Conjugates of π-electron-pair-donating heteroaromatic nitrogen-containing compounds

Abstract

To provide conjugates of π-electron-pair-donating heteroaromatic nitrogen-containing drugs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the conjugates.SOLUTION: A conjugate or a pharmaceutically acceptable salt thereof comprises at least one moiety -D conjugated via at least one moiety -L1-L2- to at least one moiety Z. The moiety -L1- is conjugated to a π-electron-pair-donating heteroaromatic N of the moiety -D. The linkage between -D and -L1- is reversible and the moiety -L2- is conjugated to Z. Each -D is independently a π-electron-pair-donating heteroaromatic N-containing moiety of a drug D-H. Each -L2- is independently a single bond or a spacer moiety. Each Z is independently a polymeric moiety or a C8-24 alkyl. Each -L1- is independently a linker moiety of formula (I) in the figure. Each -L1- is substituted with -L2- and optionally further substituted.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a conjugate of a π-electron pair-donating heterocyclic aromatic nitrogen-containing drug and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the conjugate, and the use of the conjugate as a medicine.

Background Art

[0002] To improve the physicochemical or pharmacokinetic properties of a drug, such as its in vivo circulation half-life, such a drug can be conjugated to a carrier, such as a polymer. Typically, polymers in drug delivery are used by non-covalent complexation of the drug and the polymer, entrapment of the drug in the polymer, or covalent conjugation of the drug to the polymer moiety.

[0003] However, the non-covalent approach requires highly efficient drug encapsulation to prevent the uncontrolled burst release of the drug due to the decomposition of the drug-polymer complex after administration. To suppress the diffusion of unbound water-soluble drug molecules, strong van der Waals contacts frequently mediated through hydrophobic moieties and charged moieties for electrostatic binding are required. Many conformationally sensitive drugs, such as proteins or peptides, become dysfunctional during the complexation process and / or during the subsequent storage of the non-covalently bound drug.

[0004] Alternatively, the drug can be covalently conjugated to the polymer moiety via a stable or reversible linker through which the drug is released. When the drug is stably conjugated to the polymer moiety, such a conjugate needs to exhibit sufficient residual activity to have a pharmaceutical effect, and thus the conjugate is always in an active form.

[0005] One advantage of conjugating a drug to a polymer moiety via a reversible linker is that the drug exhibits its pharmacological effect upon release from the conjugate, so that the residual activity of the conjugate is not required. The conjugate may not exhibit or may hardly exhibit drug activity, i.e., the conjugate is pharmacologically inactive. This approach applies to all classes of molecules from so-called small molecules to natural products and large proteins. Drugs of such conjugates can be released by enzymatic or non-enzymatic cleavage of the linkage between the polymer moiety and the drug moiety, or by a combination of both. However, enzyme dependence is usually not very desirable because enzyme levels can vary significantly among patients, making accurate dosing difficult.

[0006] WO2005 / 099768A2, WO2009 / 095479A2 and WO2016 / 196124A2 disclose carrier-linked prodrugs in which the drug moiety is reversibly connected to a temporary linker via an amine, such as an aliphatic amine, for example by formation of an amide bond. Such aliphatic amines consist only of hydrogen and alkyl substituents. WO2011 / 012722A1 discloses carrier-linked prodrugs in which the drug moiety is bound to a reversible linker via these aromatic amines via formation of an amide bond. Such aromatic amines contain an aromatic ring to which the nitrogen atom of the amine is attached, which means that the nitrogen atom of the aromatic amine is not part of the aromatic ring system. The aforementioned patent applications report on the ability to convert drug moieties containing aliphatic and aromatic amines into conjugates, but they do not explore the ability to explicitly use the π-electron pair donating heterocyclic aromatic nitrogen of the drug molecule as a point of attachment to the reversible linker. Since such moieties are usually good leaving groups, it is expected that any polymer conjugated to such a moiety via the aforementioned linker may be cleaved too rapidly to provide a meaningful half-life extension. Therefore, there remains a need for conjugates in which the linker bond is made at a π-electron pair donating heterocyclic aromatic nitrogen.

[0007] WO2008 / 076225A2 discloses prodrugs of non-nucleoside reverse transcriptase inhibitors in which a linker moiety is attached to one of the nitrogen atoms located within an indazole ring. These prodrugs are converted to their corresponding drugs by hydrolysis or cyclization of the urea bond, for example, by nucleophilic addition of an amine to the urea bond at physiological pH (e.g., pH above about 7). However, WO2008 / 076225A2 does not disclose attaching the drug to a polymer moiety, and thus does not teach a method of improving the pharmacokinetics and therapeutic index of a drug by reversibly and covalently conjugating the drug to a polymer moiety via a reversible linker. Accordingly, the conjugate does not, for example, significantly extend the circulating half-life of the drug. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0008] Accordingly, it is an object of the present invention to at least partially overcome the drawbacks described above. MEANS FOR SOLVING THE PROBLEM

[0009] This object is achieved by a conjugate or a pharmaceutically acceptable salt thereof comprising at least one -D moiety conjugated to at least one Z moiety via at least one -L 1 -L 2 - moiety, wherein the -L 1 - moiety is conjugated to the π-electron pair donating heterocyclic aromatic N of the -D moiety, the linkage between -D and -L 1 - is reversible, the -L 2 - moiety is conjugated to Z, each -D is independently a π-electron pair donating heterocyclic aromatic N-containing moiety of a drug D-H, each -L 2 - is independently a single bond or a spacer moiety, each Z is independently a polymer moiety or C 8~24 alkyl, each -L 1- independently has the formula (I):

[0010]

Chemical formula

[0011]

Chemical formula

[0012]

Chemical formula

[0013] In certain embodiments, the conjugate or a pharmaceutically acceptable salt thereof of the present invention comprises at least one -D moiety conjugated to at least one Z moiety via at least one -L 1 -L 2 - moiety, the -L 1 - moiety is conjugated to the π-electron donating heterocyclic aromatic N of the -D moiety, the linkage of -D and -L 1 - is reversible, the -L 2 - moiety is conjugated to Z, each -D is independently a π-electron donating heterocyclic aromatic N-containing moiety of the drug D-H, each -L 2 - is independently a single bond or a spacer moiety, each Z is independently a polymer moiety or C 8~24 alkyl, each -L 1 - is independently of formula (I):

[0014]

Chemical formula

[0015]

Chemical Structure

[0016] [Chemical formula] selected from the group consisting of, and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5, 6 or 7 atoms, and when present, the carbon - carbon double bond formed between -R 1 and -R 2 or two adjacent -R 2 is in the cis configuration] is the linker moiety of, Each -L 1 - is substituted with -L 2 - and is optionally further substituted.

[0017] Surprisingly, the reversible linker moiety -L of formula (I) 1- has been found to have advantageous properties, such as properties that provide a suitable release half-life for a drug moiety attached to the reversible linker moiety by one of these π-electron pair donating heteroaromatic nitrogens. This is surprising since a π-electron pair donating heteroaromatic nitrogen-containing moiety can be expected to be a good leaving group that results in a half-life that is not suitable for reducing the frequency of drug administration. Also surprisingly, it has been found that the Applicant has been able to identify conditions for their stable storage despite having such good leaving groups within the conjugates of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0018] Within the scope of the meaning of the present invention, the terms are used as follows.

[0019] As used herein, the term "π-electron pair donating heteroaromatic 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 heteroaromatic nitrogen atoms that donate a π-electron pair to the aromatic π-system. Examples of chemical structures containing such heteroaromatic nitrogens 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 heteroaromatic nitrogen that donates a π-electron pair to the aromatic π-system is marked with "#".

[0020]

Chemical formula

[0021] 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. For example, it does not include the nitrogen marked with "§" in the above - mentioned imidazole ring structure. The drug D - H may exist in one or more tautomeric forms, for example, where at least one hydrogen atom moves 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.

[0022] As used herein, the term "drug" refers to a substance used in the treatment, cure, prevention, or diagnosis of a disease or otherwise used to enhance the physical or mental health of a patient. When a drug conjugates to another moiety, the moiety derived from the drug in the resulting product is called the "drug moiety".

[0023] As used herein, the term "moiety" means a part of a molecule that is missing 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 part 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.

[0024] When an array of atoms or a chemical structure is provided and this array of atoms connects two moieties or interrupts a moiety, it is understood that the said array or chemical structure can connect to the two moieties in either direction unless specifically described otherwise. For example, the "-C(O)N(R x )-" moiety can connect to two moieties as either "-C(O)N(R x )-" or "-N(R x )C(O)-" or interrupt one moiety. Similarly, the following:

[0025]

Chemical formula

[0026]

Chem.

[0027]

Chem.

[0028] 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.

[0029] Those skilled in the art will recognize that the conjugate of the present invention is a prodrug. As used herein, the term "prodrug" refers to a drug moiety that is reversibly and covalently conjugated to a polymer moiety, such as Z, via at least one -L 1 -L 2 - moiety. The prodrug releases the reversibly and covalently bound drug moiety -D in the form of its corresponding drug D-H. In other words, the prodrug is a conjugate containing a drug moiety that is covalently and reversibly conjugated to a polymer moiety via at least one -L 1 -L 2 - moiety. Such a prodrug or conjugate releases the previously conjugated drug moiety in the form of a free drug.

[0030] As used herein, the term "reversible linkage" or "biodegradable linkage" is a linkage that is cleaved under physiological conditions in the absence of enzymes, where physiological conditions are an aqueous buffer at pH 7.4 and 37 °C, and the half-life ranges from 1 hour to 6 months, such as from 1 hour to 4 months, such as from 1 hour to 3 months, from 1 hour to 2 months or from 1 hour to 1 month. However, a reversible linkage can also be cleaved under other conditions, such as different pH or different temperature, with a half-life in the range of 1 hour to 6 months, but it is understood that the test for reversibility is carried out under the physiological conditions described above (aqueous buffer, pH 7.4, 37 °C). Thus, a "stable linkage" is a linkage having a half-life under physiological conditions exceeding 6 months.

[0031] As used herein, the terms "stable" and "stability" with respect to a pharmaceutical formulation or composition comprising a conjugate of the invention mean that after a storage time, such as 1 month, 2 months, 4 months, 6 months, 8 months, 12 months, 18 months, 24 months, 36 months, after a specifically indicated storage time, the pharmaceutical formulation or composition contains less than 5% of the drug in its free form.

[0032] As used herein, the term "reversible linker moiety" is covalently conjugated to a drug moiety via a reversible linkage and is also covalently conjugated to a Z moiety via a -L 2 - moiety. In certain embodiments, the linkage between Z and -L 2 - is a stable linkage.

[0033] As used herein, the term "about" when combined with a numerical value means a range from the numerical value plus or minus up to 10% of the numerical value (including this numerical value), in certain embodiments up to 8% of the numerical value (including this numerical value), in certain embodiments up to 5% of the numerical value (including this numerical value), and in certain embodiments up to 2% of the numerical value (including this numerical value). For example, the phrase "about 200" is used to mean a range from 200 + / - 10% (including this value), i.e., a range from 180 to 220 (including these values), in certain embodiments 200 + / - 8%, i.e., a range from 184 to 216 (including these values), in certain embodiments 200 + / - 5% (including this value), i.e., a range from 190 to 210 (including these values), and in certain embodiments 200 + / - 2%, i.e., a range from 196 to 204 (including these values). A percentage presented as "about 20%" does not mean "20% + / - 10%", i.e., does not mean a range from 10 to 30% (including these values), but rather "about 20%" is understood to mean a range from 18 to 22% (including these values), i.e., plus or minus 10% of the numerical value which is 20.

[0034] As used herein, the term "C 1~4 alkyl" means, alone or in combination, a straight-chain or branched-chain alkyl moiety having 1 to 4 carbon atoms. When present at the end of a molecule, examples of straight-chain or branched-chain C 1~4 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 -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 )2 - is C 1~4 Each hydrogen on the alkyl carbon may optionally be replaced by a substituent defined below. Optionally C 1~4 Alkyl may be interrupted by one or more moieties defined below.

[0035] As used herein, the term "C 1~6 alkyl" means, alone or in combination, a straight or branched alkyl moiety having 1 to 6 carbon atoms. When present at the end of a molecule, straight and branched 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 parts of a molecule are linked by a C 1~6 alkyl group, examples of such C 1~6 alkyl groups are -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )- and -C(CH 3 ) 2 -. C 1~6 Each hydrogen atom on the carbon may optionally be replaced by a substituent defined below. Optionally C 1~6 Alkyl may be interrupted by one or more moieties defined below.

[0036] Thus, "C 1~10 alkyl", "C 1~20 alkyl", "C 8~24 alkyl" or "C 1~50 alkyl" each mean an alkyl chain having 1 to 10, 1 to 20, 8 to 24 or 1 to 50 carbon atoms, respectively, and C 1~10 , C1~20 , C 8~24 or C 1~50 Each hydrogen atom in carbon may optionally be replaced with a substituent as defined below. Optionally C 1~10 alkyl, C 1~20 alkyl, C 8~24 alkyl or C 1~50 Alkyl may be interrupted by one or more moieties as defined below.

[0037] As used herein, the term "C 2~6 alkenyl" means, alone or in combination, a straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond and having from 2 to 6 carbon atoms. When present at the end of a molecule, examples are -CH=CH 2 , -CH=CH-CH 3 , -CH 2 -CH=CH 2 , -CH=CHCH 2 -CH 3 and -CH=CH-CH=CH 2 . When two portions of a molecule are linked by a C 2~6 alkenyl group, an example of such a C 2~6 alkenyl is -CH=CH-. Each hydrogen atom of the C 2~6 alkenyl moiety may optionally be replaced with a substituent as defined below. Optionally C 2~6 alkenyl may be interrupted by one or more moieties as defined below.

[0038] Accordingly, the terms "C 2~10 alkenyl", "C 2~20 alkenyl" or "C 2~50 alkenyl" mean, alone or in combination, a straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond and having from 2 to 10, from 2 to 20 or from 2 to 50 carbon atoms, respectively. Each hydrogen atom of a C 2~10 alkenyl, C 2~20 alkenyl or C 2~50 alkenyl group may optionally be replaced with a substituent as defined below. Optionally C 2~10Alkenyl, C 2~20 Alkenyl or C 2~50 The alkenyl may be interrupted by one or more moieties defined below.

[0039] As used herein, the term "C 2~6 alkynyl" means, alone or in combination, a straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon triple bond and having from 2 to 6 carbon atoms. When present at the end of a molecule, examples are -C≡CH, -CH 2 -C≡CH, CH 2 -CH 2 -C≡CH and CH 2 -C≡C-CH 3 . When two moieties of a molecule are linked by an alkynyl group, an example is -C≡C-. Each hydrogen atom of a C 2~6 alkynyl group may optionally be replaced by a substituent defined below. One or more double bonds may optionally occur. Optionally C 2~6 The alkynyl may be interrupted by one or more moieties defined below.

[0040] Accordingly, as used herein, the terms "C 2~10 alkynyl", "C 2~20 alkynyl" and "C 2~50 alkynyl" mean, alone or in combination, a straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon triple bond and having from 2 to 10, from 2 to 20 or from 2 to 50 carbon atoms, respectively. C 2~10 alkynyl, C 2~20 alkynyl or C 2~50 Each hydrogen atom of an alkynyl group may optionally be replaced by a substituent defined below. One or more double bonds may optionally occur. Optionally C 2~10 alkynyl, C 2~20 alkynyl or C 2~50 The alkynyl may be interrupted by one or more moieties defined below.

[0041] As described above, C 1~4 alkyl, C1~6 Alkyl, C 1~10 Alkyl, C 1~20 Alkyl, C 1~50 Alkyl, C 8~24 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, in certain embodiments, is as follows:

[0042]

Chemical formula

[0043] 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. C 3~10 Each hydrogen atom at the cycloalkyl carbon may be replaced by a substituent as defined below. The term "C 3~10 cycloalkyl" also includes bridged bicyclics such as norbornane or norbornene.

[0044] As used herein, the term "8- to 30-membered carbopolycyclic" or "8- to 30-membered carbopolycycle" means a polycyclic moiety having two or more rings with 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 (completely saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings). In certain embodiments, an 8- to 30-membered carbopolycyclic means a bicyclic, tricyclic, tetracyclic, or pentacyclic moiety. In certain embodiments, an 8- to 30-membered carbopolycyclic means a bicyclic, tricyclic, or tetracyclic moiety.

[0045] 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, where up to the maximum number of double bonds may be present (completely saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and at least 1 to 4 of the ring atoms are selected from sulfur (-S(O)-, -S(O) 2is replaced by a heteroatom selected from the group consisting of 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 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 defined below.

[0046] 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, wherein at least one ring atom is shared by both rings and may contain up to the maximum number of double bonds (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and from at least one ring atom to six ring atoms are sulfur (-S(O)-, -S(O) 2is replaced by a heteroatom selected from the group consisting of oxygen and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples of 8- to 11-membered bicyclic heterocycles 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 bicyclic heterocycles 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 the 8- to 11-membered heterobicyclic or 8- to 11-membered bicyclic heterocycle carbon may be replaced by a substituent defined below.

[0047] Similarly, the term "8- to 30-membered heteropolycyclic" or "8- to 30-membered heteropolycycle" refers to two or more 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 (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic rings), and in certain embodiments, a 3-, 4-, or 5-ring heterocyclic moiety, and at least 1 to 10 ring atoms from at least one ring atom are replaced by a heteroatom selected from the group consisting of sulfur (-S(O)-, -S(O) 2 -), oxygen, and nitrogen (including =N(O)-), and the ring is linked to the rest of the molecule via a carbon or nitrogen atom.

[0048] The moiety of the following structure

[0049]

Chemical formula

[0050] [Chemical formula] (wherein R is a C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclic ring) is understood to mean forming

[0051] For the moiety of the following structure

[0052] [Chemical formula] the phrase "-R x / -R y pairs, together with the atoms to which they are attached, form ring-A-" means that R x and R y have the following structures:

[0053] [Chemical formula] is also understood to mean forming

[0054] For the moiety of the following structure

[0055] [Chemical formula] the phrase "-R 1 and adjacent -R 2 form a carbon-carbon double bond, provided that n is selected from the group consisting of 1, 2, 3 and 4" means that, for example, when n is 1, -R 1 and adjacent -R 2 have the following structures:

[0056] [Chemistry] to form, for example, when n is 2, R 1 and adjacent -R 2 has the following structure:

[0057] [Chemistry] means to form, wherein the wavy bond means that -R 1a and -R 2a can be on the same side of the double bond, i.e., can be in the cis configuration, or can be on the opposite side of the double bond, i.e., can be in the trans configuration, and the term "adjacent" means that -R 1 and -R 2 are attached to adjacent carbon atoms.

[0058] The part of the following structure

[0059] [Chemistry] Regarding " 2 two adjacent -R 2 form a carbon-carbon double bond, provided that n is selected from the group consisting of 2, 3, and 4", for example, when n is 2, two adjacent -R

[0060] [Chemistry] means to form, wherein the wavy bond means that each -R 2a can be on the same side of the double bond, i.e., can be in the cis configuration, or can be on the opposite side of the double bond, i.e., can be in the trans configuration, and the term "adjacent" means that two -R 2 are attached to adjacent carbon atoms.

[0061] As used herein, the term "excipient" refers to a diluent, adjuvant or vehicle with which a therapeutic agent, such as a drug or conjugate, is administered. Such pharmaceutical excipients may be sterile liquids, such as water, or may be oils of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered orally, water is a preferred excipient. When the pharmaceutical composition is administered intravenously, saline and aqueous dextrose are preferred excipients. 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, nonfat 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 may contain detergents such as Tween (registered trademark), poloxamer, poloxamine, CHAPS, Igepal (registered trademark), 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 include 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 for proper administration to a patient.The formulation should be suitable for the mode of administration.

[0062] As used herein, the term "free form" of a drug refers to the unmodified, pharmacologically fully active form of the drug, for example, after release from a conjugate.

[0063] As used herein, the term "functional group" means a group of atoms capable of reacting 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.

[0064] As used herein, the term "halogen" means fluoro, chloro, bromo or iodo. In certain embodiments, the halogen is fluoro or chloro.

[0065] As used herein, the term "interrupted" means that a moiety is inserted between two carbon atoms, or, if the insertion is at one end of the moiety, between a carbon atom or heteroatom and a hydrogen atom, in certain embodiments between a carbon atom and a hydrogen atom.

[0066] When the conjugate of the present invention contains one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts, especially those pharmaceutically utilized salts thereof. 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 specific examples of such salts include sodium salt, potassium salt, calcium salt, magnesium salt, 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 of 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.

[0067] As used herein, the term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient, and preferably has been approved by a regulatory authority, such as EMA (Europe) and / or FDA (US), and / or by a regulatory authority of any other country, for use in animals, preferably for use in humans.

[0068] As used herein, the term "peptide" refers to a chain of at least 2 to 50 amino acid monomer moieties, when used herein, which may also be referred to as "amino acid residues" 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.

[0069] 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" 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.

[0070] As used herein, the term "small molecule drug" refers to a drug that is an organic compound having a molecular weight of less than 1000 Da, such as less than 900 Da or less than 800 Da. It is understood that nucleobase-based drug moieties, such as adenine or guanine analogs, may also be a type of small molecule drug.

[0071] As used herein, the term "mid-molecule drug" refers to a drug that is not a peptide, not a protein, and is an organic compound having a molecular weight in the range of 1 kDa to 7.5 kDa (including these values).

[0072] 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 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, a peptide or protein is understood to be a polymer 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.

[0073] As used herein, the term "polymeric" or "polymeric moiety" refers to a reagent or moiety that includes one or more polymers or polymeric moieties. The polymeric reagent or moiety may optionally also include one or more other moieties, which in certain embodiments are the following: - C 1~50Alkyl, 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, - Branching points, e.g., -CR<, >C< or -N<, and - The following:

[0074] [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, 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] a linkage selected from the group comprising selected from the group consisting of these moieties and linkages may optionally be further substituted.

[0075] It is understood by those skilled in the art that the polymerization products obtained by the polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Thus, the molecular weight range, molecular weight, range of the 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 of the polymer or polymer moiety.

[0076] Thus, in a polymer moiety containing "x" monomer units, any integer presented as "x" corresponds thereby to the arithmetic mean (arithmetic average) of the number of monomers. Any range of integers presented as "x" provides a range of integers that are the arithmetic mean of the monomers. The integer "x" presented as "about x" means that the arithmetic mean of the monomers is in the range of integers of x + / - 10%, in certain embodiments in the range of integers of x + / - 8%, in certain embodiments in the range of integers of x + / - 5%, and in certain embodiments in the range of integers of x + / - 2%.

[0077] As used herein, the term "number average molecular weight" means the ordinary arithmetic average of the molecular weights of the individual polymers.

[0078] As used herein, the term "PEG-based" in relation to a moiety or reagent means that the moiety or reagent contains PEG. In certain embodiments, such a PEG-based moiety or reagent contains at least 10% (w / w) PEG, such as at least 20% (w / w) PEG, such as at least 30% (w / w) PEG, such as at least 40% (w / w) PEG, such as at least 50% (w / w) PEG, such as at least 60% (w / w) PEG, such as at least 70% (w / w) PEG, such as at least 80% (w / w) PEG, such as at least 90% (w / w) PEG, such as at least 95% (w / w) PEG. The remaining weight percentage of the PEG-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, - a branching point, such as -CR<,>C< or -N<, and - the following:

[0079]

Chemical formula

[0080] As used herein, the term "PEG-based containing at least X% PEG" in relation to a moiety or reagent means that the moiety or reagent contains at least X% (w / w) of ethylene glycol units (-CH 2 CH 2 O-), and the ethylene glycol units may be arranged in blocks, arranged alternately, or distributed randomly within the moiety or reagent. In certain embodiments, all of the ethylene glycol units of the moiety or reagent are present in one block, and the remaining weight percentages of the PEG-based moiety or reagent are, in certain embodiments, as follows: - 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, - a branching point, such as -CR<, >C< or -N<, and - the following:

[0081] [Chemical formula] [Wherein, The dashed line indicates the bond to the remaining part of the moiety or reagent, -R and -R a 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] a linkage selected from the group comprising of other moieties selected from the group consisting of and these moieties and linkages may optionally be further substituted.

[0082] 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 a hyaluronic acid-based moiety or reagent contains at least 10% (w / w) hyaluronic acid, for example at least 20% (w / w) hyaluronic acid, for example at least 30% (w / w) hyaluronic acid, for example at least 40% (w / w) hyaluronic acid, for example at least 50% (w / w) hyaluronic acid, for example at least 60% (w / w) hyaluronic acid, for example at least 70% (w / w) hyaluronic acid, for example at least 80% (w / w) hyaluronic acid, for example at least 90% (w / w) hyaluronic acid, or for example at least 95% (w / w) hyaluronic acid. The remaining weight percentage of the hyaluronic acid-based moiety or reagent is of other moieties, for example, 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 heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, - a branching point, for example -CR<, >C< or -N<, and - the following:

[0083]

Chemical formula

[0084] 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 crosslinks. The crosslinking provides a network structure and physical integrity.

[0085] As used herein, the term "random coil" refers to a peptide or protein that adopts / has / forms a conformation substantially lacking a defined secondary and tertiary structure as determined by circular dichroism spectroscopy in an aqueous buffer at ambient temperature and pH 7.4. In certain embodiments, the ambient temperature is about 20 °C, i.e., between 18 °C and 22 °C, while in certain embodiments, the ambient temperature is 20 °C.

[0086] As used herein, the term "spacer" or "spacer moiety" refers to a moiety suitable for connecting two moieties. Suitable spacers can be selected from the group consisting of C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl, and these C1~50 Alkyl, C 2~50 Alkenyl or C 2~50 Alkynyl is optionally interrupted by one or more groups selected from -NH-, -N(C 1~4 Alkyl)-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)N(C 1~4 Alkyl)-, -O-C(O)-, -S(O)-, -S(O) 2 -, 4- to 7-membered heterocyclyl, phenyl, and naphthyl, and may be optionally substituted.

[0087] As used herein, the term "substituted" means that one or more -H atoms of a molecule or moiety have been replaced by a different atom or group of atoms called a "substituent".

[0088] As used herein, the term "substituent" in certain embodiments is halogen, -CN, -C(O)OR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 )(R x1a ), -S(O) 2 N(R x1 )(R x1a ), -S(O)N(R x1 )(R x1a ), -S(O) 2 R x1 , -S(O)R x1 , -N(R x1 )S(O) 2 N(R x1a )(R x1b ), -SR x1 , -N(R x1 )(R x1a ), -NO 2 , -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O) 2 R 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, where -T 0 , C 1~50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl may be optionally substituted with one or more -R x2 s, and C 1~50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl are interrupted 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) 2 N(R x3 )(-), -S(O)N(R x3 )(-), -S(O) 2 (-), -S(O)-, -N(R x3 )(S(O) 2 N(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 )(-), -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 may be optionally substituted with one or more -R x2and is optionally substituted, C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are each independently optionally interrupted 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) 2 N(R x3 ), -S(O)N(R x3 ), -S(O) 2 -, -S(O)-, -N(R x3 )S(O) 2 N(R x3a ), -S-, -N(R x3 ), -OC(OR x3 )(R x3a ), -N(R x3 )C(O)N(R x3a ), -OC(O)N(R x3 ), and are optionally interrupted by one or more groups selected from the group consisting of -OC(O)N(R 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 and is the same or different, Each -R x2 is halogen, -CN, oxo (=O), -C(O)OR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 )(R x4a ), -S(O) 2 N(R x4 )(R x4a ), -S(O)N(R x4 )(R x4a ), -S(O) 2 R x4 , -S(O)R x4 , -N(R x4 )S(O) 2 N(R x4a )(R x4b ), -SR x4, -N(R x4 )(R x4a ), -NO 2 , -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O) 2 R 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, independently selected from the group consisting of 1~6 alkyl may be optionally substituted with one or more halogens which are the same or different, each -R x3 , -R x3a , -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H and C 1~6 alkyl, and C 1~6 alkyl may be optionally substituted with one or more halogens which are the same or different.

[0089] In certain embodiments, the term "substituent" is halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 )(R x1a ), -S(O) 2 N(R x1 )(R x1a ), -S(O)N(R x1 )(R x1a ), -S(O) 2 R x1 , -S(O)R x1 , -N(R x1 )S(O) 2 N(R x1 )(R x1a ), -SRx1 , -N(R x1 )(R x1a ), -NO 2 , -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O) 2 R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1 )(R x1a ), -OC(O)N(R x1 )(R x1a ), -T 0 , C 1~10 alkyl, C 2~10 alkenyl, and C 2~10 alkynyl selected from the group consisting of, -T 0 , C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl are optionally substituted with one or more -R x2 , and C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl are interrupted 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) 2 N(R x3 )(-), -S(O)N(R x3 )(-), -S(O) 2 (-), -S(O)-, -N(R x3 )(S(O) 2 N(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 are optionally interrupted by, each -Rx1 ,-R x1a ,-R x1b ,-R x3 ,-R x3a is -H, halogen, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 independently selected from the group consisting of alkynyl, each T 0 is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclic, each T 0 is independently optionally substituted with one or more -R x2 in the case, each -R x2 is halogen, -CN, oxo(=O), -C(O)OR x4 , -OR x4 , -C(O)R x4 , -C(O)N(R x4 )(R x4a ), -S(O) 2 N(R x4 )(R x4a ), -S(O)N(R x4 )(R x4a ), -S(O) 2 R x4 , -S(O)R x4 , -N(R x4 ), S(O) 2 N(R x4a )(R x4b ), -SR x4 , -N(R x4 )(R x4a ), -NO 2 , -OC(O)R x4 , -N(R x4 ), C(O)R x4a , -N(R x4 ), S(O) 2 R 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 independently selected from the group consisting of alkyl, C 1~6 alkyl is optionally substituted with one or more halogens which are the same or different, each -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H, halogen, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl.

[0090] In certain embodiments, the term "substituent" is halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 )(R x1a ), -S(O) 2 N(R x1 )(R x1a ), -S(O)N(R x1 )(R x1a ), -S(O) 2 R x1 , -S(O)R x1 , -N(R x1 )S(O) 2 N(R x1a )(R x1b ), -SR x1 , -N(R x1 )(R x1a ), -NO 2 , -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O) 2 R 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(Rx1 )(R x1a )、 -T 0 、 C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl, and refers to a moiety selected from the group consisting of -T 0 、 C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl may be optionally substituted with one or more -R x2 s, and C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O) 2 N(R x3 )-, -S(O)N(R x3 )-, -S(O) 2 -, -S(O)-, -N(R x3 )S(O) 2 N(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 interrupted by one or more groups selected from the group consisting of each -R x1 、 -R x1a 、 -R x1b 、 -R x2 、 -R x3 、 -R x3a is independently selected from the group consisting of -H, halogen, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl, 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 T0 is one or more -R, which may be the same or different x2 and is optionally substituted independently thereof.

[0091] In certain embodiments, in a molecule that is optionally substituted, up to 6 -H atoms 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.

[0092] As used herein, the term "therapeutically effective amount" means an amount sufficient to cure, alleviate or partially prevent the clinical symptoms of a given disease and its complications. The effective amount for each purpose depends on the severity of the disease or injury, as well as the body weight and general condition of the subject.

[0093] As used herein, the term "water-insoluble" refers to a compound that may have less than 1 g dissolved in 1 liter of water at 20 °C to form a homogeneous solution. Accordingly, the term "water-soluble" refers to a compound that may have 1 g or more dissolved in 1 liter of water at 20 °C to form a homogeneous solution.

[0094] Generally, the term "comprise(s)" or "comprising" also encompasses "consist of" or "consisting of".

[0095] It is understood that "N" in the phrase "π - electron pair donating heteroaromatic N" refers to nitrogen.

[0096] Two adjacent -R of formula (I) 2 is understood to exist only when n is at least 2.

[0097] The expression "distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk" refers to the total number of atoms at the shortest distance between the nitrogen and carbon atoms marked with an asterisk, and it is understood that the nitrogen and carbon atoms marked with an asterisk are also included. For example, in the following structure, n is 1, and the distance between the nitrogen marked with an asterisk and the carbon marked with an asterisk is 5,

[0098] [Chemical formula] in the following structure, n is 2, -R 1 and -R 1a form cyclohexyl, and the distance between the nitrogen marked with an asterisk and the carbon marked with an asterisk is 6.

[0099] [Chemical formula]

[0100] In certain embodiments, all -D moieties of the conjugate are identical, i.e., have the same chemical structure. In such cases, all -D moieties of the conjugate are derived from the same type of drug molecule. This means that all -D moieties are derived from the same parent drug, although it is understood that there may be, for example, intramolecular rearrangements that result in different tautomeric forms.

[0101] In certain embodiments, the conjugates of the invention include different -D moieties, i.e., -D moieties having different chemical structures. These different structures are derived from different types of drug molecules. It is understood that this does not include certain intramolecular rearrangements that result in, for example, the formation of different tautomers, although this may also be present. In certain embodiments, the conjugates of the invention include two different types of -D moieties. In certain embodiments, the conjugates of the invention include three different types of -D moieties. In certain embodiments, the conjugates of the invention include four different types of -D moieties. In certain embodiments, the conjugates of the invention include five different types of -D moieties.

[0102] When the conjugate of the invention contains more than one type of -D, all -D moieties may be conjugated to the same type of -L 1 - or to different types of -L 1 -, i.e., for example, the first type of -D may be conjugated to the first type of -L 1 -, and the second type of -D may be conjugated to the second type of -L 1 - and so on. The use of different types of -L 1 - may, in certain embodiments, enable different release rates (release kinetics) with different types of -D, for example, 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 invention includes one type of -L 1 -. In certain embodiments, the conjugate of the invention includes two types of -L 1 -. In certain embodiments, the conjugate of the invention includes three types of -L 1 -. In certain embodiments, the conjugate of the invention includes four types of -L 1 -.

[0103] In certain embodiments, the conjugates of the invention comprise one type of -D and one type of -L 1 -. In certain embodiments, the conjugates of the invention comprise two types of -D and two types of -L 1 -. In certain embodiments, the conjugates of the invention comprise three types of -D and three types of -L 1 -. In certain embodiments, the conjugates of the invention comprise four types of -D and four types of -L 1 -.

[0104] In certain embodiments, all of the -L 1 - moieties of the conjugate have the same structure. In certain embodiments, the conjugate has two or more different types of -L 1 - moieties, for example 2, 3, 4 or 5 different types of -L 1 - moieties. Such two or more different types of -L 1 - moieties may be conjugated to the same or different types of -D. The use of different types of -L 1 - enables the release of the same or different types of drug D-H from the conjugates of the invention with different release half-lives, for example when a first group of -L 1 - moieties with a short release half-life are combined with a second group of -L 1 - moieties with a long release half-life.

[0105] In certain embodiments, -D is selected from the group consisting of small molecules, medium-sized, peptide and protein drug moieties.

[0106] In certain embodiments, -D is a small molecule drug moiety. In certain embodiments, such a small molecule drug moiety is a nucleobase-based drug moiety.

[0107] It is understood that the -D moiety may contain at least one π-electron pair donating heteroaromatic nitrogen atom, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 π-electron pair donating heteroaromatic nitrogen atoms. In peptide and protein drug moieties, such nitrogen may be provided by an amino acid, such as tryptophan or histidine, and in nucleobase-based drug moieties, such nitrogen may be provided by adenine or guanine.

[0108] In certain embodiments, -D is a peptide drug moiety.

[0109] In certain embodiments, -D is a peptide drug moiety selected from the group consisting of C-type natriuretic peptide, parathyroid hormone, W peptide, memno-peptide A and G1 peptide.

[0110] In certain embodiments, -D is a protein drug moiety. In certain embodiments, such protein moiety is a monoclonal or polyclonal antibody or a fragment or fusion thereof.

[0111] In certain embodiments, -D is asitazanolast, seglitide, etodolac, redazolol, N-desmethylmirameline, carbazomycin G, carbazomycin H, asperlicin C, asperlicin D, desacetylvinblastine hydrazide, jasplakinolide, ageliferin diacetate, ageliferin dihydrochloride, drotrecogin alfa, loxindole mesylate, ribromycin, tazanolast, abecarnil, bertisilatin, rialoxazole, iltemazole, omeprazole, parodoxil hemifumarate, tropisetron, topsentin B1, bromotopsentin, rifalazil, pyrindamycin A, pyrindamycin B, duocarmycin C1, duocarmycin C2, duocarmycin A, biemnidin, elopiprazole, mibefradil, luzindole, manzamine D, manzamine B, manzamine C, octreotide acetate, lazabemide hydrochloride, tetrazolast meglumine, enalkilene, cloturin, pergolide mesylate, rialoxazole hydrochloride, chloropeptin II, adozelesin, carzelesin, beta-CCM, dexmedetomidine hydrochloride, naratriptan hydrochloride, indanomycin, homoiindanomycin, mibefradil hydrochloride, drotrecogin alfa mesylate, nicotredol, duocarmycin B1, duocarmycin B2, vincristine sulfate, antiflamine-2, pantoprazole, manzamine A, janthinomycin C, albiophyllin, janthinomycin A, janthinomycin B, efalizumab, boxelolide hydrochloride, gedocarnil, temoporfin, proteglid, vinorelbine, cyclo[His-Pro], mepindolol transdermal patch, tubingenin B, methoxatin, mibazolol, atalaphillidine, atalaphillinine, discorhabdine D, lurasetron, naltindole, azetirelin, bizelesin, intoplicin, cimetidine bismuth citrate, cimetidine bismuth L-tartrate, manzamine F, resimebid, manzamine E, pyrazoloacridine, duocarmycin SA, vinflosiltine sulfate, nepaprazole, ramorelix, andrastin, taltrimeline,Lamotrigine hydrochloride, naphthalene acetic acid, cypamfiline, ropinirole, pazelliptine trihydrochloride monohydrate, pazelliptine trihydrochloride, gilacodazole, sabiprazole, pibrozeresin hydrochloride, human angiotensin II, ceruletide diethylamine, carvedilol, remikiren mesylate, lofliline, nortopsentin D, nortopsentin A, nortopsentin B, nortopsentin C, debenzepide, atipamezole, imetit, batzelline B, calcitonin, demetomidine, medetomidine, pemetrexed disodium, carbotrolin hydrochloride, sumatriptan succinate, alosetron maleate, reminoprazole, atevilzine mesylate, rifalizine hydrochloride, allophylline, nepaprazole, vinleucinol, moxonidine hydrochloride hydrate, lansoprazole, citoblastine, L-histidinol, montirelin tetrahydrate, fabesetron hydrochloride, O6-benzylguanine, indisetron hydrochloride, pyrrosporine A, antagonist-G, azatoxin, alpha-methyltryptophan, echtenacidin 722, echtenacidin 736, eptifibatide, dexmedetomidine, kistamicin A, ilomastat, histrelin acetate, verongamine, spinorphin, delavirdine mesylate, epocarbazoline A, epocarbazoline B, ilatreotide, perdesin, copper prezacide acetate, premetrexed, calcinosatin A, gabestinel sodium, thiazohalostatin, glycothiohexide alpha, cystamidin A, ciproxylene, imepip, imepil, pipamfazole hydrochloride, risatriptan sulfate, clobenpropit, nor nicotine, cabergoline, porfimer sodium, tizanpanel, tenatoprazole, almotriptan, iodoxiprofan, pralmolelin, frovatriptan, pranazepide, risatriptan benzoate, romeguatrib, 111In-pentetreotide, polydiscamide A, pimobendan, impentamine, apaxifylline, macaluvamine C, macaluvamine D, macaluvamine F, vinflunine, examorelin, pumosetrag hydrochloride, pranlukast hydrate, vilazodone hydrochloride, lanepitant, terguride, avitriptan, cimetidine, naxifylline, buserelin acetate, bopindolol, mepindolol sulfate, carprofen, leuprorelin acetate, oxypertine, elliptinium acetate, indoramin hydrochloride, resem Lupin, ergotamine tartrate, lisuride maleate, ilaprazole, chondramide A, chondramide B, chondramide C, chondramide D, lavanduzenosin, eletriptan, midaxifylline, indisulam, conivaptan hydrochloride, improgan, edotecarin, dexketoprofen imidazole salt, styloganidine, ciproxifan, roroatin B, trifluproxim, nemifitide ditriflutate, beta-methyl-6-chloromelatonin, argyrin B, argyrin A , 18-hydroxycoronaridine, 18-methoxycoronaridine, fadolmidine hydrochloride, semaxanib, kurasoin B, avorelin, gilbsumycin, tegaserod maleate, carbazomazurin A, carbazomazurin B, rafabegron, nepazutant, donitriptan mesylate, becatecarin, donitriptan hydrochloride, yttrium-90 edotreotide, methylhistaprodifen, histaprodifen, lemuteporfin, afeletecan hydrochloride, cipralisa , demethylasteriquinone B-1, indole-3-propionic acid, shermylamine D, decatromycin A, decatromycin B, venorphin, milbemycin alpha-9, alsterpawlone, secobatzelin B, alcylacyanine A, O-demethylmurayafoline A, clausenamine A, secobatzelin A, sabipolid mesilate, alosetron hydrochloride, halimide, imoproxyfan, barsiban, calotrixin A, golotimod, tadalafil, fluoroindolocarbazole C, fluoroindolocarbazole A,Fluoroindolocarbazole B, Denibulin Hydrochloride, 99mTc-c(RGDfK*)2HYNIC, Sunitinib, Sunitinib Malate, Indolmycin, 2,7-Dibromocriptrepin, Pasireotide, Carindol Dihydrochloride, Dacinostat, Gilatide, Pyridone-6, Folotyn Hydrochloride, Sotrastaurin, Gastrazole, Yatakemycin, Antiroikinat, Dobitinib Lactate, Axitinib, Prulifloxacin Hydrochloride, Sisomicin C, Sisomicin A, Sisomicin B, Purvalanol, DADMe-Imciclib-G, DADMe-Imciclib-H, Cediranib, Bremelanotide, Imetridin, Talaporfin Sodium, Methanobactin, [D-Tyr1] MS-10, [Arg(Me)9] MS-10, [D-Tyr1,Arg(Me)9] MS-10, [Trp19] MS-10, [D-Tyr1,AzaGly7,Arg(Me)9] MS-10, Vedelosin, Methimepip, Pachymedusa dacnicolor Tryptophyllin-1, Obatoclax Mesylate, Necrostatin-1, 2-Bromo-7-nitrocriptrepin, 7-Bromo-2-chlorocriptrepin, Brivanib Alaninate, Brivanib, Danusertib, Atovastatin, Centanamycin, Linifanib, Ethylthio-DADMe-Imciclib-A, 4-Chlorophenylthio-DADMe-Imciclib-A, Methylthio-DADMe-Imciclib-A, Radicicol, Shefferidin, Desacetylvinblastine Hydrazide Folic Acid Conjugate, Anamorelin Hydrochloride, Histrelin, Mercaptopurine, Histamine Dihydrochloride, Bleomycin A2 Sulfate, Bromocriptine Mesylate, Timodepressin, Yohimbine, Pepromycin, Detomidine Hydrochloride, Vincristine, Desglugastrin Tromethamine, Dihydroergotamine Mesylate, Ogulufanide Disodium, Cefpimizole Sodium, Tinazolium Chloride, Panobinostat, Lanreotide Acetate, Pindolol, Kinetin, Leucosin, Cartelamine A, Meriolin-3, Pymeprazole, 3-Indole,It is selected from the group consisting of PPI17-24, dexlansoprazole, recirelin, methyl homoyindanomycin, deslorelin, fabesetron, carmoxirole hydrochloride, galcaneztron, melanotan II, nocardicin II, theophylline, tulopexolate isopropyl, marinopyrrole A, amicoumacin, carpindactam, microbisporicin A2, beta-amyloid (12-20), 5-fluorouracil, thioguanine, pemetrexed, mercaptopurine, cibantinib, ulixertinib, MK-8353, SCH772984, idelalisib, vemurafenib, EOS-200271 and X4P-001.,

[0112] In certain embodiments, -D is axitinib.

[0113] In certain embodiments, =X 1 is =O. In certain embodiments, =X 1 is =S. In certain embodiments, =X 1 is =N(R 4 ).

[0114] In certain embodiments, -X 2 - is -O-. In certain embodiments, -X 2 - is -S-. In certain embodiments, -X 2 - is -N(R 5 ). In certain embodiments, -X 2 - is -C(R 6 )(R 6a ).

[0115] In certain embodiments, -X 3 - is as follows.

[0116] [Chemical formula]

[0117] In certain embodiments, -X3 -X is as follows.

[0118] [Chemical formula]

[0119] In certain embodiments, -X 3 -X is as follows.

[0120] [Chemical formula]

[0121] In certain embodiments, -X 3 -X is -C(R 10 )(R 10a ). In certain embodiments, -X 3 -X is -C(R 11 )(R 11a )-C(R 12 )(R 12a ). In certain embodiments, -X 3 -X is -O-. In certain embodiments, -X 3 -X is -C(O)-.

[0122] In certain embodiments, -X 2 -X is -N(R 5 )-, and -X 3 -X is as follows:

[0123] [Chemical formula] The distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5 atoms.

[0124] In certain embodiments, -X 2 is -N(R 5 )-, and -X 3 -X is as follows:

[0125] [Chemical formula] and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 6 atoms.

[0126] In certain embodiments, -X 2 - is -N(R 5 )- and -X 3 - is as follows:

[0127] [Chemical formula] and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 7 atoms.

[0128] In certain embodiments, -X 2 - is -N(R 5 )- and -X 3 - is as follows:

[0129] [Chemical formula] and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5 atoms.

[0130] In certain embodiments, -X 2 - is -N(R 5 )- and -X 3 - is as follows:

[0131] [Chemical formula] and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 6 atoms.

[0132] In certain embodiments, -X 2 - is -N(R 5) - and -X 3 - is as follows:

[0133]

Chemical formula

[0134] In certain embodiments, -X 2 - is -N(R 5 ) - and -X 3 - is as follows:

[0135]

Chemical formula

[0136] In certain embodiments, -X 2 - is -N(R 5 ) - and -X 3 - is as follows:

[0137]

Chemical formula

[0138] In certain embodiments, -X 2 - is -N(R 5 ) - and -X 3 - is as follows:

[0139]

Chemical formula

[0140] In certain embodiments, -X 2 - is -N(R 5 )-, and -X 3 - is as follows:

[0141] [Chemical formula] wherein the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5 atoms.

[0142] In certain embodiments, -X 2 - is -N(R 5 )-, and -X 3 - is as follows:

[0143] [Chemical formula] wherein the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 6 atoms.

[0144] In certain embodiments, -X 2 - is -N(R 5 )-, and -X 3 - is as follows:

[0145] [Chemical formula] wherein the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 7 atoms.

[0146] In certain embodiments, =X 1 is =O, and -X 2 - is -C(R 6 )(R 6a )-, and -X 3 - is as follows:

[0147] [Chemical formula] and -R 3 does not contain an amine.

[0148] In certain embodiments, -R 1 , -R 1a , -R 6 , -R 6a , -R 10 , -R 10a , -R 11 , -R 11a , -R 12 , -R 12a , and each -R 2 and -R 2a is independently selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl.

[0149] In certain embodiments, -R 1 is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 1 is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 1 is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 1 is selected from the group consisting of -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, -R 1 is -H. In certain embodiments, -R 1 is -C(O)OH. In certain embodiments, -R 1is a halogen. In certain embodiments, -R 1 is -F. In certain embodiments, -R 1 is -CN. In certain embodiments, -R 1 is -OH. In certain embodiments, -R 1 is C 1~6 alkyl. In certain embodiments, -R 1 is C 2~6 alkenyl. In certain embodiments, -R 1 is C 2~6 alkynyl.

[0150] In certain embodiments, -R 1 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, and 1-ethylpropyl. In this case, -R 1 / -R 1a may, together with the atom to which they are attached, form C 3~10 cycloalkyl, and -R 1 / -R 2 -R 1 / -R 5 -R 1 / -R 6 -R 1 / -R 9 and -R 1 / -R 10 one or more of the pairs may, together with the atom to which they are attached, form ring-A-, and it is understood that -A- is used as defined for formula (I).

[0151] In certain embodiments, -R 1a is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R1a is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 1a is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 1a is selected from the group consisting of -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, -R 1a is -H. In certain embodiments, -R 1a is -C(O)OH. In certain embodiments, -R 1a is halogen. In certain embodiments, -R 1a is -F. In certain embodiments, -R 1a is -CN. In certain embodiments, -R 1a is -OH. In certain embodiments, -R 1a is C 1~6 alkyl. In certain embodiments, -R 1a is C 2~6 alkenyl. In certain embodiments, -R 1a is C 2~6 alkynyl. In certain embodiments, -R 1a is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0152] In certain embodiments, -R 6 is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6is selected from the group consisting of alkynyl. In certain embodiments, -R 6 is -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 is selected from the group consisting of alkynyl. In certain embodiments, -R 6 is -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 is selected from the group consisting of alkynyl. In certain embodiments, -R 6 is -H, -C(O)OH, -OH and C 1~6 is selected from the group consisting of alkyl. In certain embodiments, -R 6 is -H. In certain embodiments, -R 6 is -C(O)OH. In certain embodiments, -R 6 is halogen. In certain embodiments, -R 6 is -F. In certain embodiments, -R 6 is -CN. In certain embodiments, -R 6 is -OH. In certain embodiments, -R 6 is C 1~6 alkyl. In certain embodiments, -R 6 is C 2~6 alkenyl. In certain embodiments, -R 6 is C 2~6 alkynyl. In certain embodiments, -R 6 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0153] In certain embodiments, -R 6a is -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C2~6 Selected from the group consisting of alkenyl and C 2~6 alkynyl. In certain embodiments, -R 6a is -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 6a is -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 6a is -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, -R 6a is -H. In certain embodiments, -R 6a is -C(O)OH. In certain embodiments, -R 6a is halogen. In certain embodiments, -R 6a is -F. In certain embodiments, -R 6a is -CN. In certain embodiments, -R 6a is -OH. In certain embodiments, -R 6a is C 1~6 alkyl. In certain embodiments, -R 6a is C 2~6 alkenyl. In certain embodiments, -R 6a is C 2~6 alkynyl. In certain embodiments, -R 6a is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0154] In certain embodiments, -R 10is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 10 is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 10 is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 10 is selected from the group consisting of -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, -R 10 is -H. In certain embodiments, -R 10 is -C(O)OH. In certain embodiments, -R 10 is halogen. In certain embodiments, -R 10 is -F. In certain embodiments, -R 10 is -CN. In certain embodiments, -R 10 is -OH. In certain embodiments, -R 10 is C 1~6 alkyl. In certain embodiments, -R 10 is C 2~6 alkenyl. In certain embodiments, -R 10 is C 2~6 alkynyl. In certain embodiments, -R 10 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0155] In certain embodiments, -R 10a is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 10a is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 10a is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 10a is selected from the group consisting of -H, -C(O)OH, -OH, and C 1~6 alkyl. In certain embodiments, -R 10a is -H. In certain embodiments, -R 10a is -C(O)OH. In certain embodiments, -R 10a is halogen. In certain embodiments, -R 10a is -F. In certain embodiments, -R 10a is -CN. In certain embodiments, -R 10a is -OH. In certain embodiments, -R 10a is C 1~6 alkyl. In certain embodiments, -R 10a is C 2~6 alkenyl. In certain embodiments, -R 10a is C 2~6 alkynyl. In certain embodiments, -R 10ais selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0156] In certain embodiments, -R 11 is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 11 is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 11 is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 11 is selected from the group consisting of -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, -R 11 is -H. In certain embodiments, -R 11 is -C(O)OH. In certain embodiments, -R 11 is halogen. In certain embodiments, -R 11 is -F. In certain embodiments, -R 11 is -CN. In certain embodiments, -R 11 is -OH. In certain embodiments, -R 11 is C 1~6 alkyl. In certain embodiments, -R 11 is C 2~6 alkenyl. In certain embodiments, -R 11 is C 2~6is alkynyl. In certain embodiments, -R 11 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, and 1-ethylpropyl.

[0157] In certain embodiments, -R 11a is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 11a is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 11a is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 11a is selected from the group consisting of -H, -C(O)OH, -OH, and C 1~6 alkyl. In certain embodiments, -R 11a is -H. In certain embodiments, -R 11a is -C(O)OH. In certain embodiments, -R 11a is halogen. In certain embodiments, -R 11a is -F. In certain embodiments, -R 11a is -CN. In certain embodiments, -R 11a is -OH. In certain embodiments, -R 11a is C 1~6 alkyl. In certain embodiments, -R 11a is C 2~6is alkenyl. In certain embodiments, -R 11a is C 2~6 is alkynyl. In certain embodiments, -R 11a is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, and 1-ethylpropyl.

[0158] In certain embodiments, -R 12 is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12 is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12 is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12 is selected from the group consisting of -H, -C(O)OH, -OH, and C 1~6 alkyl. In certain embodiments, -R 12 is -H. In certain embodiments, -R 12 is -C(O)OH. In certain embodiments, -R 12 is halogen. In certain embodiments, -R 12 is -F. In certain embodiments, -R 12 is -CN. In certain embodiments, -R 12 is -OH. In certain embodiments, -R 12 is C 1~6is alkyl. In certain embodiments, -R 12 is C 2~6 is alkenyl. In certain embodiments, -R 12 is C 2~6 is alkynyl. In certain embodiments, -R 12 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, and 1-ethylpropyl.

[0159] In certain embodiments, -R 12a is selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12a is selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12a is selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, -R 12a is selected from the group consisting of -H, -C(O)OH, -OH, and C 1~6 alkyl. In certain embodiments, -R 12a is -H. In certain embodiments, -R 12a is -C(O)OH. In certain embodiments, -R 12a is halogen. In certain embodiments, -R 12a is -F. In certain embodiments, -R 12a is -CN. In certain embodiments, -R 12ais -OH. In certain embodiments, -R 12a is C 1~6 alkyl. In certain embodiments, -R 12a is C 2~6 alkenyl. In certain embodiments, -R 12a is C 2~6 alkynyl. In certain embodiments, -R 12a is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl, and 1-ethylpropyl.

[0160] In certain embodiments, each -R 2 is independently selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, each -R 2 is independently selected from the group consisting of -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, each -R 2 is independently selected from the group consisting of -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl, and C 2~6 alkynyl. In certain embodiments, each -R 2 is independently selected from the group consisting of -H, -C(O)OH, -OH, and C 1~6 alkyl. In certain embodiments, each -R 2 is -H. In certain embodiments, each -R 2 is -C(O)OH. In certain embodiments, each -R 2is a halogen. In certain embodiments, each -R 2 is -F. In certain embodiments, each -R 2 is -CN. In certain embodiments, each -R 2 is -OH. In certain embodiments, each -R 2 is C 1~6 alkyl. In certain embodiments, each -R 2 is C 2~6 alkenyl. In certain embodiments, each -R 2 is C 2~6 alkynyl.

[0161] In certain embodiments, each -R 2 is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl. In this case, -R 2 / -R 2a and one or more of the pairs of two adjacent -R 2 may optionally, together with the atoms to which they are attached, form C 3~10 cycloalkyl, and -R 2 / -R 5 pairs may optionally, together with the atoms to which they are attached, form ring-A-, and it is understood that -A- is used as defined in formula (I).

[0162] In certain embodiments, each -R 2a is independently selected from the group consisting of -H, -C(O)OH, halogen, -CN, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, each -R 2a is -H, -C(O)OH, -CN, -OH, C 1~6 alkyl, C2~6 Selected independently from the group consisting of alkenyl and C 2~6 alkynyl. In certain embodiments, each -R 2a is -H, -C(O)OH, halogen, -OH, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, each -R 2a is -H, -C(O)OH, -OH and C 1~6 alkyl. In certain embodiments, each -R 2a is -H. In certain embodiments, each -R 2a is -C(O)OH. In certain embodiments, each -R 2a is halogen. In certain embodiments, each -R 2a is -F. In certain embodiments, each -R 2a is -CN. In certain embodiments, each -R 2a is -OH. In certain embodiments, each -R 2a is C 1~6 alkyl. In certain embodiments, each -R 2a is C 2~6 alkenyl. In certain embodiments, each -R 2a is C 2~6 alkynyl. In certain embodiments, each -R 2a is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.

[0163] In certain embodiments, -R 3 , -R 4 , -R 5 , -R 7 , -R 8and -R 9 is independently selected from the group consisting of -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 is independently selected from the group consisting of -H, -T, -CN, C 1~6 alkyl and C 2~6 alkenyl. In certain embodiments, -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 is independently selected from the group consisting of -H, -T, -CN and C 1~6 alkyl. In certain embodiments, -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 is independently selected from the group consisting of -H, -T and C 1~6 alkyl. In certain embodiments, -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 is independently selected from the group consisting of -H and C 1~6 alkyl.

[0164] In certain embodiments, -R 3 is selected from the group consisting of -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl. In certain embodiments, -R 3 is -H. In certain embodiments, -R 3 is -T. In certain embodiments, -R 3is -CN. In certain embodiments, -R 3 is C 1~6 alkyl. In certain embodiments, -R 3 is C 2~6 alkenyl. In certain embodiments, -R 3 is C 2~6 alkynyl.

[0165] In certain embodiments, -R 4 is -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl selected from the group consisting of. In certain embodiments, -R 4 is -H. In certain embodiments, -R 4 is -T. In certain embodiments, -R 4 is -CN. In certain embodiments, -R 4 is C 1~6 alkyl. In certain embodiments, -R 4 is C 2~6 alkenyl. In certain embodiments, -R 4 is C 2~6 alkynyl.

[0166] In certain embodiments, -R 5 is -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl selected from the group consisting of. In certain embodiments, -R 5 is -H. In certain embodiments, -R 5 is -T. In certain embodiments, -R 5 is -CN. In certain embodiments, -R 5 is C 1~6 alkyl. In certain embodiments, -R 5 is C 2~6 alkenyl. In certain embodiments, -R 5 is C 2~6It is alkynyl.

[0167] In certain embodiments, -R 7 is -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl selected from the group consisting of. In certain embodiments, -R 7 is -H. In certain embodiments, -R 7 is -T. In certain embodiments, -R 7 is -CN. In certain embodiments, -R 7 is C 1~6 alkyl. In certain embodiments, -R 7 is C 2~6 alkenyl. In certain embodiments, -R 7 is C 2~6 alkynyl.

[0168] In certain embodiments, -R 8 is -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6 alkynyl selected from the group consisting of. In certain embodiments, -R 8 is -H. In certain embodiments, -R 8 is -T. In certain embodiments, -R 8 is -CN. In certain embodiments, -R 8 is C 1~6 alkyl. In certain embodiments, -R 8 is C 2~6 alkenyl. In certain embodiments, -R 8 is C 2~6 alkynyl.

[0169] In certain embodiments, -R 9 is -H, -T, -CN, C 1~6 alkyl, C 2~6 alkenyl and C 2~6It is selected from the group consisting of alkynyl. In certain embodiments, -R 9 is -H. In certain embodiments, -R 9 is -T. In certain embodiments, -R 9 is -CN. In certain embodiments, -R 9 is C 1~6 alkyl. In certain embodiments, -R 9 is C 2~6 alkenyl. In certain embodiments, -R 9 is C 2~6 alkynyl.

[0170] In certain embodiments, T 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 heterobicyclic. In certain embodiments, T is phenyl. In certain embodiments, T is naphthyl. In certain embodiments, T is indenyl. In certain embodiments, T is indanyl. In certain embodiments, T is tetralinyl. In certain embodiments, T is C 3~10 cycloalkyl. In certain embodiments, T is 3- to 10-membered heterocyclyl. In certain embodiments, T is 8- to 11-membered heterobicyclic.

[0171] In certain embodiments, T is substituted with one or more -R 13 which are the same or different. In certain embodiments, T is substituted with one -R 13 . In certain embodiments, T is not substituted with -R 13 .

[0172] In certain embodiments, -R 13 is -H, -NO 2 , -OCH 3 , -CN, -N(R 14 )(R 14a)、 -OH, -C(O)OH, and C 1~6 is selected from the group consisting of alkyl. In certain embodiments, -R 13 is -H. In certain embodiments, -R 13 is -NO 2 In certain embodiments, -R 13 is -OCH 3 In certain embodiments, -R 13 is -CN. In certain embodiments, -R 13 is -N(R 14 )(R 14a ) In certain embodiments, -R 13 is -OH. In certain embodiments, -R 13 is -C(O)OH. In certain embodiments, -R 13 is C 1~6 alkyl.

[0173] In certain embodiments, -R 14 and -R 14a are independently selected from the group consisting of -H and C 1~6 alkyl. In certain embodiments, -R 14 is -H. In certain embodiments, -R 14 is C 1~6 alkyl. In certain embodiments, -R 14a is -H. In certain embodiments, -R 14a is C 1~6 alkyl.

[0174] In certain embodiments, -R 3 / -R 9 together with the nitrogen atom to which they are attached forms a 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclic ring. In certain embodiments, -R 3 / -R 9together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclic ring, and the attachment of the 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclic ring to the remainder of the linker moiety of formula (I) is via sp 3 hybridized nitrogen.

[0175] In certain embodiments, -R 3 / -R 9 together with the nitrogen atom to which they are attached form a ring selected from the group consisting of aziridine, azetidine, pyrroline, imidazoline, pyrazoline, 4-thiazoline, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, piperazine, piperidine, morpholine, triazolidine, tetrazolidine, diazepane, homopiperazine, indoline, benzimidazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, decahydroisoquinoline, tetrahydroisoquinoline and dihydroisoquinoline. Each hydrogen atom of such a ring may be replaced by a substituent as defined above.

[0176] In certain embodiments, n is selected from the group consisting of 0, 1, 2 and 3. In certain embodiments, n is selected from the group consisting of 0, 1 and 2. In certain embodiments, n is selected from the group consisting of 0 and 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0177] In certain embodiments, -L 1 - is connected to -D via a linkage selected from the group consisting of amide, carbamate, dithiocarbamate, O-thiocarbamate, S-thiocarbamate, urea, thiourea, thioamide, amidine and guanidine. Some of these linkages may not be reversible per se, but in the present invention, -L1 - The adjacent groups present in, for example, amides, primary amines, secondary amines and tertiary amines are understood to reversibly effect these linkages.

[0178] In certain embodiments, -L 1 - is conjugated to -D via an amide linkage, i.e., =X 1 is =O and -X 2 - is -C(R 6 )(R 6a )-.

[0179] In certain embodiments, -L 1 - is conjugated to -D via a carbamate linkage, i.e., =X 1 is =O and -X 2 - is -O-.

[0180] In certain embodiments, -L 1 - is conjugated to -D via a dithiocarbamate linkage, i.e., =X 1 is =S and -X 2 - is -S-.

[0181] In certain embodiments, -L 1 - is conjugated to -D via an O-thiocarbamate linkage, i.e., =X 1 is =S and -X 2 - is -O-.

[0182] In certain embodiments, -L 1 - is conjugated to -D via an S-thiocarbamate linkage, i.e., =X 1 is =O and -X 2 - is -S-.

[0183] In certain embodiments, -L 1 - is conjugated to -D via a urea linkage, i.e., =X 1 is =O and -X 2 - is -N(R 5 )-.

[0184] In certain embodiments, -L 1 - is conjugated to -D via a thiourea linkage, i.e., =X 1 is =S, and -X 2 - is -N(R 5 ).

[0185] In certain embodiments, -L 1 - is conjugated to -D via a thioamide linkage, i.e., =X 1 is =S, and -X 2 - is -C(R 6 )(R 6a ).

[0186] In certain embodiments, -L 1 - is conjugated to -D via an amidine linkage, i.e., =X 1 is =N(R 4 ), and -X 2 - is -C(R 6 )(R 6a ).

[0187] In certain embodiments, -L 1 - is conjugated to -D via a guanidine linkage, i.e., =X 1 is =N(R 4 ), and -X 2 - is -N(R 5 ).

[0188] In certain embodiments, -L 1 - is further substituted with one or more substituents.

[0189] In certain embodiments, -L 1 - is not further substituted.

[0190] In certain embodiments, all of the -L 2 - moieties of the conjugates of the invention are the same. In certain embodiments, the conjugates of the invention have more than one type of -L2 - For example, two, three, four or five different -L 2 - portions are included. More than one such type of -L 2 - may be connected only to one type of -L 1 - or may be connected to more than one type of -L 1 -

[0191] In certain embodiments, -L 2 - is a chemical bond.

[0192] In certain embodiments, -L 2 - is a spacer portion.

[0193] In certain embodiments, -L 2 - is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl selected from the group consisting of, -T'-, C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are optionally substituted with one or more -R y2 and C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O)2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -,-S(O)-,-N(R y3 )S(O) 2 N(R y3a )-, -S-,-N(R y3 )-, -OC(OR y3 )(R y3a ), -N(R y3 )(R y3a )- and -OC(O)N(R y3 )- are optionally interrupted by one or more groups selected from the group consisting of, -R y1 and -R y1a are independently selected from the group consisting of -H, -T', C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl, -T', C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are optionally substituted with one or more -R y2 which are the same or different, and C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 ), -S(O) 2 N(R y4 ), -S(O)N(R y4 ), -S(O) 2 -, -S(O)-, -N(R y4 )S(O) 2 N(R y4a ), -S-, -N(R y4 ), -OC(OR y4 )(R y4a ), -N(R y4 )(R y4a ), - and -OC(O)N(R y4 ), - are optionally interrupted by one or more groups selected from the group consisting of, each T' is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3~10 Independently selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic and 8- to 30-membered heteropolycyclic, each T' is one or more -R that are the same or different y2 and is optionally substituted independently by each -R y2 is halogen, -CN, oxo(=O), -C(O)OR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 )(R y5a ), -S(O) 2 N(R y5 )(R y5a ), -S(O)N(R y5 )(R y5a ), -S(O) 2 R y5 , -S(O)R y5 , -N(R y5 )( 2 N(R y5 )(R y5a ), -SR y5 , -N(R y5 )(R y5a ), -NO 2 , -OC(O)R y5 , -N(R y5 )(C(O)R y5a , -N(R y5 )(S(O) 2 R y5a , -N(R y5 )(S(O)R y5a , -N(R y5 )(C(O)OR y5a , -N(R y5 )(C(O)N(R y5 )(R y5a ), -OC(O)N(R y5 )(R y5a ), and C 1~6 alkyl is independently selected from the group consisting of, where C 1~6 alkyl is optionally substituted by one or more halogens that are the same or different each -R y3 , -R y3a , -Ry4 , -R y4a , -R y5 , -R y5a and -R y5b 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.

[0194] In certain embodiments, -L 2 - is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 ), -, -S(O) 2 N(R y1 ), -, -S(O)N(R y1 ), -, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a ), -, -S-, -N(R y1 ), -, -OC(OR y1 )(R y1a ), -, -N(R y1 )C(O)N(R y1a ), -, -OC(O)N(R y1 ), C 1~50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, and -T'-, C 1~20 alkyl, C 2~20 alkenyl and C 2~20 alkynyl are optionally substituted with one or more -R y2 which are the same or different, and C 1~20 alkyl, C 2~20 alkenyl and C 2~20 alkynyl are -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 ), -, -S(O) 2 N(R y3 ), -, -S(O)N(R y3 ), -, -S(O) 2 -, -S(O)-, -N(R y3 )S(O) 2 N(R y3a)-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- is optionally interrupted by one or more groups selected from the group consisting of, -R y1 and -R y1a is independently selected from the group consisting of -H, -T', C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl, -T', C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl is optionally substituted with one or more -R y2 which are the same or different, and C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -, -S(O)-, -N(R y4 )S(O) 2 N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- is optionally interrupted by one or more groups selected from the group consisting of, each T' is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic and 8- to 30-membered heteropolycyclic, and each T' is optionally substituted with one or more -R y2is optionally substituted independently when alone, -R y2 is halogen, -CN, oxo(=O), -C(O)OR y5 -OR y5 -C(O)R y5 -C(O)N(R y5 )(R y5a )、-S(O) 2 N(R y5 )(R y5a )、-S(O)N(R y5 )(R y5a )、-S(O) 2 R y5 -S(O)R y5 -N(R y5 )S(O) 2 N(R y5a )(R y5b )、-SR y5 -N(R y5 )(R y5a )、-NO 2 -OC(O)R y5 -N(R y5 )C(O)R y5a -N(R y5 )S(O) 2 R y5a -N(R y5 )S(O)R y5a -N(R y5 )C(O)OR y5a -N(R y5 )C(O)N(R y5a )(R y5b 、-OC(O)N(R y5 )(R y5a ) and C 1~6 alkyl selected from the group consisting of, where C 1~6 alkyl is optionally substituted with one or more halogens which are the same or different, each -R y3 -R y3a -R y4 -R y4a -R y5 -R y5a and -R y5b is independently selected from the group consisting of -H and C 1~6 alkyl, C 1~6The alkyl is optionally substituted with one or more halogens which are the same or different.

[0195] In certain embodiments, -L 2 - is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1~50 alkyl, C 2~50 alkenyl, and C 2~50 alkynyl, and is selected from the group consisting of -T'-, C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are optionally substituted with one or more -R y2 s, and C 1~50 alkyl, C 2~50 alkenyl and C 2~50 alkynyl are -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O) 2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -, -S(O)-, -N(R y3 )S(O) 2 N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )- and -OC(O)N(R y3)- optionally interrupted by one or more groups selected from the group consisting of -R y1 and -R y1a is independently selected from the group consisting of -H, -T', C 1~10 alkyl, C 2~10 alkenyl and C 2~10 alkynyl, each T' is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic and 8- to 30-membered heteropolycyclic, each -R y2 is independently selected from the group consisting of halogen and C 1~6 alkyl, and each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b 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.

[0196] In certain embodiments, -L 2 - is a C y1 alkyl chain optionally interrupted by one or more groups independently selected from the group consisting of -O-, -T'- and -C(O)N(R 1~20 ), and the C 1~20 alkyl chain is optionally substituted with one or more groups independently selected from the group consisting of -OH, -T' and -C(O)N(R y6 R y6a ), and -R y1 , -R y6 , -R y6a is independently selected from the group consisting of H and C 1~4 alkyl, and T' is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3~10It is selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, 8- to 30-membered carbopolycyclic, and 8- to 30-membered heteropolycyclic.

[0197] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0198] In certain embodiments, -L 2 - is the following:

[0199]

Chemical formula

[0200] Generally, -L 2 - is -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 4 , -R 5 , -R 6 , -R 6a , -R 7 , -R 8 , -R 9 , -R 10 , -R 10a , -R 11 , -R 11a , -R 12 , -R 12a , -R 13 , -R 14or -R 14a One hydrogen presented by -L 2 At any position where -L 1 is replaced by - can be bonded to -L

[0201] In certain embodiments, one hydrogen presented by -R 1 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 1a is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 2 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 2a is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 3 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 4 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 5 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 6 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 6a is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 7 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 8 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 9 is replaced by -L 2 In certain embodiments, one hydrogen presented by -R 10 is replaced by -L 2- is replaced by. In certain embodiments, -R 10a One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 11 One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 11a One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 12 One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 12a One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 13 One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 14 One hydrogen presented by is -L 2 - is replaced by. In certain embodiments, -R 14a One hydrogen presented by is -L 2 - is replaced by.

[0202] In certain embodiments, -L 1 -L 2 - portion is as follows:

[0203]

Chemical formula

[0204] In certain embodiments, -L 1 -L 2 - moiety is of formula (a - 1). In certain embodiments, -R of formula (a - 1) a is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a - 1) a is -H. In certain embodiments, -R of formula (a - 1) a is methyl. In certain embodiments, -R of formula (a - 1) a is ethyl. In certain embodiments, n of formula (a - 1) is selected from the group consisting of 1, 2 and 3. In certain embodiments, n of formula (a - 1) is selected from the group consisting of 1 and 2. In certain embodiments, n of formula (a - 1) is 1. In certain embodiments, n of formula (a - 1) is 2. In certain embodiments, -R b1 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a - 1) b1 is -H. In certain embodiments, -R of formula (a - 1) b1is methyl. In certain embodiments, -R of formula (a-1) b1 is ethyl. In certain embodiments, -R b2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-1) b2 is -H. In certain embodiments, -R of formula (a-1) b2 is methyl. In certain embodiments, -R of formula (a-1) b2 is ethyl. In certain embodiments, -R of formula (a-1) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-1) is 1, and -R of formula (a-1) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-1) is 1, and -R of formula (a-1) a and -R b1 form C 5 cycloalkyl, and -R b2 is -H. In certain embodiments, -R c1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-1) c1 is -H. In certain embodiments, -R of formula (a-1) c1 is methyl. In certain embodiments, -R of formula (a-1) c1 is ethyl. In certain embodiments, -R c2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-1) c2 is -H. In certain embodiments, -R of formula (a-1) c2 is methyl. In certain embodiments, -R of formula (a-1) c2 is ethyl. In certain embodiments, -R d1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-1) d1is -H. In certain embodiments, -R of formula (a-1) d1 is methyl. In certain embodiments, -R of formula (a-1) d1 is ethyl. In certain embodiments, -R of formula (a-1) d2 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-1) d2 is -H. In certain embodiments, -R of formula (a-1) d2 is methyl. In certain embodiments, -R of formula (a-1) d2 is ethyl. In certain embodiments, m of formula (a-1) is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6. In certain embodiments, m of formula (a-1) is 0. In certain embodiments, m of formula (a-1) is 1. In certain embodiments, m of formula (a-1) is 2. In certain embodiments, m of formula (a-1) is 4. In certain embodiments, m of formula (a-1) is 5. In certain embodiments, m of formula (a-1) is 6.

[0205] In certain embodiments, -L 1 -L 2 - moiety is of formula (a-2). In certain embodiments, -R of formula (a-2) a is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-2) a is -H. In certain embodiments, -R of formula (a-2) a is methyl. In certain embodiments, -R of formula (a-2) a is ethyl. In certain embodiments, n of formula (a-2) is selected from the group consisting of 1, 2 and 3. In certain embodiments, n of formula (a-2) is selected from the group consisting of 1 and 2. In certain embodiments, n of formula (a-2) is 1. In certain embodiments, n of formula (a-2) is 2. In certain embodiments, -R b1is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-2) b1 is -H. In certain embodiments, -R of formula (a-2) b1 is methyl. In certain embodiments, -R of formula (a-2) b1 is ethyl. In certain embodiments, -R b2 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-2) b2 is -H. In certain embodiments, -R of formula (a-2) b2 is methyl. In certain embodiments, -R of formula (a-2) b2 is ethyl. In certain embodiments, -R of formula (a-2) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-2) is 1, and -R of formula (a-2) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-2) is 1, and -R of formula (a-2) a and -R b1 form C 5 cycloalkyl, and -R b2 is -H. In certain embodiments, -R c1 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-2) c1 is -H. In certain embodiments, -R of formula (a-2) c1 is methyl. In certain embodiments, -R of formula (a-2) c1 is ethyl. In certain embodiments, -R c2 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (a-2) c2 is -H. In certain embodiments, -R of formula (a-2) c2 is methyl. In certain embodiments, -R of formula (a-2) c2is ethyl. In certain embodiments, -R d1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-2) d1 is -H. In certain embodiments, -R of formula (a-2) d1 is methyl. In certain embodiments, -R of formula (a-2) d1 is ethyl. In certain embodiments, -R d2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-2) d2 is -H. In certain embodiments, -R of formula (a-2) d2 is methyl. In certain embodiments, -R of formula (a-2) d2 is ethyl. In certain embodiments, m in formula (a-2) is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In certain embodiments, m in formula (a-2) is 0. In certain embodiments, m in formula (a-2) is 1. In certain embodiments, m in formula (a-2) is 2. In certain embodiments, m in formula (a-2) is 4. In certain embodiments, m in formula (a-2) is 5. In certain embodiments, m in formula (a-2) is 6. In certain embodiments, -R e is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-2) e is -H. In certain embodiments, -R of formula (a-2) e is methyl. In certain embodiments, -R of formula (a-2) eis ethyl. In certain embodiments, p of formula (a-2) is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In certain embodiments, p of formula (a-2) is 0. In certain embodiments, p of formula (a-2) is 1. In certain embodiments, p of formula (a-2) is 2. In certain embodiments, p of formula (a-2) is 4. In certain embodiments, p of formula (a-2) is 5. In certain embodiments, p of formula (a-2) is 6. In certain embodiments, -R f1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-2) f1 is -H. In certain embodiments, -R of formula (a-2) f1 is methyl. In certain embodiments, -R of formula (a-2) f1 is ethyl. In certain embodiments, -R f2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-2) f2 is -H. In certain embodiments, -R of formula (a-2) f2 is methyl. In certain embodiments, -R of formula (a-2) f2 is ethyl.

[0206] In certain embodiments, -L 1 -L 2 - moiety is of formula (a-3). In certain embodiments, -R of formula (a-3) a is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-3) a is -H. In certain embodiments, -R of formula (a-3) a is methyl. In certain embodiments, -R of formula (a-3) ais ethyl. In certain embodiments, n in formula (a-3) is selected from the group consisting of 1, 2, and 3. In certain embodiments, n in formula (a-3) is selected from the group consisting of 1 and 2. In certain embodiments, n in formula (a-3) is 1. In certain embodiments, n in formula (a-3) is 2. In certain embodiments, -R b1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (a-3) b1 is -H. In certain embodiments, -R in formula (a-3) b1 is methyl. In certain embodiments, -R in formula (a-3) b1 is ethyl. In certain embodiments, -R b2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (a-3) b2 is -H. In certain embodiments, -R in formula (a-3) b2 is methyl. In certain embodiments, -R in formula (a-3) b2 is ethyl. In certain embodiments, -R in formula (a-3) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-3) is 1, and -R in formula (a-3) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-3) is 1, and -R in formula (a-3) a and -R b1 form C 5 cycloalkyl, and -R b2 is -H. In certain embodiments, A* in formula (a-3) is C 5 cycloalkyl. In certain embodiments, A* in formula (a-3) is C 6 cycloalkyl.

[0207] In certain embodiments, -L 1 -L 2- The part has the formula (a-4). In certain embodiments, -R in formula (a-4) a is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (a-4) a is -H. In certain embodiments, -R in formula (a-4) a is methyl. In certain embodiments, -R in formula (a-4) a is ethyl. In certain embodiments, n in formula (a-4) is selected from the group consisting of 1, 2, and 3. In certain embodiments, n in formula (a-4) is selected from the group consisting of 1 and 2. In certain embodiments, n in formula (a-4) is 1. In certain embodiments, n in formula (a-4) is 2. In certain embodiments, -R b1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (a-4) b1 is -H. In certain embodiments, -R in formula (a-4) b1 is methyl. In certain embodiments, -R in formula (a-4) b1 is ethyl. In certain embodiments, -R b2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R in formula (a-4) b2 is -H. In certain embodiments, -R in formula (a-4) b2 is methyl. In certain embodiments, -R in formula (a-4) b2 is ethyl. In certain embodiments, -R in formula (a-4) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-4) is 1, and -R in formula (a-4) a and -R b1 form C 5 cycloalkyl. In certain embodiments, n in formula (a-4) is 1, and -R in formula (a-4) a and -R b1 form C 5 cycloalkyl, and -Rb2 is -H. In certain embodiments, A* of formula (a-4) is C 5 is cycloalkyl. In certain embodiments, A* of formula (a-4) is C 6 is cycloalkyl. In certain embodiments, -R e is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-4) e is -H. In certain embodiments, -R of formula (a-4) e is methyl. In certain embodiments, -R of formula (a-4) e is ethyl. In certain embodiments, p of formula (a-4) is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. In certain embodiments, p of formula (a-4) is 0. In certain embodiments, p of formula (a-4) is 1. In certain embodiments, p of formula (a-4) is 2. In certain embodiments, p of formula (a-4) is 4. In certain embodiments, p of formula (a-4) is 5. In certain embodiments, p of formula (a-4) is 6. In certain embodiments, -R f1 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-4) f1 is -H. In certain embodiments, -R of formula (a-4) f1 is methyl. In certain embodiments, -R of formula (a-4) f1 is ethyl. In certain embodiments, -R f2 is selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, -R of formula (a-4) f2 is -H. In certain embodiments, -R of formula (a-4) f2 is methyl. In certain embodiments, -R of formula (a-4) f2 is ethyl.

[0208] In certain embodiments, -L 1 -L 2 - moiety is as follows:

[0209]

Chem.

[0210] In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (a). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (b). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (c). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (d). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (e). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (f). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (g). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (h). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (i). In a particular embodiment, -L 1 -L 2 - moiety has the structure of formula (j).

[0211] In certain embodiments, the dashed lines marked with asterisks in formulas (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j) represent the bonds of axitinib's π - electron pair donating heterocyclic aromatic N. In certain embodiments, the unmarked dashed lines in formulas (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j) represent the bonds to a hydrogel, particularly a PEG - based hydrogel.

[0212] In certain embodiments, Z is a polymer moiety.

[0213] In certain embodiments, Z is C 8~24 alkyl.

[0214] In certain embodiments, Z is water - soluble.

[0215] In certain embodiments, Z is a water - soluble polymer moiety.

[0216] When Z is a water - soluble polymer moiety, such a polymer moiety has a molecular weight in the range of 1 kDa to 1000 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 5 kDa to 1000 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 5 kDa to 500 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 10 kDa to 250 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 10 kDa to 150 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 12 kDa to 100 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 15 kDa to 80 kDa (including these values). In certain embodiments, Z has a molecular weight in the range of 10 kDa to 80 kDa (including these values).

[0217] In certain embodiments, Z has a molecular weight of about 80 kDa. In certain embodiments, Z has a molecular weight of about 70 kDa. In certain embodiments, Z has a molecular weight of about 60 kDa. In certain embodiments, Z has a molecular weight of about 50 kDa. In certain embodiments, Z has a molecular weight of about 40 kDa. In certain embodiments, Z has a molecular weight of about 30 kDa. In certain embodiments, Z has a molecular weight of about 20 kDa. In certain embodiments, Z has a molecular weight of about 10 kDa. In certain embodiments, Z has a molecular weight of about 5 kDa.

[0218] In certain embodiments, Z is a water-soluble polymer moiety comprising a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0219] In certain embodiments, Z is a protein, such as the carboxyl terminal peptide of chorionic gonadotropin described in US2012 / 0035101A1, which is incorporated herein by reference; albumin; the XTEN sequence described in WO2011123813A2, which is incorporated herein by reference; the proline / alanine random coil sequence described in WO2011 / 144756A1, which is incorporated herein by reference; the proline / alanine / serine random coil sequences described in WO2008 / 155134A1 and WO2013 / 024049A1, which are incorporated herein by reference; and a protein selected from the group consisting of Fc fusion proteins, and is a water-soluble polymer moiety.

[0220] In certain embodiments, Z is polysarcosine. In certain embodiments, Z comprises poly(N-methylglycine). In certain embodiments, Z comprises a random coil protein moiety.

[0221] In certain embodiments, such a random coil protein moiety comprises at least 25 amino acid residues and up to 2000 amino acids. In certain embodiments, such a random coil protein moiety comprises at least 30 amino acid residues and up to 1500 amino acid residues. In certain embodiments, such a random coil protein moiety comprises at least 50 amino acid residues and up to 500 amino acid residues.

[0222] In certain embodiments, Z comprises a random coil protein moiety, wherein at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein moiety are selected from alanine and proline. In certain embodiments, at least 10% but less than 75%, in certain embodiments less than 65% of the total number of amino acid residues of such a random coil protein moiety are proline residues. In certain embodiments, such a random coil protein moiety is as described in WO2011 / 144756A1, which is hereby incorporated by reference in its entirety. In certain embodiments, Z comprises at least one moiety selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:51, and SEQ ID NO:61, as disclosed in WO2011 / 144756, which is hereby incorporated by reference. A moiety comprising such a random coil protein containing alanine and proline is referred to as a "PA" or "PA moiety". Thus, in certain embodiments, Z comprises a PA moiety.

[0223] In certain embodiments, Z comprises a random coil protein portion, wherein at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments at least 99% of the total number of amino acids forming the random coil protein portion are selected from alanine, serine, and proline. In certain embodiments, at least 4% but less than 40% of the total number of amino acid residues of such a random coil protein portion are proline residues. In certain embodiments, such a random coil protein portion is as described in WO2008 / 155134A1, which is hereby incorporated by reference in its entirety. In certain embodiments, Z comprises at least one portion selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, and SEQ ID NO:56 as disclosed in WO2008 / 155134A1, which is hereby incorporated by reference. A portion containing such a random coil protein portion containing alanine, serine, and proline is referred to as a "PAS" or "PAS portion". Thus, in certain embodiments, Z comprises a PAS portion.

[0224] In certain embodiments, Z comprises a random coil protein portion, wherein at least 80%, in certain embodiments at least 85%, in certain embodiments at least 90%, in certain embodiments at least 95%, in certain embodiments at least 98%, and in certain embodiments 99% of the total number of amino acids forming said random coil protein portion are selected from alanine, glycine, serine, threonine, glutamate and proline. In certain embodiments, such random coil protein portions are as described in WO2010 / 091122A1, which is incorporated herein by reference. In certain embodiments, Z comprises at least one portion selected from the group consisting of SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184; SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 759, SEQ ID NO: 760, SEQ ID NO: 761, SEQ ID NO: 762, SEQ ID NO: 763, SEQ ID NO: 764, SEQ ID NO: 765, SEQ ID NO: 766, SEQ ID NO: 767, SEQ ID NO: 768, SEQ ID NO: 769, SEQ ID NO: 770, SEQ ID NO: 771, SEQ ID NO: 772, SEQ ID NO: 773, SEQ ID NO: 774, SEQ ID NO: 775, SEQ ID NO: 776, SEQ ID NO: 777, SEQ ID NO: 778, SEQ ID NO: 779, SEQ ID NO: 1715, SEQ ID NO: 1716, SEQ ID NO: 1718, SEQ ID NO: 1719, SEQ ID NO: 1720, SEQ ID NO: 1721 and SEQ ID NO: 1722, as disclosed in WO2010 / 091122A1, which is incorporated herein by reference.Such a portion containing a random coil protein portion comprising alanine, glycine, serine, threonine, glutamate and proline is referred to as "XTEN" or "XTEN portion" in accordance with its nomenclature in WO2010 / 091122A1. Thus, in certain embodiments, Z comprises an XTEN portion.

[0225] In certain embodiments, Z is a hyaluronic acid-based polymer.

[0226] In certain embodiments, Z is a polymer portion disclosed in WO2013 / 024047A1, which is incorporated herein by reference. In certain embodiments, Z is a polymer portion disclosed in WO2013 / 024048A1, which is incorporated herein by reference.

[0227] In certain embodiments, Z is a PEG-based polymer, such as a linear, branched or multi-arm PEG-based polymer.

[0228] In certain embodiments, Z is a linear PEG-based polymer.

[0229] In certain embodiments, Z is a branched-chain C 8~24 alkyl having 1, 2, 3, 4, 5 or 6 branch points. In certain embodiments, Z is a branched-chain C 8~24 alkyl having 1, 2 or 3 branch points. In certain embodiments, Z is a branched-chain C 8~24 alkyl having 1 branch point. In certain embodiments, Z is a branched-chain C 8~24 alkyl having 2 branch points. In certain embodiments, Z is a branched-chain C 8~24 alkyl having 3 branch points.

[0230] In certain embodiments, Z is a branched polymer. In certain embodiments, Z is a branched polymer having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, Z is a branched polymer having 1, 2, or 3 branch points. In certain embodiments, Z is a branched polymer having 1 branch point. In certain embodiments, Z is a branched polymer having 2 branch points. In certain embodiments, Z is a branched polymer having 3 branch points.

[0231] In certain embodiments, the branch point is selected from the group consisting of -N<, -CH<, and C<.

[0232] In certain embodiments, such a branched Z moiety is PEG-based.

[0233] In certain embodiments, Z is a multi-arm PEG-based polymer.

[0234] In certain embodiments, Z is a multi-arm PEG-based polymer having at least 2 PEG-based arms, such as 2, 3, 4, 5, 6, 7, or 8 PEG-based arms.

[0235] In certain embodiments, Z is a branched PEG-based polymer containing at least 10% PEG, having 1 branch point and 2 PEG-based polymer arms, and having a molecular weight of about 40 kDa. Thus, each of the 2 PEG-based polymer arms has a molecular weight of about 20 kDa. In certain embodiments, the branch point is -CH<.

[0236] In certain embodiments, Z is a branched PEG-based polymer containing at least 10% PEG, having 3 branch points and 4 PEG-based polymer arms, and having a molecular weight of about 40 kDa. Thus, each of the 4 PEG-based polymer arms has a molecular weight of about 10 kDa. In certain embodiments, each of the 3 branch points is -CH<.

[0237] In certain embodiments, Z is water-insoluble.

[0238] In certain embodiments, Z is a water-insoluble polymer moiety.

[0239] In certain embodiments, Z is a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy) polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartoamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyloxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinyl pyrrolidone), silicone, cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof, and is a water-insoluble polymer moiety.

[0240] In certain embodiments, Z is a hydrogel.

[0241] In certain embodiments, Z is a PEG-based or hyaluronic acid-based hydrogel. In certain embodiments, Z is a PEG-based hydrogel. In certain embodiments, Z is a hyaluronic acid-based hydrogel.

[0242] In certain embodiments, Z is a hydrogel described in WO2006 / 003014A2, WO2011 / 012715A1 or WO2014 / 056926A1, the entireties of which are incorporated herein by reference.

[0243] In certain embodiments, Z is a polymer network formed by physical aggregation of polymer chains, which physical aggregation is preferably caused by hydrogen bonding, crystallization, helix formation or complexation. In certain embodiments, such a polymer network is a thermogel polymer.

[0244] In certain embodiments, Z is the following:

[0245]

Chemical formula

[0246] In certain embodiments, the conjugate of the present invention or a pharmaceutically acceptable salt thereof has the formula (Ia), (Ib), (Ic) or (Id):

[0247]

Chemical formula

[0248] One -D is conjugated to a plurality of -L 1 Even if the drug moiety can conjugate to the - moiety, it is understood that the drug moiety is represented by "-D" and the drug is represented by "D-H".

[0249] In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), and Z is a hydrogel. In such cases, the plurality of -L 2 -L 1 It is understood that the -D moiety conjugates to Z and no upper limit can be set for x.

[0250] In certain embodiments, the conjugate is of formula (Ia). In certain embodiments, the conjugate is of formula (Ib). In certain embodiments, the conjugate is of formula (Ic). In certain embodiments, the conjugate is of formula (Id). In certain embodiments, the conjugate is of formula (Ia) and Z is a hydrogel.

[0251] In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x ranges from 2 to 1000, such as 2 to 1500, such as 2 to 1000, such as 2 to 500, such as 2 to 250 or such as 2 to 100. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 20.

[0252] In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 19. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 18. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 17. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 16. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 15. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 14. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 13. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 12. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 11. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 10. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 9. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 8. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 7. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 6. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (I It is of (d), Z is a water-soluble polymer moiety, and x is 5. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 4. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 3. In certain embodiments, the conjugate is of formula (Ia), (Ic) or (Id), Z is a water-soluble polymer moiety, and x is 2.

[0253] In certain embodiments, the conjugate is of formula (Ib), Z is a water-soluble polymer moiety, and y is 1. In certain embodiments, the conjugate is of formula (Ib), Z is a water-soluble polymer moiety, and y is 2. In certain embodiments, the conjugate is of formula (Ib), Z is a water-soluble polymer moiety, and y is 3. In certain embodiments, the conjugate is of formula (Ib), Z is a water-soluble polymer moiety, and y is 4. In certain embodiments, the conjugate is of formula (Ib), Z is a water-soluble polymer moiety, and y is 5.

[0254] In certain embodiments, -L of formula (I) 1 - is of formula (Ix):

[0255]

Chemical formula

[0256] In certain embodiments, n in formula (Ix) is 0. In certain embodiments, n in formula (Ix) is 1. In certain embodiments, n in formula (Ix) is 2.

[0257] In certain embodiments, -R 1 and -R 1ais 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 this case, -R 1 / -R 1a may optionally combine with the atoms to which they are attached to form a C 3~10 cycloalkyl, and -R 1 / -R 2 and -R 1 / -R 5 one or more of the pairs may optionally combine with the atoms to which they are attached to form ring-A-, and it is understood that -A- is used as defined for formula (I).

[0258] In certain embodiments, -R 2 and -R 2a of formula (Ix) 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 this case, -R 2 / -R 2a and one or more of the pairs of two adjacent -R 2 may optionally combine with the atoms to which they are attached to form a C 3~10 cycloalkyl, and -R 2 / -R 5 pairs may optionally combine with the atoms to which they are attached to form ring-A-, and it is understood that -A- is used as defined in formula (I).

[0259] In certain embodiments, =X 1 of formula (Ix) is =O.

[0260] In certain embodiments, -R of formula (Ix) 1 and -R 1a are both -H.

[0261] In certain embodiments, -R of formula (Ix) 1 is -H, and -R of formula (Ix) 1a is 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.

[0262] In certain embodiments, -R of formula (Ix) 3 is C 1~6 alkyl.

[0263] In certain embodiments, -R of formula (Ix) 5 is -H. In certain embodiments, -R of formula (Ix) 5 is methyl. In certain embodiments, -R of formula (Ix) 5 is ethyl.

[0264] In certain embodiments, -R of formula (Ix) 7 is hydrogen. In certain embodiments, -R of formula (Ix) 7 is methyl. In certain embodiments, -R of formula (Ix) 7 is ethyl.

[0265] In certain embodiments, -L of formula (I) 1 - is of formula (I'):[[]]

[0266]

Chemical formula

[0267] In certain embodiments, -R 1 and -R 1a of formula (I') 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 this case, -R 1 / -R 1a may optionally form a C 3~10 cycloalkyl together with the atoms to which they are attached, and -R 1 / -R 5 pairs may optionally form a 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclic ring together with the atoms to which they are attached, it is understood.

[0268] In certain embodiments, -R 1 and -R 1a of formula (I') are both -H.

[0269] In certain embodiments, -R 1 of formula (I') is -H, and -R 1a of formula (I') is C1~6 is alkyl. In certain embodiments, -R in formula (I') 1 is -H, and -R in formula (I') 1a is 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.

[0270] In certain embodiments, -R in formula (I') 3 is C 1~6 alkyl.

[0271] In certain embodiments, -R in formula (I') 5 is methyl. In certain embodiments, -R in formula (I') 5 is ethyl.

[0272] In certain embodiments, -R in formula (I') 5 is -CH 3 and -R in formula (I') 1 and -R 1a are -H, and -R in formula (I') 3 is -H, which is replaced by one -L 2 -Z moiety.

[0273] In certain embodiments, -R in formula (I') 5 is -CH 3 and -R in formula (I') 1 is -H, and -R in formula (I') 1a is -CH 3 and -R in formula (I') 3 is -H, which is replaced by one -L 2 -Z moiety.

[0274] In certain embodiments, -R in formula (I') 5 is ethyl, and -R in formula (I') 1 and -R1a is -H, and -R of formula (I') 3 is -H, and this is one -L 2 is replaced by the -Z moiety.

[0275] In certain embodiments, -L of formula (I) 1 - is formula (Iy):

[0276]

Chemical formula

[0277] In certain embodiments, n of the formula (Iy) is 1. In certain embodiments, n of the formula (Iy) is 2. In certain embodiments, n of the formula (Iy) is 3.

[0278] In certain embodiments, -R 1 and -R 1a are independently selected from the group consisting of -H and C 1~6 alkyl. In certain embodiments, -R 1 and -R 1a 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 this case, -R 1 / -R 1a may optionally form C 3~10 cycloalkyl together with the atoms to which they are attached, and -R 1 / -R 5 , -R 1 / -R 9 and -R 1 / -R 10One or more of the pairs may optionally form ring-A- together with the atoms to which they are attached, and it is understood that -A- is used as defined for formula (I).

[0279] In certain embodiments, -R 1 and -R 1a are both -H.

[0280] In certain embodiments, -R 2 and -R 2a are independently selected from the group consisting of -H and C 1~6 alkyl. In certain embodiments, -R 2 and -R 2a 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 this case, -R 2 / -R 2a and one or more of the pairs of two adjacent -R 2 may optionally form C 3~10 cycloalkyl together with the atoms to which they are attached, and it is understood that the pair of -R 2 / -R 5 may optionally form a 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclic together with the atoms to which they are attached.

[0281] In certain embodiments, -R 2 and -R 2a are both -H.

[0282] In certain embodiments, -R 3 is H. In certain embodiments, -R 3 is methyl.

[0283] In certain embodiments, -R of formula (Iy) 5 is H. In certain embodiments, -R of formula (Iy) 5 is methyl.

[0284] The conjugates of the present invention release one or more drugs over an extended period of time, i.e., they are sustained release conjugates. In certain embodiments, the release occurs with a release half-life in the range of 1 day to 1 month. In certain embodiments, the release occurs with a release half-life in the range of 1 day to 20 days. In certain embodiments, the release occurs with a release half-life in the range of 1 day to 15 days. In certain embodiments, the release half-life may be in the range of 2 to 20 days, 4 to 15 days, or 3 to 6 days.

[0285] Another aspect of the present invention is a pharmaceutical composition comprising at least one conjugate of the present invention or a pharmaceutically acceptable salt thereof.

[0286] In certain embodiments, the pharmaceutical composition comprises one conjugate of the present invention or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises two conjugates of the present invention. In certain embodiments, the pharmaceutical composition comprises three conjugates of the present invention.

[0287] Such pharmaceutical compositions may have a pH in the range of pH 3 to pH 8, for example, in the range of pH 4 to pH 6 or in the range of pH 4 to pH 5. In certain embodiments, the pH of the pharmaceutical composition is about 4. In certain embodiments, the pH of the pharmaceutical composition is about 4.5. In certain embodiments, the pH of the pharmaceutical composition is about 5. In certain embodiments, the pH of the pharmaceutical composition is about 5.5.

[0288] In certain embodiments, the pH of the pharmaceutical composition is 4. In certain embodiments, the pH of the pharmaceutical composition is 4.5. In certain embodiments, the pH of the pharmaceutical composition is 5. In certain embodiments, the pH of the pharmaceutical composition is 5.5.

[0289] In certain embodiments, such pharmaceutical compositions are suspension formulations.

[0290] In certain embodiments, such pharmaceutical compositions are dry compositions. It is understood that such dry compositions can be obtained by drying a suspension composition, for example, by lyophilization.

[0291] When the pharmaceutical composition is a parenteral composition, suitable excipients can be classified, for example, as buffers, isotonicity regulators, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, viscosifiers / viscosity enhancers, anti-agglomeration agents, and other adjuvants. However, in some cases, one excipient can have a dual or triple function. The excipient can be selected from the group consisting of the following. (i) Buffer: A physiologically tolerated buffer solution that maintains the pH within a desired range, for example, sodium phosphate, bicarbonate, succinate, histidine, citrate, acetate, sulfate, nitrate, chloride, or pyruvate, and antacids such as Mg(OH) 2 or ZnCO 3 can also be used. (ii) Isotonicity regulator: To minimize pain that can result from cell damage caused by differences in osmotic pressure in an injection depot. Glycerol and sodium chloride are examples, and the effective concentration can be determined by osmometry using an estimated osmotic pressure of 285 - 315 mOsmol / kg of serum. (iii) Preservatives and / or antimicrobial agents: Multiple-dose parenteral formulations require the addition of preservatives at a concentration sufficient to minimize the risk of patient infection during injection, and corresponding regulatory requirements have been established; typical preservatives include m-cresol, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, benzoic acid, chlorocresol, and benzalkonium chloride. (iv) Stabilizers: Stabilization is achieved by enhancing the protein-stabilizing power, by destabilizing the denatured state, or by directly binding excipients to the protein. Stabilizers include amino acids such as alanine, arginine, aspartic acid, glycine, histidine, lysine, proline; saccharides such as glucose, sucrose, trehalose; polyols such as glycerol, mannitol, sorbitol; salts such as potassium phosphate, sodium sulfate; chelating agents such as EDTA, hexaphosphate; ligands such as divalent metal ions (zinc, calcium, etc.); other salts and organic molecules such as phenol derivatives; and in addition, oligomers or polymers such as cyclodextrin, dextran, dendrimer, PEG, or PVP may be used, or protamine or HSA can be used. (v) Anti-adsorption agents: Mainly ionic or non-ionic surfactants, or other proteins or soluble polymers are used to coat the inner surface of the formulation container or to competitively adsorb thereto. For example, poloxamer (Pluronic F-68), PEG dodecyl ether (Brij 35), polysorbates 20 and 80, dextran, polyethylene glycol, PEG-polyhistidine, BSA, and HSA, as well as gelatin. The concentration and type of excipient selected are determined by the effects to be avoided, but typically a monolayer of surfactant is formed at a boundary slightly above the CMC value. (vi) Antioxidants: antioxidants such as ascorbic acid, ectoine, methionine, glutathione, monothioglycerol, morin, polyethyleneimine (PEI), propyl gallate, and vitamin E, and chelating agents such as citric acid, EDTA, hexaphosphate, and thioglycolic acid can also be used. (vii) Thickening agent or viscosity enhancer: It retards the sedimentation of particles in vials and syringes, promotes the mixing and resuspension of particles, and facilitates the injection of the suspension (i.e., reduces the force on the syringe plunger). Suitable thickening agents or viscosity enhancers include, for example, carbomer thickeners such as Carbopol 940, Carbopol Ultrez 10, cellulose derivatives such as hydroxypropylmethylcellulose (hypromellose, HPMC) or diethylaminoethyl cellulose (DEAE or DEAE-C), colloidal magnesium silicate (Veegum) or sodium silicate, hydroxyapatite gel, tricalcium phosphate gel, xanthan, carrageenan such as Satia gum UTC 30, aliphatic poly(hydroxy acids), for example, poly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA), and copolymers thereof (PLGA), D,Terpolymers of L-lactide, glycolide and caprolactone, poloxamers, hydrophilic poly(oxyethylene) blocks and hydrophobic poly(oxypropylene) blocks that constitute the triblock of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (e.g., Pluronic®), polyether ester copolymers, such as polyethylene glycol terephthalate / polybutylene terephthalate copolymers, sucrose isobutyrate acetate (SAIB), dextran or its derivatives, combinations of dextran and PEG, polydimethylsiloxane, collagen, chitosan, polyvinyl alcohol (PVA) and derivatives, polyalkylimide, poly(acrylamide-co-diallyldimethylammonium (DADMA)), polyvinylpyrrolidone (PVP), glycosaminoglycans (GAGs), such as dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate, hyaluronan, hydrophobic A blocks, such as polylactide (PLA) or poly(lactide-co-glycoside) (PLGA) and hydrophilic B blocks, such as polyethylene glycol (PEG) or polyvinylpyrrolidone, are ABA triblock or AB block copolymers, and such block copolymers, as well as the poloxamers described above, may exhibit inverse thermogelation behavior (being in a fluid state at room temperature to facilitate administration and becoming gel-like above the sol-gel transition temperature at body temperature after injection). (viii) Spreading or diffusing agents: Components of the extracellular matrix of the interstitial space, for example, those that modify the permeability of connective tissue through hydrolysis of hyaluronic acid, a polysaccharide found in the intercellular spaces of connective tissue, such as, but not limited to, hyaluronidase, which temporarily reduces the viscosity of the extracellular matrix and promotes the diffusion of the injected drug. (ix) Anti-aggregation agents: For example, propylene glycol. (x) Other adjuvants: For example, wetting agents, viscosity modifiers, antibiotics, hyaluronidase, and acids and bases, such as hydrochloric acid and sodium hydroxide, are adjuvants necessary for pH adjustment during production.

[0292] In another aspect, the present invention relates to a conjugate of the present invention or a pharmaceutical composition comprising the conjugate of the present invention for use as a medicament.

[0293] In another aspect, the present invention relates to a conjugate of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the conjugate of the present invention for use in a method of treating a disease that can be treated with D-H or a pharmaceutically acceptable salt thereof.

[0294] In a further aspect, the present invention is a method of preventing a disease that can be prevented or treated by D-H or treating a patient suffering from a disease, the method comprising administering to the patient an effective amount of a conjugate of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said conjugate.

[0295] Since the present invention is applicable to all drug molecules containing a π-electron pair-donating heterocyclic aromatic N, it is not possible to further specify the diseases that can be treated. However, it will be apparent to those skilled in the art which diseases can be treated with a particular conjugate.

[0296] [Examples] Materials and Methods Unless otherwise specified, all materials were obtained commercially.

[0297] Amino Hydrogel PEG-based amino hydrogels were synthesized as described in Example 3 of WO2011 / 012715A1 using different crosslinking agents and degrees of crosslinking to obtain different levels of amine content. All crosslinking agents were based on 2 kDa PEG and were synthesized as described in Example 2 of WO2011 / 012715A1 using adipic acid (C6), suberic acid (C8) or azelaic acid (C9). The choice of crosslinking agent is indicated in parentheses. The hydrogels were characterized by these free amine contents: HG-1: 0.309 mmol / g (C6), HG-2: 0.300 mmol / g (C6), HG-3: 0.134 mmol / g (C6); HG-4: 0.668 mmol / g (C9); HG-5: 0.303 mmol / g (C6); HG-6: 0.668 mmol / g (C9); HG-7: 0.331 mmol / g (C6); HG-8: 0.686 mmol / g (C9); HG-9: 0.393 mmol / g; (C9): HG-10: 0.474 mmol / g (C8); HG-16: 0.483 mmol / g (C9)

[0298] The following hydrogels were prepared by modification of amine hydrogels with lysine as described in Example 5 of WO2011 / 042450A1 and characterized by their free amine content: HG-11: 0564 mmol / g (from HG-5); HG-12: 0.614 mmol / g (from HG-7), HG-13: 0.691 mmol / g (from HG-9), HG-14: 0.934 mmol / g (from HG-10). HG-15: 0.621 mmol / g (from HG-7); HG-17: 0.864 mmol / g (from HG-16)

[0299] Reaction The reaction was carried out using dry solvents (CH 2 Cl 2 , DMF, THF) stored on molecular sieves purchased from Sigma-Aldrich Chemie GmbH, Munich, Germany. Generally, the reactants were stirred at room temperature and monitored by LCMS.

[0300] Solid-phase synthesis Solid-phase synthesis was carried out in a syringe reactor equipped with a frit. A standard Fmoc protocol was used. The first amino acid was loaded onto 2-chlorotrityl chloride resin (100 - 200 mesh), 1% DVB (Merck, Darmstadt, Germany) using DIPEA in DCM. Fmoc deprotection was carried out using 2:2:96 piperidine / DBU / DMF. The coupling of the next amino acid was carried out using PyBOP / DIPEA or HATU / DIPEA in DMF. Cleavage from the resin was carried out using HFIP or TFA / TES / water / DCM 48:2:2:48. The product was concentrated in vacuo.

[0301] RP-HPLC purification Preparative RP-HPLC purification was carried out using a Waters XBridge BEH300 Prep C18 10μm, 150×30mm column as the stationary phase, with a Waters 600 controller together with a 2487 Dual Absorbance Detector or an Agilent Infinity 1260 preparative system. The product was detected at 215 nm, 320 nm or 360 nm. A linear gradient of solvent system A (water containing 0.1% TFA v / v) and solvent system B (acetonitrile containing 0.1% TFA v / v) was used. HPLC fractions containing the product were pooled and lyophilized if not specified otherwise.

[0302] Flash chromatography Flash chromatography purification was carried out using a Biotage AB, Sweden's Isolera One system or Isolera Four system, using a Biotage KP-Sil silica cartridge. The product was detected at 254 nm, 280 nm or 360 nm.

[0303] RP-LPLC purification Low-pressure RP chromatography purification was performed using a Biotage SNAP C18 cartridge on a Biotage AB, Sweden's Isolera One system or Isolera Four system. The product was detected at 215 nm and 360 nm. Linear gradient of solvent system A (water containing 0.1% TFA v / v) and solvent system B (acetonitrile containing 0.1% TFA v / v). The LPLC fractions containing the product were pooled and lyophilized if not otherwise specified.

[0304] UPLC-MS analysis Ultra-high performance LC (UPLC)-MS for analysis was performed on a Waters Acquity system or Agilent 1290 Infinity II equipped with a Waters BEH300 C18 column (2.1×50 mm, 1.7 μm particle size or 2.1×100 mm, 1.7 μm particle size) connected to a Waters Micromass ZQ or an Agilent Single Quad MS system; solvent A: water containing 0.04% TFA (v / v), solvent B: acetonitrile containing 0.05% TFA (v / v).

[0305] Determination of drug moiety content from hydrogel The drug moiety content of the hydrogel was determined from the total release of the drug after basic incubation and LCMS quantification (UV-based).

[0306] [Example 1] Synthesis of indazole conjugate 1e Linker reagent 1e was synthesized according to the following scheme:

[0307]

Chemical formula

[0308] N-Methyl-N-boc-ethylenediamine (2 g, 11.48 mmol) and NaCNBH in MeOH (20 mL)3 (819 mg, 12.63 mmol) of the solution was added portionwise with 2,4,6-trimethoxybenzaldehyde (2.08 mg, 10.61 mmol). The mixture was stirred at room temperature (RT) for 90 min, acidified with 3M HCl (4 mL), and stirred for an additional 15 min. The reaction mixture was added to saturated NaHCO 3 solution (200 mL), and extracted 5 times with CH 2 Cl 2 . The combined organic phases were dried over Na 2 SO 4 , and the solvent was evaporated in vacuo. The resulting N-methyl-N-boc-N'-tmob-ethylenediamine 1a was dried under high vacuum and used in the next reaction step without further purification. Yield: 3.76 g (11.48 mmol, purity 89%, 1a: double Tmob-protected product = 8:1) MS: m / z 355.22 = [M+H] + , (calculated value = 354.21).

[0309] CH 2 Cl 2 To a solution of 1a (2 g, 5.65 mmol) in CH 2 Cl 2 (24 ml) were added COMU (4.84 g, 11.3 mmol), N-Fmoc-N-Me-Asp(OBn)-OH (2.08 g, 4.52 mmol) and collidine (2.65 mL, 20.34 mmol). The reaction mixture was stirred at RT for 3 h, diluted with CH 2 Cl 2 (250 mL), and washed 3 times with 0.1M H 2 SO 4 (100 mL) and 3 times with brine (100 mL). The aqueous phase was extracted again with CH 2 Cl 2 (100 mL). The combined organic phases were dried over Na 2 SO 4 , filtered, and the residue was concentrated to a volume of 24 mL. 1b was purified using flash chromatography. Yield: 5.31 g (148%, 6.66 mmol) MS: m / z 796.38 = [M+H]+ , (Calculated value = 795.37).

[0310] To a solution of 1b (5.31 g, up to 4.51 mmol based on N-Fmoc-N-Me-Asp(OBn)-OH) in THF (60 mL), DBU (1.8 mL, 3% v / v) was added. The solution was stirred at RT for 12 min, and CH 2 Cl 2 (400 ml) was diluted, and washed three times with 0.1 M H 2 SO 4 (150 ml) and three times with brine (150 ml). The aqueous phase was extracted again with CH 2 Cl 2 (100 ml). The combined organic phases were dried over Na 2 SO 4 and filtered. 1c was isolated upon evaporation of the solvent and used in the next reaction without further purification. MS: m / z 574.31 = [M+H] + , (Calculated value = 573.30).

[0311] 1c (5.31 g, 4.51 mmol, crude) was dissolved in acetonitrile (26 mL), and COMU (3.87 g, 9.04 mmol), 6-tritylmercaptohexanoic acid (2.12 g, 5.42 mmol) and collidine (2.35 mL, 18.08 mmol) were added. The reaction mixture was stirred at RT for 4 h, and CH 2 Cl 2 (400 mL) was diluted, and washed three times with 0.1 M H 2 SO 4 (100 mL) and three times with brine (100 mL). The aqueous phase was extracted again with CH 2 Cl 2 (100 ml). The combined organic phases were dried over Na 2 SO 4 and filtered, and 1d was isolated upon evaporation of the solvent. The product 1d was purified using flash chromatography. Yield: 2.63 g (62%, purity 94%) MS: m / z 856.41 = [M+H] + , (Calculated value = 855.41).

[0312] A solution of 1d (2.63 g, 2.78 mmol) in i-PrOH (33 mL) and H 2 O (11 mL) was treated with LiOH (267 mg, 11.12 mmol), and the reaction mixture was stirred at RT for 70 min. The mixture was diluted with CH 2 Cl 2 (200 ml), washed three times with 0.1 M H 2 SO 4 (50 ml) and three times with brine (50 ml). The aqueous phase was extracted again with CH 2 Cl 2 (100 mL). The combined organic phases were dried over Na 2 SO 4 and filtered, and 1e was isolated upon evaporation of the solvent. 1e was purified using flash chromatography. Yield: 2.1 g (88 %) MS: m / z 878.4 = [M+Na] + , (calcd = 878.40).

[0313] Indazole (50 mg, 0.42 mmol) and PyBOP (264 mg, 0.51 mmol) were dissolved in DMF (1.5 mL). To the solution was added 1e (435 mg, 0.51 mmol) and DIPEA (222 μL, 1.27 mmol) with stirring. After 18 h, the reaction solution was transferred to a separatory funnel, diluted with 10 mL of ethyl acetate, and the organic phase was washed with 1×10 mL of 0.1 N HCl, 1×10 mL of water and 1×10 mL of brine. The organic phase was dried over Na 2 SO 4 and filtered, and all volatiles were evaporated. 1f was purified by flash chromatography. Yield: 173 mg (43 %) MS: m / z 956.72 = [M+H] + , (calcd = 956.47).

[0314] 1f (80 mg, 84 μmol) was taken in HFIP / TES / H 2It was dissolved in O 39 / 1 / 1 (v / v / v) (1 mL). TFA (200 μL, 2.6 mmol) was added to the solution. All volatile substances were removed under an argon stream. 1 g of the crude product was purified by RP-HPLC. Yield: 9.6 mg (21%) TFA salt MS: m / z 434.51 = [M+H] + , (calculated value = 434.22).

[0315] A mixture of 450 μL of formic acid and 50 μL of hydrogen peroxide was incubated at RT for 1 h and pre-cooled in the refrigerator. 100 μL of this solution was added to 1 g (2.50 mg; 4.6 μmol). After 10 min, 100 μL of water was added, and the product was isolated by repeated freeze-drying for 1 h. Yield: 2 mg (86%) formate MS: m / z 482.46 = [M+H] + , (calculated value = 482.21).

[0316] [Example 2] Synthesis of 1-((4-nitrophenoxy)carbonyl)-1H-indazole-3-carboxylic acid 2 1H-Indazole-3-carboxylic acid (249 mg, 1.54 mmol) was suspended in DCM (5 mL), and a solution of 4-nitrophenyl chloroformate (343 mg; 1.70 mmol) in DCM (5 mL) was added with stirring. A suspension was obtained. TEA (645 μL, 4.63 mmol) was added with stirring. After 2 h, the reaction solution was diluted with 150 ml of ethyl acetate, and the organic phase was washed 3 times with 50 mL of 0.1 M HCl. The aqueous phase was extracted twice again with 50 mL of ethyl acetate. The combined organic phases were dried over Na 2 SO 4 and filtered, and the solvent was evaporated. The product 1-((4-nitrophenoxy)carbonyl)-1H-indazole-3-carboxylic acid 2 was used without further purification. Yield: 486 mg (97%) MS: m / z 327.99 = [M+H] + , (calculated value = 328.06).

[0317] [Example 3] Synthesis of Compound 3

[0318] [Chem.]

[0319] 4-Nitrophenyl chloroformate (188 mg, 0.93 mmol) was dissolved in THF (8 mL). This solution was added to axitinib (100 mg, 0.26 mmol), and the reaction mixture was heated at 80 °C for 7 h with stirring (yellow suspension). The reaction suspension was allowed to stand overnight at RT. The suspension was centrifuged, the supernatant was removed, and the precipitate was washed with ethyl acetate (2 times, 6 mL). The precipitate was dried under high vacuum. Yield: 139 mg (92%, HCl salt) MS: m / z 552.11 = [M+H] + , (calculated value = 552.14).

[0320] [Example 4] Synthesis of Compound 4a

[0321] [Chem.]

[0322] N-Benzyloxycarbonyl sarcosine (100 mg, 0.45 mmol) and HOBt (59 mg, 0.44 mmol) were suspended in DCM (1 mL). 1-Propylamine (44 μL, 0.54 mmol) was added to obtain a solution. EDC HCl (91 mg, 0.48 mmol) was added, and the reaction mixture was stirred. After 4.5 h, the reaction mixture was concentrated in vacuo, and the crude product was purified by RP-HPLC. The product was dissolved in THF (1.95 mL) by sonication. To the solution, 10% palladium on activated carbon (42 mg, 0.04 mmol) was added, and the reaction mixture was stirred in a hydrogen atmosphere. After 3 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. Yield: 50 mg (86%) MS: m / z 130.93 = [M+H] + , (Calculated value = 131.12).

[0323] [Example 5] Synthesis of Compound 4b

[0324] [Chemical formula]

[0325] N-benzyloxycarbonyl sarcosine (103 mg, 0.46 mmol) was dissolved in DMF (1 mL), and 2-butylamine (54 μL, 0.53 mmol) and PyBOP (257 mg, 0.49 mmol) were added while stirring to obtain a solution. DIPEA (156 μL, 0.90 mmol) was added. After 5 h, the reaction was quenched with TFA (50 μL), and the product was purified by RP-HPLC. The step product was dissolved in THF (2 mL). To the solution, 10% palladium on activated carbon (4.5 mg, 0.04 mmol) was added, and the reaction mixture was stirred in a hydrogen atmosphere. After 3 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. Yield: 67 mg (quantitative) MS: m / z 144.97 = [M+H] + , (Calculated value = 145.14).

[0326] [Example 6] Synthesis of Compound 4c

[0327] [Chemical formula]

[0328] Boc-Sar-OH (99 mg, 0.52 mmol) was dissolved in DCM (1 mL). While stirring, L-valine tert-butyl ester hydrochloride (111 mg, 0.53 mmol), EDC HCl (109 mg, 0.57 mmol) and DIPEA (276 μL, 1.59 mmol) were added. After 3 h, the reaction was diluted with 30 mL of DCM and washed three times with 30 mL of 0.1 N HCl, twice with saturated NaHCO3 and once with brine. The organic phase was dried over Na 2 SO 4 and filtered and evaporated. The product was purified by RP-HPLC. The product was dissolved in 0.5 ml of DCM. 0.5 ml of TFA was added while stirring in an open flask. After 5 h, the reaction was concentrated under a nitrogen stream and the product was co-evaporated three times with DCM. Yield: 44 mg (28%, TFA salt) MS: m / z 188.88 = [M+H] + , (calculated = 189.13).

[0329] [Example 7] Synthesis of Compound 4d

[0330] [Chemical formula]

[0331] 3-[(tert-Butoxycarbonyl)(methyl)amino]propanoic acid (102 mg, 0.50 mmol) was dissolved in DMF (0.5 mL). 1-Propylamine (49 μL, 0.59 mmol), PyBOP (286 mg, 0.55 mmol) and DIPEA (171 μL, 0.98 mmol) were added. After 3 h, the reaction was quenched with TFA (50 μl) and the product was purified by RP-HPLC. The product was dissolved in 0.5 ml of DCM. 0.5 mL of TFA was added while stirring in an open flask. After 1 h, the reaction was concentrated under a nitrogen stream and the product was co-evaporated twice with DCM. The residue was dissolved in water (2 mL) and lyophilized. Yield: 128 mg (99%, TFA salt) MS: m / z 144.92 = [M+H] + , (calculated value = 145.14).

[0332] [Example 8] Synthesis of Compound 4e

[0333] [Chemical formula]

[0334] Methyl 6-oxo-heptanoate (2 g, 12.64 mmol) was dissolved in methanol (13 mL) and ammonium acetate (9.75 g, 126.43 mmol), and sodium cyanoborohydride (1.19 g, 18.96 mmol) was added while stirring. The resulting suspension changed to a solution, and stirring was continued overnight. The mixture was diluted with water (70 mL), and ethyl acetate was added (80 mL). The pH of the aqueous phase was adjusted to approximately pH 11 with 25 mL of 4M NaOH. The aqueous phase was extracted three more times with 70 mL of ethyl acetate. The combined organic phases were dried (MgSO 4 ), filtered, and concentrated in vacuo. The crude product from the first step was dissolved in DMF (20 mL), and N-Boc-N-ethylglycine (2.55 g, 12.56 mmol), PyBOP (7.19 g, 13.82 mmol), and DIPEA (6.56 mL, 37.68 mmol) were added while stirring. After 1 h, the reaction was diluted with 60 mL of ethyl acetate and washed with 0.1M HCl (three times 80 mL), 0.5M NaOH (three times 50 mL), and brine (50 mL). The organic phase was dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was purified using flash chromatography (heptane / ethyl acetate). The product was dissolved in THF (10 mL), and LiOH (0.46 g, 19.21 mmol) was dissolved in water (4 mL). The solutions were combined and stirred vigorously. After 3 h, the reaction was diluted with 80 mL of ethyl acetate, and 60 mL of 1M HCl was added. The pH of the aqueous phase was less than 2. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (two times 50 mL). The combined organic solutions were dried (MgSO 4) It was filtered and concentrated in vacuo. The residue was dissolved in DCM (10 mL), and TFA (5 mL) was added while stirring vigorously in an open flask. After 30 min, the reaction mixture was concentrated in vacuo and co-evaporated once with 5 mL of DCM. The crude product was dissolved in water (40 mL) and lyophilized. Yield: 2.54 g (59%, TFA salt) MS: m / z 230.94 = [M+H] + , (calculated value = 231.17).

[0335] [Example 9] Synthesis of Compound 4f

[0336] [Chemical formula]

[0337] Compound 4f was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH and Boc-N-ethylglycine as building blocks. During cleavage from the resin, the BOC protecting group was removed simultaneously using a TFA cleavage cocktail. The cleavage solution was concentrated in vacuo, and the residue was dissolved in acetonitrile / water and lyophilized. Yield: 1.01 g (quantitative, TFA salt) MS: m / z 216.92 = [M+H] + , (calculated value = 217.16).

[0338] [Example 10] Synthesis of Compound 4g

[0339] [Chemical formula]

[0340] N-Boc-N-ethylglycine (100 mg, 0.49 mmol) and HOBt (66 mg, 0.49 mmol) were suspended in DCM (1 mL). H-beta-Ala-OtBu hydrochloride (107 mg, 0.59 mmol) was added to obtain a solution. EDC HCl (99 mg, 0.52 mmol) was added and the reaction mixture was stirred for 1.5 h. Volatiles were removed in vacuo and the product was purified by RP-HPLC. The product was dissolved in 0.5 mL of DCM. 0.5 mL of TFA was added with stirring in an open flask. After 30 min, the reaction mixture was concentrated in vacuo and the product was co-evaporated twice with DCM. The residue was dissolved in acetonitrile / water 1:1 (2 mL) and lyophilized. Yield: 125 mg (88 %, TFA salt) MS: m / z 174.98 = [M+H] + , (calculated = 175.11).

[0341] [Example 11] Synthesis of Compound 4h

[0342] [Chemical formula]

[0343] N-Boc-N-ethylglycine (102 mg, 0.50 mmol) was dissolved in DMF (0.5 mL). 1-Propylamine (49 μL, 0.59 mmol), PyBOP (281 mg, 0.54 mmol) and DIPEA (171 μL, 0.98 mmol) were added. After 3.5 h, TFA (40 μL) was added and the product was purified by RP-HPLC. The product was dissolved in 0.5 ml of DCM. 0.5 ml of TFA was added with stirring in an open flask. After 1 h, the reaction mixture was concentrated in vacuo and the product was co-evaporated twice with DCM (2 mL). Yield: 122 mg (94 %, TFA salt) MS: m / z 144.89 = [M+H] + , (calculated = 145.14).

[0344] [Example 12] Synthesis of Compound 4i

[0345] [Chemical formula]

[0346] To a suspension of trans-4-hydroxycyclohexanoic acid (61 mg, 0.43 mmol) in DCM (0.8 mL), HOBt (63 mg, 0.47 mmol) was added, followed by DIC (73 μL, 0.47 mmol). DMF (0.2 mL) was added to the suspension. H-beta-Ala-OtBu hydrochloride (86 mg, 0.47 mmol) in DCM (0.2 mL) was added. After 4.5 h, DIPEA (60 μL) was added. After 5 h, the reaction mixture was diluted with DCM (ca. 10 mL) and filtered. The filtrate was washed with 0.1 M aqueous HCl and then brine. The organic phase was dried over MgSO 4 and filtered, and concentrated in vacuo. The product was purified by RP-HPLC. The product (57.00 mg, 0.21 mmol) was dissolved in DCM (2.5 mL), and DMAP (26 mg, 0.21 mmol) was added. 4-Nitrophenyl chloroformate (85 mg, 0.42 mmol) in DCM (0.5 mL) and DIPEA (110 μL, 0.63 mmol) were added. After 1 h, 0.1 M aqueous HCl (15 mL) was added, and the mixture was diluted with ethyl acetate (30 mL). The organic phase was washed with 0.1 M aqueous HCl (2×10 mL). The aqueous phase was re-extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over MgSO 4 and filtered, and concentrated in vacuo. Yield: 119 mg (65%) MS: m / z 437.21 = [M+H] + , (calcd = 437.19).

[0347] [Example 13] Synthesis of Compound 4j

[0348] [Chemical formula]

[0349] Boc-Sar-OH (103 mg, 0.54 mmol) was dissolved in DCM (1 mL). Tert-butyl-(3S)-3-aminobutanoate (84 mg, 0.53 mmol), EDC HCl (113 mg, 0.59 mmol) and DIPEA (0.28 mL, 1.58 mmol) were added. After 3 h, the reaction mixture was diluted with 30 mL of DCM and washed three times with 30 mL of 0.1 N HCl, twice with saturated NaHCO 3 and twice with brine. The organic phase was dried over Na 2 SO 4 and filtered and evaporated. The product was purified by RP-HPLC. The product was dissolved in 0.5 mL of DCM. 0.5 ml of TFA was added with stirring in an open flask. After 3 h, the reaction was concentrated in vacuo and the product was co-evaporated three times with DCM (5 mL). Yield: 73 mg (47%) MS: m / z 437.21 = [M+H] + , (calcd = 437.19).

[0350] [Example 14] Synthesis of Compound 5a

[0351] [Chemical formula]

[0352] 5a was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, Fmoc-β-homoalanine-OH and Fmoc-Sar-OH as building blocks.

[0353] [Example 15] Synthesis of Compound 5b

[0354] [Chemical formula]

[0355] 5b was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, Fmoc-Ala-OH, and Fmoc-Sar-OH as building blocks.

[0356] [Example 16] Synthesis of Compound 5c

[0357] [Chemical formula]

[0358] 5c was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH and Fmoc-N-methyl-Ala-OH as building blocks.

[0359] [Example 17] Synthesis of Compound 5d

[0360] [Chemical formula]

[0361] 5d was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH and Fmoc-Pro-OH as building blocks.

[0362] [Example 18] Synthesis of Compound 6a

[0363] [Chemical formula]

[0364] 1H-Indazole-3-carboxylic acid (40 mg, 0.25 mmol) was dissolved in DMF (0.5 mL). DIPEA (172 μL, 0.99 mmol) and n-butyl chloroformate (63 μL, 0.49 mmol) were added. The mixture was stirred for 2.5 h. TFA (95 μL) was added and the product was purified by RP-HPLC. Yield: 0.8 mg (1%) MS: m / z 262.91 = [M+H] + , (calculated value = 263.11).

[0365] [Example 19] Synthesis of Compound 6b

[0366]

Chemical Structure

[0367] 4-Nitrophenyl chloroformate (50 mg, 0.25 mmol) was dissolved in DCM (0.50 mL). To the stirred reaction mixture, 2-pentanol (25 μL, 0.23 mmol) and TEA (79 μL, 0.57 mmol) were added. After 4 h, the volatiles were removed under a nitrogen stream, and the product was purified by RP-HPLC. The product (17 mg, 0.07 mmol) was dissolved in 0.5 mL of acetonitrile, and 1H-indazole-3-carboxylic acid (10 mg, 0.06 mmol) was added. DIPEA (27 μL, 0.15 mmol) was added. After 2 h, DIPEA (27 μL, 0.15 mmol) was added again. After 4 h, acetic acid (100 μL) was added, and the product was purified by RP-HPLC. Yield: 15 mg (53%) MS: m / z 277.12 = [M+H] + , (calculated value = 277.12).

[0368] [Example 20] Synthesis of Compound 6c

[0369]

Chemical Structure

[0370] 1H-Indazole-3-carboxylic acid (20 mg, 0.12 mmol) and di-tert-butyl dicarbonate (30 mg, 0.14 mmol) were suspended in acetonitrile (0.50 mL). DMAP (1.5 mg, 0.01 mmol) and DIPEA (32 μL, 0.19 mmol) were added, and the reaction mixture was stirred for 2.25 h. The product was purified by RP-HPLC. Yield: 18 mg (56 %) MS: m / z 547.18 = [2M+Na] + , (calculated value = 547.18).

[0371] [Example 21] Synthesis of Compound 6d

[0372] [Chemical formula]

[0373] H-β-Ala-OtBu hydrochloride (245 mg, 1.35 mmol) was dissolved in DMF (3 mL), cooled for 10 min with stirring in an ice bath, and then DIPEA (250 μL, 1.44 mmol), γ-valerolactone (86 μL, 0.90 mmol) and tin(II) acetate (46 mg, 0.20 mmol) were added sequentially. After an additional 5 min of cooling, the solution was heated to 80 °C with stirring for 6.75 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 0.1 M aqueous HCl (30 mL) and brine (25 mL twice). The combined organic phases were dried (MgSO 4 )), filtered, and concentrated in vacuo. The product was purified by RP-HPLC.

[0374] The aforementioned product (4 mg, 16 μmol) was dissolved in DCM (0.2 mL), and 4-nitrophenyl chloroformate (6.5 mg, 32 μmol) in DCM (50 μL) was added. DIPEA (8 μL, 46 μmol) and DMAP (1.9 mg, 16 μmol) were added. After 2 h, the reaction was quenched by adding 0.1 M aqueous HCl solution (2 mL) and diluted with ethyl acetate (ca. 2 mL). The organic phase was extracted, and then the aqueous phase was extracted again with ethyl acetate (4 times ca. 2 mL). The organics were combined, dried over MgSO 4 and filtered, and the volatiles were removed in vacuo. The activated PNP carbonate from the previous step was used without further purification. 1H-Indazole-3-carboxylic acid (3.2 mg, 20 μmol) in DCM (0.4 ml) was added. DIPEA (9 μL, 52 μmol) was added and the reaction was stirred overnight. The product was purified by RP-HPLC.

[0375] The product from the previous step was dissolved in DCM (0.4 mL), and TFA (0.2 mL) was added. After 1 h, the volatiles were removed in vacuo, the residue was dissolved in water and lyophilized. Yield: 1.7 mg (0.6 %) MS: m / z 378.06 = [M+H] + , (calculated = 378.13).

[0376] [Example 22] Synthesis of Compound 6e

[0377] [Chemical Structure]

[0378] H-Thr-OtBu (59 mg, 0.28 mmol) was dissolved in DMF (0.5 mL), and DIPEA (145 μL, 0.84 mmol) was added. After 5 min, N-acetoxysuccinimide (54 mg, 0.34 mmol) in DMF (0.2 mL) was added dropwise. After 40 min, the reaction was diluted with ethyl acetate (15 mL), and then 0.1 M aqueous HCl solution (3 times 10 mL), saturated NaHCO3 (Washed sequentially with (2 x 10 mL) and brine (2 x 10 mL). The organic phase was dried over MgSO 4 and filtered, then concentrated in vacuo. The product was purified by RP-HPLC.)

[0379] (To a stirred solution of the product from the previous step (4.6 mg, 21 μmol) in DCM (0.2 mL), 4-nitrophenyl chloroformate (8.7 mg, 43 μmol) in DCM (0.1 mL) was added. DIPEA (11 μL, 63 μmol) and DMAP (2.7 mg, 22 μmol) were added with stirring. After 2.25 h, the reaction was diluted with ethyl acetate (ca. 2 mL), then washed with 0.1 M aqueous HCl (2 mL). The aqueous phase was re-extracted with ethyl acetate (3 x ca. 3 mL). The organics were combined, dried over MgSO 4 and filtered, then concentrated in vacuo.)

[0380] (The activated PNP carbonate from the previous step was used without further purification. 1H-Indazole-3-carboxylic acid (4.7 mg, 29 μmol) in DCM (0.4 mL) was added. DIPEA (11 μL, 63 μmol) was added. After stirring overnight, the volatiles were removed in vacuo and the product was purified by RP-HPLC. The product from the previous step was dissolved in DCM (0.4 mL) and TFA (0.2 mL) was added. After 4 h, the volatiles were removed in vacuo, the residue was dissolved in water and lyophilized.) Yield: 1.1 mg (11.2%, TFA salt) MS: m / z 350.06 = [M+H] + , (calcd = 350.10).

[0381] [Example 23] Synthesis of Compound 6f

[0382] [Chemical Structure]

[0383] 4i (22.9 mg, 52 μmol) and 1H-indazole-3-carboxylic acid (7.5 mg, 46 μmol) were suspended in DCM (0.55 mL). DIPEA (25 μL, 144 μmol) was added and the reaction mixture was stirred overnight. Additional DIPEA (8.5 μl three times) was added at 1 h, 1.5 h, and 3.5 h. The next day, the reaction mixture was diluted with ethyl acetate (25 mL) and washed with 0.1 M aqueous HCl (10 mL twice) and brine (10 mL). The organic phase was dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The product was purified by RP-HPLC. The product from the previous step (2.3 mg) was dissolved in DCM (0.1 mL) and TFA (0.1 mL) was added. After 2.25 h, the volatiles were removed in vacuo, the residue was dissolved in water and lyophilized. Yield: 1.6 mg (38%) MS: m / z 460.15 = [M+H] + , (calcd = 460.21).

[0384] [Example 24]

[0385] [Chemical formula] TIFF2025087701000078.tif94167

[0386] Conjugates 7a~k were synthesized by reacting 1 equivalent of 2 with 1.0~1.2 equivalents of each amine 4a~h, or for 7i: 1-propylamine, for 7j: N,N,N'-trimethylethylene, for 7k: N,N,N'-trimethyl-1,3-propanediamine using excess DIPEA in excess DMF. The reaction was quenched using excess TFA and purified by RP-HPLC. 7a: 2: 19 mg, 59 μmol, 4a: 9 mg, 69 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 2.1 mg (11%), MS: m / z 319.09 = [M+H] +, (Calculated value = 319.14). 7b:2:20 mg, 60 μmol, 4b:12 mg, 69 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 5.5 mg (27 %), MS: m / z 333.11 = [M+H] + , (Calculated value = 333.16). 7c:2:10 mg, 31 μmol, 4c:11 mg, 35 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 2.3 mg (19 %), MS: m / z 377.06 = [M+H] + , (Calculated value = 377.15). 7d:2:21 mg, 65 μmol, 4d:18 mg, 66 μmol, DIPEA: 43 μL, 0.25 mmol: Yield: 6.5 mg (30 %), MS: m / z 333.11 = [M+H] + , (Calculated value = 333.16). 7e:2:17 mg, 51 μmol, 4e:17 mg, 49 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 3.9 mg (18 %), MS: m / z 419.17 = [M+H] + , (Calculated value = 419.20). 7f:2:10 mg, 31 μmol, 4f:11 mg, 34 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 1.7 mg (14 %), MS: m / z 405.03 = [M+H] + , (Calculated value = 405.18). 7g:2:20 mg, 60 μmol, 4g:24 mg, 69 μmol, DIPEA: 21 μL, 0.12 mmol: Yield: 1.9 mg (9 %), MS: m / z 363.03 = [M+H] + , (Calculated value = 363.13). 7h:2:20 mg, 60 μmol, 4h:24 mg, 68 μmol, DIPEA: 43 μL, 0.25 mmol: Yield: 4 mg (20 %), MS: m / z 333.18 = [M+H] + , (calculated value = 333.16). 7i:2:22mg, 66μmol, 4i:5μl, 61μmol, DIPEA:21μL, 0.12mmol: Yield: 4.7 mg (29 %), MS: m / z 247.96 = [M+H] + , (calculated value = 248.11). 7j:2:16mg, 50μmol, 4j:8μl, 62μmol, DIPEA:21μL, 0.12mmol: Yield: 8 mg (52 %), MS: m / z 291.03 = [M+H] + , (calculated value = 291.15). 7k:2:21mg, 65μmol, 4k:9.4μl, 64μmol, DIPEA:21μL, 0.12mmol: Yield: 0.4 mg (1 %), MS: m / z 305.06= [M+H] + , (calculated value = 305.16).

[0387] [Example 25]

[0388] [Chemical formula]

[0389] Conjugates 8a - e were synthesized by performing Fmoc deprotection of 5a - d using 2:2:96 piperidine / DBU / DMF, followed by reacting excess 2 with each amine on the resin using DIPEA in excess DMF. The products were cleaved from the resin using HFIP and purified by RP - HPLC. 8a:5a:7mg, 5μmol, 2:5mg, 16μmol, DIPEA:5μL, 31μmol Yield: 1.1 mg (45 %), MS: m / z 476.02 = [M+H] + , (calculated value = 476.22). 8b: 5b: 7mg, 5 μmol, 2: 5mg, 15 μmol, DIPEA: 5 μl, 31 μmol Yield: 1.3 mg (55 %), MS: m / z 462.12 = [M+H] + , (calculated value = 462.20). 8c: 5c: 50 μmol, 2: 44mg, 0.13 mmol, DIPEA: 50 μl, 0.29 mmol Yield: 6.5 mg (32 %), MS: m / z 405.16 = [M+H] + , (calculated value = 405.18). 8d: 5d: 55 μmol, 2: 52mg, 0.16 mmol, DIPEA: 55 μl, 0.32 mmol Yield: 11 mg (48 %), MS: m / z 417.16 = [M+H] + , (calculated value = 417.18).

[0390] [Example 26] Synthesis of Compound 9a

[0391] [Chemical formula]

[0392] 4g (29mg, 82 μmol) was dissolved in 100 μL of DMF, and DIPEA (48 μL, 0.27 mmol) was added. A suspension of 3 (40mg, 68 μmol) (0.79 mL in DMF) was added. After 3.5 h, 4g (14mg, 41 μmol) in 50 μL of DMF was added. After 4.75 h, TFA (21 μL) was added, and the reaction mixture was purified by RP-HPLC. Yield: 22 mg (45 %, TFA salt) MS: m / z 350.06 = [M+H] + , (calculated value = 350.10).

[0393] [Example 27] Synthesis of Compound 9b

[0394] [Chemical formula]

[0395] 4j (28 mg, 88 μmol) was dissolved in 100 μL of DMF, and DIPEA (38 μL, 0.22 mmol) was added. A suspension of 3 (26 mg, 44 μmol) (508 μL in DMF) was added. After 30 min, TFA (6.7 μL) was added, and the product was purified by RP-HPLC. Yield: 31 mg (quantitative, TFA salt) MS: m / z 587.16 = [M+H] + , (calculated value = 587.21).

[0396] [Example 28] Synthesis of Compound 9c

[0397] [Chemical formula]

[0398] 4c (22 mg, 68 μmol) was dissolved in 100 μL of DMF, and DIPEA (30 μL, 0.17 mmol) was added. A suspension of 3 (20 mg, 34 μmol) (393 μL in DMF) was added. After 1 h, TFA (5.2 μl) was added, and the product was purified by RP-HPLC. Yield: 26 mg (quantitative, TFA salt) MS: m / z 601.10 = [M+H] + , (calculated value = 601.23).

[0399] [Example 29] Synthesis of Compounds 9d and 9e

[0400] [Chemical formula]

[0401] 4f (689 mg, 2.09 mmol) was dissolved in 4 mL of DMF, and DIPEA (0.9 mL, 5.2 mmol) was added. A suspension of 3 (0.61 g, 0.98 mmol) in 8.2 mL of DMF was added. After 30 min, the reaction mixture was added to a solution of 4N HCl in 2.6 mL of dioxane and 237 mL of ethyl acetate. The precipitate was centrifuged, the supernatant was decanted, and the residue was washed once with 180 mL of ethyl acetate. The residue was purified by RP-LPLC to give compound 9d. Yield: 0.34 g (46%, TFA salt) MS: m / z 629.34 = [M+H] + , (calcd = 629.26).

[0402] 9d (0.34 g; 0.45 mmol) was dissolved in DMF (6.76 mL), and bis(pentafluorophenyl) carbonate (0.21 g, 0.54 mmol) was added. DIPEA (0.48 mL, 2.73 mmol) was added. After 45 min, acetic acid (0.48 mL) was added, and the product was purified by RP-LPLC to give compound 9e. Yield: 0.40 g (98%, TFA salt) MS: m / z 795.39 = [M+H] + , (calcd = 795.24).

[0403] [Example 30] Synthesis of compound 9f

[0404]

Chemical Structure

[0405] A suspension of 3 in DMF (8.50 mL, 0.13 mol / L; 1.04 mmol) was added to 4e (0.72 g, 2.08 mmol), and DIPEA (0.91 mL, 5.21 mmol) was added. After 45 min, the reaction mixture was added to a solution of 4N HCl in 2.6 mL of dioxane and 160 mL of ethyl acetate. The precipitate was centrifuged, the supernatant was decanted, and the residue was purified by RP-LPLC.

[0406] The product from the previous step (0.42 g, 0.55 mmol) was dissolved in DMF (8.40 mL), and bis(pentafluorophenyl) carbonate (0.27 g, 0.67 mmol) was added. DIPEA (0.58 mL, 3.33 mmol) was added. After 1 h, acetic acid (0.48 mL) was added, and the product was purified by RP-LPLC. Yield: 0.27 g (28%, TFA salt) MS: m / z 809.36 = [M+H] + , (calculated = 809.26).

[0407] [Example 31] Synthesis of Compound 9g

[0408] [Chemical formula]

[0409] A solution of 4i (49 mg, 0.11 mmol) in THF (1.60 mL) was added to axitinib (22 mg, 56 μmol). DIPEA (49 μL, 0.28 mmol) was added. The reaction mixture was heated at 60 °C for 6 h and stirred overnight at RT. DMF (0.5 ml) was added. The reaction mixture was heated at 60 °C for 6.5 h and stirred at RT for 3 days. DMAP (>1 equivalent) was added, and the reaction mixture was stirred at RT for 1 day. TFA (25 μL) was added, and the product was purified by RP-HPLC.

[0410] The product from the previous step (16 mg, 20 μmol) was dissolved in a mixture of DCM (1 mL) and TFA (1 mL). After 2 h, the volatile substances were removed in vacuo, and the residue was dissolved in 3 mL of acetonitrile / water / TFA 1:1:0.002 and lyophilized.

[0411] The product from the previous step (15 mg, 20 μmol) was dissolved in DMF (0.29 mL), and bis(pentafluorophenyl) carbonate (9.4 mg, 24 μmol) was added. DIPEA (21 μL; 0.12 mmol) was added. After 1.5 h, TFA (10 μL) was added, and the reaction mixture was purified by RP-HPLC. Yield: 13 mg (25%, TFA salt) MS: m / z 794.25 = [M+H] + , (calculated value = 794.21).

[0412] [Example 32] Synthesis of Compounds 10a-d

[0413] [Chemical Structure]

[0414] Methoxypolyethylene glycol amine - 5 kDa PEG, PyBOP, DIPEA, and 9 were stirred at RT. After the reaction was completed, acetic acid was added, and the product was purified by RP-HPLC. 10a: PEG: 33 mg, 6.0 μmol, PyBOP: 3.6 mg, 6.9 μmol, DIPEA: 3.1 μl, 18 μmol, 9a: 4.2 mg, 6 μmol, Yield: 21 mg (58%, TFA salt). 10b: PEG: 21 mg, 3.8 μmol, PyBOP: 3.5 mg, 6.7 μmol, DIPEA: 1.9 μl, 11 μmol, 9b: 2.6 mg, 3.7 μmol, Yield: 18 mg (77%, TFA salt). 10c: PEG: 47 mg, 8.5 μmol, PyBOP: 4.9 mg, 9.4 μmol, DIPEA: 4.4 μl, 25 μmol, 9c: 6 mg, 8.4 μmol, Yield: 31 mg (60%, TFA salt). 10d: PEG: 31 mg, 5.6 μmol, PyBOP: 3.5 mg, 6.8 μmol, DIPEA: 2.8 μL, 16 μmol, 9d: 4 mg, 5.4 μmol, Yield: 34 mg (quantitative, TFA salt).

[0415] [Example 33] Synthesis of Compounds 11a - d

[0416] [Chemical Formula]

[0417] The hydrogel was swollen in a syringe reactor containing a PE frit in 1% DIPEA in DMF. The syringe reactor was filled three times, shaken for 1 min, and discharged. 9 was dissolved in DMF, and DIPEA was added. The solution was drawn into a syringe containing the hydrogel. The syringe was shaken for more than 16 h at RT. The syringe was discharged, and the hydrogel was washed several times with DMF and ethanol and dried in vacuo, or washed several times with DMF, water, and 20 mM sodium succinate aqueous buffer at pH 5.5 to obtain a hydrogel suspension in the pH 5.5 aqueous buffer. 11a: HG - 1: 14 mg, DIPEA: 1.6 μL, 9e: 3 mg, Yield: 15 mg, 39 mg / g axitinib dried in the dried hydrogel. 11b: HG - 2: 0.82 g, DIPEA: 0.21 mL, 9e: 0.40 g Yield: Suspension, 7.55 mg / mL axitinib in the hydrogel suspension. 11c: HG - 3: 30 mg, DIPEA: 3.5 μL, 9f: 6.7 mg, Yield: Suspension, 2.93 mg / mL axitinib in the hydrogel suspension. 11d: HG - 3: 30 mg, DIPEA: 3.5 μL, 9g: 13 mg Yield: Suspension, 3.65 mg / mL axitinib in the hydrogel suspension.

[0418] [Example 34] In vitro Release Kinetics The cleavage rates of the reversible bonds from conjugates 6a - f, 7a - k, 8a - d, 10a - d, 11a - d were monitored at pH 7.4 and 37 °C in aqueous buffer (48 mM sodium phosphate, 20% acetonitrile at pH 7.4 or 60 mM sodium phosphate at pH 7.4). For soluble examples, the disappearance of the conjugate was determined by LCMS (UV detection) and fitted to curve - fitting software to obtain a preliminary half - life of release. For insoluble examples (hydrogels), the increase in the released heterocyclic aromatic moiety - containing molecules in the supernatant was determined by LCMS (UV detection) and used as input for curve - fitting software to obtain a preliminary half - life of release.

[0419]

Table 1

[0420] 「 * 」and「 ** 」- labeled compounds are not linked to the Z - moiety for efficiency reasons and are not according to the present invention. Nevertheless, they show the release half - lives of such - L 1 - moieties. The compound labeled「 ** 」was synthesized for comparison.

[0421] [Example 35] Synthesis of Compound 12a

[0422]

Chem.

[0423] 12a was synthesized using solid - phase synthesis according to a general protocol, using Fmoc - N - methyl - beta - alanine, Fmoc - beta - homoalanine - OH and Fmoc - Sar - OH as building blocks.

[0424] [Example 36] Synthesis of Compound 12b

[0425] [Chemical formula]

[0426] 12b was synthesized using solid-phase synthesis according to a general protocol and using Fmoc-beta-homoalanine-OH and Fmoc-Sar-OH as building blocks.

[0427] [Example 37] Synthesis of Compound 12c

[0428] [Chemical formula]

[0429] 12c was synthesized using solid-phase synthesis according to a general protocol and using Fmoc-Ahx-OH, (S)-Fmoc-4-aminopentanoic acid, and Fmoc-Sar-OH as building blocks.

[0430] [Example 38] Synthesis of Compound 12d

[0431] [Chemical formula]

[0432] 12d was synthesized using solid-phase synthesis according to a general protocol and using Fmoc-8-amino-3,6-dioxaoctanoic acid and Fmoc-N-ethyl-Gly-OH as building blocks.

[0433] [Example 39] Synthesis of Compound 12e

[0434] [Chemical formula]

[0435] 12e was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, Fmoc-aminooxyacetic acid, and Fmoc-Sar-OH as building blocks and HFIP for cleavage from the resin. It was then purified by RP-HPLC. Yield: 2.4 mg MS: m / z 484.20 = [M+H] + , (calculated = 484.20).

[0436] [Example 40] Synthesis of Compounds 13a - d

[0437] [Chemical Structure Diagram]

[0438] Conjugates 13a - d were synthesized by performing Fmoc deprotection of 12a - d using 2:2:96 piperidine / DBU / DMF, followed by reacting excess 2 with each amine on the resin using DIPEA in excess DMF. The products were cleaved from the resin using HFIP and purified by RP-HPLC. 13a: 12a: 32 mg, 24 μmol, 2: 20 mg, 60 μmol, DIPEA: 17 μL, 96 μmol Yield: 5.1 mg (48 %), MS: m / z 448.15 = [M+H] + , (calculated = 448.18). 13b: 12b: 37 mg, 27 μmol, 2: 22 mg, 68 μmol, DIPEA: 19 μL, 109 μmol Yield: 5.2 mg (43 %), MS: m / z 448.15 = [M+H] + , (calculated = 448.18). 13c: 12c: 32 μmol, 2: 26 mg, 79 μmol, DIPEA: 22 μL, 127 μmol Yield: 6.5 mg (42 %), MS: m / z 490.20 = [M+H] +, (Calculated value = 490.23). 13d: 12d: 26 μmol, 2: 21 mg, 64 μmol, DIPEA: 18 μL, 102 μmol Yield: 2.9 mg (26 %), MS: m / z 437.14 = [M+H] + , (Calculated value = 437.16).

[0439] [Example 41] Synthesis of Compound 13e

[0440] [Chemical Structure]

[0441] Compound 12e (2.4 mg, 0.005 mmol) in DMF (0.5 mL) was treated with piperidine (50 μL). After stirring for 1 h at RT, the mixture was diluted with DCM and the volatile substances were removed in vacuo. The residue was combined with 2 (2.4 mg; 0.007 mmol) in DMF (0.2 mL), and DIPEA (2.6 μL; 0.015 mmol; 3.0 eq) was added. After stirring for 65 min at RT, TFA (1.1 μL) was added. The volatile substances were removed in vacuo, and the residue was redissolved in 1:3 acetonitrile / H 2 O and freeze-dried. The residue was combined again with 2 (2.7 mg; 0.008 mmol) in DMF (0.2 mL), and DIPEA (5.0 μL; 0.029 mmol; 3.0 eq) was added. After stirring for 2.5 h at RT, TFA (1.5 μL) was added. The volatile substances were removed in vacuo, and the residue was redissolved in 1:3 acetonitrile / H 2 O and freeze-dried, and the crude product was purified by RP-HPLC. Yield: 0.1 mg (3%) MS: m / z 450.10 = [M+H] + , (Calculated value = 450.16)

[0442] [Example 42] Synthesis of Compound 14a

[0443] [Chem.]

[0444] Methyl 6-oxo-heptanoate (2 g, 12.6 mmol) was dissolved in methanol (13 mL) and ammonium acetate (9.75 g, 126 mmol), and sodium cyanoborohydride (1.19 g, 19.0 mmol) was added with stirring. The resulting suspension changed to a solution, and stirring was continued overnight. The mixture was diluted with water (70 mL), and ethyl acetate was added (80 mL). The pH of the aqueous phase was adjusted to about pH 11 with 25 mL of 4M NaOH. The aqueous phase was extracted with ethyl acetate (3 times 70 mL). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated in vacuo to give a yellow oil (1.83 g). A portion (200 mg) of the crude oil from the first step was dissolved in DMF (2 mL), and N-Boc-Sar-OH (238 mg, 1.26 mmol), PyBOP (719 mg, 1.38 mmol), and DIPEA (656 μL, 3.77 mmol) were added with stirring. The reaction was stirred at RT for 2 h. The mixture was diluted with 25 mL of ethyl acetate and washed with 0.1N HCl (3 times 15 mL), 0.5M NaOH (3 times 15 mL), and brine (15 mL). The organic phase was dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was purified using flash chromatography (heptane / ethyl acetate). The product (235 mg) was dissolved in THF (1 mL), and LiOH (51 mg, 2.13 mmol) was dissolved in water (0.4 mL). The solutions were combined and stirred vigorously at RT. After 5 h, the mixture was diluted with 80 mL of ethyl acetate, and 60 mL of 1N HCl was added. The pH of the aqueous phase was less than 2. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (3 times 20 mL). The combined organics were dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was dissolved in DCM (1.0 mL), and TFA (0.5 mL) was added with vigorous stirring in an open flask. After 75 min, the reaction was concentrated in vacuo and co-evaporated once with 5 mL of DCM. The crude product was 1:2 acetonitrile / H 2It was dissolved in O + 0.1% TFA (20 mL) and lyophilized. Yield: 213 mg (47%, TFA salt) MS: m / z 217.05 = [M+H] + , (calculated value = 217.15).

[0445] [Example 43] Synthesis of Compound 14b

[0446] [Chemical formula]

[0447] Methyl 5-oxohexanoate (2.00 g, 13.9 mmol) was dissolved in THF (60 mL), and LiOH (1.00 g, 41.6 mmol) and water (20 mL) were added. The mixture was stirred at RT for 5 h and then diluted with ethyl acetate (300 mL). 1N aqueous HCl solution (80 mL) was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic matter was dried (MgSO 4 ), and concentrated in vacuo. The resulting colorless oil (1.6 g) was dissolved in DMF (32 mL), and PyBOP (7.68 g, 14.8 mmol) and then DIPEA (10.7 mL, 61.5 mmol) were added to the mixture. After stirring for 5 min, tert-butyl 3-aminopropanoate hydrochloride (2.69 g, 14.8 mmol) was added, and the mixture was stirred at RT for 105 min. The mixture was diluted with ethyl acetate (400 mL) and washed with 0.55M aqueous HCl solution (100 mL), 0.1M aqueous HCl solution (2×100 mL), saturated NaHCO 3 (3×100 mL) and brine (100 mL). The organic matter was dried (MgSO 4) Concentrated in vacuo and then purified by flash chromatography (ethyl acetate / heptane). The purified material was then dissolved in MeOH (14.2 mL), and ammonium acetate (6.60 g, 85.6 mmol) and sodium cyanoborohydride (801 mg; 12.8 mmol) were added. The mixture was stirred overnight at RT. The mixture was diluted with water (70 ml) and ethyl acetate (80 ml). 4M NaOH (15 mL) was used to adjust the pH of the aqueous phase to approximately pH 2. The aqueous phase was extracted with ethyl acetate (3 x 70 mL), the organics were combined, and TFA (648 μL) was added. To the aqueous phase, an additional 4M NaOH (5 mL) was added, and this was again extracted with ethyl acetate (3 x 70 mL), these organics were combined, and TFA (400 μL) was added. The organics were dried (MgSO 4 ), filtered, and the volatiles were removed in vacuo. Yield: 3.40 g (66 %, TFA salt) MS: m / z 259.12 = [M+H] + , (calcd = 259.20).

[0448] [Example 44] Synthesis of Compound 14c

[0449] [Chemical formula]

[0450] Compound 14b (249 mg, 0.62 mmol) was dissolved in DMF (2.30 mL), and N-Boc-N-ethylglycine (132 mg, 0.65 mmol) and PyBOP (353 mg; 0.68 mmol), followed by DIPEA (326 μL, 1.87 mmol) were added to form a pale yellow solution. After stirring for 90 min at RT, the mixture was diluted with ethyl acetate (50 mL) and washed with 0.1M HCl (3 x 25 mL), saturated NaHCO 3 aqueous solution (25 mL), brine and saturated NaHCO 3 aqueous solution 3:5 v / v mixture (2 x 40 mL), and brine (30 mL). The organics were dried (MgSO 4) The volatile substances were removed under vacuum. The intermediate was purified by flash chromatography (methanol / DCM) and then by RP-HPLC to obtain a colorless oil. The oil was dissolved in DCM (0.5 mL), and TFA (0.5 mL) was added. After stirring at RT for 55 min, the volatile substances were removed under a nitrogen stream. The residue was diluted with acetonitrile / H 2 O 1:1 + 0.1% TFA (2 mL) + 0.1% TFA and water (4 mL). The mixture was lyophilized to obtain a colorless oil. Yield: 136 mg (52%, TFA salt) MS: m / z 288.19 = [M+H] + , (calculated value = 288.19).

[0451] [Example 45] Synthesis of Compound 14d

[0452] [Chemical formula]

[0453] Compound 14b (251 mg, 0.63 mmol) was dissolved in DMF (2.30 mL), N-Boc-Sar-OH (121 mg, 0.64 mmol) and PyBOP (358 mg; 0.69 mmol), followed by DIPEA (326 μL, 1.87 mmol) were added to form a pale yellow solution. After stirring at RT for 90 min, the mixture was diluted with ethyl acetate (50 mL) and washed with 0.1 M HCl (3 times 25 mL), saturated NaHCO 3 aqueous solution (25 mL), brine and saturated NaHCO 3 aqueous solution 3:5 v / v mixture (2 times 40 mL), and brine (30 mL). The organic matter was dried over MgSO4 and the volatile substances were removed under vacuum. The intermediate was purified by flash chromatography (methanol / DCM) to obtain a colorless oil. The oil was dissolved in DCM (0.5 mL), and the solution was treated with TFA (0.5 mL). After stirring at RT for 55 min, the volatile substances were removed under a nitrogen stream. The residue was diluted with 1:1 acetonitrile / H 2It was diluted with O + 0.1% TFA (2 mL), 0.1% TFA and water (4 mL). The mixture was lyophilized to obtain a colorless oil. Yield: 129 mg (51%, TFA salt) MS: m / z 274.18 = [M+H] + , (calculated value = 274.17).

[0454] [Example 46] Synthesis of Compound 14e

[0455] [Chemical formula]

[0456] 14e was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-trans-1,4-ACHC-OH and Fmoc-Pro-OH as building blocks.

[0457] [Example 47] Synthesis of Compound 14f

[0458] [Chemical formula]

[0459] 14f was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, (S)-Fmoc-4-aminopentanoic acid and Fmoc-N-methyl-Ala-OH as building blocks.

[0460] [Example 48] Synthesis of Compound 14g

[0461] [Chemical formula]

[0462] 14g was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, Fmoc-trans-1,4-ACHC-OH, and Fmoc-Sar-OH as building blocks.

[0463] [Example 49] Synthesis of Compound 14h

[0464] [Chemical Structure]

[0465] 14h was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-N-methyl-β-Ala-OH, (S)-Fmoc-4-aminopentanoic acid, and Fmoc-N-methyl-Ala-OH as building blocks.

[0466] [Example 50] Synthesis of Compound 14i

[0467] [Chemical Structure]

[0468] 14i was synthesized using solid-phase synthesis according to a general protocol, using Fmoc-Ahx-OH, (S)-Fmoc-4-aminopentanoic acid, and Fmoc-N-ethyl-Gly-OH as building blocks.

[0469] [Example 51] Synthesis of 15a

[0470] [Chemical Structure]

[0471] 14a (213 mg, 0.64 mmol) was dissolved in 500 μL of DMF, and DIPEA (247 μL, 1.42 mmol) was added. A suspension of 3 (162 mg, 0.28 mmol, in 2.0 mL of DMF) was added. After 2 h, TFA (110 μl, 1.44 mmol) was added, and the product was purified by RP-HPLC. Yield: 111 mg (54%, TFA salt) MS: m / z 629.20 = [M+H] + , (calculated value = 629.25).

[0472] [Example 52] Synthesis of 15b

[0473] [Chemical formula]

[0474] Compound 14c (136 mg, 0.338 mmol) was dissolved in DMF (0.25 mL), and DIPEA (147 μL, 0.845 mmol) was added. To the stirred colorless solution, 3 (100 mg, 0.169 mmol) in DMF (1.23 mL) was added, and the mixture immediately changed to a clear yellow. The mixture was stirred at RT for 105 min, then TFA (65 μL, 0.845 mmol) was added. The product was purified by RP-HPLC to give a yellow solid. Yield: 100 mg (72%, TFA salt) MS: m / z 700.24 = [M+H] + , (calculated value = 700.29).

[0475] [Example 53] Synthesis of 15c

[0476] [Chemical formula]

[0477] Compound 14d (129 mg, 0.333 mmol) was dissolved in DMF (0.25 mL), and DIPEA (145 μL, 0.83 mmol) was added. To the stirred colorless solution, 3 (98 mg, 0.169 mmol) in DMF (1.21 mL) was added, and the mixture immediately changed to a clear yellow. The mixture was stirred at RT for 105 min, then TFA (65 μL, 0.845 mmol) was added. The product was purified by RP-HPLC to give a yellow solid. Yield: 101 mg (75%, TFA salt) MS: m / z 686.19 = [M+H] + , (calcd = 686.27).

[0478] [Example 54] Synthesis of 15d - h

[0479] [Chemical formula]

[0480] The conjugates 15d - h were prepared from their respective resin - loaded Fmoc - protected amines 14e - i. These were treated with 96:2:2 DMF / piperidine / DBU (5 ml) and shaken at RT for 15 min. The filtrate was drained, and the procedure was repeated twice, then the resin was washed with DMF (5 times). Next, the resin was treated with a suspension of 3 in DMF and DIPEA. The mixture was shaken at RT for 90 - 200 min, then washed with DMF (5 times) and DCM (5 times). The resin was treated with 1:9 TFA / DCM and shaken at RT for 10 min. The filtrate was collected and this was repeated at least once. Volatiles were removed from the combined filtrates in vacuo to give the acid. 15d: 14e: 493 mg, 0.453 mmol, 3: 266 mg, 0.453 mmol, DMF: 3.5 mL, DIPEA: 485 μL, 2.72 mmol. Yield: 331 mg (95%, TFA salt). MS: m / z = 653.29 [M+H] + , (calcd = 653.25). 15e: 14f: 195 mg, 0.16 mmol, 3: 119 mg, 0.20 mmol, DMF: 1.5 mL, DIPEA: 173 μL, 0.97 mmol. Yield: 136 mg (quantitative, TFA salt). MS: m / z = 728.36 [M+H] + , (calculated value = 728.32). 15f: 14g: 312 mg, 0.26 mmol, 3: 188 mg, 0.32 mmol, DMF: 2.3 mL, DIPEA: 275 μL, 1.54 mmol. Yield: 274 mg (quantitative, TFA salt). MS: m / z = 740.34 [M+H] + , (calculated value = 740.32). 15g: 14h: 170 mg, 0.15 mmol, 3: 108 mg, 0.18 mmol, DMF: 1.3 mL DIPEA: 158 μL, 0.88 mmol. Yield: 124 mg (quantitative, TFA salt). MS: m / z = 700.32 [M+H] + , (calculated value = 700.29). 15h: 14i: 201 mg, 0.17 mmol 3: 123 mg, 0.21 mmol, DMF: 1.5 mL DIPEA: 0.18 mL, 1.00 mmol. Yield: 155 mg (quantitative, TFA salt). MS: m / z = 728.34 [M+H] + , (calculated value = 728.32).

[0481] [Example 55] Synthesis of Compounds 16a - f

[0482] [Chemical Formula]

[0483] Each acid selected from 15a - e, h was dissolved in DCM, and bis(pentafluorophenyl) carbonate was added. DIPEA was added, and the reaction mixture was stirred at RT. When the reaction was complete, it was quenched with TFA, and the product was purified by flash chromatography (THF / ethyl acetate). 16a: DCM: 4.0 mL, bis(pentafluorophenyl) carbonate: 213 mg, 0.54 mmol, DIPEA: 377 μL, 2.16 mmol, 15d: 331 mg, 0.43 mmol, TFA: 165 μL, 2.16 mmol. Yield: 273 mg (68%, TFA salt). MS: m / z 819.34 = [M+H] + , (calculated value = 819.23). 16b: DCM: 2.0 mL, bis(pentafluorophenyl) carbonate: 70 mg, 0.178 mmol, DIPEA: 130 μL, 0.746 mmol, 15a: 111 mg, 0.149 mmol, TFA: 57 μL, 0.746 mmol. Yield: 122 mg (90%, TFA salt). MS: m / z 795.25 = [M+H] + , (calculated value = 795.23). 16c: DCM: 1.50 mL, bis(pentafluorophenyl) carbonate: 91 mg, 0.23 mmol, DIPEA: 162 μL, 0.93 mmol, 15e: 156 mg, 0.19 mmol, TFA: 71 μL, 0.93 mmol. Yield: 94 mg (50%, TFA salt). MS: m / z 894.30 = [M+H] + , (calculated value = 894.30). 16d: DCM: 1.50 mL, bis(pentafluorophenyl) carbonate: 91 mg, 0.23 mmol, DIPEA: 161 μL, 0.92 mmol, 15h: 155 mg, 0.18 mmol, TFA: 71 μL, 0.92 mmol. Yield: 105 mg (56%, TFA salt). MS: m / z 894.31 = [M+H] + , (calculated value = 894.30). 16e: DCM: 2.00 mL, bis(pentafluorophenyl) carbonate: 58 mg, 0.147 mmol, DIPEA: 107 μL, 0.61 mmol, 15b: 100 mg, 0.12 mmol, TFA: 47 μL, 0.61 mmol. Yield: 77 mg (64%, TFA salt). MS: m / z = 866.26 [M+H] + , (calculated value = 866.27). 16f: DCM: 2.00 mL, bis(pentafluorophenyl) carbonate: 59 mg, 0.151 mmol, DIPEA: 110 μL, 0.63 mmol, 15c: 101 mg, 0.126 mmol, TFA: 48 μL, 0.63 mmol. Yield: 96 mg (79%, TFA salt). MS: m / z = 852.21 [M+H] + , (calculated value = 852.26).

[0484] [Example 56] Synthesis of Compound 16g

[0485] [Chemical formula]

[0486] To a solution of 15f (274 mg, 0.32 mmol) in DCM (2.5 mL) was added bis(pentafluorophenyl) carbonate (158 mg, 0.40 mmol), followed by DIPEA (280 μL, 1.60 mmol). Further DCM (2.5 mL) and DIPEA (280 μL, 1.60 mmol) were added to the suspension. Acetonitrile (1 mL) and DMF (2 mL) were added. The suspension was stirred at RT for 1 d. The mixture was filtered and the precipitate was washed with DCM. The combined filtrate was washed with water and dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The concentrate was diluted with DCM and then TFA (245 μL, 3.18 mmol) was added, and the product was purified by flash chromatography (THF / ethyl acetate). Yield: 66 mg (20%, TFA salt) MS: m / z 906.41 = [M+H] + , (calculated value = 906.30).

[0487] [Example 57] Synthesis of Compound 16h

[0488] [Chemical Structure]

[0489] To a solution of 15 g (124 mg, 0.15 mmol) in DCM (1.5 mL), bis(pentafluorophenyl) carbonate (75 mg, 0.19 mmol) was added, followed by DIPEA (133 μL, 0.76 mmol). After stirring at RT for 3 h, additional bis(pentafluorophenyl) carbonate (19 mg, 0.05 mmol) was added, and after another 1 h, DIPEA (65 μL, 0.37 mmol) was added. The mixture was stirred at RT for an additional 18 h. The product was purified directly by flash chromatography (THF / ethyl acetate). Yield: 24 mg (16%, TFA salt) MS: m / z 866.30 = [M+H] + , (calculated value = 866.27).

[0490] [Example 58] Synthesis of Compounds 17a - q Various hydrogels (amine content 0.564 - 0.934 mmol / g) were reacted with axitinib - linker - conjugate according to the following scheme:

[0491] [Chemical Structure] TIFF2025087701000113.tif183166

[0492] The hydrogel was swollen in 1% DIPEA in DMF in a syringe reactor containing a PE frit. The syringe reactor was filled three times, shaken for 1 min, and discharged. A PFP-ester selected from 9e–f or 16a–h was dissolved in DMF, and DIPEA was added. The solution was drawn into a syringe containing the hydrogel. The syringe was shaken at RT for more than 16 h. The syringe was discharged, and the hydrogel was washed several times with DMF, then water, and then a 20 mM sodium succinate aqueous buffer at pH 5.5. A hydrogel suspension in a pH 5.5 aqueous buffer was obtained. The proportion of amine from the conjugated hydrogel was determined by comparing the determined drug content of the product with the amine content of the starting amine hydrogel. 17a: HG-6: 21 mg, DIPEA: 12.1 μL, 16a: 29 mg Yield: suspension, 94% axitinib loading, 17.93 mg / mL axitinib in the hydrogel suspension. 17b: HG-12: 20 mg, DIPEA: 10.8 μL, 16a: 27 mg Yield: suspension, 69% axitinib loading, 11.69 mg / mL axitinib in the hydrogel suspension. 17c: HG-11: 19 mg, DIPEA: 9.3 μL, 16b: 17 mg Yield: suspension, 100% axitinib loading, 16.24 mg / mL axitinib in the hydrogel suspension. 17d: HG-8: 20 mg, DIPEA: 11.7 μL, 16b: 22 mg Yield: suspension, 95% axitinib loading, 16.10 mg / mL axitinib in the hydrogel suspension. 17e: HG-13: 16 mg, DIPEA: 9.5 μL, 16b: 18 mg Yield: suspension, 97% axitinib loading, 18.63 mg / mL axitinib in the hydrogel suspension. 17f: HG-11: 19 mg, DIPEA: 9.5 μL, 16c: 20 mg Yield: suspension, 100% axitinib loading, 16.43 mg / mL axitinib in the hydrogel suspension. 17g: HG-11: 20 mg, DIPEA: 10.0 μL, 16g: 21 mg Yield: suspension, 95% axitinib loading, 14.03 mg / mL axitinib in hydrogel suspension. 17h: HG-11: 20 mg, DIPEA: 9.9 μL, 16h: 24 mg Yield: suspension, 84% axitinib loading, 11.17 mg / mL axitinib in hydrogel suspension. 17i: HG-11: 20 mg, DIPEA: 9.9 μL, 16d: 20 mg Yield: suspension, 94% axitinib loading, 14.66 mg / mL axitinib in hydrogel suspension. 17j: HG-8: 20 mg, DIPEA: 11.8 μL, 16d: 25 mg Yield: suspension, 96% axitinib loading, 15.72 mg / mL axitinib in hydrogel suspension. 17k: HG-13: 15 mg, DIPEA: 9.1 μL, 16d: 19 mg Yield: suspension, 100% axitinib loading, 19.46 mg / mL axitinib in hydrogel suspension. 17l: HG-4: 15 mg, DIPEA: 8.5 μL, 9e: 15 mg Yield: suspension, 98% axitinib loading, 18.27 mg / mL axitinib in hydrogel suspension. 17m: HG-11: 21 mg, DIPEA: 10.2 μL, 9e: 19 mg Yield: suspension, 100% axitinib loading, 15.60 mg / mL axitinib in hydrogel suspension. 17n: HG-14: 20 mg, DIPEA: 16.2 μL, 9e: 32 mg Yield: suspension, 81% axitinib loading, 21.15 mg / mL axitinib in hydrogel suspension. 17o: HG-13: 16 mg, DIPEA: 9.4 μL, 16e: 19 mg Yield: suspension, 99% axitinib loading, 19.28 mg / mL axitinib in hydrogel suspension. 17p: HG-13: 16 mg, DIPEA: 9.7 μL, 16f: 19 mg Yield: Suspension, 100% axitinib loading, 20.66 mg / mL axitinib in hydrogel suspension. 17q: HG-15: 20 mg, DIPEA: 10.6 μL, 9f: 21 mg Yield: Suspension, 93% axitinib loading, 15.75 mg / mL axitinib in hydrogel suspension.

[0493] [Example 59] In vitro Release Kinetics The rate of cleavage of the reversible bond from conjugates 9a-d, 13a-e and 17b-q was monitored at 37 °C in aqueous buffers (Condition A: pH 7.4 60 mM sodium phosphate, 1% acetonitrile, B: pH 7.4 48 mM sodium phosphate, 20% acetonitrile, 0.1% Pluronic F68, C: pH 7.4 48 mM sodium phosphate with 16 mM L-methionine 2.4 mM EDTA, 0.1% pluronic and 20% acetonitrile, D: pH 7.0 48 mM sodium phosphate with 16 mM L-methionine 2.4 mM EDTA, 0.1% pluronic and 20% acetonitrile, E: pH 7.4 60 mM sodium phosphate, F: pH 7.4 48 mM sodium phosphate, 20% acetonitrile). For soluble examples, the disappearance of the conjugate was determined by LCMS (UV detection) and curve fitting software was used to obtain the half-life of release. For insoluble examples (hydrogels), the increase in released axitinib in the supernatant was determined by LCMS (UV detection) and used as input for curve fitting software to obtain the half-life of release. The release rate at pH 7.4 of conjugates incubated only at pH 7.0 is estimated to increase 2-3 fold.

[0494] [Table 2]

[0495] “ *The compounds labeled with "」" are not linked to the Z moiety for efficiency reasons and thus are not according to the present invention. Nevertheless, they exhibit the release half-life of such -L 1 - moiety.

[0496] [Example 60] Synthesis of Compounds 17r - t Hydrogel HG - 17 was reacted with axitinib - linker - conjugate according to the following scheme:

[0497] [Chemical formula]

[0498] The hydrogel was swollen in 1% DIPEA in DMF in a syringe reactor containing a PE frit. The syringe reactor was filled three times, shaken for 1 min, and discharged. A PFP - ester selected from 16b or 16c was dissolved in DMF and DIPEA was added. The solution was drawn into the syringe containing the hydrogel. The syringe was shaken at RT for more than 16 h. The syringe was discharged and the hydrogel was washed several times with DMF, then water, and then pH 5.5 buffer (20 mM sodium succinate, 77 g / l trehalose dihydrate, 0.2% Pluronic F - 68). A hydrogel suspension in pH 5.5 aqueous buffer was obtained. The proportion of amine from the conjugated hydrogel was determined by comparing the determined drug content of the product with the amine content of the starting amine hydrogel. 17r: HG - 17: 24 mg, DIPEA: 17.8 μL, 16b: 15 mg Yield: suspension, 73% axitinib loading, 17.63 mg / mL axitinib in the hydrogel suspension. 17s: HG - 17: 24 mg, DIPEA: 18.1 μL, 16b: 20 mg Yield: suspension, 94% axitinib loading, 22.40 mg / mL axitinib in the hydrogel suspension. 17t: HG - 17: 24 mg, DIPEA: 18.2 μL, 16c: 17 mg Yield: Suspension, 62% axitinib-loaded, 14.87 mg / mL axitinib in hydrogel suspension.

[0499] [Example 61] In vitro release kinetics The cleavage rate of the reversible bond from conjugates 17r - t was monitored at 37 °C in a pH 7.0 48 mM sodium phosphate buffer with 16 mM L-methionine, 2.4 mM EDTA, 0.1% pluronic, and 20% acetonitrile. The increase in released axitinib in the supernatant was determined by LCMS (UV detection) and used as input for curve fitting software to obtain the half-life of release. The release rate of these conjugates at pH 7.4 is estimated to be 2 - 3 times faster.

[0500] [Table 3]

[0501] [Example 62]

[0502] [Chemical Structure]

[0503] For 17u, a PEG-based amino hydrogel is synthesized using a backbone synthesized using Boc-L-Lys(Boc)-OH as described in Example 1 of WO2011 / 012715A1 and a 2 kDa PEG-based crosslinker synthesized using adipic acid as described in Example 2 of WO2011 / 012715A1, as described in Example 3 of WO2011 / 012715A1. The hydrogel is then modified with lysine using Fmoc-L-Lys(Fmoc)-OH as described in Example 5 of WO2011 / 042450A1 to obtain a hydrogel with an amine content of 0.700 mmol / g. The hydrogel is swollen in 1% DIPEA in DMF in a syringe reactor fitted with a frit and washed three times with a 1% DIPEA / DMF solution. 16b (1.8 equivalents per hydrogel amine) is dissolved in DMF and DIPEA (5.0 equivalents) is added. The solution is drawn into the reactor containing the hydrogel and shaken at RT for 16 hours. The syringe is emptied and the hydrogel is washed several times with DMF, several times with water, and then several times with a 20 mM sodium succinate aqueous buffer at pH 5.5. A hydrogel suspension in a pH 5.5 aqueous buffer with an axitinib loading exceeding 95% is obtained.

[0504] Hydrogel 17v is prepared as described for 17u, but using Boc-D-Lys(Boc)-OH instead of Boc-L-Lys(Boc)-OH for backbone synthesis and Fmoc-D-Lys(Fmoc)-OH instead of Fmoc-L-Lys(Fmoc)-OH for lysine modification.

[0505] [Example 63] Synthesis of Compound 18

[0506] [Chemical Formula]

[0507] 14a (20 mg, 61 μmol) was dissolved in THF (0.5 mL). DIPEA (26 μL, 151 μmol) was added and a precipitate formed. The precipitate was finely dispersed using sonication and stirring to form an emulsion suspension. 1,1'-Carbonyldiimidazole (9.8 mg, 61 μmol) was dissolved in 0.15 ml THF and added to the suspension with stirring. After 40 minutes, the reaction was quenched with acetic acid (30 μl) and diluted with water to a total volume of 1 ml. The product was purified by RP-HPLC to give 18. Yield: 0.8 mg (4%) MS: m / z 311.08 = [M+H] + , (calculated = 311.17).

[0508] [Example 64] Synthesis of Compound 19

[0509] [Chemical Structure]

[0510] A solution of methyl 1H-benzo[d]imidazole-5-carboxylate (25 mg, 117.6 μmol) in THF (500 μl) was cooled to 0 °C, and 1-methylimidazole (19.2 μl, 241 μmol) was added. A solution of 4-nitrophenyl chloroformate (24.9 mg, 123.5 μmol) in THF (250 μl) was added dropwise. To improve the solubility of the formed precipitate, DMF (500 μl) was added to the reaction mixture. The mixture was slowly warmed to ambient temperature in a cooling bath. After 1.5 h, additional 1-methylimidazole (19.2 μl, 241 μmol) was added, and the reaction mixture was stirred at ambient temperature for about 17 h. The reaction mixture was cooled to 0 °C. A solution of 4-nitrophenyl chloroformate (12.5 mg, 62 μmol) in THF (200 μl) was added dropwise. The reaction mixture was stirred at 0 °C for 75 min, then additional 4-nitrophenyl chloroformate (12.5 mg, 62 μmol) in THF (200 μl) was added. The reaction mixture was stirred at 0 °C for 53 min, diluted with ethyl acetate (ca. 15 ml), and washed with 0.1 M HCl (3 × 5 ml) and brine (ca. 10 ml). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. 19 was purified using flash chromatography. Yield: 35 mg (87.2%, a mixture of benzimidazole positional isomers) MS: m / z 342.06 = [M+H] + , (calcd = 342.07).

[0511] [Example 65] Synthesis of Compound 20

[0512]

Chemical Structure

[0513] To a solution of Compound 19 (11.5 mg, 30.3 μmol) in DMF (314 μl) was added DIPEA (21.2 μl, 121.3 μmol) and Compound 14a (11.2 mg, 33.4 μmol) successively, and the reaction mixture was stirred at ambient temperature for 3 h. The reaction was quenched by adding TFA (9.3 μl, 121.3 μmol), and the reaction product was purified by RP-HPLC. Yield: 2.2 mg (17.3%, a mixture of benzimidazole positional isomers) MS: m / z 419.18 = [M+H] + , (calculated value = 419.19).

[0514] [Example 66] Synthesis of Compound 21

[0515]

Chemical formula

[0516] A suspension of NaH (60% in mineral oil, 8.3 mg, 207.5 μmol) in THF (250 μl) was cooled to 0 °C, and a solution of tert-butyl 1H-indole-5-carboxylate (15 mg, 69 μmol) in THF (400 μl) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 h. This mixture was added to a cooled solution of 4-nitrophenyl chloroformate (34.8 mg, 172.6 μmol) in THF (500 μl). Additional THF (250 μl) was used to rinse the flask and added to the 4-nitrophenyl chloroformate solution. After 1.5 h, the cooling bath was removed and the mixture was stirred at ambient temperature. After 30 min, 4-nitrophenyl chloroformate (69.6 mg, 346.8 μmol) was added all at once. After 3 h, the reaction mixture was diluted with ethyl acetate (15 ml), washed with HCl (0.1 M, 3 × 5 ml), brine (5 ml), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. 21 was purified using flash chromatography. Yield: 16 mg (60.6%) MS: m / z 327.04 = [M - tBu + 2H] + , (calculated value = 327.06).

[0517] [Example 67] Synthesis of Compound 22

[0518] [Chemical formula]

[0519] To a solution of Compound 21 (8 mg, 18.8 μmol) in DMF (250 μl), DIPEA (13.1 μl, 75.3 μmol) and N,N,N'-trimethylethylenediamine (2.7 μl, 20.7 μmol) were successively added. The mixture was stirred at ambient temperature for 1 h 45 min and then quenched by adding TFA (5.6 μl, 75.3 μmol). 22 was purified using RP-HPLC. Yield: 4.6 mg (70.7%, TFA salt) MS: m / z 346.18 = [M + H] + , (calculated value = 346.21).

[0520] [Example 68] Synthesis of Compound 23

[0521] [Chemical formula]

[0522] To a solution of Compound 22 (1.15 mg, 3.3 μmol) in DCM (250 μl), TFA (250 μl) was added and the mixture was stirred at ambient temperature for 25 min. The reaction was diluted with toluene and concentrated under reduced pressure. The resulting material was used directly in the in vitro release kinetics. MS: m / z 290.15 = [M + H] + , (calculated value = 290.15).

[0523] [Example 69] In vitro release rate theory The cleavage rate of the reversible bond from conjugates 18, 20, and 23 was monitored in an aqueous buffer (pH 7.4, 48 mM sodium phosphate, 20% acetonitrile) at pH 7.4 and 37 °C. The disappearance of the conjugate was determined by LCMS (UV detection) and fitted to curve fitting software to obtain the half-life of the release.

[0524] [Table 4]

[0525] Abbreviations ACHC Aminocyclohexanecarboxylic acid Ahx 6-Aminohexanoic acid aq. Aqueous Asp Aspartate (aspartate salt) Bn Benzyl Boc tert-Butyloxycarbonyl COMU (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DCM Dichloromethane DIC N,N'-Diisopropylcarbodiimide, DIPEA Diisopropylethylamine DMAP Dimethylaminopyridine DMF Dimethylformamide eq. Equivalent EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Fmoc Fluorenylmethyloxycarbonyl HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate HFIP 1,1,1,3,3,3-Hexafluoroisopropanol HOBt 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography LC Liquid Chromatography LCMS Liquid Chromatography-Mass Spectrometry LPLC Low Pressure Liquid Chromatography MeOH Methanol MS Mass Spectrometry PEG Polyethylene Glycol PFP Pentafluorophenyl PNP para-Nitrophenyl PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate RP Reverse Phase RT Room Temperature Sar Sarcosine sat. Saturated tBu and t-Bu tert-Butyl TES Triethylsilane TEA Triethylamine TFA Trifluoroacetic Acid THF Tetrahydrofuran Thr Threonine Tmob 2,4,6-Trimethoxybenzyl Trt Trityl UPLC Ultra Performance Liquid Chromatography UPLC-MS Ultra Performance Liquid Chromatography Coupled to Mass Spectrometry

Claims

1. At least one -L 1 -L 2 A conjugate comprising at least one -D moiety conjugated to at least one Z moiety via a -L moiety, or a pharma- ceutically acceptable salt thereof. 1 - moiety is conjugated to the π electron pair donating heteroaromatic N of the -D moiety, and -D and -L 1 The linkage of - is reversible, and -L 2 the - moiety is conjugated to Z, each -D is independently a π electron pair donating heteroaromatic N-containing moiety of a drug D; Each-L 2 - is independently a bond or a spacer moiety; Each Z is independently a polymer moiety or C 8～24 is alkyl, Each-L 1 - independently represents formula (I): 【Chemistry 1】 [In the formula, The dashed line indicates the bond of -D to the π-electron pair donating heteroaromatic N; n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; =X 1 =O, =S and =N(R 4 ) selected from the group consisting of -X 2 - is -O-, -S-, -N(R 5 )- and -C(R 6 )(R 6a )-, -X 3 -teeth, 【Chemistry 2】 -C(R 10 )(R 10a )-, -C(R 11 )(R 11a )-C(R 12 )(R 12a )-, -O-, and -C(O)-; -R 1 , -R 1a , -R 6 , -R 6a , -R 10 , -R 10a , -R 11 , -R 11a , -R 12 , -R 12a , and each -R 2 and -R 2a are -H, -C(O)OH, halogens, -CN, -OH, C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 alkynyl, C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 Alkynyl is one or more -R 13 Optionally substituted with C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 Alkynyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 14 )-, -S(O) 2 N(R 14 )-, -S(O)N(R 14 )-, -S(O) 2 -, -S(O)-, -N(R 14 )S(O) 2 N(R 14a )-, -S-, -N(R 14 ), -OC(OR 14 )(R 14a )-, -N(R 14 )C(O)N(R 14a )- and -OC(O)N(R 14 )-, -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 -H, -T, -CN, C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 alkynyl, C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 Alkynyl is one or more -R 13 Optionally substituted with C 1～6 Alkyl, C 2～6 Alkenyl and C 2～6 Alkynyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R 14 )-, -S(O) 2 N(R 14 )-, -S(O)N(R 14 )-, -S(O) 2 -, -S(O)-, -N(R 14 )S(O) 2 N(R 14a )-, -S-, -N(R 14 )-, -OC(OR 14 )(R 14a )-, -N(R 14 )C(O)N(R 14a )- and -OC(O)N(R 14 )-, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl, each T being the same or different, and 13 and -R 13 -H, -NO 2 , -OCH 3 , -CN, -N(R 14 )(R 14a ), -OH, -C(O)OH and C 1～6 alkyl, C 1～6 the alkyl is optionally substituted with one or more halogens, which may be the same or different; -R 14 and -R 14a -H and C 1～6 alkyl, C 1～6 The alkyl is optionally substituted with one or more halogens, which may be the same or different, and optionally includes -R 1 / -R 1a , -R 2 / -R 2a , two adjacent -R 2 , -R 6 / -R 6a , -R 10 / -R 10a , -R 11 / -R 11a , -R 12 / -R 12a and -R 3 / -R 9 One or more of the pairs, together with the atoms to which they are attached, form a C 3～10 forming a cycloalkyl, a 3- to 10-membered heterocyclyl, or an 8- to 11-membered heterobicyclyl; In some cases, -R 1 / -R 2 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 9 , -R 1 / -R 10 , -R 2 / -R 5 , -R 3 / -R 6a , -R 4 / -R 5 , -R 4 / -R 6 , -R 5 / -R 10 , -R 6 / -R 10 and -R 11 / -R 12 one or more of the pairs together with the atoms to which they are attached form a ring -A-; -A- is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3～10 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; In some cases, -R 1 and adjacent-R 2 forms a carbon-carbon double bond, with the proviso that n is selected from the group consisting of 1, 2, 3, and 4; In some cases, two adjacent -R 2 forms a carbon-carbon double bond, with the proviso that n is selected from the group consisting of 2, 3 and 4; However, -X 2 -N(R 5 )-, then -X 3 - The following: 【Chemistry 3】 and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5, 6 or 7 atoms; and, if present, -R 1 and-R 2 or two adjacent -R 2 The carbon-carbon double bond formed between is in a cis configuration. is the linker portion of Each-L 1 -But, -L 2 -substituted with -, and optionally further substituted; The conjugate or a pharma- ceutically acceptable salt thereof.

2. 2. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein -D is selected from the group consisting of small molecule, medium size, peptide and protein drug moieties.

3. 3. The conjugate of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein -D is a small molecule drug moiety.

4. 4. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a polymer moiety.

5. 5. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a water-insoluble polymer moiety.

6. Z is 2-methacryloyl-oxyethyl phosphorylcholine, poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amidoamine), poly(amino acid), poly(anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl-oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate), poly(milk), poly(ethyl acrylate), poly(ethyl acrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxypropyl oxazoline), poly(iminocarbonate ...

6. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the water insoluble polymeric moiety comprises a polymer selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicones, cellulose, carbomethylcellulose, hydroxypropyl methylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and derivatives, functionalized hyaluronic acid, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate based polymers, xylan, and copolymers thereof.

7. 7. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a hydrogel.

8. 8. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a PEG-based or hyaluronic acid-based hydrogel.

9. 9. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a PEG-based hydrogel.

10. 9. The conjugate according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a hyaluronic acid-based hydrogel.

11. 5. The conjugate of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is a water soluble polymer moiety.

12. =X 1 is =O and -X 2 12. The conjugate according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein - is -O-.

13. =X 1 is =O and -X 2 -N(R 5 12. The conjugate according to claim 1, wherein R is -R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 2

14. -L 2 14. The conjugate according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein - is a spacer moiety.

15. -L 2 15. The conjugate according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein has a molecular weight in the range of 14 g / mol to 750 g / mol.

16. -L 2 - is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R y1 )S(O) 2 N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-, -N(R y1 )C(O)N(R y1a )-, -OC(O)N(R y1 )-, C 1～50 Alkyl, C 2～50 Alkenyl, and C 2～50 alkynyl; -T'-, C 1～50 Alkyl, C 2～50 Alkenyl and C 2～50 The alkynyl group may be one or more -R y2 Optionally substituted with C 1～50 Alkyl, C 2～50 Alkenyl and C 2～50 Alkynyl is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y3 )-, -S(O) 2 N(R y3 )-, -S(O)N(R y3 )-, -S(O) 2 -, -S(O)-, -N(R y3 )S(O) 2 N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-, -N(R y3 )C(O)N(R y3a )- and -OC(O)N(R y3 )-, -R y1 and -R y1a But, -H, -T', C 1～50 Alkyl, C 2～50 Alkenyl and C 2～50 alkynyl; -T', C 1～50 Alkyl, C 2～50 Alkenyl and C 2～50 The alkynyl group may be one or more -R y2 Optionally substituted with C 1～50 Alkyl, C 2～50 Alkenyl and C 2～50 Alkynyl is -T'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -, -S(O)-, -N(R y4 )S(O) 2 N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-, -N(R y4 )C(O)N(R y4a )- and -OC(O)N(R y4 )-, Each T' is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3～10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl, each T' being the same or different and independently selected from the group consisting of one or more -R y2 and Each-R y2 is halogen, -CN, oxo(=O), -COOR y5 , -OR y5 , -C(O)R y5 , -C(O)N(R y5 R y5a ), -S(O) 2 N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O) 2 R y5 , -S(O)R y5 , -N(R y5 )S(O) 2 N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO 2 , -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O) 2 R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1～6 alkyl, wherein C 1～6 the alkyl is optionally substituted with one or more halogens which are the same or different; Each-R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b But -H and C 1～6 alkyl, C 1～6 alkyl is optionally substituted with one or more halogens which are the same or different; 16. The conjugate according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof.

17. -R 3 One hydrogen presented by -L 2 17. The conjugate of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein:

18. Z and -L 2 18. The conjugate according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein the linkage - is stable.

19. -L 1 - is a compound of formula (Ix): 【Chemistry 4】 wherein the dashed line indicates the bond of -D to the π electron pair donating heteroaromatic N; =X 1 , -R 1 , -R 1a , -R 2 , -R 2a , -R 3 , -R 5 and n are used as defined in claim 1, In some cases, -R 1 / -R 1a , -R 2 / -R 2a , two adjacent -R 2 One or more of the pairs, together with the atoms to which they are attached, form a C 3～10 forming a cycloalkyl, a 3- to 10-membered heterocyclyl, or an 8- to 11-membered heterobicyclyl; In some cases, -R 1 / -R 2 , -R 1 / -R 5 , -R 2 / -R 5 and -R 4 / -R 5 one or more of the pairs together with the atoms to which they are attached form a ring -A-; -A- is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3～10 selected from the group consisting of cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; In some cases, -R 1 and adjacent-R 2 forms a carbon-carbon double bond, with the proviso that n is selected from the group consisting of 1, 2, 3, and 4; In some cases, two adjacent -R 2 forms a carbon-carbon double bond, with the proviso that n is selected from the group consisting of 2, 3 and 4; The distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (Ix) is 5, 6 or 7 atoms, and if present, -R 1 and-R 2 or two adjacent -R 2 The carbon-carbon double bond formed between is in a cis configuration.

19. The conjugate according to any one of claims 1 to 11 and 13 to 18, or a pharma- ceutically acceptable salt thereof, which is of the formula:

20. -R in formula (Ix) 5 20. The conjugate of claim 19, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

21. -R in formula (Ix) 1 and -R 1a The conjugate according to claim 19 or 20, or a pharma- ceutically acceptable salt thereof, wherein both are -H.

22. 22. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof.

23. 22. A conjugate according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for use as a medicament.

24. 23. A conjugate according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for use in a method for treating a disease that can be treated with DH.

25. 23. A method for preventing or treating a patient suffering from a disease that can be prevented or treated by DH, comprising administering to the patient an effective amount of a conjugate described in any one of claims 1 to 21 or a pharma- ceutical composition described in claim 22.

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