodiments, -R of formula (A) 9a is ethyl. In certain embodiments, -R of formula (A) 10 is -H. In certain embodiments, -R of formula (A) 10 is methyl. In certain embodiments, -R of formula (A) 10 is ethyl. In certain embodiments, -R of formula (A) 10a is -H. In certain embodiments, -R of formula (A) 10a is methyl. In certain embodiments, -R of formula (A) 10a is ethyl. In certain embodiments, -R of formula (A) 11 is -H. In certain embodiments, -R of formula (A) 11 is methyl. In certain embodiments, -R of formula (A) 11 is ethyl. In certain embodiments, -R of formula (A) 12 is -H. In certain embodiments, -R of formula (A) 12 is methyl. In certain embodiments, -R of formula (A) 12 is ethyl. In certain embodiments, -R of formula (A) 12a is -H. In certain embodiments, -R of formula (A) 12a is methyl. In certain embodiments, -R of formula (A) 12a is ethyl. In certain embodiments, -R of formula (A) 13 is -H. In certain embodiments, -R of formula (A) 13 is methyl. In certain embodiments, -R of formula (A) 13 is ethyl. In certain embodiments, -R of formula (A) 14 is -H. In certain embodiments, -R of formula (A) 14 is methyl. In certain embodiments, -R of formula (A) 14 is ethyl. In certain embodiments, -R of formula (A) 14ais -H. In certain embodiments, -R of formula (A) 14a is methyl. In certain embodiments, -R of formula (A) 14a is ethyl.

[0157] In certain embodiments, -D of formula (A) 1 - is -O-. In certain embodiments, -D of formula (A) 1 - is -NR 11 -. In certain embodiments, -D of formula (A) 1 - is -N + R 12 R 12a -. In certain embodiments, -D of formula (A) 1 - is -S-. In certain embodiments, -D of formula (A) 1 - is -(S=O). In certain embodiments, -D of formula (A) 1 - is -(S(O)2)-. In certain embodiments, -D of formula (A) 1 - is -C(O)-. In certain embodiments, -D of formula (A) 1 - is -P(O)R 13 -. In certain embodiments, -D of formula (A) 1 - is -P(O)(OR 13 )-. In certain embodiments, -D of formula (A) 1 - is -CR 14 R 14a -.

[0158] In certain embodiments, -D of formula (A) 2 - is -O-. In certain embodiments, -D of formula (A) 2 - is -NR 11 -. In certain embodiments, -D of formula (A) 2 - is -N + R 12 R 12a -. In certain embodiments, -D of formula (A) 2 - is -S-. In certain embodiments, -D of formula (A) 2- is -(S=O). In certain embodiments, -D of formula (A) 2 - is -(S(O)2)-. In certain embodiments, -D of formula (A) 2 - is -C(O)-. In certain embodiments, -D of formula (A) 2 - is -P(O)R 13 -. In certain embodiments, -D of formula (A) 2 - is -P(O)(OR 13 )-. In certain embodiments, -D of formula (A) 2 - is -CR 14 R 14a -.

[0159] In certain embodiments, -D of formula (A) 3 - is -O-. In certain embodiments, -D of formula (A) 3 - is -NR 11 -. In certain embodiments, -D of formula (A) 3 - is -N + R 12 R 12a -. In certain embodiments, -D of formula (A) 3 - is -S-. In certain embodiments, -D of formula (A) 3 - is -(S=O). In certain embodiments, -D of formula (A) 3 - is -(S(O)2)-. In certain embodiments, -D of formula (A) 3 - is -C(O)-. In certain embodiments, -D of formula (A) 3 - is -P(O)R 13 -. In certain embodiments, -D of formula (A) 3 - is -P(O)(OR 13 )-. In certain embodiments, -D of formula (A) 3 - is -CR 14 R 14a -.

[0160] In certain embodiments, -D of formula (A) 4- is -O-. In certain embodiments, -D of formula (A) 4 - is -NR 11 -. In certain embodiments, -D of formula (A) 4 - is -N + R 12 R 12a -. In certain embodiments, -D of formula (A) 4 - is -S-. In certain embodiments, -D of formula (A) 4 - is -(S=O). In certain embodiments, -D of formula (A) 4 - is -(S(O)2)-. In certain embodiments, -D of formula (A) 4 - is -C(O)-. In certain embodiments, -D of formula (A) 4 - is -P(O)R 13 -. In certain embodiments, -D of formula (A) 4 - is -P(O)(OR 13 )-. In certain embodiments, -D of formula (A) 4 - is -CR 14 R 14a -.

[0161] In certain embodiments, -D of formula (A) 5 - is -O-. In certain embodiments, -D of formula (A) 5 - is -NR 11 -. In certain embodiments, -D of formula (A) 5 - is -N + R 12 R 12a -. In certain embodiments, -D of formula (A) 5 - is -S-. In certain embodiments, -D of formula (A) 5 - is -(S=O)-. In certain embodiments, -D of formula (A) 5 - is -(S(O)2)-. In certain embodiments, -D of formula (A) 5 - is -C(O)-. In certain embodiments, -D of formula (A) 5 - is -P(O)R 13- is. In certain embodiments, -D in formula (A) 5 - is -P(O)(OR 13 )-. In certain embodiments, -D in formula (A) 5 - is -CR 14 R 14a -.

[0162] In certain embodiments, -D in formula (A) 6 - is -O-. In certain embodiments, -D in formula (A) 6 - is -NR 11 -. In certain embodiments, -D in formula (A) 6 - is -N + R 12 R 12a -. In certain embodiments, -D in formula (A) 6 - is -S-. In certain embodiments, -D in formula (A) 6 - is -(S=O)-. In certain embodiments, -D in formula (A) 6 - is -(S(O)2)-. In certain embodiments, -D in formula (A) 6 - is -C(O)-. In certain embodiments, -D in formula (A) 6 - is -P(O)R 13 -. In certain embodiments, -D in formula (A) 6 - is -P(O)(OR 13 )-. In certain embodiments, -D in formula (A) 6 - is -CR 14 R 14a -.

[0163] In certain embodiments, -D in formula (A) 7 - is -O-. In certain embodiments, -D in formula (A) 7 - is -NR 11 -. In certain embodiments, -D in formula (A) 7 - is -N + R 12 R 12a -. In certain embodiments, -D in formula (A) 7- is -S-. In certain embodiments, -D in formula (A) 7 - is -(S=O)-. In certain embodiments, -D in formula (A) 7 - is -(S(O)2)-. In certain embodiments, -D in formula (A) 7 - is -C(O)-. In certain embodiments, -D in formula (A) 7 - is -P(O)R 13 -. In certain embodiments, -D in formula (A) 7 - is -P(O)(OR 13 )-. In certain embodiments, -D in formula (A) 7 - is -CR 14 R 14a -.

[0164] In certain embodiments, -CL- is of formula (B)

[0165]

Chemical formula

[0166] In certain embodiments, a1 and a2 in formula (B) are different. In certain embodiments, a1 and a2 in formula (B) are the same.

[0167] In certain embodiments, a1 of formula (B) is 1. In certain embodiments, a1 of formula (B) is 2. In certain embodiments, a1 of formula (B) is 3. In certain embodiments, a1 of formula (B) is 4. In certain embodiments, a1 of formula (B) is 5. In certain embodiments, a1 of formula (B) is 6. In certain embodiments, a1 of formula (B) is 7. In certain embodiments, a1 of formula (B) is 8. In certain embodiments, a1 of formula (B) is 9. In certain embodiments, a1 of formula (B) is 10.

[0168] In certain embodiments, a2 of formula (B) is 1. In certain embodiments, a2 of formula (B) is 2. In certain embodiments, a2 of formula (B) is 3. In certain embodiments, a2 of formula (B) is 4. In certain embodiments, a2 of formula (B) is 5. In certain embodiments, a2 of formula (B) is 6. In certain embodiments, a2 of formula (B) is 7. In certain embodiments, a2 of formula (B) is 8. In certain embodiments, a2 of formula (B) is 9. In certain embodiments, a2 of formula (B) is 10.

[0169] In certain embodiments, both a1 and a2 of formula (B) are 1. In certain embodiments, both a1 and a2 of formula (B) are 2. In certain embodiments, both a1 and a2 of formula (B) are 3. In certain embodiments, both a1 and a2 of formula (B) are 4. In certain embodiments, both a1 and a2 of formula (B) are 5. In certain embodiments, both a1 and a2 of formula (B) are 6. In certain embodiments, both a1 and a2 of formula (B) are 7. In certain embodiments, both a1 and a2 of formula (B) are 8. In certain embodiments, both a1 and a2 of formula (B) are 9. In certain embodiments, both a1 and a2 of formula (B) are 10.

[0170] In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 1, and b of formula (B) is 25.

[0171] In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 2, and b of formula (B) is 25.

[0172] In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 3, and b of formula (B) is 25.

[0173] In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 4 and b of formula (B) is 25.

[0174] In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 5 and b of formula (B) is 25.

[0175] In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 6 and b of formula (B) is 25.

[0176] In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 7 and b of formula (B) is 25.

[0177] In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 8 and b of formula (B) is 25.

[0178] In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 9, and b of formula (B) is 25.

[0179] In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 3. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 4. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 5. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 6. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 7. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 8. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 9. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 10. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 20. In certain embodiments, both a1 and a2 of formula (B) are 10, and b of formula (B) is 25.

[0180] In certain embodiments, b of formula (B) ranges from 1 to 500. In certain embodiments, b of formula (B) ranges from 2 to 250. In certain embodiments, b of formula (B) ranges from 3 to 100. In certain embodiments, b of formula (B) ranges from 3 to 50. In certain embodiments, b of formula (B) ranges from 3 to 25. In certain embodiments, b of formula (B) is 2. In certain embodiments, b of formula (B) is 3. In certain embodiments, b of formula (B) is 4. In certain embodiments, b of formula (B) is 5. In certain embodiments, b of formula (B) is 6. In certain embodiments, b of formula (B) is 7. In certain embodiments, b of formula (B) is 8. In certain embodiments, b of formula (B) is 9. In certain embodiments, b of formula (B) is 10. In certain embodiments, b of formula (B) is 20. In certain embodiments, b of formula (B) is 25.

[0181] In certain embodiments, -CL- is of formula (B-i)

[0182]

Chemical formula

[0183] In certain embodiments, -CL- is of formula (C)

[0184]

Chemical formula

[0185] In certain embodiments, a1 and a2 of formula (C) are different. In certain embodiments, a1 and a2 of formula (B) are the same.

[0186] In certain embodiments, a1 of formula (C) is 1. In certain embodiments, a1 of formula (C) is 2. In certain embodiments, a1 of formula (C) is 3. In certain embodiments, a1 of formula (C) is 4. In certain embodiments, a1 of formula (C) is 5. In certain embodiments, a1 of formula (C) is 6. In certain embodiments, a1 of formula (C) is 7. In certain embodiments, a1 of formula (C) is 8. In certain embodiments, a1 of formula (C) is 9. In certain embodiments, a1 of formula (C) is 10.

[0187] In certain embodiments, a2 of formula (C) is 1. In certain embodiments, a2 of formula (C) is 2. In certain embodiments, a2 of formula (C) is 3. In certain embodiments, a2 of formula (C) is 4. In certain embodiments, a2 of formula (C) is 5. In certain embodiments, a2 of formula (C) is 6. In certain embodiments, a2 of formula (C) is 7. In certain embodiments, a2 of formula (C) is 8. In certain embodiments, a2 of formula (C) is 9. In certain embodiments, a2 of formula (C) is 10.

[0188] In certain embodiments, both a1 and a2 of formula (C) are 1. In certain embodiments, both a1 and a2 of formula (C) are 2. In certain embodiments, both a1 and a2 of formula (C) are 3. In certain embodiments, both a1 and a2 of formula (C) are 4. In certain embodiments, both a1 and a2 of formula (C) are 5. In certain embodiments, both a1 and a2 of formula (C) are 6. In certain embodiments, both a1 and a2 of formula (C) are 7. In certain embodiments, both a1 and a2 of formula (C) are 8. In certain embodiments, both a1 and a2 of formula (C) are 9. In certain embodiments, both a1 and a2 of formula (C) are 10.

[0189] In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 1, and b of formula (C) is 25.

[0190] In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 2, and b of formula (C) is 25.

[0191] In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 3, and b of formula (C) is 25.

[0192] In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 4 and b of formula (C) is 25.

[0193] In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 5 and b of formula (C) is 25.

[0194] In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 6, and b of formula (C) is 25.

[0195] In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 7, and b of formula (C) is 25.

[0196] In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 8, and b of formula (C) is 25.

[0197] In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 9, and b of formula (C) is 25.

[0198] In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 3. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 4. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 5. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 6. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 7. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 8. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 9. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 10. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 20. In certain embodiments, both a1 and a2 of formula (C) are 10, and b of formula (C) is 25.

[0199] In certain embodiments, b of formula (C) ranges from 1 to 500. In certain embodiments, b of formula (C) ranges from 2 to 250. In certain embodiments, b of formula (C) ranges from 3 to 100. In certain embodiments, b of formula (C) ranges from 3 to 50. In certain embodiments, b of formula (C) ranges from 3 to 25. In certain embodiments, b of formula (C) is 2. In certain embodiments, b of formula (C) is 3. In certain embodiments, b of formula (C) is 4. In certain embodiments, b of formula (C) is 5. In certain embodiments, b of formula (C) is 6. In certain embodiments, b of formula (C) is 7. In certain embodiments, b of formula (C) is 8. In certain embodiments, b of formula (C) is 9. In certain embodiments, b of formula (C) is 10. In certain embodiments, b of formula (C) is 20. In certain embodiments, b of formula (C) is 25.

[0200] In certain embodiments, -R in formula (C) 11 is -H. In certain embodiments, -R in formula (C) 11 is methyl. In certain embodiments, -R in formula (C) 11 is ethyl. In certain embodiments, -R in formula (C) 11 is n-propyl. In certain embodiments, -R in formula (C) 11 is isopropyl. In certain embodiments, -R in formula (C) 11 is n-butyl. In certain embodiments, -R in formula (C) 11 is isobutyl. In certain embodiments, -R in formula (C) 11 is sec-butyl. In certain embodiments, -R in formula (C) 11 is tert-butyl. In certain embodiments, -R in formula (C) 11 is n-pentyl. In certain embodiments, -R in formula (C) 11 is 2-methylbutyl. In certain embodiments, -R in formula (C) 11 is 2,2-dimethylpropyl. In certain embodiments, -R in formula (C) 11 is n-hexyl. In certain embodiments, -R in formula (C) 11 is 2-methylpentyl. In certain embodiments, -R in formula (C) 11 is 3-methylpentyl. In certain embodiments, -R in formula (C) 11 is 2,2-dimethylbutyl. In certain embodiments, -R in formula (C) 11 is 2,3-dimethylbutyl. In certain embodiments, -R in formula (C) 11 is 3,3-dimethylpropyl.

[0201] In certain embodiments, -CL- is of formula (C-i)

[0202]

Chemical formula

[0203] -R of the first embodiment a1 , -R a2 , -L 1 -, -L 2 -, -L 3 -, -L 4 -, -SP-, -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E -, -X 0F - and -D are as described in detail below.

[0204] In certain embodiments, -CL- is of formula (D)

[0205] [Chemical formula] [wherein the dashed line represents the bond to the -X 0F - moiety, and m2, m3 and m4 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25]. It is of.

[0206] In certain embodiments, m2 of formula (D) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m2 of formula (D) is 3. In certain embodiments, m2 of formula (D) is 4. In certain embodiments, m2 of formula (D) is 5. In certain embodiments, m2 of formula (D) is 6. In certain embodiments, m2 of formula (D) is 7. In certain embodiments, m3 of formula (D) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D) is 1. In certain embodiments, m3 of formula (D) is 2. In certain embodiments, m3 of formula (D) is 3. In certain embodiments, m3 of formula (D) is 4. In certain embodiments, m4 of formula (D) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D) is 3. In certain embodiments, m4 of formula (D) is 4. In certain embodiments, m4 of formula (D) is 5. In certain embodiments, m4 of formula (D) is 6. In certain embodiments, m4 of formula (D) is 7.

[0207] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-i)

[0208]

Chemical formula

[0209] In certain embodiments, m1 of formula (D-i) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-i) is 3. In certain embodiments, m2 of formula (D-i) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D-i) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m2 of formula (D-i) is 3. In certain embodiments, m2 of formula (D-i) is 4. In certain embodiments, m2 of formula (D-i) is 5. In certain embodiments, m2 of formula (D-i) is 6. In certain embodiments, m2 of formula (D-i) is 7. In certain embodiments, m3 of formula (D-i) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-i) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-i) is 1. In certain embodiments, m3 of formula (D-i) is 2. In certain embodiments, m3 of formula (D-i) is 3. In certain embodiments, m3 of formula (D-i) is 4. In certain embodiments, m4 of formula (D-i) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-i) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D-i) is 3. In certain embodiments, m4 of formula (D-i) is 4. In certain embodiments, m4 of formula (D-i) is 5. In certain embodiments, m4 of formula (D-i) is 6. In certain embodiments, m4 of formula (D-i) is 7. In certain embodiments, m5 of formula (D-i) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m5 of formula (D-1) is 3.

[0210] In certain embodiments, -CL- is formula (D-ii)

[0211] [Chemical formula] [wherein, the dashed line indicates the bond to the -X 0F - moiety, and m3, m4 and m5 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] is of this kind.

[0212] In certain embodiments, m3 of formula (D-ii) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m3 of formula (D-ii) is 2. In certain embodiments, m4 of formula (D-ii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-ii) is 1. In certain embodiments, m4 of formula (D-ii) is 2. In certain embodiments, m4 of formula (D-ii) is 3. In certain embodiments, m4 of formula (D-ii) is 4. In certain embodiments, m5 of formula (D-ii) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m5 of formula (D-ii) is 3. In certain embodiments, m5 of formula (D-ii) is 4. In certain embodiments, m5 of formula (D-ii) is 5. In certain embodiments, m5 of formula (D-ii) is 6. In certain embodiments, m5 of formula (D-ii) is 7.

[0213] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-iii)

[0214] [Chemical formula] [wherein the broken line indicates the bond to the carbonyl of hyaluronic acid, m1, m2, m3, m4, m5 and m6 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] has the structure of.

[0215] In certain embodiments, m1 of formula (D-iii) is an integer selected from the group consisting of 2, 3, 4, 5 and 6. In certain embodiments, m1 of formula (D-iii) is 3. In certain embodiments, m2 is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m2 of formula (D-iii) is 2. In certain embodiments, m3 of formula (D-iii) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m3 of formula (D-iii) is 2. In certain embodiments, m4 of formula (D-iii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-iii) is 1. In certain embodiments, m4 of formula (D-iii) is 2. In certain embodiments, m4 of formula (D-iii) is 3. In certain embodiments, m4 of formula (D-iii) is 4. In certain embodiments, m5 of formula (D-iii) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m5 of formula (D-iii) is 3. In certain embodiments, m5 of formula (D-iii) is 4. In certain embodiments, m5 of formula (D-iii) is 5. In certain embodiments, m5 of formula (D-iii) is 6. In certain embodiments, m5 of formula (D-iii) is 7. In certain embodiments, m6 of formula (D-iii) is an integer selected from the group consisting of 2, 3, 4, 5 and 6. In certain embodiments, m6 of formula (D-iiii) is 3.

[0216] In certain embodiments, -CL- is of formula (D-iv)

[0217] [Chemical formula] [wherein The dashed line indicates the bond to the -X 0F - moiety, and The dashed line indicates the bond to the carbonyl of hyaluronic acid, m3, m4 and m5 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] is of this kind.

[0218] In certain embodiments, m3 of formula (D-iv) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m3 of formula (D-iv) is 2. In certain embodiments, m4 of formula (D-iv) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-iv) is 1. In certain embodiments, m4 of formula (D-iv) is 2. In certain embodiments, m4 of formula (D-iv) is 3. In certain embodiments, m4 of formula (D-iv) is 4. In certain embodiments, m5 of formula (D-iv) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m5 of formula (D-iv) is 3. In certain embodiments, m5 of formula (D-iv) is 4. In certain embodiments, m5 of formula (D-iv) is 5. In certain embodiments, m5 of formula (D-iv) is 6. In certain embodiments, m5 of formula (D-iv) is 7.

[0219] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-v)

[0220] [Chemical formula] [wherein, The dashed line indicates the bond to the carbonyl of hyaluronic acid, m1, m2, m3, m4, m5 and m6 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] has the structure of.

[0221] In certain embodiments, m1 of formula (D-v) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-v) is 3. In certain embodiments, m2 is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-v) is 2. In certain embodiments, m3 of formula (D-v) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-v) is 2. In certain embodiments, m4 of formula (D-v) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-v) is 1. In certain embodiments, m4 of formula (D-v) is 2. In certain embodiments, m4 of formula (D-v) is 3. In certain embodiments, m4 of formula (D-v) is 4. In certain embodiments, m5 of formula (D-v) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-v) is 3. In certain embodiments, m5 of formula (D-v) is 4. In certain embodiments, m5 of formula (D-v) is 5. In certain embodiments, m5 of formula (D-v) is 6. In certain embodiments, m5 of formula (D-v) is 7. In certain embodiments, m6 of formula (D-v) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m6 of formula (D-v) is 3.

[0222] In certain embodiments, -CL- is of formula (D-vi)

[0223]

Chemical formula

[0224] In certain embodiments, m3 of formula (D-vi) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-vi) is 1. In certain embodiments, m3 of formula (D-vi) is 2. In certain embodiments, m4 of formula (D-vi) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-vi) is 1. In certain embodiments, m4 of formula (D-vi) is 2. In certain embodiments, m4 of formula (D-vi) is 3. In certain embodiments, m4 of formula (D-vi) is 4. In certain embodiments, m5 of formula (D-vi) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-vi) is 3. In certain embodiments, m5 of formula (D-vi) is 4. In certain embodiments, m5 of formula (D-vi) is 5. In certain embodiments, m5 of formula (D-vi) is 6. In certain embodiments, m5 of formula (D-vi) is 7.

[0225] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-vii)

[0226]

Chemical formula

[0227] In certain embodiments, m1 of formula (D-vii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-vii) is 3. In certain embodiments, m2 of formula (D-vii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-vii) is 1. In certain embodiments, m2 of formula (D-vii) is 2. In certain embodiments, m3 of formula (D-vii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-vii) is 1. In certain embodiments, m3 of formula (D-vii) is 2. In certain embodiments, m4 of formula (D-vii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-vii) is 1. In certain embodiments, m4 of formula (D-vii) is 2. In certain embodiments, m4 of formula (D-vii) is 3. In certain embodiments, m4 of formula (D-vii) is 4. In certain embodiments, m5 of formula (D-vii) is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-vii) is 3. In certain embodiments, m5 of formula (D-vii) is 4. In certain embodiments, m5 of formula (D-vii) is 5. In certain embodiments, m5 of formula (D-vii) is 6. In certain embodiments, m5 of formula (D-vii) is 7. In certain embodiments, m6 of formula (D-vii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m6 of formula (D-vii) is 3.

[0228] In certain embodiments, -CL- is of formula (D-viii)

[0229]

Chemical formula

[0230] In certain embodiments, m1 of formula (D-viii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-viii) is 3. In certain embodiments, m2 is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-viii) is 2. In certain embodiments, m2 of formula (D-viii) is 5. In certain embodiments, m3 of formula (D-viii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-viii) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of formula (D-viii) is 1. In certain embodiments, m3 of formula (D-viii) is 2. In certain embodiments, m3 of formula (D-viii) is 3. In certain embodiments, m3 of formula (D-viii) is 4. In certain embodiments, m4 of formula (D-viii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-viii) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D-viii) is 3. In certain embodiments, m4 of formula (D-viii) is 4. In certain embodiments, m4 of formula (D-viii) is 5. In certain embodiments, m4 of formula (D-viii) is 6. In certain embodiments, m4 of formula (D-viii) is 7. In certain embodiments, m5 of formula (D-viii) is an integer selected from 2, 3, 4, 5, and 6. In certain embodiments, m5 of formula (D-viii) is 3.

[0231] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-ix)

[0232]

Chemical formula

[0233] In certain embodiments, m1 of formula (D-ix) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-ix) is 3. In certain embodiments, m2 is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-ix) is 2. In certain embodiments, m2 of formula (D-ix) is 5. In certain embodiments, m3 of formula (D-ix) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-ix) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of formula (D-ix) is 1. In certain embodiments, m3 of formula (D-ix) is 2. In certain embodiments, m3 of formula (D-ix) is 3. In certain embodiments, m3 of formula (D-ix) is 4. In certain embodiments, m4 of formula (D-ix) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-ix) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D-ix) is 3. In certain embodiments, m4 of formula (D-ix) is 4. In certain embodiments, m4 of formula (D-ix) is 5. In certain embodiments, m4 of formula (D-ix) is 6. In certain embodiments, m4 of formula (D-ix) is 7. In certain embodiments, m5 of formula (D-ix) is an integer selected from 2, 3, 4, 5, and 6. In certain embodiments, m5 of formula (D-ix) is 3.

[0234] In certain embodiments, -CL- is of formula (D-x)

[0235]

Chemical formula

[0236] In certain embodiments, m3 of formula (D-x) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m3 of formula (D-x) is an integer selected from the group consisting of 1, 2, 3 and 4. In certain embodiments, m3 of formula (D-x) is 1. In certain embodiments, m3 of formula (D-x) is 2. In certain embodiments, m3 of formula (D-x) is 3. In certain embodiments, m3 of formula (D-x) is 4. In certain embodiments, m4 of formula (D-x) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-x) is an integer selected from the group consisting of 3, 4, 5, 6 and 7. In certain embodiments, m4 of formula (D-x) is 3. In certain embodiments, m4 of formula (D-x) is 4. In certain embodiments, m4 of formula (D-x) is 5. In certain embodiments, m4 of formula (D-x) is 6. In certain embodiments, m4 of formula (D-x) is 7.

[0237] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-xi)

[0238]

Chemical formula

[0239] In certain embodiments, m1 of formula (D-xi) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xi) is 3. In certain embodiments, m2 is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xi) is 2. In certain embodiments, m2 of formula (D-xi) is 5. In certain embodiments, m3 of formula (D-xi) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xi) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of formula (D-xi) is 1. In certain embodiments, m3 of formula (D-xi) is 2. In certain embodiments, m3 of formula (D-xi) is 3. In certain embodiments, m3 of formula (D-xi) is 4. In certain embodiments, m4 of formula (D-xi) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xi) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D-xi) is 3. In certain embodiments, m4 of formula (D-xi) is 4. In certain embodiments, m4 of formula (D-xi) is 5. In certain embodiments, m4 of formula (D-xi) is 6. In certain embodiments, m4 of formula (D-xi) is 7. In certain embodiments, m5 of formula (D-xi) is an integer selected from 2, 3, 4, 5, and 6. In certain embodiments, m5 of formula (D-xi) is 3.

[0240] In certain embodiments, -CL- is of formula (D-xii)

[0241] [Chemical formula] [wherein the dashed line indicates the bond to the -X 0F - moiety, and m4, m5 and m6 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] is as such.

[0242] In certain embodiments, m4 of formula (D-xii) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m4 of formula (D-xii) is 1. In certain embodiments, m4 of formula (D-xii) is 5. In certain embodiments, m5 of formula (D-xii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m5 of formula (D-xii) is an integer selected from the group consisting of 1, 2, 3 and 4. In certain embodiments, m5 of formula (D-xii) is 1. In certain embodiments, m5 of formula (D-xii) is 2. In certain embodiments, m5 of formula (D-xii) is 3. In certain embodiments, m5 of formula (D-xii) is 4. In certain embodiments, m6 of formula (D-xii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m6 of formula (D-xii) is an integer selected from the group consisting of 3, 4, 5, 6 and 7. In certain embodiments, m6 of formula (D-xii) is 3. In certain embodiments, m6 of formula (D-xii) is 4. In certain embodiments, m6 of formula (D-xii) is 5. In certain embodiments, m6 of formula (D-xii) is 6. In certain embodiments, m6 of formula (D-xii) is 7.

[0243] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - The moiety has the formula (D-xiii)

[0244]

Chemical formula

[0245] In certain embodiments, m1 of formula (D-xiii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xiii) is 3. In certain embodiments, m2 of formula (D-xiii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xiii) is 1. In certain embodiments, m3 of formula (D-xiii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-xiii) is 1. In certain embodiments, m4 of formula (D-xiii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m4 of formula (D-xiii) is 1. In certain embodiments, m4 of formula (D-xiii) is 5. In certain embodiments, m5 of formula (D-xiii) is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xiii) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m5 of formula (D-xiii) is 1. In certain embodiments, m5 of formula (D-xiii) is 2. In certain embodiments, m5 of formula (D-xiii) is 3. In certain embodiments, m5 of formula (D-xiii) is 4. In certain embodiments, m6 of formula (D-xiii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m6 of formula (D-xiii) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m6 of formula (D-xiii) is 3. In certain embodiments, m6 of formula (D-xiii) is 4. In certain embodiments, m6 of formula (D-xiii) is 5. In certain embodiments, m6 of formula (D-xiii) is 6. In certain embodiments, m6 of formula (D-xiii) is 7. In certain embodiments, m7 of formula (D-xiii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m7 of formula (D-xiii) is 3.In certain embodiments, m7 of formula (D-xiii) is 4.

[0246] In certain embodiments, -CL- is of formula (D-xiv)

[0247]

Chemical formula

[0248] In certain embodiments, m3 of formula (D-xiv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 is 1. In certain embodiments, m3 of formula (D-xiv) is 5. In certain embodiments, m4 of formula (D-xiv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m4 of formula (D-xiv) is 1. In certain embodiments, m5 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xiv) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m5 of formula (D-xiv) is 1. In certain embodiments, m5 of formula (D-xiv) is 2. In certain embodiments, m5 of formula (D-xiv) is 3. In certain embodiments, m5 of formula (D-xiv) is 4. In certain embodiments, m6 of formula (D-xiv) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m6 of formula (D-xiv) is 3. In certain embodiments, m6 of formula (D-xiv) is 4. In certain embodiments, m6 of formula (D-xiv) is 5. In certain embodiments, m6 of formula (D-xiv) is 6. In certain embodiments, m6 of formula (D-xiv) is 7.

[0249] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-xv)

[0250]

Chemical formula

[0251] In certain embodiments, m1 of formula (D-xv) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xv) is 3. In certain embodiments, m2 of formula (D-xv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xv) is 1. In certain embodiments, m3 of formula (D-xv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 is 1. In certain embodiments, m3 of formula (D-xv) is 5. In certain embodiments, m4 of formula (D-xv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m4 of formula (D-xv) is 1. In certain embodiments, m5 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xv) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m5 of formula (D-xv) is 1. In certain embodiments, m5 of formula (D-xv) is 2. In certain embodiments, m5 of formula (D-xv) is 3. In certain embodiments, m5 of formula (D-xv) is 4. In certain embodiments, m6 of formula (D-xv) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m6 of formula (D-xv) is 3. In certain embodiments, m6 of formula (D-xv) is 4. In certain embodiments, m6 of formula (D-xv) is 5. In certain embodiments, m6 of formula (D-xv) is 6. In certain embodiments, m6 of formula (D-xv) is 7. In certain embodiments, m7 of formula (D-xv) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m7 of formula (D-xv) is 4.

[0252] In certain embodiments, -CL- is of formula (D-xvi)

[0253] [Chemistry] [wherein, the dashed line indicates the bond to the -X 0F - moiety, and m2, m3, m4 and m5 are independently integers selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] is such that.

[0254] In certain embodiments, m2 of formula (D-xvi) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m2 of formula (D-xvi) is 1. In certain embodiments, m3 of formula (D-xvi) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m3 is 1. In certain embodiments, m4 of formula (D-xvi) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-xvi) is an integer selected from the group consisting of 1, 2, 3 and 4. In certain embodiments, m4 of formula (D-xvi) is 1. In certain embodiments, m4 of formula (D-xvi) is 2. In certain embodiments, m4 of formula (D-xvi) is 3. In certain embodiments, m4 of formula (D-xvi) is 4. In certain embodiments, m5 is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m5 of formula (D-xvi) is an integer selected from the group consisting of 3, 4, 5, 6 and 7. In certain embodiments, m5 of formula (D-xvi) is 3. In certain embodiments, m5 of formula (D-xvi) is 4. In certain embodiments, m5 of formula (D-xvi) is 5. In certain embodiments, m5 of formula (D-xvi) is 6. In certain embodiments, m5 of formula (D-xvi) is 7.

[0255] In certain embodiments, -X 0E-SP-X 0F -CL-X 0F -SP-X 0E - The part has the formula (D-xvii)

[0256] [Chemical formula] [In the formula, The dashed line indicates the bond to the carbonyl of hyaluronic acid, m1, m2, m3, m4, m5 and m6 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] and has the structure of

[0257] In certain embodiments, m1 of formula (D-xvii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xvii) is 3. In certain embodiments, m1 of formula (D-xvii) is 4. In certain embodiments, m2 of formula (D-xvii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xvii) is 1. In certain embodiments, m3 of formula (D-xvii) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 is 1. In certain embodiments, m4 of formula (D-xvii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xvii) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m4 of formula (D-xvii) is 1. In certain embodiments, m4 of formula (D-xvii) is 2. In certain embodiments, m4 of formula (D-xvii) is 3. In certain embodiments, m4 of formula (D-xvii) is 4. In certain embodiments, m5 of formula (D-xvii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xvii) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m5 of formula (D-xvii) is 3. In certain embodiments, m5 of formula (D-xvii) is 4. In certain embodiments, m5 of formula (D-xvii) is 5. In certain embodiments, m5 of formula (D-xvii) is 6. In certain embodiments, m5 of formula (D-xvii) is 7. In certain embodiments, m6 of formula (D-xvii) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m6 of formula (D-xvii) is 3.

[0258] In certain embodiments, -CL- is of formula (D-xviii)

[0259] [Chem.] [wherein, the dashed line indicates the bond to the -X 0F - moiety, and m2, m3 and m4 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25.] is of this kind.

[0260] In certain embodiments, m2 of formula (D-xviii) is an integer selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, m2 of formula (D-xviii) is 1. In certain embodiments, m3 of formula (D-xviii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m3 of formula (D-xviii) is an integer selected from the group consisting of 1, 2, 3 and 4. In certain embodiments, m3 of formula (D-xviii) is 1. In certain embodiments, m3 of formula (D-xviii) is 2. In certain embodiments, m3 of formula (D-xix) is 3. In certain embodiments, m3 of formula (D-xviii) is 4. In certain embodiments, m4 of formula (D-xviii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m4 of formula (D-xviii) is an integer selected from the group consisting of 3, 4, 5, 6 and 7. In certain embodiments, m4 of formula (D-xviii) is 3. In certain embodiments, m4 of formula (D-xviii) is 4. In certain embodiments, m4 of formula (D-xviii) is 5. In certain embodiments, m4 of formula (D-xviii) is 6.

[0261] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X0E - part is of formula (D-xix)

[0262]

Chem.

[0263] In certain embodiments, m1 of formula (D-xix) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, m1 of formula (D-xix) is 1. In certain embodiments, m2 of formula (D-xix) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xix) is 1. In certain embodiments, m3 of formula (D-xix) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xix) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of formula (D-xix) is 1. In certain embodiments, m3 of formula (D-xix) is 2. In certain embodiments, m3 of formula (D-xix) is 3. In certain embodiments, m3 of formula (D-xix) is 4. In certain embodiments, m4 of formula (D-xix) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xix) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of formula (D-xix) is 3. In certain embodiments, m4 of formula (D-xix) is 4. In certain embodiments, m4 of formula (D-xix) is 5. In certain embodiments, m4 of formula (D-xix) is 6. In certain embodiments, m4 of formula (D-xix) is 7. In certain embodiments, m5 of formula (D-xix) is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m5 of formula (D-xix) is 3.

[0264] In certain embodiments, -CL- is of formula (D-xx)

[0265]

Chemical Formula

[0266] In certain embodiments, m3 of formula (D-xx) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xx) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m3 of formula (D-xx) is 3. In certain embodiments, m3 is 4. In certain embodiments, m3 of formula (D-xx) is 5. In certain embodiments, m3 of formula (D-xx) is 6. In certain embodiments, m3 of formula (D-xxi) is 7. In certain embodiments, m4 of formula (D-xx) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xx) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m4 of formula (D-xx) is 1. In certain embodiments, m4 of formula (D-xx) is 2. In certain embodiments, m4 of formula (D-xx) is 3. In certain embodiments, m4 of formula (D-xx) is 4. In certain embodiments, m5 of formula (D-xx) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xx) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m5 of formula (D-xx) is 3. In certain embodiments, m5 of formula (D-xx) is 4. In certain embodiments, m5 of formula (D-xx) is 5. In certain embodiments, m5 of formula (D-xx) is 6. In certain embodiments, m5 of formula (D-xx) is 7.

[0267] In certain embodiments, -X 0E -SP-X0F -CL-X 0F -SP-X 0E - The part is represented by formula (D-xxi) or (D-xxi')

[0268] [Chemical formula] [In the formula, The dashed line indicates the bond to the carbonyl of hyaluronic acid, each of m1, m2, m3, m4, m5 and m6 is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] and has the structure of

[0269] In certain embodiments, m1 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xxi) or (D-xxi') is 3. In certain embodiments, m1 of formula (D-xxi) or (D-xxi') is 4. In certain embodiments, m2 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m2 of formula (D-xxi) or (D-xxi') is 1. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is 3. In certain embodiments, m3 is 4. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is 5. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is 6. In certain embodiments, m3 of formula (D-xxi) or (D-xxi') is 7. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is 1. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is 2. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is 3. In certain embodiments, m4 of formula (D-xxi) or (D-xxi') is 4. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10.In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is 3. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is 4. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is 5. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is 6. In certain embodiments, m5 of formula (D-xxi) or (D-xxi') is 7. In certain embodiments, m6 of formula (D-xxi) or (D-xxi') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m6 of formula (D-xxi) or (D-xxi') is 3. In certain embodiments, m6 of formula (D-xxi) or (D-xxi') is 4.

[0270] In certain embodiments, -CL- is of formula (D-xxii)

[0271] [Chemical formula] [wherein the dashed line indicates the bond to the -X 0F - moiety, and m2, m3, and m4 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.] is as such.

[0272] In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 4. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 5. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 6. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 7. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 1. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 2. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 4. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m4 is 4. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 5. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 6.In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 7.

[0273] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety has the formula (D-xxiii) or (D-xxiii')

[0274]

Chemical formula

[0275] In certain embodiments, m1 of formula (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m1 of (D-xxiii) or (D-xxiii') is 1. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 4. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 5. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 6. In certain embodiments, m2 of (D-xxiii) or (D-xxiii') is 7. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 1. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 2. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m3 of (D-xxiii) or (D-xxiii') is 4. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 3.In certain embodiments, m4 is 4. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 5. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 6. In certain embodiments, m4 of (D-xxiii) or (D-xxiii') is 7. In certain embodiments, m5 of (D-xxiii) or (D-xxiii') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m5 of (D-xxiii) or (D-xxiii') is 3. In certain embodiments, m5 of (D-xxiii) or (D-xxiii') is 4.

[0276] In certain embodiments, -CL- is of formula (D-xxiv)

[0277] [Chemical Formula] [wherein the dashed line indicates the bond to the -X 0F - moiety, and m3, m4, and m5 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25] is as such.

[0278] In certain embodiments, m3 of formula (D-xxiv) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-xxiv) is 1. In certain embodiments, m4 of formula (D-xxiv) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xxiv) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m4 of formula (D-xxiv) is 1. In certain embodiments, m4 of formula (D-xxiv) is 2. In certain embodiments, m4 of formula (D-xxiv) is 3. In certain embodiments, m4 of formula (D-xxiv) is 4. In certain embodiments, m5 of formula (D-xxiv) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m5 of formula (D-xxiv) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m5 of formula (D-xxiv) is 3. In certain embodiments, m5 of formula (D-xxiv) is 4. In certain embodiments, m5 of formula (D-xxiv) is 5. In certain embodiments, m5 of formula (D-xxiv) is 6. In certain embodiments, m5 of formula (D-xxiv) is 7.

[0279] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-xxv) or (D-xxv')

[0280]

Chemical formula

[0281] In certain embodiments, m1 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xxv) or (D-xxv') is 3. In certain embodiments, m1 of formula (D-xxv) or (D-xxv') is 4. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is 3. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is 4. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is 5. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is 6. In certain embodiments, m2 of formula (D-xxv) or (D-xxv') is 7. In certain embodiments, m3 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In certain embodiments, m3 of formula (D-xxv) or (D-xxv') is 1. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is 1. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is 2. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is 3. In certain embodiments, m4 of formula (D-xxv) or (D-xxv') is 4. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10.In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is 3. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is 4. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is 5. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is 6. In certain embodiments, m5 of formula (D-xxv) or (D-xxv') is 7. In certain embodiments, m6 of formula (D-xxv) or (D-xxv') is an integer selected from 2, 3, 4, 5, and 6. In certain embodiments, m6 of formula (D-xxv) or (D-xxv') is 3. In certain embodiments, m6 of formula (D-xxv) or (D-xxv') is 4.

[0282] In certain embodiments, -CL- is of formula (D-xxvi)

[0283] [Chemical formula] [wherein the dashed line indicates a bond to the -X 0F - moiety, and m2 and m3 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.] is as such.

[0284] In certain embodiments, m2 of formula (D-xxvi) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D-xxvi) is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m2 of formula (D-xxvi) is 1. In certain embodiments, m2 of formula (D-xxvi) is 2. In certain embodiments, m2 of formula (D-xxvi) is 3. In certain embodiments, m2 of formula (D-xxvi) is 4. In certain embodiments, m3 of formula (D-xxvi) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xxvi) is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m3 of formula (D-xxvi) is 3. In certain embodiments, m3 of formula (D-xxvi) is 4. In certain embodiments, m3 of formula (D-xxvi) is 5. In certain embodiments, m3 of formula (D-xxvi) is 6. In certain embodiments, m3 of formula (D-xxvi) is 7.

[0285] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety is of formula (D-xxvii) or (D-xxvii')

[0286]

Chemical formula

[0287] In certain embodiments, m1 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xxvii) or (D-xxvii') is 3. In certain embodiments, m1 of formula (D-xxvii) or (D-xxvii') is 4. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is 1. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is 2. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is 3. In certain embodiments, m2 of formula (D-xxvii) or (D-xxvii') is 4. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is 3. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is 4. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is 5. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is 6. In certain embodiments, m3 of formula (D-xxvii) or (D-xxvii') is 7. In certain embodiments, m4 of formula (D-xxvii) or (D-xxvii') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m4 of formula (D-xxvii) or (D-xxvii') is 3.In certain embodiments, m4 of formula (D-xxvii) or (D-xxvii') is 4.

[0288] In certain embodiments, -CL- is of formula (D-xxviii)

[0289]

Chemical formula

[0290] In certain embodiments, m2 of formula (D-xxviii) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m2 of formula (D-xxviii) is an integer selected from the group consisting of 1, 2, 3 and 4. In certain embodiments, m2 of formula (D-xxviii) is 1. In certain embodiments, m2 of formula (D-xxviii) is 2. In certain embodiments, m2 of formula (D-xxviii) is 3. In certain embodiments, m2 of formula (D-xxviii) is 4. In certain embodiments, m3 of formula (D-xxviii) is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, m3 of formula (D-xxviii) is an integer selected from the group consisting of 3, 4, 5, 6 and 7. In certain embodiments, m3 of formula (D-xxviii) is 3. In certain embodiments, m3 of formula (D-xxviii) is 4. In certain embodiments, m3 of formula (D-xxviii) is 5. In certain embodiments, m3 of formula (D-xxviii) is 6. In certain embodiments, m3 of formula (D-xxviii) is 7.

[0291] In certain embodiments, -X 0E -SP-X 0F -CL-X 0F -SP-X 0E - moiety has the formula (D-xxix) or (D-xxix')

[0292] [Chemical formula] [wherein the dashed line indicates a bond to the carbonyl of hyaluronic acid, m1, m2, m3 and m4 are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] and has the structure of

[0293] In certain embodiments, m1 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m1 of formula (D-xxix) or (D-xxix') is 3. In certain embodiments, m1 of formula (D-xxix) or (D-xxix') is 4. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is 1. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is 2. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is 3. In certain embodiments, m2 of formula (D-xxix) or (D-xxix') is 4. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 3, 4, 5, 6, and 7. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is 3. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is 4. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is 5. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is 6. In certain embodiments, m3 of formula (D-xxix) or (D-xxix') is 7. In certain embodiments, m4 of formula (D-xxix) or (D-xxix') is an integer selected from the group consisting of 2, 3, 4, 5, and 6. In certain embodiments, m4 of (D-xxix) or (D-xxix') is 3. In certain embodiments, m4 of formula (D-xxix) or (D-xxix') is 4.

[0294] In the second embodiment, the -CL- moiety is

[0295] [Chemical Formula] (wherein each dashed line represents a bond to the -X 0F - moiety, and -L 1 -, -L 2 -, -X 0D - and -D are used as defined for Z 2 ).) selected from the group consisting of

[0296] In formula (C-i), the two functional groups of the drug are each conjugated to one -L 1 - moiety, and in formula (C-ii), the three functional groups of the drug are each conjugated to one -L 1 - moiety. It is understood that the -CL- moiety of formula (C-i) is connected to two Z 3 moieties, and the -CL- moiety of formula (C-ii) is connected to three Z 3 moieties, which may be the same or different hyaluronic acid chains. In this embodiment, -CL- contains at least two degradable bonds when -CL- is of formula (C-i), or at least three degradable bonds when -CL- is of formula (C-ii), i.e., it contains degradable bonds connecting D and the -L 1 - moiety. The conjugate may contain only the -CL- moiety of formula (C-i), only the -CL- moiety of formula (C-ii), or both the -CL- moieties of formula (C-i) and formula (C-ii).

[0297] Thus, the conjugate of this second embodiment contains a cross-linked hyaluronic acid chain to which a plurality of drug moieties are covalently and reversibly conjugated, and the conjugate

[0298] [Chemical Formula] comprising a plurality of connecting units selected from the group consisting of The dashed lines without labels indicate the bonding points to the adjacent units of the dashed lines labeled with # or to hydrogen, The dashed lines labeled with # indicate the bonding points to the adjacent units of the dashed lines without labels or to hydroxyl, The dashed lines labeled with § indicate the connection points of at least two Z 3 units via the -CL- moiety, each -CL- contains at least one degradable bond between two carbon atoms labeled with * that are connected by the -CL- moiety, and each -CL- is of the formulas (C-i) and (C-ii)

[0299] [Chemical formula] (wherein the dashed line indicates the bond to the -X 3 moiety of the Z 0F unit) independently selected from the group consisting of -D, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -SP-, -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E -, -X 0F -, -R a1 and -R a2 is used as defined above, all Z 1 units present in the conjugate may be the same or different, all Z 2 units present in the conjugate may be the same or different, all Z 3 units present in the conjugate may be the same or different, Z 1 the number of units ranges from 1% to 98% of the total number of units present in the conjugate, Z 2The number of units ranges from 0% to 98% of the total number of units present in the conjugate, Z 3 The number of units ranges from 1% to 97% of the total number of units present in the conjugate, provided that there is at least one Z 3 unit present per chain and connected to at least one Z of different hyaluronic acid chains. 3 is a condition.

[0300] The conjugate according to this second embodiment is the Z described above 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 and Z 10 may also include units selected from the group consisting of. For Z 4 , in the -CL- part of formula (C-i), the variable element a is 1, b is 0, and when -CL- is of formula (C-ii), the variable element a can be 1 and b can also be 1, or the variable element a can be 2 and b is 0.

[0301] This embodiment, when synthesizing the conjugate of the present invention, bis-conjugate Y 0G -L 2 -X 0D -L 1 -D-L 1 -X 0D -L 2 -Y 0G , or further, from a tris-conjugate in which three Y 0G -L 2 -X 0D -L 1 - part is conjugated to one D part, there is an effect that there is no need to separate the mono-conjugate Y 0G -L 2 -X 0D -L 1 -D. Both or all three mixtures can be used directly for conjugation, and the mono-conjugate Y 0G -L 2 -X 0D -L 1 -D's Z 7By conjugation to the unit, Z 2 units are formed, while bis- and / or tris-conjugates are Z 5 units conjugate to form, and thus cross-linking becomes possible, Z 3 units are formed. -Y 0G is a functional group used as defined for the following -Y 0A , -Y 0B , -Y 0C and -Y 0D Such synthesis can also be carried out with mixtures containing higher conjugates, such as tetra-, penta-, hexa- or hepta-conjugates, -CL-, i.e. one moiety D is conjugated to 4, 5, 6 or more than 7 -L 1 - moieties, and such embodiments for the -CL- moiety conjugated to the -L- moieties are also included in the present invention. Thus, conjugates containing the -CL- moiety in the form of tetra-, penta-, hexa- and / or hepta- or higher conjugates are also covered.

[0302] In the conjugate according to this second embodiment, the number of Z 2 units ranges from 0 to 70% of all units present in the conjugate, such as 2 to 15%, 2 to 10%, 16 to 39, 40 to 65%, or 50 to 60% of all units present in the conjugate.

[0303] In the conjugate according to this second embodiment, the number of Z 3 units ranges from 1 to 30% of all units present in the conjugate, such as 2 to 5%, 5 to 20%, 10 to 18%, or 14 to 18% of all units present in the conjugate.

[0304] In the conjugate according to this second embodiment, the number of Z 1 units ranges from 10 to 97% of all units present in the conjugate, such as 20 to 40%, such as 25 to 35%, such as 41 to 95%, such as 45 to 90%, such as 50 to 70% of all units present in the conjugate.

[0305] -D and -L of the second embodiment 1 - and -L 2 - and -L 3 - and -L 4 - and -SP- and -X 0A - and -X 0B - and -X 0C - and -X 0D - and -X 0E - and -X 0F - and -R a1 and -R a2 More detailed embodiments thereof are as described below.

[0306] In the third embodiment, the -CL- part is the part

[0307]

Chemical formula

[0308] The -CL- part of formula (D-i) includes at least one branch point, and this branch point

[0309]

Chemical formula

[0310] In certain embodiments, -R B is selected from the group consisting of -H, methyl and ethyl.

[0311] Thus, the conjugate of the third embodiment comprises a cross-linked hyaluronic acid chain to which a plurality of drug moieties are covalently and reversibly conjugated, and the conjugate is

[0312] [wherein the dashed line without a label indicates a point of attachment to an adjacent unit labeled with # or to hydrogen, the dashed line labeled with # indicates a point of attachment to an adjacent unit labeled with the dashed line without a label or to a hydroxyl group, the dashed line labeled with § indicates a point of connection of two Z units via a -CL- moiety, 3 and Each -CL- contains at least one degradable bond between two carbon atoms marked with *, which are connected by the -CL- moiety. Each -CL- is independently of the formula (D-i)

[0313]

Chemical formula

[0314] The conjugate according to this third embodiment may also include a unit selected from the group consisting of Z as described above 4 Z 5 Z 6 Z 7 Z 8 Z 9 and Z 10 In this third embodiment, in Z 4 , the variable element a is 1 and the variable element b is 0.

[0315] In the conjugate according to this third embodiment, the number of Z 2 units is in the range of 0 to 70% of all the units present in the conjugate, for example, 2 to 15%, 2 to 10%, 16 to 39, 40 to 65%, or 50 to 60% of all the units present in the conjugate.

[0316] In the conjugate according to this third embodiment, the number of Z 3 units is in the range of 1 to 30% of all the units present in the conjugate, for example, 2 to 5%, 5 to 20%, 10 to 18%, or 14 to 18% of all the units present in the conjugate.

[0317] In the conjugate according to this third embodiment, the number of Z 1 units is in the range of 10 to 97% of all the units present in the conjugate, for example, 20 to 40%, for example 25 to 35%, for example 41 to 95%, for example 45 to 90%, for example 50 to 70% of all the units present in the conjugate.

[0318] In this third embodiment, -CL- includes -L 2 -X 0C -L 1 -D part, so the presence of Z 2 unit is optional in this embodiment. In a particular embodiment, Z 2 unit does not exist in the third embodiment. In a particular embodiment, the conjugate according to the third embodiment also includes Z 2 unit. Z 2The presence of the unit can have the effect of avoiding undesired high cross-linking, which also means high drug loading in this embodiment, in cases where high drug loading is desirable, where the undesired high cross-linking is Z 2 can be avoided by the presence of the unit.

[0319] -D, -L of the second embodiment 1 -, -L 2 -, -L 3 -, -L 4 -, -SP-, -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E -, -X 0F -, -R a1 and -R a2 More detailed embodiments for are as described below.

[0320] In certain embodiments, each -X 0A - and -X 0E - is independently absent or

[0321]

Chemical formula

[0322] In certain embodiments, each -X 0A - and -X 0E - are independently a linkage selected from the group consisting of formulae x-1, x-2, x-3, x-4, x-6, x-9, x-10, x-11, x-12, x-13, x-14, x-15 and x-16.

[0323] In certain embodiments, each -X 0A - and -X 0E - is independently a linkage selected from the group consisting of x-1, x-2, x-3, x-4, x-6, x-9, x-10, x-12, x-13, and x-15.

[0324] In certain embodiments, each -X 0A - and -X 0E - is independently a linkage selected from the group consisting of x-1, x-2, x-9, and x-10.

[0325] In certain embodiments, each -X 0A - and -X 0E - is independently a linkage selected from the group consisting of x-1, x-2, and x-10.

[0326] In certain embodiments, -X 0A - is of formula x-1. In certain embodiments, -X 0A - is of formula x-2. In certain embodiments, -X 0A - is of formula x-3. In certain embodiments, -X 0A - is of formula x-4. In certain embodiments, -X 0A - is of formula x-5. In certain embodiments, -X 0A - is of formula x-6. In certain embodiments, -X 0A - is of formula x-7. In certain embodiments, -X 0A - is of formula x-8. In certain embodiments, -X 0A - is of formula x-9. In certain embodiments, -X 0A - is of formula x-10. In certain embodiments, -X 0A - is of formula x-11. In certain embodiments, -X 0A - is of formula x-12. In certain embodiments, -X 0A- is of the formula x - 13. In certain embodiments, -X 0A - is of the formula x - 14. In certain embodiments, -X 0A - is of the formula x - 15. In certain embodiments, -X 0A - is of the formula x - 16.

[0327] In certain embodiments, -X 0E - is of the formula x - 1. In certain embodiments, -X 0E - is of the formula x - 2. In certain embodiments, -X 0E - is of the formula x - 3. In certain embodiments, -X 0E - is of the formula x - 4. In certain embodiments, -X 0E - is of the formula x - 5. In certain embodiments, -X 0E - is of the formula x - 6. In certain embodiments, -X 0E - is of the formula x - 7. In certain embodiments, -X 0E - is of the formula x - 8. In certain embodiments, -X 0E - is of the formula x - 9. In certain embodiments, -X 0E - is of the formula x - 10. In certain embodiments, -X 0E - is of the formula x - 11. In certain embodiments, -X 0E - is of the formula x - 12. In certain embodiments, -X 0E - is of the formula x - 13. In certain embodiments, -X 0E - is of the formula x - 14. In certain embodiments, -X 0E - is of the formula x - 15. In certain embodiments, -X 0E - is of the formula x - 16.

[0328] In certain embodiments, each -X 0B -, -X 0C -, -X 0D - and -X 0F- is independently non-existent or

[0329]

Chemical formula

[0330] In certain embodiments, each -X 0B -, -X 0C -, -X 0D -and -X 0F- is a linkage selected from the group consisting of x - 17, x - 18, x - 19, x - 20, x - 21, x - 22, x - 23, x - 25, x - 26, x - 27, x - 28, x - 29, x - 30, x - 31, x - 32, x - 35, x - 36, x - 37, x - 38, x - 39, x - 41, x - 42, x - 43, x - 45, x - 46, x - 47, x - 48, x - 49, x - 50, x - 51, x - 52, x - 53, x - 54, x - 55, x - 56, x - 57, x - 58, x - 59, x - 60, x - 61, x - 62, x - 64, x - 65, x - 66, x - 75, x - 76, x - 77, x - 78, x - 79, x - 80, x - 81, x - 82, x - 83, x - 84, x - 85, x - 87, x - 88, x - 89, x - 90, x - 91, x - 92, x - 93, x - 97, x - 98, x - 101, x - 102, x - 103, x - 104, x - 105, x - 106, x - 107, x - 108, x - 109, x - 110, x - 111, x - 112, x - 113, x - 114, x - 115, x - 116, x - 117, x - 118, x - 119, x - 132, x - 133, x - 134, x - 135, x - 137, x - 138, x - 139, x - 140, x - 141, x - 142, x - 146, x - 147, x - 148, x - 150, x - 151, x - 154, x - 155, x - 156, x - 157, x - 159, x - 160, x - 161, x - 162, x - 163, x - 167, x - 170, x - 174, x - 175 and x - 176.

[0331] In certain embodiments, each -X 0B -, -X 0C -, -X 0D - and -X 0F- is a linkage selected independently from the group consisting of formulas x-17, x-18, x-21, x-22, x-23, x-26, x-28, x-29, x-31, x-32, x-36, x-37, x-38, x-41, x-42, x-43, x-45, x-47, x-48, x-49, x-50, x-51, x-52, x-53, x-54, x-56, x-57, x-59, x-60, x-61, x-62, x-64, x-65, x-66, x-75, x-77, x-79, x-80, x-81, x-82, x-83, x-87, x-88, x-89, x-90, x-91, x-92, x-93, x-97, x-98, x-101, x-102, x-103, x-104, x-111, x-112, x-113, x-132, x-133, x-134, x-135, x-137, x-138, x-139, x-140, x-141, x-142, x-146, x-147, x-148, x-150, x-151, x-154, x-155, x-156, x-157, x-159, x-160, x-161, x-162, x-163, x-167, x-170, x-174, x-175 and x-176.

[0332] In certain embodiments, each -X 0B -, -X 0C -, -X 0D - and -X 0F - is a linkage selected independently from the group consisting of formulas x-17, x-18, x-21, x-22, x-31, x-36, x-37, x-38, x-42, x-45, x-47, x-50, x-51, x-54, x-56, x-59, x-88, x-89, x-90, x-91, x-92, x-93, x-97, x-101, x-102, x-104, x-113, x-132, x-135, x-147, x-148, x-150, x-151, x-154, x-155, x-156, x-157, x-159, x-163, x-167, x-170, x-174, x-175 and x-176.

[0333] In certain embodiments, each -X 0B -, -X 0C -, -X 0D - and -X 0F- is a linkage independently selected from the group consisting of formulas x-18, x-22, x-37, x-45, x-47, x-50, x-51, x-101, x-135, x-148, x-150 and x-151.

[0334] In certain embodiments, -X 0B - is of formula x-18. In certain embodiments, -X 0B - is of formula x-22. In certain embodiments, -X 0B - is of formula x-37. In certain embodiments, -X 0B - is of formula x-45. In certain embodiments, -X 0B - is of formula x-47. In certain embodiments, -X 0B - is of formula x-50. In certain embodiments, -X 0B - is of formula x-51. In certain embodiments, -X 0B - is of formula x-101. In certain embodiments, -X 0B - is of formula x-135. In certain embodiments, -X 0B - is of formula x-148. In certain embodiments, -X 0B - is of formula x-150. In certain embodiments, -X 0B - is of formula x-151.

[0335] In certain embodiments, -X 0C - is of formula x-18. In certain embodiments, -X 0C - is of formula x-22. In certain embodiments, -X 0C - is of formula x-37. In certain embodiments, -X 0C - is of formula x-45. In certain embodiments, -X 0C - is of formula x-47. In certain embodiments, -X 0C - is of formula x-50. In certain embodiments, -X 0C- is of the formula x - 51. In certain embodiments, -X 0C - is of the formula x - 101. In certain embodiments, -X 0C - is of the formula x - 135. In certain embodiments, -X 0C - is of the formula x - 148. In certain embodiments, -X 0C - is of the formula x - 150. In certain embodiments, -X 0C - is of the formula x - 151.

[0336] In certain embodiments, -X 0D - is of the formula x - 18. In certain embodiments, -X 0D - is of the formula x - 22. In certain embodiments, -X 0D - is of the formula x - 37. In certain embodiments, -X 0D - is of the formula x - 45. In certain embodiments, -X 0D - is of the formula x - 47. In certain embodiments, -X 0D - is of the formula x - 50. In certain embodiments, -X 0D - is of the formula x - 51. In certain embodiments, -X 0D - is of the formula x - 101. In certain embodiments, -X 0D - is of the formula x - 135. In certain embodiments, -X 0D - is of the formula x - 148. In certain embodiments, -X 0D - is of the formula x - 150. In certain embodiments, -X 0D - is of the formula x - 151.

[0337] In certain embodiments, -X 0F - is of the formula x - 18. In certain embodiments, -X 0F - is of the formula x - 22. In certain embodiments, -X 0F - is of the formula x - 37. In certain embodiments, -X0F - is of the formula x - 45. In certain embodiments, -X 0F - is of the formula x - 47. In certain embodiments, -X 0F - is of the formula x - 50. In certain embodiments, -X 0F - is of the formula x - 51. In certain embodiments, -X 0F - is of the formula x - 101. In certain embodiments, -X 0F - is of the formula x - 135. In certain embodiments, -X 0F - is of the formula x - 148. In certain embodiments, -X 0F - is of the formula x - 150. In certain embodiments, -X 0F - is of the formula x - 151.

[0338] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D is

[0339]

Chemical formula

[0340] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D and -Y 0E is independently a functional group selected from the group consisting of formulae y-1, y-2, y-3, y-7, y-8, y-9, y-10, y-11, y-12, y-13, y-14, y-15, y-16, y-17, y-18, y-21, y-22, y-22a, y-23, y-24, y-27, y-28, y-29, y-31, y-33, y-35, y-37, y-39, y-40, y-41, y-42, y-43, y-45, y-46, y-47, y-49, y-52, y-53, y-54, y-55, y-56, y-57, y-59, y-61, y-62, y-64, y-70, y-71, y-72, y-73, y-74, y-77, y-79, y-80, y-85 and y-86.

[0341] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D and -Y 0Eis a functional group independently selected from the group consisting of formulae y-1, y-2, y-3, y-7, y-8, y-9, y-12, y-13, y-14, y-15, y-16, y-17, y-18, y-21, y-22, y-22a, y-23, y-24, y-27, y-28, y-29, y-31, y-39, y-45, y-46, y-47, y-52, y-53, y-54, y-55, y-56, y-57, y-59, y-61, y-68, y-70, y-71, y-72, y-73, y-74, y-77, y-79, y-80, y-85 and y-86.

[0342] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D and -Y 0E is a functional group independently selected from the group consisting of formulae y-1, y-2, y-7, y-8, y-9, y-13, y-14, y-15, y-16, y-21, y-22, y-22a, y-24, y-39, y-56, y-57, y-60, y-70, y-71 and y-86.

[0343] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D and -Y 0E is a functional group independently selected from the group consisting of formulae y-1, y-2, y-8, y-9, y-13, y-14, y-16, y-22, y-22a, y-39, y-56, y-57, y-61, y-70, y-71 and y-86.

[0344] In certain embodiments, each -Y 0A , -Y 0B , -Y 0C , -Y 0D and -Y 0E is a functional group independently selected from the group consisting of formulae y-1, y-2, y-8, y-9, y-16, y-22, y-22a, y-39, y-56, y-57, y-61, y-70, y-71 and y-86.

[0345] In certain embodiments, -Y 0A is of the formula y-1. In certain embodiments, -Y 0A is of the formula y-2. In certain embodiments, -Y 0A is of the formula y-8. In certain embodiments, -Y 0A is of the formula y-9. In certain embodiments, -Y 0A is of the formula y-16. In certain embodiments, -Y 0A is of the formula y-22. In certain embodiments, -Y 0A is of the formula y-22a. In certain embodiments, -Y 0A is of the formula y-39. In certain embodiments, -Y 0A is of the formula y-56. In certain embodiments, -Y 0A is of the formula y-57. In certain embodiments, -Y 0A is of the formula y-61. In certain embodiments, -Y 0A is of the formula y-70. In certain embodiments, -Y 0A is of the formula y-71. In certain embodiments, -Y 0A is of the formula y-86.

[0346] In certain embodiments, -Y 0B is of the formula y-1. In certain embodiments, -Y 0B is of the formula y-2. In certain embodiments, -Y 0B is of the formula y-8. In certain embodiments, -Y 0B is of the formula y-9. In certain embodiments, -Y 0B is of the formula y-16. In certain embodiments, -Y 0B is of the formula y-22. In certain embodiments, -Y 0B is of the formula y-22a. In certain embodiments, -Y 0B is of the formula y-39. In certain embodiments, -Y 0Bis of the formula y - 56. In certain embodiments, -Y 0B is of the formula y - 57. In certain embodiments, -Y 0B is of the formula y - 61. In certain embodiments, -Y 0B is of the formula y - 70. In certain embodiments, -Y 0B is of the formula y - 71. In certain embodiments, -Y 0B is of the formula y - 86.

[0347] In certain embodiments, -Y 0C is of the formula y - 1. In certain embodiments, -Y 0C is of the formula y - 2. In certain embodiments, -Y 0C is of the formula y - 8. In certain embodiments, -Y 0C is of the formula y - 9. In certain embodiments, -Y 0C is of the formula y - 16. In certain embodiments, -Y 0C is of the formula y - 22. In certain embodiments, -Y 0C is of the formula y - 22a. In certain embodiments, -Y 0C is of the formula y - 39. In certain embodiments, -Y 0C is of the formula y - 56. In certain embodiments, -Y 0C is of the formula y - 57. In certain embodiments, -Y 0C is of the formula y - 61. In certain embodiments, -Y 0C is of the formula y - 70. In certain embodiments, -Y 0C is of the formula y - 71. In certain embodiments, -Y 0C is of the formula y - 86.

[0348] In certain embodiments, -Y 0D is of the formula y - 1. In certain embodiments, -Y 0D is of the formula y - 2. In certain embodiments, -Y 0Dis of formula y - 8. In certain embodiments, -Y 0D is of formula y - 9. In certain embodiments, -Y 0D is of formula y - 16. In certain embodiments, -Y 0D is of formula y - 22. In certain embodiments, -Y 0D is of formula y - 22a. In certain embodiments, -Y 0D is of formula y - 39. In certain embodiments, -Y 0D is of formula y - 56. In certain embodiments, -Y 0D is of formula y - 57. In certain embodiments, -Y 0D is of formula y - 61. In certain embodiments, -Y 0D is of formula y - 70. In certain embodiments, -Y 0D is of formula y - 71. In certain embodiments, -Y 0D is of formula y - 86.

[0349] In certain embodiments, -Y 0E is of formula y - 1. In certain embodiments, -Y 0E is of formula y - 2. In certain embodiments, -Y 0E is of formula y - 8. In certain embodiments, -Y 0E is of formula y - 9. In certain embodiments, -Y 0E is of formula y - 16. In certain embodiments, -Y 0E is of formula y - 22. In certain embodiments, -Y 0E is of formula y - 22a. In certain embodiments, -Y 0E is of formula y - 39. In certain embodiments, -Y 0E is of formula y - 56. In certain embodiments, -Y 0E is of formula y - 57. In certain embodiments, -Y 0E is of formula y - 61. In certain embodiments, -Y 0Eis of formula y-70. In certain embodiments, -Y 0E is of formula y-71. In certain embodiments, -Y 0E is of formula y-86.

[0350] In certain embodiments, -Y 0F is

[0351] [Chemical formula] [wherein, each n is independently 1, 2, 3 or 4] is selected from the group consisting of.

[0352] In certain embodiments, each -Y 0F is independently a functional group selected from the group consisting of formulae y-87, y-88, y-89, y-90 and y-91.

[0353] In certain embodiments, each -Y 0F is independently a functional group selected from the group consisting of formulae y-87, y-88 and y-93.

[0354] In certain embodiments, all -Y present in the conjugate of the present invention 0F is of formula y-87. In certain embodiments, all -Y present in the conjugate of the present invention 0F is of formula y-88. In certain embodiments, all -Y present in the conjugate of the present invention 0F is of formula y-93.

[0355] In certain embodiments, each -Y 0F is independently a functional group selected from the group consisting of formulae y-87 and y-88.

[0356] Each -Y 0H is

[0357] [Chemical formula] It is independently selected from the group consisting of TIFF0007701873000087.tif67158.

[0358] In certain embodiments, -Y 0H is of the formula y'-1. In certain embodiments, -Y 0H is of the formula y'-2. In certain embodiments, -Y 0H is of the formula y'-3. In certain embodiments, -Y 0H is of the formula y'-4. In certain embodiments, -Y 0H is of the formula y'-5. In certain embodiments, -Y 0H is of the formula y'-6. In certain embodiments, -Y 0H is of the formula y'-7. In certain embodiments, -Y 0H is of the formula y'-8. In certain embodiments, -Y 0H is of the formula y'-9. In certain embodiments, -Y 0H is of the formula y'-10.

[0359] The -D moieties present in the conjugates of the present invention may be the same or different.

[0360] -D is -L 1 - is a drug moiety that is covalently and reversibly conjugated to -. -D can be selected from the group consisting of peptide, protein, oligonucleotide, and small molecule drug moieties. In certain embodiments, -D is a peptide drug moiety. In certain embodiments, -D is a protein drug moiety. In certain embodiments, -D is an oligonucleotide drug moiety. In certain embodiments, -D is a small molecule drug moiety. In certain embodiments, -D is a peptide or a protein.

[0361] In one embodiment, all the -D moieties of the conjugate are the same. In another embodiment, the conjugate comprises more than one type of -D, i.e., two or more different types of -D, such as two different types of -D, three different types of -D, four different types of -D or five different types of -D.

[0362] When the conjugate of the present invention comprises more than one type of -D, all the -D moieties are connected to the same type of -L 1 - or may be connected to different types of -L 1 - i.e., for example, the first type of -D may be connected to the first type of -L 1 - and the second type of -D may be connected to the second type of -L 1 -. The use of different types of -L 1 - may, in certain embodiments, enable different release rates (release kinetics) with different types of -D, e.g., fast release with the first type of -D, medium release with the second type of -D, and slow release with the third type of -D. Thus, in certain embodiments, the conjugate of the present invention comprises one type of -L 1 -. In certain embodiments, the conjugate of the present invention comprises two types of -L 1 -. In certain embodiments, the conjugate of the present invention comprises three types of -L 1 -. In certain embodiments, the conjugate of the present invention comprises four types of -L 1 -.

[0363] In certain embodiments, the conjugate of the present invention comprises one type of -D and one type of -L 1 -. In certain embodiments, the conjugate of the present invention comprises two types of -D and two types of -L 1 -. In certain embodiments, the conjugate of the present invention comprises three types of -D and three types of -L 1-including. In certain embodiments, the conjugates of the invention comprise four types of -D and four types of -L 1 -including. In certain embodiments, the conjugates of the invention comprise two types of -D and one type of -L 1 -including, i.e., both types of drugs are released at the same release rate. In certain embodiments, the conjugates of the invention comprise three types of -D and one type of -L 1 -including. Alternatively, the conjugates of the invention may comprise one type of -D, but more than one type of -L 1 -such as two, three, or four types of -L 1 -including. Thereby, combinations of different release rates with the same drug, for example, an initial rapid acceleration achieved from the -L 1 -portion with a short release half-life, followed by sustained release from the -L 1 -portion with a long release half-life are made possible.

[0364] -L 1 -The L portion is conjugated to -D via a functional group of -D, which in certain embodiments is selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphoric acid, phosphonic acid, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, aziridine, amide, imide, imine, urea, amidine, guanidine, sulfonamide, phosphonamide, phosphoramide, hydrazide, and selenol. In certain embodiments, -L 1- conjugates to -D via a functional group -D selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphoric acid, phosphonic acid, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, amidine and aziridine. In certain embodiments, -L 1 - conjugates to -D via a functional group -D selected from the group consisting of hydroxyl, primary amine, secondary amine, amidine, thiol and carboxylic acid.

[0365] In certain embodiments, -L 1 - conjugates to -D via the hydroxyl group of -D.

[0366] In certain embodiments, -L 1 - conjugates to -D via the primary amine group of -D.

[0367] In certain embodiments, -L 1 - conjugates to -D via the secondary amine group of -D.

[0368] In certain embodiments, -L 1 - conjugates to -D via the carboxylic acid group of -D.

[0369] In certain embodiments, -L 1 - conjugates to -D via the amidine group of -D.

[0370] -L 1 The - part may be connected to -D via any type of linkage, provided that it is reversible. In certain embodiments, -L 1- is connected to -D via a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminals, imine, oxime, hydrazine, disulfide, acylguanidine, acylamidine, carbonate, phosphate, sulfate, urea, hydrazide, thioester, thiophosphate, thiosulfate, sulfonamide, sulfoamidine, sulfaguanidine, phosphoramide, phosphoamidine, phosphoguanidine, phosphonamide, phosphonamidine, phosphonguanidine, phosphonate, borate and imide. In certain embodiments, -L 1 - is connected to -D via a linkage selected from the group consisting of amide, ester, carbonate, carbamate, acetal, aminals, imine, oxime, hydrazine, disulfide, acylamidine and acylguanidine. In certain embodiments, -L 1 - is connected to -D via a linkage selected from the group consisting of amide, ester, carbonate, acylamide and carbamate. Some of these linkages may not be reversible by themselves, but in the present invention, -L 1 It is understood that the adjacent groups contained in -L render these linkages reversible.

[0371] In certain embodiments, -L 1 - is connected to -D via an ester linkage. In certain embodiments, -L 1 - is connected to -D via a carbonate linkage. In certain embodiments, -L 1 - is connected to -D via an acylamidine linkage. In certain embodiments, -L 1 - is connected to -D via a carbamate linkage. In certain embodiments, -L 1 - is connected to -D via an amide linkage.

[0372] In certain embodiments, -D is an antibiotic moiety selected from the group consisting of aminoglycosides, tetracycline antibiotics, amphenicols, pleuromutilins, macrolid antibiotics, lincosamides, steroid antibiotics, anti-folate antibiotics, sulfonamides, topoisomerase inhibitors, quinolones, fluoroquinolones, nitroimidazole antibiotics, nitrofurantoin antibiotics, rifamycins, glycopeptides, penicillins, cephalosporins, monobactams, beta-lactamase inhibitors, polymyxin antibiotics, lipopeptide antibiotics, oxazolidinon, antimicrobial peptides, antimicrobial proteins, porphyrins, azole antifungals, polyenes, antiprotozoals, fosfomycin, cycloserine, and bacitracin.

[0373] In certain embodiments, -D is an aminoglycoside selected from the group consisting of streptomycin, dihydrostreptomycin, neomycin, paromomycin, amikacin, kanamycin, tobramycin, spectinomycin, hygromycin b, gentamicin, plazomycin, verdamycin, netilmicin, astromicin, and sisomicin. In certain embodiments, -D is amikacin. In certain embodiments, -D is kanamycin. In certain embodiments, -D is tobramycin. In certain embodiments, -D is gentamicin. In another embodiment, -D is plazomycin.

[0374] In certain embodiments, -D is a tetracycline antibiotic selected from the group consisting of tetracycline antibiotics such as doxycycline, chloretetracycline, tetracycline, methacycline, minocycline, oxytetracycline, and glycocycle antibiotics such as tigecycline, omadacycline, and sarecycline. In certain embodiments, -D is tetracycline. In certain embodiments, -D is minocycline. In certain embodiments, -D is oxytetracycline. In certain embodiments, -D is tigecycline. In certain embodiments, -D is omadacycline. In another embodiment, -D is sarecycline.

[0375] In certain embodiments, -D is an amphenicol selected from the group consisting of amphenicols such as chloramphenicol, thiamphenicol, azidamfenicol, and florfenicol.

[0376] In certain embodiments, -D is a pleuromutilin selected from the group consisting of pleuromutilins such as azamulin, lefamulin, tiamulin, and valnemulin.

[0377] In certain embodiments, -D is a macrolide antibiotic selected from the group consisting of macrolide antibiotics such as azithromycin, boromycin, clarithromycin, oleandomycin, erythromycin, roxithromycin, spiramycin, telithromycin, and tylosine.

[0378] In certain embodiments, -D is a lincosamide selected from the group consisting of lincosamides such as clindamycin and lincomycin. In certain embodiments, -D is clindamycin.

[0379] In certain embodiments, -D is a steroid antibiotic, such as fusidic acid.

[0380] In certain embodiments, -D is an anti-folate antibiotic, such as an anti-folate antibiotic selected from the group consisting of trimethoprim and iclaprim.

[0381] In certain embodiments, -D is a sulfonamide, such as a sulfonamide selected from the group consisting of sulfathiazole, sulfamethoxazole, sulfadiazine, and sulfamerazine.

[0382] In certain embodiments, -D is a topoisomerase inhibitor, such as a topoisomerase inhibitor selected from the group consisting of flumequine, nalidixic acid, oxolinic acid, and pipemidic acid. In certain embodiments, -D is nalidixic acid.

[0383] In certain embodiments, -D is a quinolone or fluoroquinolone, such as a quinolone or fluoroquinolone selected from the group consisting of nemonoxacin, ciprofloxacin, ofloxacin, norfloxacin, pefloxacin, levofloxacin, sparfloxacin, moxifloxacin, gemifloxacin, difloxacin, enrofloxacin, marbofloxacin, delafloxacin, and nemonobrobiosin. In certain embodiments, -D is ciprofloxacin. In certain embodiments, -D is levofloxacin. In certain embodiments, -D is delafloxacin.

[0384] In certain embodiments, -D is a nitroimidazole antibiotic, such as metronidazole.

[0385] In certain embodiments, -D is a nitrofurantoin antibiotic, such as a nitrofurantoin antibiotic selected from the group consisting of nitrofurantoin and furazolidone.

[0386] In certain embodiments, -D is rifamycin, such as rifampicin.

[0387] In certain embodiments, -D is a glycopeptide, such as a glycoprotein selected from the group consisting of vancomycin, oritavancin, telavancin, dalbavancin, and teicoplanin. In certain embodiments, -D is vancomycin. In certain embodiments, -D is oritavancin. In certain embodiments, -D is telavancin. In another embodiment, -D is dalbavancin.

[0388] In certain embodiments, -D is a penicillin, such as a penicillin selected from the group consisting of penam, penem, and carbapenem. In certain embodiments, such penams are selected from the group consisting of amoxicillin, ampicillin, carbenicillin, ticarcillin, temocillin, azidocillin, piperacillin, mezlocillin, mecillinam, benzylpenicillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, methicillin, and nafcillin. In certain embodiments, such penems and carbapenes are selected from the group consisting of faropenem, ertapenem, doripenem, thienepenem, sulopenem, imipenem, and meropenem. In certain embodiments, -D is imipenem. In another embodiment, -D is meropenem.

[0389] In certain embodiments, -D is a cephalosporin selected from the group consisting of cephalosporins such as cefazolin, cefadroxil, cefradine, cefaclor, cefamandole, cefminox, cefotiam, cefprozil, cefuroxime, cefoxitin, cefotetan, cefmetazole, cefixime, ceftriaxone, ceftazidime, cefoperazone, cefpodoxime, cefdinir, cefditoren, cefotaxime, cefosulodin, cefotiam hexetil, cefibuten, ceftezole, cefepime, cefozopran, cefpirome, ceftobiprole, and ceftobiprole. In certain embodiments, -D is cefazolin. In certain embodiments, -D is cephalexin. In certain embodiments, -D is ceftobiprole. In certain embodiments, -D is ceftobiprole. Cephalosporin is also known as cephamycin.

[0390] In certain embodiments, -D is a monobactam such as aztreonam.

[0391] In certain embodiments, -D is a beta-lactamase inhibitor selected from the group consisting of beta-lactamase inhibitors such as sulbactam, tazobactam, clavulanic acid, and cefdinir.

[0392] In certain embodiments, -D is a polymyxin antibiotic selected from the group consisting of polymyxin antibiotics such as colistin and polymyxin B. In certain embodiments, -D is colistin. In certain embodiments, -D is polymyxin B.

[0393] In certain embodiments, -D is a lipopeptide antibiotic selected from the group consisting of lipopeptide antibiotics such as daptomycin, arylomycin, and gramicidin. In certain embodiments, -D is daptomycin. Daptomycin has the following chemical structure

[0394] [Chemistry] has

[0395] In certain embodiments, -D is an oxazolidinone selected from the group consisting of oxazolidinones such as linezolid, tedizolid, esperezolid, posizolid, radezolid, sutezolid, and cadazolid. In certain embodiments, -D is tedizolid.

[0396] In certain embodiments, -D is an antimicrobial peptide selected from the group consisting of antimicrobial peptides such as cationic amphiphilic peptides (CAP) and host defense proteins (HDP). In certain embodiments, such CAP is selected from the group consisting of omiganan pentahydrochloride and novispirin g-10. In certain embodiments, such HDP is brellidin.

[0397] In certain embodiments, -D is an antimicrobial protein such as lysin.

[0398] In certain embodiments, -D is a porphyrin such as exeporfinium chloride.

[0399] In certain embodiments, -D is an azole antifungal agent selected from the group consisting of azole antifungal agents such as fluconazole, isavuconazonium sulfate, posaconazole, itraconazole, voriconazole, albaconazole, and miconazole. In certain embodiments, -D is fluconazole. In certain embodiments, -D is voriconazole. In certain embodiments, -D is albaconazole.

[0400] In certain embodiments, -D is a polyene selected from the group consisting of polyenes such as amphotericin, echinocandin, flucytosine, terbinafine, and triterpinoid. In certain embodiments, the echinocandin is selected from the group consisting of caspofungin, micafungin, anidulafungin, sirolimus, and rezafungin. In certain embodiments, -D is amphotericin. In certain embodiments, -D is caspofungin. In certain embodiments, -D is micafungin. In certain embodiments, -D is anidulafungin. In certain embodiments, -D is sirolimus. In certain embodiments, -D is rezafungin.

[0401] In certain embodiments, -D is an antiprotozoal drug moiety selected from the list including eflornithine, furazolidone, melarsoprol, nifulsemizone, ornidazole, pentamidine, pyrimethamine, quinapyramine, tinidazole, chlorproguanil, proguanil, atovaquone, dehydroemetine, diloxanide, eflornithine, halofantrine, lumefantrine, mepacrine, miltefosine, nitazoxanide, tizoxanide, pyronaridine, suramin, amodiaquine, chloroquine, hydroxychloroquine, primaquine, pamaquine, tafenoquine, mefloquine, artemether, artemisinin, artemotil, artesunate, and dihydroartemisinin.

[0402] If the conjugate contains more than one type of -D, one such combination can be a beta-lactamase inhibitor and an antibiotic selected from the group consisting of penicillins, cephalosporins, and monobactam antibiotics. Thus, in certain embodiments, the conjugate of the present invention can contain a beta-lactamase inhibitor and a penicillin. In certain embodiments, the conjugate of the present invention can contain a beta-lactamase inhibitor and a cephalosporin. In certain embodiments, the conjugate of the present invention can contain a beta-lactamase inhibitor and a monobactam antibiotic.

[0403] When -D is daptomycin, -L 1 - is, in certain embodiments, connected via the primary amine of the ornithine side chain. In certain embodiments, such daptomycin is connected to -L via the primary amine of the ornithine side chain through an amide linkage. 1 - is connected.

[0404] In certain embodiments, -D is a pattern recognition receptor agonist ("PRRA"). Such PRRAs can be selected from the group consisting of, for example, Toll-like receptor (TLR) agonists, NOD-like receptors (NLRs), RIG-I-like receptors, cytosolic DNA sensors, STING, and aryl hydrocarbon receptor (AhR).

[0405] In certain embodiments, -D is a Toll-like receptor agonist. In certain embodiments, -D is a NOD-like receptor. In certain embodiments, -D is a RIG-I-like receptor. In certain embodiments, -D is a cytosolic DNA sensor. In certain embodiments, -D is STING. In certain embodiments, -D is an aryl hydrocarbon receptor.

[0406] - When -D is a Toll-like receptor agonist, such Toll-like receptor agonists include agonists of TLR1 / 2, such as peptidoglycan, lipoprotein, Pam3CSK4, Amplivant, SLP-Amplivant, HESPECTA, ISA101 and ISA201; agonists of TLR2, such as LAM-MS, LPS-PG, LTA-BS, LTA-SA, PGN-BS, PGN-EB, PGN-EK, PGN-SA, CL429, FSL-1, Pam2CSK4, Pam3CSK4, zymosan, CBLB612, SV-283, ISA204, SMP105, heat-killed Listeria monocytogenes; agonists of TLR3, such as poly(A:U), poly(I:C) (poly-ICLC), lintatrimod, apoxxim, IPH3102, poly-ICR, PRV300, RGCL2, RGIC.1, Riboxxim (RGC100, RGIC100), Riboxxol (RGIC50) and Riboxxon; agonists of TLR4, such as lipopolysaccharide (LPS), neoseptin-3, glucopyranosyl lipid adjuvant (GLA), GLA-SE, G100, GLA-AF, clinical center reference endotoxin (CCRE), monophosphoryl lipid A, glass MATA MPL, PEPA10, ONT-10 (PET-Lipid A, oncothyreon), G-305, ALD046, CRX527, CRX675 (RC527, RC590), GSK1795091, OM197MPAC, OM294DP and SAR439794; agonists of TLR2 / 4, such as lipid A, OM174 and PGN007; agonists of TLR5, such as flagellin, entrimod, mobiran, protectan CBLB501; agonists of TLR6 / 2, such as diacylated lipoprotein, diacylated lipopeptide, FSL-1, MALP-2 and CBLB613;Agonists of TLR7, such as CL264, CL307, imiquimod (R837), TMX-101, TMX-201, TMX-202, TMX302, gardiquimod, S-27609, 851, UC-IV150, 852A (3M-001, PF-04878691), roquinimex, polyuridylic acid, GSK2245035, GS-9620, RO6864018 (ANA773, RG7795), RO7020531, isatoribine, AN0331, ANA245, ANA971, ANA975, DSP0509, DSP3025 (AZD8848), GS986, MBS2, MBS5, RG7863 (RO6870868), sotirimod, SZU101 and TQA3334; agonists of TLR8, such as ss polyuridine, ssRNA40, TL8-506, XG-1-236, VTX-2337 (motolimod), VTX-1463, VTX378, VTX763, DN1508052 and GS9688; agonists of TLR7 / 8, such as CL075, CL097, poly(dT), resiquimod (R-848, VML600, S28463), MEDI9197 (3M-052), NKTR262, DV1001, IMO4200, IPH3201 and VTX1463; agonists of TLR9, such as CpG DNA, CpG ODN, lefitolimod (MGN1703), SD-101, QbG10, CYT003, CYT003-QbG10, DUK-CpG-001, CpG-7909 (PF-3512676), GNKG168, EMD 1201081, IMO-2125, IMO-2055, CpG10104, AZD1419, AST008, IMO2134, MGN1706, IRS954, 1018ISS, Actilon (CPG10101), ATP00001, AVE0675, AVE7279, CMP001, DIMS0001, DIMS9022, DIMS9054, DIMS9059, DV230, DV281, EnanDIM, Heprisub (V270), kappaproct (DIMS0150), NJP834, NPI503, SAR21609 and tramba; and agonists of TLR7 / 9, such as DV1179, may be selected from the group consisting of;

[0407] In certain embodiments, -D is an agonist of TLR1 / 2. In certain embodiments, -D is an agonist of TLR2. In certain embodiments, -D is an agonist of TLR3. In certain embodiments, -D is an agonist of TLR4. In certain embodiments, -D is an agonist of TLR2 / 4. In certain embodiments, -D is an agonist of TLR5. In certain embodiments, -D is an agonist of TLR6 / 2. In certain embodiments, -D is an agonist of TLR7. In certain embodiments, -D is an agonist of TLR8. In certain embodiments, -D is an agonist of TLR7 / 8. In certain embodiments, -D is an agonist of TLR9.

[0408] Examples of CpG ODNs are ODN 1585, ODN 2216, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN BW006, ODN D-SL01, ODN 2395, ODN M362, and ODN D-SL03.

[0409] In certain embodiments, at least a portion of the -D moiety of the conjugate, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or 100% of all -D moieties present in the conjugate, is imiquimod. In certain embodiments, at least a portion of the -D moiety of the conjugate, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or 100% of all -D moieties present in the conjugate, is resiquimod. In certain embodiments, at least a portion of the -D moiety of the conjugate, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or 100% of all -D moieties present in the conjugate, is SD-101. In certain embodiments, at least a portion of the -D moiety of the conjugate, e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or 100% of all -D moieties present in the conjugate, is CMP001.

[0410] When -D is a NOD-like receptor, such NOD-like receptor can be selected from the group consisting of agonists of NOD1, e.g., C12-iE-DAP, C14-Tri-LAN-Gly, iE-DAP, iE-Lys and Tri-DAP; and agonists of NOD2, e.g., L18-MDP, MDP, M-TriLYS, murabutide and N-glycolyl-MDP.

[0411] In certain embodiments, -D is an agonist of NOD1. In certain embodiments, -D is an agonist of NOD2.

[0412] When -D is a RIG-I like receptor, such RIG-I like receptor can be selected from the group consisting of 3p-hpRNA, 5'ppp-dsRNA, 5'ppp RNA (M8), entangled 5'OH RNA (CBS-13-BPS), 5'PPP SLR, KIN100, KIN 101, KIN1000, KIN1400, KIN1408, KIN1409, KIN1148, KIN131A, poly(dA:dT), SB9200, RGT100 and hiltonol.

[0413] When -D is a cytosolic DNA sensor, such cytosolic DNA sensor can be selected from the group consisting of cGAS agonist, dsDNA-EC, G3-YSD, HSV-60, ISD, ODN TTAGGG (A151), poly(dG:dC) and VACV-70.

[0414] When -D is STING, such STING can be selected from the group consisting of MK-1454, ADU-S100 (MIW815), 2'3'-cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, cAIMP (CL592), cAIMP difluoro (CL614), cAIM(PS)2 difluoro (Rp / Sp) (CL656), 2'2'-cGAMP, 2'3'-cGAM(PS)2 (Rp / Sp), fluorinated 3'3'-cGAM, fluorinated c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AM(PS)2 (Rp,Rp), fluorinated c-di-GMP, 2'3'-c-di-GMP, c-di-IMP, c-di-UMP and DMXAA (vadimezan, ASA404).

[0415] In certain embodiments, -D is MK-1454. In certain embodiments, -D is ADU-S100 (MIW815). In certain embodiments, -D is 2'3'-cGAMP.

[0416] When -D is an aryl hydrocarbon receptor (AhR), such AhR can be selected from the group consisting of FICZ, ITE and L-kynurenine.

[0417] In certain embodiments, -D is selected from the group consisting of bactericidal molecules, cytotoxic agents, chemotherapeutic agents, antihormonal agents, radioisotopes, photosensitizers, enzymes, hormones, antibodies, interleukins, immunostimulatory molecules, immunosuppressive molecules, and DNA damaging agents. It is understood that the conjugates of the present invention may include combinations of two or more such drugs.

[0418] In one embodiment, -D is a cytotoxic agent that inhibits or prevents cell function and / or causes cell destruction. Examples of cytotoxic agents include chemotherapeutic agents and toxins of bacterial, fungal, plant or animal origin, such as small molecule toxins or enzymatically active toxins, including synthetic analogs and derivatives thereof. The cytotoxic agent may be selected from the group consisting of auristatin, DNA minor groove binder, DNA minor groove alkylating agent, tubulin disrupting substance, enediynes, rexitropsin, duocarmycin, taxane, anthracycline, puromycin, dolastatin, maytansinoid, and vinca alkaloid or combinations of two or more thereof. It is understood that the conjugates of the present invention may include combinations of two or more such drugs.

[0419] In one embodiment, -D is a topoisomerase inhibitor; an alkylating agent such as nitrogen mustard; ethylenime; an alkyl sulfonate; a triazene; a piperazine; a nitrosourea; an antimetabolite such as mercaptopurine, thioguanine or 5-fluorouracil; an antibiotic such as anthracycline, dactinomycin, bleomycin, adriamycin, mitramycin or dactinomycin; a mitotic disruptor such as a plant alkaloid, for example vincristine and / or a microtubule antagonist, for example paclitaxel; a DNA intercalator such as carboplatin and / or cisplatin; a DNA synthesis inhibitor; a DNA-RNA transcription regulator; an enzyme inhibitor; a gene regulator; a hormone response modifier; a hypoxia-selective cytotoxin such as tirapazamine; an epidermal growth factor inhibitor; an anti-angiogenic agent such as xanthenone 5,6-dimethylxanthenone-4-acetic acid; a radiation-activated prodrug such as a quaternary nitroarylmethyl salt (NMQ); and a chemotherapeutic agent selected from the group consisting of in vivo reducing drugs. It is understood that the conjugates of the present invention may include combinations of two or more such drugs.

[0420] The chemotherapeutic agent can be selected from the group consisting of erlotinib (TARCEVA (registered trademark)), bortezomib (VELCADE (registered trademark)), fulvestrant (FASLODEX (registered trademark)), sunitinib (Sutent (registered trademark)), letrozole (FEMARA (registered trademark)), anastrozole (Arimidex (registered trademark)), imatinib mesylate (GLEEVEC (registered trademark)), batatinib (PTK787 / ZK 222584), oxaliplatin (Eloxatin (registered trademark)), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE (registered trademark)), everolimus (Afinitor (registered trademark)), lapatinib (Tykerb / Tyverb (registered trademark)), lonafarnib (Lonafamib) (SCH 66336), sorafenib (Nexavar (registered trademark)), gefitinib (IRESSA (registered trademark)), AG1478, and AG1571 (SU 5271; Sugen). It is understood that the conjugate of the present invention may include a combination of two or more such chemotherapeutic agents.

[0421] Chemotherapeutic agents include alkylating agents such as thiotepa, CYTOXAN® and / or cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and / or piposulfan; aziridines such as benzodopa, carboquone, meturedopa and / or uredopa; ethyleneimine and / or methylmelamine such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and / or trimethylmelamine; acetogenins such as bullatacin and / or bullatacinone; camptothecin; bryostatin; calistatin; cryptophycin; dolastatin; duocarmycin; erythrovidins; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chromaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbine, phenesterine, prednimustine, trofosfamide and / or uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and / or ranimustine; dynemicin; bisphosphonates such as clodronate; esperamicin; neocarzinostatin chromophore; aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, calminomycin, cardinophilin, chromomycinsis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®, doxorubicin such as morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C;Mycophenolic acid, nogalamycin, oligomycin, peplomycin, potfiromycin, puromycin, keramycin, daunorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; metabolic antagonists, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diacodone; elfomomycin; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; macrocyclic depsipeptides, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; rizoxin; sizofiran; spirogermanium; tenuazonic acid; triacodone; 2,2',2''-trichlorotriethylamine; trichothecenes, such as verracurin A, loridin A and / or anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; taxoids, such as TAXOL (registered trademark), paclitaxel, abraxane, and / or TAXOTERE (registered trademark), docetaxel;Chlorambucil; GEMZAR (registered trademark), gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; NAVELBINE (registered trademark), vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronate; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids; and derivatives thereof. It is understood that the conjugates of the present invention may include combinations of two or more such chemotherapeutic agents.;

[0422] -D is a tubulin-disrupting substance such as a taxane, for example paclitaxel and docetaxel, vinca alkaloids, discodermolide, epothilones A and B, desoxyepothilone, cryptophycin, curacin A, combretastatin A-4-phosphate, BMS247550, BMS184476, BMS188791; RPR109881A, EPO906, TXD258, ZD6126, vinflunine, LU103793, dolastatin 10, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), E7010, T138067 and T900607, colchicine, phenylstatine, chalcone, indanocine, onocidin, vincristine, vinblastine, vinorelbine, vinflunine, halicondrin B, isohomohalicondrin B, ER-86526, pyronetin, spongistatin 1, spiket P, cryptophycin 1, LU103793 (sematodine or semadotin), lysocine, sarcodictyin, erythrobine, laurylamide, VP-16 and D-24851, and pharmaceutically acceptable salts, acids, derivatives and combinations of two or more of any of the above. The drug may also be a drug that inhibits cyclin-dependent kinase (CDK), for example dinaciclib (SCH-727965).

[0423] -D can be a DNA intercalating agent, such as acridine, actinomycin, anthracycline, benzothiopyranoindazole, pixantrone, crisnatol, brostallicin, CI-958, doxorubicin (adriamycin), actinomycin D, daunorubicin (daunomycin), bleomycin, idarubicin, mitoxantrone, cyclophosphamide, melphalan, mitomycin C, bizelesin, etoposide, mitoxantrone, SN-38, carboplatin, cis-platin, actinomycin D, amsacrine, DACA, pyrazoloacridine, irinotecan and topotecan, and pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the above.

[0424] -D can be an antihormonal agent that acts to regulate or inhibit the hormonal action on tumors, such as tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LYl17018, onapristone and / or ferlestrant tremifen and pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the above, including antiestrogens or selective estrogen receptor modulators.

[0425] -D can be an aromatase inhibitor that inhibits the enzyme aromatase that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, AROMASIN (registered trademark), exemestane, formestanie, fadrozole, RIVISOR (registered trademark), vorozole, FEMARA (registered trademark), letrozole, ARIMIDEX (registered trademark) and / or anastrozole, and pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the above.

[0426] -D can be an antiandrogen such as flutamide, nilutamide, bicalutamide, leuprorelin, goserelin, triptorelin and / or troxacitabine, abiraterone, enzalutamide, and pharmaceutically acceptable salts, acids, derivatives or combinations of any two or more of the foregoing.

[0427] -D can be a protein kinase inhibitor, a lipid kinase inhibitor, or an anti-angiogenic agent. Exemplary kinase inhibitors include lapatinib, AZD-2171, ET18OCH, indirubin-3'-oxime, NSC-154020, PD169316, quercetin, roscovitine, triciribine, ZD1839, 5-iodotubercidin, adafostin, alloisoleucine, alsterpaullone, aminogenistein, API-2, apigenin, arctigenin, ARRY-334543, axitinib (AG-013736), AY-22989, AZD-2171, bisindolylmaleimide IX, CC1-779, celerin, DMPQ, DRB, edelfosine, ENMD-981693, erbstatin analog, erlotinib, fasudil, gefitinib (ZD1839), H-7, H-8, H-89, HA-100, HA-1004, HA-1077, HA-1100, hydroxyfasudil, kempaurone, KN-62, KY12420, LFM-A13, luteolin, LY294002, marotoxin, ML-9, MLN608, NSC226080, NSC-231634, NSC-664704, NSC-680410, NU6102, oromucin, oxyindole I, PD153035, PD98059, phloridzin, piceatannol, picropodophyllin, PKI, PP1, PP2, PTK787 / ZK222584, purvalanol A, rapamycin, rapamune, rapamycin, Ro31-8220, rottlerin, SB202190, SB203580, sirolimus, SL327, SP600 125, staurosporine, STI-571, SU1498, SU4312, SU5416, SU5416 (semaxanib), SU6656, SU6668, syk inhibitor, TBB, TCN, tyrphostin AG1024, tyrphostin AG490, tyrphostin AG825, tyrphostin AG957, U0126, W-7, wortmannin, Y-27632, zactima (ZD6474), and ZM252868. TKIs approved for cancer treatment include, for example, sorafenib and sunitinib.KIs currently in clinical trials for use in anti-cancer therapies and / or novel indications include, for example, MK0457, VX-680, ZD6474, MLN8054, AZD2171, SNS-032, PTK787 / ZK222584, Sorafinib (BAY43-9006), SU5416, SU6668, AMG706, Zactima (ZD6474), MP-412, Dasatinib, CEP-701 (lestaurtinib), XL647, XL999, Tykerb (lapatinib), MLN518 (formerly known as CT53518), PKC412, ST1571, AMN107, AEE788, OSI-930, OSI-817, Sunitinib maleate (Sutent SU11248), Batalanib (PTK787 / ZK 222584), SNS-032, SNS-314, and Axitinib (AG-013736). Gefitinib and Erlotinib are two orally available EGFR-TKIs. Thus, in certain embodiments, the kinase inhibitor is a tyrosine kinase inhibitor, such as a multi-kinase inhibitor. A "multi-kinase inhibitor" is an inhibitor that acts on more than one specific kinase. Multi-kinase inhibitors include, for example, so-called DGF out-binders such as Imatinib, Sorafinib, Lapatinib, BIRB-796, and AZD-1152. Other multi-kinase inhibitors include AMG706, Zactima (ZD6474), MP-412, Sorafinib (BAY43-9006), Dasatinib, CEP-701 (lestaurtinib), XL647, XL999, Tykerb (lapatinib), MLN518 (formerly known as CT53518), PKC412, ST1571, AEE788, OSI-930, OSI-817, Sutent (Sunitinib maleate), Axitinib (AG-013736), Erlotinib, Gefitinib, Lenvatinib, Temsirolimus, and Nilotinib AMN107. In certain embodiments, such multi-kinase inhibitors are selected from the group consisting of sunitinib, axitinib, lenvatinib, and / or sorafinib, or pharmaceutically acceptable salts or derivatives thereof, such as their malate or tosylate salts.The term "derivative" refers to a chemical modification that still retains the kinase inhibitory function of the parent molecule. Examples of derivatives are disclosed in, for example, the patent applications referred to below. Sunitinib is a potent and selective anti-angiogenic agent that targets multiple receptor tyrosine kinase inhibitors including PDGFR, KIT, and VEGFR. Sunitinib or its L-malate salt is also called SU11248, SUO11248, sunitinib malate (USAN / WHO nomenclature), or Sutent (L-malate).

[0428] In certain embodiments, -D is an antisense RNA, antisense DNA, ribozyme, or RNAi molecule that targets VEGF nucleic acid; an anti-VEGF aptamer, anti-VEGF antibody, anti-VEGF antibody fragment, DARPins, and soluble VEGF decoy receptor that prevent the binding of VEGF to its cognate receptor; an antisense, ribozyme, and RNAi molecule that targets cognate VEGF receptor (VEGFR) nucleic acid; an anti-VEGFR aptamer or anti-VEGFR antibody that binds to the cognate VEGFR receptor; an anti-VEGFR antibody fragment that binds to the cognate VEGFR receptor, and a VEGF neutralizing prodrug selected from the group consisting of VEGFR tyrosine kinase inhibitors.

[0429] Such VEGF neutralizing prodrugs can be selected from the group consisting of ranibizumab, bevacizumab, pegaptanib, aflibercept, MP0112, KH902, ESBA1008, AL39324, ALG-1001, and bevaciranib and / or their fragments.

[0430] In certain embodiments, -D is an anti-CTLA-4 antibody in an amount that inhibits the CTLA-4 pathway or an anti-PD-1 / anti-PD-L1 antibody in an amount that inhibits the PD-1 pathway. With respect to anti-PD-1 and anti-PD-L1 antibodies, these are known and include nivolumab and pembrolizumab, AMP-224, atezolizumab, durvalumab, avelumab, semiprimab, tremelimumab, and ipilimumab.

[0431] Such antibodies (or fragments thereof) antagonize immune checkpoint functions. Many such antibodies, such as pembrolizumab (MK-3475, Merck), nivolumab (BMS936558, Bristol-Myers Squibb), pidilizumab (CT-011, Cure Tech Ltd.), AMP-224 (Merck), MDX-1105 (Medarex), MEDI4736 (MedImmune), atezolizumab (MPDL3280A) (Genentech), avelumab (Merck KGaA / Pfizer), BMS-936559 (Bristol-Myers Squibb), ipilimumab (Bristol-Myers Squibb), durvalumab (Astrazeneca) and tremelimumab (Pfizer) are known in the art. Anti-KIR antibodies, such as lirilumab (Innate Pharma) and IPH2101 (Innate Pharma), can perform similar functions in NK cells.

[0432] An assay for determining whether a given compound can act as an anti-CTLA-4 antibody, an anti-PD-L1 antibody or an anti-PD-1 antibody can be determined by routine experimentation by one of ordinary skill in the art.

[0433] In alternative embodiments, a combination with an antibody-drug conjugate (ADC) may be desirable. ADCs are particularly effective in reducing tumor burden without significant systemic toxicity and may act to improve the effectiveness of the immune response induced by checkpoint inhibitor antibodies. Exemplary ADCs approved for therapeutic use include gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, and trastuzumab emtansine in AML. A number of other candidate ADCs, such as glembatumomab vedotin, SAR3419, SAR56658, AMG-172, AMG-595, BAY-94-9343, BIIB015, BT062, SGN-75, SGN-CD19A, volociximab mafodotin, ABT-414, ASG-5ME, ASG-22ME, ASG-16M8F, IMGN-529, IMGN-853, MDX-1203, MLN-0264, RG-7450, RG-7458, RG-7593, RG-7596, RG-7598, RG-7599, RG-7600, RG-7636, anti-PSMA ADC, lorvotuzumab mertansine, mirvetuximab doxorubicin, IMMU-130, and IMMU-132 are currently in clinical testing.

[0434] In certain embodiments, the radioisotope of -D is a radioisotope of, for example, technetium, indium, yttrium, copper, lutetium, or rhenium.

[0435] -D can be an antibody that can be used for cancer treatment, such as hA19 (anti-CD19, US Patent No. 7,109,304), hR1 (anti-IGF-1R, US Patent No. 9,441,043), hPAM4 (anti-MUC5ac, US Patent No. 7,282,567), hA20 (anti-CD20, US Patent No. 7,151,164), hIMMU31 (anti-AFP, US Patent No. 7,300,655), hLL1 (anti-CD74, US Patent No. 7,312,318), hLL2 (anti-CD22, US Patent No. 5,789,554), hMu-9 (anti-CSAP, US Patent No. 7,387,772), hL243 (anti-HLA-DR, US Patent No. 7,612,180), hMN-14 (anti-CEACAMS, US Patent No. 6,676,924), HMN15 (anti-CEACAM6, US Patent No. 8,287,865), hRS7 (anti-EGP-1, US Patent No. 7,238,785), hMN-3 (anti-CEACAM, US Patent No. 7,541,440), Ab124 and Ab125 (anti-CXCR4, US Patent No. 7,138,496). The example sections of each cited patent or application are incorporated herein by reference. The antibody can be of various isotypes, such as human IgG1, IgG2, IgG3 or IgG4, or can contain human IgG1 hinge and constant region sequences. The antibody or its fragment can be chimeric human-mouse, humanized (human framework and mouse hypervariable (CDR) regions) or fully human, as described by van der Neut Kolfschoten et al. (Science 2007; 317: 1554-1557), and their modifications, such as half-IgG4 antibodies (referred to as "unibodies"). In certain embodiments, the antibody or its fragment can be designed or selected to contain a human constant region sequence belonging to a particular allotype that can cause a reduction in immunogenicity when administered to a human subject. Preferred allotypes for administration include non-Glm1 allotypes (nGlml), such as Glm3, Glm3,1, Glm3,2 or Glm3,1,2. More preferably, the allotype is selected from the group consisting of nGlm1, Glm3, nGlm1,2 and Km3 allotypes. Combination therapy with immunostimulatory antibodies has been reported to improve the efficacy against tumor cells, for example.Morales - Kastresana et al. (Clin Cancer Res 19:6151 - 62, 2013) showed that the combination of the anti - PD - 1 (10B5) antibody with anti - CD137 (108) and anti - OX40 (OX86) antibodies improved efficacy in a transgenic mouse model of hepatocellular carcinoma. Alternative antibodies that can be used in - D include abciximab (anti - glycoprotein IIb / IIIa), alemtuzumab (anti - CD52), bevacizumab (anti - VEGF), cetuximab (anti - EGFR), gemtuzumab (anti - CD33), ibritumomab (anti - CD20), panitumumab (anti - EGFR), rituximab (anti - CD20), tositumomab (anti - CD20), trastuzumab (anti - ErbB2), pembrolizumab (anti - PD - 1 receptor), nivolumab (anti - PD - 1 receptor), ipilimumab (anti - CTLA - 4), abagovomab (anti - CA - 125), adecatumumab (anti - EpCAM), atorizumab (anti - IL - 6 receptor), benralizumab (anti - CD125), obinutuzumab (GA101, anti - CD20), CC49 (anti - TAG - 72), AB - PG1 - XG1 026 (anti - PSMA), D2 / B (anti - PSMA), tocilizumab (anti - IL - 6 receptor), basiliximab (anti - CD25), daclizumab (anti - CD25), efalizumab (anti - CD11a), GA101 (anti - CD20), natalizumab (atalizumab) (anti - alpha4 integrin), omalizumab (anti - IgE); anti - TNF - alpha antibodies such as anti - transforming growth factor beta, anti - colony - stimulating factor - 1 receptor (CSF1 - R) Ab, CDP571, MTNFAI, M2TNFAI, M3TNFAI, M3TNFABI, M302B, M303, infliximab, certolizumab pegol, anti - CD40L, adalimumab, BENLYSTA; anti - CD38 antibodies such as MORO3087, MOR202, HuMax - CD38 or daratumumab. These checkpoint inhibitors can be administered in combination with one or more other immunomodulatory substances to improve the immune response.Immune regulatory substances can be selected from the group consisting of cytokines, chemokines, stem cell growth factors, lymphotoxins, hematopoietic factors, colony-stimulating factors (CSF), erythropoietin, thrombopoietin, tumor necrosis factor alpha (TNF), TNF beta, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon alpha, interferon beta, interferon gamma, interferon lambda, a stem cell growth factor named "S1 factor", human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), liver growth factor, prostaglandins, fibroblast growth factor, prolactin, placental lactogen, OB protein, Müllerian inhibiting substance, mouse gonadotropin-related peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF beta, platelet growth factor, TGF alpha, TGF beta, insulin-like growth factor I, insulin-like growth factor II, macrophage-CSF (M-CSF), IL-1, IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, LIF, FLT-3, angiostatin, thrombospondin, endostatin and lymphotoxin.

[0436] Examples of antibodies, including their fragments, also include bispecific antibodies, bispecific T-cell engagers (BiTE), dual affinity retargeting (DART) and nanobodies, such as those described in US8,907,065, WO2017087589A2 and WO2017087588A1, which are incorporated herein by reference.

[0437] -D can be a RIG-I agonist, such as RIG-I agonists KIN700, KIN1148, KIN600, KIN500, KIN100, KIN101, KIN400, KIN2000, RGT100 or SB-9200.

[0438] -D may be an MDA-5 agonist, such as MDA-5 agonist nucleic acid band 2 (NAB2) or poly(I:C).

[0439] -D may be a NOD1 or NOD2 agonist, such as iE-DAP or MDP, respectively.

[0440] -D may be a TLR1 agonist, TLR2 agonist, TLR3 agonist, TLR4 agonist, TLR5 agonist, TLR6 agonist, TLR7 agonist, TLR8 agonist, TLR9 agonist or TLR10 agonist. The drug may be selected from the group consisting of S-27609, CL307, UC IV150, imiquimod, gardiquimod, resiquimod, motolimod, Rintatolimod, VTS-1463GS-9620, GSK224.5035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, CL663, CBLB612, CBLB613, MALP2S, OPN305, OM174, SMP105, MCT475, Apoxxim (registered trademark), RGIC (registered trademark) 100, RGIC (registered trademark) 50, G100 Glucopyranosyl lipid, GSK1795091, IMO8400, loxoribine, Agatolimod, IMO2125, Lefitolimod, SD101, Litenimod, CMP001, IMO2055, AST008, DV281 or GNKG168.

[0441] -D may be a STING activator containing one or more cyclic dinucleotides including, but not limited to, one or more of c-di-AMP, c-di-GMP, c-di-IMP, c-AMP-GMP, c-AMP-IMP, c-GMP-IMP and analogs thereof. The drug may be selected from the group consisting of ADU-S100, MK-1454, SRCB-0001, SB11285 or GSK53.

[0442] -D may be selected from the group consisting of antibodies, nanobodies and ligands that target immune regulatory receptors, such as Lag-3, Tim-3, TIGIT, GITR, CD28, CD40, ICOS, ILT2 (PMID: 29123965), ILT3 (PMID: 30126665), ILT4 (PMID: 29649510), MARCO (PMID: 27210762), LAIR1 (PMID: 25915125), BAG3). -D may be selected from the group consisting of Relatlimab (BMS-986016), AVA017, BI754111, ENUM006, GSK2831781, IKT2013, IMP761, INCAGN2385, LAG525, MK4280, REGN3767, Sym016, Sym022, TSR033, TSR075, XmAB22841, BGB-A425, ENUM005, IMM1802, INCAGN2390, LY3321367, MBG453, Sym016, Sym023, MK7684, AB154, AGEN1307, BMS986207, CASC674, COM902, ENUM009, EOS884448, NB6253, OMP313M32, Tisagolumab (RG6058), MS-986156, AMG228, AVA018, CK302, FPA154, GITRL-Fc, GWN323, INCAGN1876, JNJ64164711, LKZ145, MEDI1873, MK1248, MK4166, TRX518, ADC1013, APX005M, CD40 agonist, CD40 ligand CELLDEX, CDX1140, CGEN40, ChiLob 7 / 4, DNP005, HCD122 (Lucatumumab), MEDI5083, Mega CD40L, SEACD40, SGN40 (Dacetuzumab), JTX2011, HP-F1 anti-ILT2 / CD85j blocking antibody (IgG1) and TRX385.

[0443] In addition, -D can be a modulator of tumor metabolism, for example, a drug that inhibits the adenosine pathway (anti-CD73 antibody or nanobody, adenosine receptor agonist or antagonist), inhibits tryptophan metabolism (IDO, TDO, and IDO / TDO dual inhibitors), or inhibits the arginine pathway (arginase or arginase inhibitor). -D can be selected from the group consisting of, but not limited to, IPH53, SRF373, IB-MECA, Cl-IB-MECA, TP455, and PBF-509.

[0444] -D can also be a small molecule drug, antibody, or nanobody that targets chemokines and chemokine receptors. Examples of chemokines and chemokine receptors that can be targeted are CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CCR2, CCR4, CCR5, CCR10, CXCR2, and CXCR4. -D can be selected from the group consisting of, but not limited to, AT008, HGS004, PRO140, CXCR2 monoclonal antibody, 515H7 monoclonal antibody PIERRE FABRE, AT007, AT009, and CXCR4 monoclonal antibody NORTHWEST.

[0445] In certain embodiments, D-H or D-OH is basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), angiogenin, platelet-derived endothelial cell growth factor (PD-ECGF), interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12, vascular endothelial growth factor (VEGF), angiopoietin-I, Del-I, follistatin, granulocyte colony-stimulating factor (G-CSF), hepatocyte growth factor (HGF), leptin, midkine, placental growth factor, pleiotrophin (PTN), progranulin, proliferin, tumor necrosis factor alpha (TNF alpha), angioarrestin, angiostatin plasminogen fragment, anti-angiogenic antithrombin III, cartilage-derived inhibitor (CDI), CDS9 complement fragment, endostatin collagen XVIII fragment, fibronectin fragment, gro-beta, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha / beta / gamma, interferon-induced protein (IP-IO), kringle S plasminogen fragment, metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor 4 (PF4), prolactin 16kD fragment, proliferin-related protein (PRP), retinoid, tetrahydrocortisol-S, thrombospondin-I (TSP-I), vasculostatin, vasculostatin calreticulin fragment, prostaglandin receptor, insulin-like growth factor-I (IGF-I), sphingosine-1-phosphate, factor D, RTP801, complement inhibitor, α2 adrenergic agonist, mTOR, ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), lens epithelial cell-derived growth factor (LEDGF), rod-derived cone viabilitya drug that modulates the activity of one or more proteins selected from the group consisting of pigment epithelium-derived factor (PEDF), neutrophil-activating protein, monocyte chemoattractant protein, macrophage inflammatory protein, small inducible secreted (SIS) protein, platelet factor, platelet basic protein, melanoma growth-stimulating activity, epithelial growth factor, nerve growth factor, bone morphogenetic protein, bone growth cartilage-inducing factor, interleukin, interleukin inhibitor, interleukin receptor, hematopoietic factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, inhibin, and activin. In some embodiments, -D is a VEGF antagonist.

[0446] In certain embodiments, -D can be an antibody moiety. Any suitable antibody (e.g., an anti-VEGF antibody) can be used. For example, the antibody can specifically bind to an antigen selected from the group consisting of VEGF, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-6 receptor (IL-6R), interleukin-13 (IL-13), IL-13 receptor (IL-13R), PDGF (e.g., PDGF-BB), angiopoietin, angiopoietin 2 (Ang2), Tie2, S1P, integrin αvβ3, αvβ5 and α5β1, betacellulin, apelin / APJ, erythropoietin, complement factor D, TNFα, HtrA1, VEGF receptors (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptor (mbVEGFR) or soluble VEGF receptor (sVEGFR)), ST-2 receptor, and proteins genetically associated with the risk of age-related macular degeneration (AMD) (e.g., C2, factor B, factor H, CFHR3, C3b, C5, C5a and C3a components of the complement pathway, HtrA1, ARMS2, TIMP3, HLA, interleukin-8 (IL-8), CX3CR1, TLR3, TLR4, CETP, LIPC, COL10A1, and TNFRSF10A). Such antibodies can be useful, for example, for reducing angiogenesis and / or treating or delaying the progression of disorders associated with pathological angiogenesis (e.g., ocular disorders or cell proliferative disorders).

[0447] In certain embodiments, -D can be an anti-VEGF antibody or a fragment thereof. Anti-VEGF antibody fragments can be selected, for example, from Fab, Fab-C, Fab'-SH, Fv, scFv and (Fab')2 fragments.

[0448] In certain embodiments, the antibody may be G6.31 AARR or a variant thereof as described in U.S. Patent No. 10,072,075 and International Application No. PCT / US2018 / 023857, the disclosures of which are incorporated herein by reference. In such embodiments, the antibody may be, for example, G6.31 AARR expressed in Fab format or a variant of G6.31 AARR lacking reactivity to anti-human IgG.

[0449] In certain embodiments, -D is a TKI moiety.

[0450] In certain embodiments, -D is selected from the group consisting of receptor tyrosine kinase inhibitors, intracellular kinase inhibitors, cyclin-dependent kinase inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, mitogen-activated protein kinase inhibitors, nuclear factor kappa β kinase inhibitors (IKK), and Wee-1 inhibitors.

[0451] In certain embodiments, -D is a receptor tyrosine kinase inhibitor. Examples of such receptor tyrosine kinase inhibitors are EGF receptor inhibitors, VEGF receptor inhibitors, C-KIT receptor inhibitors, ERBB2 (HER2) inhibitors, ERBB3 receptor inhibitors, FGF receptor inhibitors, AXL receptor inhibitors, and MET receptor inhibitors.

[0452] In certain embodiments, -D is an EGF receptor inhibitor, such as afatinib, cetuximab, erlotinib, gefitinib, pertuzumab, and matuzumab.

[0453] In certain embodiments, -D is a VEGF receptor inhibitor, such as axitinib, lenvatinib, pegaptanib, and linifanib (ABT-869). In certain embodiments, -D is axitinib. In certain embodiments, -D is lenvatinib.

[0454] In certain embodiments, -D is a C-KIT receptor inhibitor, such as CDX0158 (KTN0158).

[0455] In certain embodiments, -D is an ERBB2 (HER2) inhibitor, such as Herceptin (trastuzumab).

[0456] In certain embodiments, -D is an ERBB3 receptor inhibitor, such as CDX3379 (MEDI3379, KTN3379) and AZD8931 (sapitinib).

[0457] In certain embodiments, -D is an FGF receptor inhibitor, such as erdafitinib.

[0458] In certain embodiments, -D is an AXL receptor inhibitor, such as BGB324 (BGB324, R428, R428, bemcentinib) and SLC391.

[0459] In certain embodiments, -D is a MET receptor inhibitor, such as CGEN241 or tivantinib. In certain embodiments, -D is tivantinib.

[0460] In certain embodiments, -D is an intracellular kinase inhibitor. Examples of such intracellular kinase inhibitors are Bruton tyrosine kinase (BTK) inhibitors, spleen tyrosine kinase inhibitors, Bcr-Abl tyrosine kinase inhibitors, Janus kinase inhibitors, and multi-specific tyrosine kinase inhibitors.

[0461] In certain embodiments, -D is a BTK inhibitor, such as ibrutinib, acalabrutinib, GS-4059, spebrutinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI-BTK1, and vecabrutinib.

[0462] In certain embodiments, -D is a spleen tyrosine kinase inhibitor, such as fostamatinib.

[0463] In certain embodiments, -D is a Bcr-Abl tyrosine kinase inhibitor, such as imatinib and nilotinib.

[0464] In certain embodiments, -D is a Janus kinase inhibitor, such as ruxolitinib, tofacitinib, and fedratinib.

[0465] In certain embodiments, -D is a multi-specific tyrosine kinase inhibitor, such as bosutinib, crizotinib, cabozantinib, dasatinib, enzooticinib, lapatinib, mubritinib, pazopanib, sorafenib, sunitinib, SU6656, and vandetanib. In certain embodiments, -D is crizotinib. In certain embodiments, -D is cabozantinib, an inhibitor of c-Met, VEGFR2, AXL, and RET.

[0466] In certain embodiments, -D is a cyclin-dependent kinase inhibitor. Examples of cyclin-dependent kinase inhibitors are copanlisib, ribociclib, palbociclib, abemaciclib, trilaciclib, purvalanol A, olomoucine II, and MK-7965. In certain embodiments, -D is copanlisib.

[0467] In certain embodiments, -D is a phosphoinositide-3-kinase inhibitor. Examples of phosphoinositide-3-kinase inhibitors are IPI549, GDC-0326, pictilisib, serabelisib, IC-87114, AMG319, selitrectinib, idelalisib, and CUDC907.

[0468] In certain embodiments, -D is a mitogen-activated protein kinase inhibitor. Examples of mitogen-activated protein kinase inhibitors are Ras / farnesyltransferase inhibitors, Raf inhibitors, MEK inhibitors, and ERK inhibitors.

[0469] In certain embodiments, -D is a Ras / farnesyl transferase inhibitor, such as tipifarnib and LB42708.

[0470] In certain embodiments, -D is a Raf inhibitor, such as regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, lifirafenib, PLX7904, and RO5126766.

[0471] In certain embodiments, -D is a MEK inhibitor, such as cobimetinib, trametinib, binimetinib, selumetinib, pimasertib, refametinib, and PD0325901. In certain embodiments, -D or the drug is cobimetinib.

[0472] In certain embodiments, -D is an ERK inhibitor, such as MK-8353, GDC-0994, ulixertinib, and SCH772984.

[0473] In certain embodiments, -D is an inhibitor of the nuclear factor inhibitor IKK. Examples of nuclear factor kappa β kinase inhibitors (IKK) are BPI-003 and AS602868.

[0474] In certain embodiments, -D is a Wee-1 inhibitor. An example of a Wee-1 inhibitor is adavosertib.

[0475] In certain embodiments, -D is selected from the group consisting of lenvatinib, axitinib, cobimetinib, crizotinib, cibitinib, copanlisib, and cabozantinib.

[0476] In certain embodiments, -D is an anti-CTLA4 moiety.

[0477] In certain embodiments, -D is wild-type F cIt is selected from the group consisting of anti-CTLA4 antibodies, effector function-enhanced Fc / FcγR-binding anti-CTLA4 antibodies, anti-CTLA4 antibodies that are conditionally active in the tumor microenvironment, anti-CTLA4 small molecules, CTLA4 antagonist-conjugated proteins, anti-CTLA4 anticalins, anti-CTLA4 nanobodies, and anti-CTLA4 multispecific biologics based on antibodies, scFvs or other formats. In certain embodiments, -D is wild-type F c is an anti-CTLA4 antibody. In certain embodiments, -D is an effector function-enhanced Fc / FcγR-binding anti-CTLA4 antibody. In certain embodiments, -D is an anti-CTLA4 antibody that is conditionally active in the tumor microenvironment. In certain embodiments, -D is an anti-CTLA4 small molecule. In certain embodiments, -D is a CTLA4 antagonist-conjugated protein. In certain embodiments, -D is an anti-CTLA4 anticalin. In certain embodiments, -D is an anti-CTLA4 nanobody. In certain embodiments, -D is an anti-CTLA4 multispecific biologic based on an antibody, scFv or other format. In certain embodiments, -D is an anti-CTLA4 multispecific biologic based on an antibody. In certain embodiments, -D is an anti-CTLA4 multispecific biologic based on an scFv.

[0478] Exemplary wild-type Fc anti-CTLA4 antibodies are selected from the group consisting of ipilimumab, tremelimumab, MK-1308, CBT509 (also known as APL-509), ONC392, IBI310, CG0161, BCD145, ADU1604, AGEN1884 and CS1002. In certain embodiments, -D is ipilimumab. In certain embodiments, -D is tremelimumab.

[0479] Exemplary effector function-enhanced Fc / FcγR-binding anti-CTLA4 antibodies are selected from the group consisting of AGEN1181 and anti-CTLA-4 SIF body.

[0480] The conditionally active anti-CTLA4 antibodies in the exemplary tumor microenvironment are selected from the group consisting of BMS-986249 and BA3071.

[0481] The exemplary anti-CTLA4 small molecule is BPI-002.

[0482] The exemplary CTLA4 antagonist fusion protein is FPT155.

[0483] The exemplary anti-CTLA4 anti-carlin is PRS010.

[0484] The exemplary anti-CTLA4 multispecific biologic is selected from the group consisting of TE1254, XmAb22841, XmAb20717, MEDI5752, MGD019, ALPN-202, ATOR-1015, and ATOR-1144.

[0485] It is understood that the conjugate of the present invention is a prodrug.

[0486] -L 1 The - part is a linker part, from which -D is preferably released in its free form, i.e., in the form of D-H or D-OH. Such parts are also known as "prodrug linkers" or "reversible prodrug linkers" and are known in the art, for example, the reversible linker parts disclosed in WO2005 / 099768A2, WO2006 / 136586A2, WO2011 / 089216A1, WO2013 / 024053A1, WO2011 / 012722A1, WO2011 / 089214A1, WO2011 / 089215A1, WO2013 / 024052A1, and WO2013 / 160340A1, which are incorporated herein by reference.

[0487] In certain embodiments, the -L 1 - part is as disclosed in WO2009 / 095479A2. Thus, in certain embodiments, the -L 1 - part is of formula (I):

[0488] [Chemical formula] [In the formula, the broken line indicates the bond to nitrogen, hydroxyl or thiol of -D, -X- is selected from the group consisting of -C(R 4 R 4a ), -N(R 4 ), -O-, -C(R 4 R 4a )-C(R 5 R 5a )-, -C(R 5 R 5a )-C(R 4 R 4a )-, -C(R 4 R 4a )-N(R 6 ), -N(R 6 )-C(R 4 R 4a )-, -C(R 4 R 4a )-O-, -O-C(R 4 R 4a ), and -C(R 7 R 7a ), and is selected from the group consisting of: X 1 is selected from the group consisting of C and S(O); -X 2 - is selected from the group consisting of -C(R 8 R 8a ), and -C(R 8 R 8a )-C(R 9 R 9a ); =X 3 is selected from the group consisting of =O, =S, and =N-CN; -R 1 , -R 1a , -R 2 , -R 2a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 8 , -R 8a , -R 9 and -R9a is independently selected from the group consisting of -H and C 1~6 alkyl, provided that when one or both of -R 3 and -R 3a is other than -H, -R 1~6 and -R 3 are connected via an sp 3a hybridized carbon atom to the N to which they are attached, 3 -R 3a is selected from the group consisting of -N(R 3 R 3 ) and -NR -R 7 -(C=O)-R 10 R 10a ), and -R 10 -R 11 -R -R 7a and -R 10 -R 10a are independently selected from the group consisting of -H and C 11 alkyl, and optionally, one or more of the pairs of 1~6 -R / -R 1a -R 4a / -R 1a -R 5a / -R 1a -R 7a / -R 4a -R 5a / -R 8a form a chemical bond, and optionally, one or more of the pairs of 9a -R / -R 1 -R 1a / -R 2 -R 2a / -R 4 -R 4a / -R 5 -R 5a / -R 8 -R 8a / -R 9 -R 9a / -R 3~10forms a cycloalkyl or 3- to 10-membered heterocyclyl, optionally, -R 1 / -R 4 、-R 1 / -R 5 、-R 1 / -R 6 、-R 1 / -R 7a 、-R 4 / -R 5 、-R 4 / -R 6 、-R 8 / -R 9 and -R 2 / -R 3 one or more of the pairs of which, together with the atoms to which they are attached, form ring A, optionally, -R 3 / -R 3a forms a 3- to 10-membered heterocycle together with the nitrogen atom to which it is attached, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclicyl] and is such that -L 1 - is replaced by -X 0D -L 2 -, and -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (I) is not replaced by -X 0D -L 2 - or a substituent.

[0489] Any optional further substituent of -L 1 - in formula (I) is as described above.

[0490] In certain embodiments, -L 1 - in formula (I) is replaced by one -X 0D -L 2 - moiety.

[0491] In certain embodiments, -L in formula (I)1 - is not further substituted.

[0492] -R in formula (I) 3 / -R 3a However, when these are combined with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is sp 3 It is understood that only 3- to 10-membered heterocyclic rings can be formed that are hybridized carbon atoms. 3 / -R 3a However, the 3- to 10-membered heterocycle formed together with the nitrogen atom to which they are bonded has the following structure:

[0493] [ka] [In the formula, A dashed line without a mark is -L 1 - indicates the bond to the remainder of The ring contains 3 to 10 atoms, including at least one nitrogen atom; R # and R ## sp 3 represents a hybridized carbon atom] has.

[0494] It is also understood that the 3- to 10-membered heterocycle can be further substituted.

[0495] -R in formula (I) 3 / -R 3a However, exemplary embodiments of suitable 3-10 membered heterocyclic rings formed together with the nitrogen atom to which they are attached are as follows:

[0496] [ka] [In the formula, The dashed lines indicate the bonds to the rest of the molecule; -R is -H and C 1~6 alkyl] It is of the following.

[0497] -L in formula (I)1 - may optionally be further substituted. In general, as long as the cleavage principle is not affected, i.e., as long as the hydrogen marked with an asterisk in formula (I) is not replaced, and as long as the nitrogen in the moiety of formula (I):

[0498]

Chemical formula

[0499] In certain embodiments, -R 1 in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 1a in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 2 in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 2a in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 3 in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 3a in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R 4 in formula (I) is -H, and -H is replaced by -X 0D -L 2 -. In certain embodiments, -R5 in formula (I) is -H, and -H is replaced by -X 0D -L 2- is replaced. In certain embodiments, -R in formula (I) 5a is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 6 is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 7 is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 7a is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 8 is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 8a is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 9 is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 9a is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 10 is -H, and -H is -X 0D -L 2 - is replaced. In certain embodiments, -R in formula (I) 11 is -H, and -H is -X 0D -L 2 - is replaced.

[0500] In certain embodiments, -X- in formula (I) is selected from the group consisting of -C(R 4 R 4a )-, -N(R 4 )- and -C(R 7 R 7a )-.

[0501] In certain embodiments, -X- in formula (I) is -C(R 4 R 4a ).

[0502] In certain embodiments, -X- in formula (I) is -N(R 4 ).

[0503] In certain embodiments, -X- in formula (I) is -C(R 7 R 7a ).

[0504] In certain embodiments, -R 7 in formula (I) is -NR 10 -(C=O)-R 11 .

[0505] In certain embodiments, -R 7a in formula (I) is selected from -H, methyl, and ethyl.

[0506] In certain embodiments, -R 7a in formula (I) is -H.

[0507] In certain embodiments, -R 10 in formula (I) is selected from -H, methyl, and ethyl.

[0508] In certain embodiments, -R 10 in formula (I) is methyl. In certain embodiments, -R 10 is -H.

[0509] In certain embodiments, -R 10a in formula (I) is selected from -H, methyl, and ethyl.

[0510] In certain embodiments, -R 10a in formula (I) is methyl. In certain embodiments, -R 10a is -H.

[0511] In certain embodiments, -R of formula (I) 11 is selected from -H, methyl, and ethyl. In certain embodiments, -R 11 is -H.

[0512] In certain embodiments, -R of formula (I) 11 is -X 0D -L 2 -substituted.

[0513] In certain embodiments, X of formula (I) 1 is C.

[0514] In certain embodiments, =X of formula (I) 3 is =O.

[0515] In certain embodiments, -X of formula (I) 2 - is -C(R 8 R 8a ).

[0516] In certain embodiments, -X of formula (I) 2 - is -C(R 8 R 8a )-C(R 9 R 9a ).

[0517] In certain embodiments, -R of formula (I) 8 and -R 8a are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, at least one of -R 8 and -R 8a of formula (I) is -H. In certain embodiments, both -R 8 and -R 8a of formula (I) are -H.

[0518] In certain embodiments, -R of formula (I) 1 and -R 1ais independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (I) 1 and -R 1a at least one of which is -H. In certain embodiments, -R of formula (I) 1 and -R 1a are both -H.

[0519] In certain embodiments, -R of formula (I) 2 and -R 2a is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (I) 2 and -R 2a at least one of which is -H. In certain embodiments, -R of formula (I) 2 and -R 2a are both -H.

[0520] In certain embodiments, -R of formula (I) 3 and -R 3a is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. In certain embodiments, -R of formula (I) 3 and -R 3a at least one of which is -H. In certain embodiments, -R of formula (I) 3 and -R 3a are both -H. In certain embodiments, -R of formula (I) 3 and -R 3a at least one of which is methyl. In certain embodiments, -R of formula (I) 3 and -R 3a are both methyl.

[0521] In certain embodiments, -R of formula (I) 4 and -R4a is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. In certain embodiments, -R 4 and -R 4a of formula (I) is at least one of -H. In certain embodiments, -R 4 and -R 4a of formula (I) are both -H. In certain embodiments, -R 4 and -R 4a of formula (I) is at least one of methyl. In certain embodiments, -R 4 and -R 4a of formula (I) are both methyl.

[0522] In certain embodiments, -R 5 and -R 5a of formula (I) is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. In certain embodiments, -R 5 and -R 5a of formula (I) is at least one of -H. In certain embodiments, -R 5 and -R 5a of formula (I) are both -H. In certain embodiments, -R 5 and -R 5a of formula (I) is at least one of methyl. In certain embodiments, -R 5 and -R 5a of formula (I) are both methyl.

[0523] In certain embodiments, -R of formula (I) 6 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. In certain embodiments, -R of formula (I) 6 is -H. In certain embodiments, -R of formula (I) 6 is methyl.

[0524] In certain embodiments, -R of formula (I) 9 and -R 9a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. In certain embodiments, at least one of -R of formula (I) 9 and -R 9a is -H. In certain embodiments, both -R of formula (I) 9 and -R 9a are -H. In certain embodiments, at least one of -R of formula (I) 9 and -R 9a is methyl. In certain embodiments, both -R of formula (I) 9 and -R 9a are methyl.

[0525] In certain embodiments, -D is connected to -L of formula (I) via the nitrogen of -D by forming an amide bond. It is understood that the carbonyl on the left side of the dashed line and the nitrogen of -D form an amino bond. 1

[0526] ​In certain embodiments, -D is connected to -L by forming an amide bond 1 The nitrogen connecting to - is provided by a primary or secondary amine of -D.

[0527] In certain embodiments, -L 1 - moiety has the formula (Ia):

[0528] [wherein the dashed line indicates the bond to the nitrogen of -D by forming an amide bond, -R -R 3 -R 3a -R 10 -R 11 and -X 2 - are used as defined in formula (I)] is such that -L 1 - is replaced by -X 0D -L 2 - and -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (Ia) is not replaced by -X 0D -L 2 - or a substituent.

[0529] Any optional further substituents of -L 1 - in formula (Ia) are as described above.

[0530] In certain embodiments, -L 1 - in formula (Ia) is replaced by one -X 0D -L 2 - moiety.

[0531] In certain embodiments, -L 1 - moiety in formula (Ia) is not further substituted.

[0532] In certain embodiments, -X 2 - in formula (Ia) is -C(R 8 R 8a)-is as follows.

[0533] In certain embodiments, -X in formula (Ia) 2 -is -C(R 4 R 4a )-C(R 5 R 5a )-.

[0534] In certain embodiments, -R in formula (Ia) 8 and -R 8a are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (Ia) 8 and -R 8a at least one of which is -H. In certain embodiments, -R in formula (Ia) 8 and -R 8a are both -H.

[0535] In certain embodiments, -R in formula (Ia) 3 and -R 3a are independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. In certain embodiments, -R in formula (Ia) 3 and -R 3a at least one of which is methyl. In certain embodiments, -R in formula (Ia) 3 is methyl and -R in formula (Ia) 3a is -H. In certain embodiments, -R in formula (Ia) 3 and -R 3a are both methyl.

[0536] In certain embodiments, -R in formula (Ia) 10 is selected from -H, methyl, and ethyl. In certain embodiments, -R in formula (Ia) 10 is methyl.

[0537] In certain embodiments, -R of formula (Ia) 11 is selected from -H, methyl and ethyl. In certain embodiments, -R of formula (Ia) 11 is -H.

[0538] In certain embodiments, -R of formula (Ia) 11 is -X 0D -L 2 -substituted.

[0539] -D connects to -L of formula (Ia) via the nitrogen of -D by forming an amide bond 1 -. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0540] In certain embodiments, -L 1 - moiety has the formula (Ib):

[0541]

Chemical formula

[0542] Any optional further substituent of -L 1 - in formula (Ib) is as described above.

[0543] In certain embodiments, -L of formula (Ib) 1 - moiety is further unsubstituted.

[0544] In certain embodiments, -X of formula (Ib) 2 - is -C(R 8 R 8a )-.

[0545] In certain embodiments, -X of formula (Ib) 2 - is -C(R 4 R 4a )-C(R 5 R 5a )-.

[0546] In certain embodiments, -R of formula (Ib) 8 and -R 8a are independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (Ib) 8 and -R 8a at least one of which is -H. In certain embodiments, -R of formula (Ib) 8 and -R 8a are both -H.

[0547] In certain embodiments, -R of formula (Ib) 3 and -R 3a are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. In certain embodiments, -R of formula (Ib) 3 and -R 3a at least one of which is methyl. In certain embodiments, -R of formula (Ia) 3 is methyl and -R of formula (Ib) 3a is -H. In certain embodiments, -R of formula (Ib) 3and -R 3a are both methyl.

[0548] In certain embodiments, -R of formula (Ib) 10 is selected from -H, methyl and ethyl. In certain embodiments, -R of formula (Ib) 10 is methyl.

[0549] -D connects to -L of formula (Ib) via the nitrogen of -D by forming an amide bond 1 -. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0550] In certain embodiments, -L 1 - moiety is of formula (Ic):

[0551]

Chemical formula

[0552] The optional further substituent of -L 1 - in formula (Ic) is as described above.

[0553] In certain embodiments, the -L 1 - moiety in formula (Ic) is replaced by one -X 0D -L 2 - moiety.

[0554] In certain embodiments, the -L 1- The part is not further substituted.

[0555] -D is connected to -L of formula (Ic) via the nitrogen of -D by forming an amide bond. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D. 1 - is connected to. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0556] In certain embodiments, -L 1 - part is of formula (Id):

[0557]

Chemical formula

[0558] In certain embodiments, -L of formula (Id) 1 - part is not further substituted.

[0559] -D is connected to -L of formula (Id) via the nitrogen of -D by forming an amide bond. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D. 1 - is connected to. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0560] In certain embodiments, -L 1 - part is of formula (Ie):

[0561]

Chemical formula

[0562] The -L in formula (Ie) 1 - any optional further substituents are as described above.

[0563] In certain embodiments, the -L in formula (Ie) 1 - is one -X 0D -L 2 - moiety.

[0564] In certain embodiments, the -L in formula (Ie) 1 - moiety is not further substituted.

[0565] -D is connected to -L in formula (Ie) via the nitrogen of -D by forming an amide bond. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D. 1 - is connected to. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0566] In certain embodiments, -L 1 - moiety is of formula (If):

[0567]

Chemical formula

[0568] In certain embodiments, -L in formula (If) 1 - moiety is not further substituted.

[0569] -D is connected to -L in formula (If) via the nitrogen of -D by forming an amide bond. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D. 1 - is connected to. In certain embodiments, said nitrogen is provided by a primary or secondary amine of -D.

[0570] In certain embodiments, -L 1 - is as disclosed in WO2016 / 020373A1. Thus, in certain embodiments, -L 1 - moiety has the formula (II):

[0571]

Chemical formula

[0572] The -L- of formula (II) 1 Any optional further substituents of - are as described above.

[0573] In certain embodiments, the -L- of formula (II) 1 - is substituted with one -X 0D -L 2 - moiety.

[0574] In certain embodiments, the -L- of formula (II) 1 - is not further substituted.

[0575] -L 1 Additional embodiments of -L- are disclosed in EP1536334B1, WO2009 / 009712A1, WO2008 / 034122A1, WO2009 / 143412A2, WO2011 / 082368A2 and US8,618,124B2, the entireties of which are incorporated herein by reference.

[0576] -L 1 Further embodiments of -L- are disclosed in US8,946,405B2 and US8,754,190B2, the entireties of which are incorporated herein by reference. Accordingly, in certain embodiments, -L1 - is formula (III):

[0577] [Chemical formula] [wherein, The dashed line indicates a bond to -D via a functional group of -D selected from the group consisting of -OH, -SH and -NH2, m is 0 or 1, -R 1 and -R 2 at least one or both of them are independently selected from the group consisting of -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 , -S(O)R 3 , -S(O)2R 3 and -SR 4 selected independently of each other from the group consisting of, -R 1 and -R 2 only one of them is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl, -R 3 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2, -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, each -R 5is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, -R 9 is selected from the group consisting of -H and optionally substituted alkyl, -Y- is absent, -X- is -O- or -S-, or -Y- is -N(Q)CH2-, -X- is -O-, Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, Optionally, -R 1 and -R 2 may together form a 3- to 8-membered ring, Optionally, both -R 9 together with the nitrogen to which they are attached form a heterocyclic ring] are those of, -L 1 - is substituted by -X 0D -L 2 - and -L 1 - is optionally further substituted.

[0578] Only in the context of formula (III), the terms used have the following meanings.

[0579] The term "alkyl", as used herein, includes straight-chain, branched-chain or cyclic saturated hydrocarbon groups having 1 to 8 carbon atoms, or in some embodiments 1 to 6 or 1 to 4 carbon atoms.

[0580] The term "alkoxy" includes an alkyl group bonded to oxygen and includes methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, etc.

[0581] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon double bond.

[0582] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons having a carbon-carbon triple bond.

[0583] The term "aryl" includes aromatic hydrocarbon groups having 6 to 18 carbons, preferably 6 to 10 carbons, and includes, for example, phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes an aromatic ring containing at least one N, O, or S atom and containing 3 to 15 carbons, preferably containing at least one N, O, or S atom and containing 3 to 7 carbons, and includes groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, etc.

[0584] In some cases, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be bonded to the remainder of the molecule via an alkylene linkage. Under these circumstances, the substituent is called alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene portion is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is bonded.

[0585] The term "halogen" includes bromo, fluoro, chloro, and iodo.

[0586] The term "heterocyclic ring" refers to a 4- to 8-membered aromatic or non-aromatic ring containing 3 to 7 carbon atoms and at least one N, O, or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, and the exemplary groups presented for the term "heteroaryl" above.

[0587] When the ring system is optionally substituted, suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or additional rings, each optionally further substituted. Optional substituents in any of the groups included above include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atoms to which they are attached form a ring.

[0588] In certain embodiments, -L of formula (III) 1 - is substituted with one -X 0D -L 2 - moiety.

[0589] -L 1 Another embodiment of -L is disclosed in WO2013 / 036857A1, which is hereby incorporated by reference in its entirety. Thus, in certain embodiments, -L 1 - is of formula (IV):

[0590]

Chemical formula

[0591] The terms used have the following meanings only in the context of formula (IV).

[0592] "Alkyl", "alkenyl" and "alkynyl" include straight-chain, branched-chain or cyclic hydrocarbon groups having 1 to 8 carbons or 1 to 6 carbons or 1 to 4 carbons, alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 Cs.

[0593] "Aryl" includes aromatic hydrocarbon groups having 6 to 18 carbons, preferably 6 to 10 carbons, and includes, for example, groups of phenyl, naphthyl and anthracene. "Heteroaryl" contains at least one N, O or S atom and includes an aromatic ring containing 3 to 15 carbons, preferably containing at least one N, O or S atom and containing 3 to 7 carbons, and includes, for example, groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (thiszolyl), isothiazolyl, quinolyl, indolyl, indenyl and the like.

[0594] The term "substituted" means an alkyl, alkenyl, alkynyl, aryl or heteroaryl group containing one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogen including F, Cl, Br and I; lower alkyl including linear, branched and cyclic ones; lower haloalkyl including fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl; OH; lower alkoxy including linear, branched and cyclic ones; SH; lower alkylthio including linear, branched and cyclic ones; amino, alkylamino, dialkylamino; silyl including alkylsilyl, alkoxysilyl and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxylic acid ester, carboxylic acid amide, aminocarbonyl; aminoacyl; carbamate; urea; thiocarbamate; thiourea; ketene (ketne); sulfone; sulfonamide; aryl including phenyl, naphthyl and anthracenyl; 5-membered heteroaryl including pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole and tetrazole; 6-membered heteroaryl including pyridine, pyrimidine and pyrazine; heteroaryl; and fused heteroaryl including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole and benzoisothiazole, which may be selected from.

[0595] In certain embodiments, -L of formula (IV)1 - is one -X 0D -L 2 - is replaced by a moiety.

[0596] -L 1 - Further embodiments of -L are disclosed in US7,585,837B2, which is hereby incorporated by reference in its entirety. Thus, in certain embodiments, -L 1 - is of formula (V):

[0597]

Chemical formula

[0598] Suitable substituents for formula (V) are alkyl (e.g., C 1~6 alkyl), alkenyl (e.g., C 2~6 alkenyl), alkynyl (e.g., C 2~6 alkynyl), aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., aromatic 4 - 7 membered heterocycle) or halogen moieties.

[0599] The terms used have the following meanings only in the context of formula (V).

[0600] The terms "alkyl", "alkoxy", "alkoxyalkyl", "aryl", "alkaryl" and "aralkyl" mean an alkyl group having 1 to 8, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl, and an aryl group having 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro and iodo.

[0601] In certain embodiments, -L of formula (V) 1 - is one -X 0D -L 2 - moiety substituted.

[0602] In certain embodiments, -L of formula (V) 1 - is further unsubstituted.

[0603] -L 1 Further embodiments of -L are disclosed in WO2002 / 089789A1, which is hereby incorporated by reference in its entirety. Thus, in certain embodiments, -L 1 - is of formula (VI):

[0604]

Chemical formula

[0605] The terms used have the following meanings only in the context of formula (VI).

[0606] The term "alkyl" includes, for example, straight-chain, branched-chain, substituted C 1~12 alkyl and is understood to include alkoxy, C 3~8 cycloalkyl or substituted cycloalkyl, etc.

[0607] The term "substituted" is understood to include the addition or replacement of one or more different atoms for one or more atoms contained within a functional group or compound.

[0608] The substituted alkyl includes carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl and mercaptoalkyl, the substituted cycloalkyl includes, for example, a 4-chlorocyclohexyl moiety, the aryl includes, for example, a naphthyl moiety, the substituted aryl includes, for example, a 3-bromo-phenyl moiety, the aralkyl includes, for example, a toluyl moiety, the heteroalkyl includes, for example, an ethylthiophene moiety, the substituted heteroalkyl includes, for example, a 3-methoxythiophene moiety, the alkoxy includes, for example, a methoxy moiety, and the phenoxy includes, for example, a 3-nitrophenoxy moiety. It is understood that halo- includes fluoro, chloro, iodo and bromo.

[0609] In certain embodiments, -L of formula (VI) 1 - is one -X 0D -L 2 - moiety substituted.

[0610] In certain embodiments, -L of formula (VI) 1 - is fur...

Claims

1. A conjugate comprising a crosslinked hyaluronic acid chain in which a plurality of drug moieties are covalently and reversibly conjugated, wherein the conjugate is as follows: 【Chemical 1】 [In the formula, The unlabeled dashed line indicates a bonding point to an adjacent unit of the dashed line labeled # or to hydrogen, The dashed line labeled # indicates a bonding point to an adjacent unit of the unlabeled dashed line or to a hydroxyl group, The dashed line marked with § indicates the connection point of two Z units via the -CL- part 3 and Two Zs connected via the -CL- part 3 units have the following structure 【Chemical 2】 having, each -D is independently a drug moiety, each - L 1 - is independently a linker moiety to which - D is covalently and reversibly conjugated, -L1- is of formula (I): 【Chemical Formula 3】 [In the formula, the dashed line indicates a bond to nitrogen, hydroxyl or thiol of -D, -X- is selected from the group consisting of -C(R4R4a)-, -N(R4)-, -O-, -C(R4R4a)-C(R5R5a)-, -C(R5R5a)-C(R4R4a)-, -C(R4R4a)-N(R6)-, -N(R6)-C(R4R4a)-, -C(R4R4a)-O-, -O-C(R4R4a)-, and -C(R7R7a)-, X1 is selected from the group consisting of C and S(O), -X2- is selected from the group consisting of -C(R8R8a)- and -C(R8R8a)-C(R9R9a)-, =X3 is selected from the group consisting of =O, =S and =N-CN, -R1, -R1a, -R2, -R2a, -R4, -R4a, -R5, -R5a, -R6, -R8, -R8a, -R9 and -R9a are independently selected from the group consisting of -H and C1-6 alkyl, -R3 and -R3a are independently selected from the group consisting of -H and C1-6 alkyl, provided that when one or both of -R3 and -R3a are other than -H, -R3 and -R3a are connected via an sp3 hybridized carbon atom to the N to which they are attached, -R7 is selected from the group consisting of -N(R10R10a) and -NR10-(C=O)-R11, -R7a, -R10, -R10a and -R11 are independently selected from the group consisting of -H and C1-6 alkyl, alternatively, one or more of the pairs of -R1a / -R4a, -R1a / -R5a, -R1a / -R7a, -R4a / -R5a and -R8a / -R9a form a chemical bond, Alternatively, one or more of the pairs of -R 1 / -R 1a, -R 2 / -R 2a, -R 4 / -R 4a, -R 5 / -R 5a, -R 8 / -R 8a and -R 9 / -R 9a, together with the atoms to which they are attached, form a C 3-10 cycloalkyl or 3-10 membered heterocyclyl, Alternatively, one or more of the pairs of -R 1 / -R 4, -R 1 / -R 5, -R 1 / -R 6, -R 1 / -R 7a, -R 4 / -R 5, -R 4 / -R 6, -R 8 / -R 9 and -R 2 / -R 3, together with the atoms to which they are attached, form ring A, Alternatively, -R 3 / -R 3a, together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclic ring, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl and 8-11 membered heterobicyclic, -L 1 - is substituted by -X 0D -L 2 -, and -L 1 - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (I) is not replaced by -X 0D -L 2 - or a substituent of which, Each -L 2 -, -L 3 - and -L 4 - and -L are each independently either non-existent or a spacer portion, Each -CL- is independently two Z 3 units are connecting parts, and there is at least one degradable bond in the direct connection between any two carbon atoms marked with * that are connected by the -CL- part. each -SP- is independently absent or a spacer moiety, Each -R a1 is independently selected from the group consisting of -H, C 1～4 alkyl, ammonium ion, tetrabutylammonium ion, cetylmethylammonium ion, alkali metal ion and alkaline earth metal ion, Each -R a2 is independently selected from the group consisting of -H and C 1～10 alkyl Each -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E - and -X 0F - is independently either non-existent or linked, Optionally -X 0A - and / or -X 0B - is -L 4 - or -L 4 - together with a part of - forms one or more ring structures selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclic, and adamantyl. Optionally -X 0B - and / or -X 0C - is -L 3 - or -L 3 - together with a part of - forms one or more ring structures selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclic, and adamantyl Optionally -X 0C - and / or -X 0D - is -L 2 - or -L 2 - together with a part of - forms one or more ring structures selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclic, and adamantyl. Optionally -X 0E - and / or -X 0F - together with -SP- or a part of -SP- forms one or more ring structures selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclic, and adamantyl] comprising a plurality of linking units selected from the group consisting of All Z present in the conjugate 1 units may be the same or different, All Z present in the conjugate 2 units may be the same or different, All Z units present in the conjugate 3 may be the same or different At least one Z 3 unit is present for each hyaluronic acid chain and is connected to one Z 3 unit of a different hyaluronic acid chain, The conjugate comprises at least one -L 1 -D moiety, and -CL- is of formula (D) [Chemical Formula 4] [wherein, the dashed line indicates a bond to the -X 0F - moiety, m2, m3 and m4 are independently integers selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25] is a moiety of said conjugate.

2. Said conjugate comprises a crosslinked hyaluronic acid chain to which a plurality of drug moieties are covalently and reversibly conjugated, Said conjugate is as follows: 【Chemical Formula 5】 [wherein, the unmarked dashed line indicates a bonding point to the adjacent unit of the dashed line marked with # or to hydrogen, the dashed line marked with # indicates a bonding point to the adjacent unit of the unmarked dashed line or to hydroxyl, The dashed line marked with § indicates the connection point of two Z units via the -CL- part, 3 and, -D, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -SP-, -CL-, -X 0A -, -X 0B -, -X 0C -, -X 0D -, -X 0E -, -X 0F -, -R a1 and -R a2 is used as claimed in claim 1 comprising a plurality of linking units selected from the group consisting of All Z units present in the conjugate 1 may be the same or different All Z units present in the conjugate 2 may be the same or different, All Z units present in the conjugate 3 may be the same or different Z 1 The number of units is in the range of 1% to 98% of the total number of units present in the conjugate, Z 2 The number of units ranges from 1% to 98% of the total number of units present in the conjugate, provided that at least one Z 2 unit is present in the conjugate Z 3 The number of units ranges from 1% to 97% of the total number of units present in the conjugate, provided that at least one Z 3 is present per chain At least 70% of all hyaluronic acid chains contain at least one Z 2 moiety and at least one Z 3 moiety, The conjugate according to claim 1.

3. Z 2 The conjugate according to claim 2, wherein the number of units is in the range of 1% to 70% of all the units present in the conjugate.

4. Z 3 The conjugate according to claim 2 or 3, wherein the number of units is in the range of 1% to 30%.

5. Z 1 The conjugate according to any one of claims 2 to 4, wherein the number of units is in the range of 10% to 97%.

6. The conjugate according to any one of claims 1 to 5, wherein -D is an antibiotic moiety.

7. -The conjugate according to any one of claims 1 to 5, wherein D is an anti-VEGF antibody moiety or a fragment thereof.

8. A pharmaceutical composition comprising at least one conjugate according to any one of claims 1 to 7 and at least one excipient.

9. The conjugate according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 for use in the manufacture of a medicament.

10. The conjugate according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 for use in a method of treating a disease that can be treated by D-H or D-OH.

11. A method of preparing a pharmaceutical formulation comprising a conjugate according to any one of claims 1 to 7, comprising: (a) preparing the conjugate; (b) subjecting the conjugate of step (a) to a solution containing a buffer, a surfactant, and a salt containing a polyvalent ion, and adding a swelling agent after adding the solution; (c) homogenizing the mixture of step (b); (d) swelling the conjugate of step (c) with a swelling solution containing at least one swelling agent; (e) isolating the conjugate from the mixture of step (d); (f) subjecting the conjugate of step (e) to a solution containing a buffer, a surfactant, a salt containing a divalent ion, a hydrophilic polymer having a molecular weight exceeding 10 kDa, a density regulator, and a polarity regulator, and adding a swelling agent after adding the solution; (g) homogenizing the mixture of step (f); (h) swelling the conjugate of step (g) with a swelling solution containing at least one swelling agent; (i) isolating the conjugate from the mixture of step (h); comprising, wherein there may be optional washing steps between steps (c) and (d), (f) and (g), and (g) and (h).

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