Steroid compounds and their conjugates

Abstract

The present application relates to steroid compounds and conjugates thereof, in particular to the compounds and conjugates thereof, or their tautomers, mesomers, racemates, enantiomers or diastereoisomers, or mixtures thereof, or pharma- ceutically acceptable salts thereof. The present application also relates to the preparation and use of the compounds and conjugates thereof.

Description

[Technical field]

[0001] The present application relates to the biomedical field, and in particular to steroid compounds and their conjugates. [Background technology]

[0002] Inflammation is an adaptive response triggered by various noxious stimuli and conditions, and underlies many diseases associated with the human immune system. Steroid compounds are a type of anti-inflammatory drug that affect immune system function and have the potential to treat or prevent diseases and / or conditions associated with glucocorticoid receptor signaling. However, some existing steroid compounds have less potent anti-inflammatory effects or are accompanied by many undesirable side effects. Therefore, there is an urgent need for further development of steroid compounds formed from antibody-drug conjugates and various steroids as drugs that can exert better therapeutic effects or safety. Summary of the Invention

[0003] The present application provides a compound, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or mixtures thereof, or pharma- ceutically acceptable salts thereof, that may have one or more effects selected from the group consisting of: (1) having an ability to affect the activity of immune cells; (2) its conjugates having a targeting effect; (3) having plasma stability; (4) having biological safety; (5) having an ability to affect cytokine release from immune cells; (6) having an ability to affect the transcription of responsive genes of the IFN signaling pathway; (7) having an ability to affect the degree of fibrosis in the skin; (8) having an ability to affect the number and / or percentage of dendritic cells; (9) having an ability to affect collagen content in the skin; (10) having an ability to affect GRE expression levels; (11) having an ability to affect cytokine release from monocytes; (12) having an ability to affect contact hypersensitivity; (13) having an ability to affect skin swelling; and (14) having an ability to affect arthritis symptoms.

[0004] The present application provides immunoconjugates that include a glucocorticoid receptor agonist linked to a protein (e.g., an antibody or antigen-binding fragment thereof and a soluble receptor protein). In some embodiments, the antibody or antigen-binding fragment thereof is human, humanized, chimeric, or murine. In some embodiments, the protein (e.g., an antibody, antigen-binding fragment thereof, or a soluble receptor protein) can bind to a target on the cell surface and be internalized.

[0005] In one aspect, the present application provides a compound of formula I: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; A1 is a substituted benzene ring; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy, each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0006] In another aspect, the present invention provides a compound of the formula [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0007] In another aspect, the present application relates to a compound of formula IIa or IIb: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; A2 is a substituted benzene ring; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Y 2 is selected from the group consisting of -O-, -S- and -NR-; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0008] In another aspect, the present application provides a conjugate comprising the compound described above, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, the present application provides a pharmaceutical composition comprising the compound as described above, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or mixtures thereof, or pharma- ceutically acceptable salts thereof, and / or a conjugate as described above, and optionally a pharma- ceutically acceptable carrier.

[0010] In another aspect, the present application provides a method of affecting immune system function comprising administering to a subject a compound as described above, or a tautomer, mesomeric, racemic, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, a conjugate as described above, and / or a pharmaceutical composition as described above.

[0011] Other aspects and advantages of the present application will become readily apparent to those skilled in the art from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. As those skilled in the art will recognize, the contents of the present application will enable those skilled in the art to make changes to the specific embodiments disclosed without departing from the spirit and scope of the invention to which the present application pertains. Accordingly, the description herein is intended to be illustrative rather than limiting.

[0012] Embodiments of the present invention are described below with reference to specific examples, and other advantages and benefits of the present invention will be readily apparent to those skilled in the art from the disclosure herein. (Definition of terms)

[0013] In this application, the term "glucocorticoid" generally refers to a naturally occurring or synthetic steroid hormone that interacts with the glucocorticoid receptor.

[0014] In this application, the term "halogen" generally refers to fluorine, chlorine, bromine or iodine and can be, for example, fluorine or chlorine.

[0015] In this application, the term "alkyl" generally refers to a residue derived from an alkane by removal of a hydrogen atom. The alkyl may be substituted or unsubstituted, substituted or unsubstituted. The term "alkyl" generally refers to a saturated linear or branched aliphatic hydrocarbon group having a residue derived from a parent alkane by removal of a hydrogen atom from the same carbon atom or from two different carbon atoms, and may be a linear or branched group containing 1 to 20 carbon atoms, such as 1 to 12 carbon atoms, such as a chain alkyl containing 1 to 6 carbon atoms. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, and the like. The alkyl may be substituted or unsubstituted, substituted or unsubstituted. For example, when substituted, the substitution with a substituent may occur at any available linkage site and the substituent may be independently optionally selected from the group consisting of one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo, which may be, for example, hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H or C 1~6 It may be an aliphatic group.

[0016] In this application, the term "alkylene" generally refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms, and may be a linear or branched group containing 1 to 20 carbon atoms; for example, the term "methylene" may refer to a residue derived from a one carbon atom group by removing two hydrogen atoms. The methylene may be substituted or unsubstituted, substituted or unsubstituted. For example, alkylene includes alkylene groups containing 1 to 12 carbon atoms, e.g., 1 to 6 carbon atoms. Non-limiting examples of alkylene include methylene (-CH 2 -), 1,1-ethylidene (-CH(CH 3 )-), 1,2-ethylidene (-CH 2 CH 2 )-, 1,1-propylidene(-CH(CH 2 CH 3 )-), 1,2-propylidene (-CH 2 CH(CH 3 )-), 1,3-propylidene (-CH 2 CH 2 CH 2 -), 1,4-butylidene (-CH 2 CH 2 CH 2 CH 2 -), 1,5-butylidene (-CH 2 CH 2 CH 2 CH 2 CH 2Alkylene may be substituted or unsubstituted, substituted or unsubstituted. For example, when substituted, the substitution with a substituent may occur at any available linkage site, and the substituent may be independently selected from the group consisting of one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo, which may be, for example, hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H or C 1~6 It may be an aliphatic group. The methylene or alkylene may be substituted or unsubstituted.

[0017] In this application, the term "alkenyl" generally refers to a straight-chain or branched hydrocarbon group containing one or more double bonds. Examples of alkenyl include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, etc. Examples of C2-6 alkenyl containing two or more double bonds include butadienyl, pentadienyl, hexadienyl, and hexatrienyl, as well as branched forms thereof. The position of the unsaturated bond (double bond) may be anywhere on the carbon chain. The alkenyl may be substituted or unsubstituted.

[0018] In this application, the term "alkenylene" generally refers to a group having two residues derived from an alkene by removing two hydrogen atoms from a carbon atom. For example, alkenylene can be acrole, vinylene, butenylene, pentenylene, hexenylene, etc. Alkenylene can be substituted or unsubstituted.

[0019] In this application, the term "alkynyl" generally refers to unsaturated straight-chain or branched alkynyl, such as ethynyl, 1-propynyl, propargyl, or butynyl. Alkynyl can be substituted or unsubstituted.

[0020] In this application, the term "alkynylene" generally refers to a group having two residues derived from an alkyne by removing two hydrogen atoms from a carbon atom. For example, alkynylene can be ethynylene, propynylene, propargylene, butynylene, etc. Alkynylene can be substituted or unsubstituted.

[0021] In this application, the term "aryl" generally refers to a group having a residue derived from an aromatic ring by removal of a hydrogen atom. The term "aromatic ring" refers to a 6-14 membered all-carbon monocyclic ring or fused polycyclic ring (i.e., rings sharing adjacent pairs of carbon atoms) having a conjugated pi-electron system, which may be 6-10 membered, such as benzene and naphthalene. The aromatic ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring. The aryl may be substituted or unsubstituted, and when substituted, the substituents may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. The aryl may be substituted or unsubstituted.

[0022] In this application, the term "arylene" generally refers to a group having two residues derived from an aromatic ring by removing two hydrogen atoms from the carbon atoms of the ring. For example, arylene can be phenylene and naphthylene. Arylene can be substituted or unsubstituted.

[0023] In this application, the term "heteroaryl" generally refers to a group having a residue derived from a heteroaromatic ring by removing a hydrogen atom from a carbon atom. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryls may be 5-10 membered, and may be 5 or 6 membered, such as furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl and tetrazolyl. Heteroaryl rings may be fused to aryl, heterocyclyl or cycloalkyl rings, where the ring connected to the parent structure is a heteroaryl ring. Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. Heteroaryl can be substituted or unsubstituted.

[0024] In this application, the term "heteroarylene" generally refers to a group having two residues derived from a heteroaromatic ring by removing two hydrogen atoms from the carbon atoms of the ring. For example, heteroarylene can be furylene, thienylene, pyridylidene, pyrrolylene, pyrimidinylene, pyrazinylene, imidazolylene, tetrazolylene, etc. Heteroarylene can be substituted or unsubstituted.

[0025] In this application, the terms "alcyl" and "cycloalkyl" are used interchangeably, and the term "alcyl" generally refers to a group having a residue derived from an aliphatic ring by removing hydrogen atoms from the same carbon atom or from multiple different carbon atoms. The term "cycloalkane" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, which may contain 3 to 20 carbon atoms, contain 3 to 12 carbon atoms, contain 3 to 10 carbon atoms, contain 3 to 8 carbon atoms. Non-limiting examples of alcyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic carbocycles may include spirocarbocycles, fused carbocycles, and bridged carbocycles. Alcyl may be substituted or unsubstituted. In this application, the term "carbocyclyl" generally refers to a group having a residue derived from a carbocycle by removing a hydrogen atom from a carbon atom. The term "carbocycle" generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, which may contain 3 to 20 carbon atoms, contain 3 to 12 carbon atoms, contain 3 to 10 carbon atoms, contain 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, and the like. Polycyclic carbocycles may include spirocarbocycles, fused carbocycles, and bridged carbocycles. Carbocyclyls may be substituted or unsubstituted. In some cases, alicyclic and carbocyclic rings may be used in place of each other.

[0026] In this application, the term "partially unsaturated" generally means that the cyclic structure contains at least one double or triple bond between the ring molecules. The term "partially unsaturated" encompasses cyclic structures having multiple sites of unsaturation, but is not intended to include aromatic or heteroaromatic rings as defined herein. The term "unsaturated" means that the moiety has one or more degrees of unsaturation.

[0027] In this application, the terms "alcylene" and "cycloalkylene" are used interchangeably, and the term "alcylene" generally refers to a group having a residue derived from an alicyclic ring by removing two hydrogen atoms from a carbon atom. For example, an alkyne can be cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptylene, cycloheptatrienylene, cyclooctylene, etc. Polycyclic carbocycles can include spirocarbocycles, fused carbocycles, and bridged carbocycles. An alkyne can be substituted or unsubstituted.

[0028] In this application, the terms "aliphatic heterocyclyl" and "heterocyclyl" are used interchangeably, and the term "aliphatic heterocyclyl" generally refers to a stable, non-aromatic 3- to 7-membered monocyclic carbocyclic ring structure, a fused 7- to 10-membered bicyclic heterocyclic ring structure, or a bridged 6- to 10-membered bicyclic heterocyclic ring structure. These ring structures may be saturated or partially saturated and may contain one or more heteroatoms in addition to carbon atoms, which may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, containing 1 to 4 heteroatoms, as defined above. When used to refer to an atom on an aliphatic heterocyclic ring structure, the term "nitrogen" may include nitrogen that undergoes substitution reactions. For example, aliphatic heterocyclyl may include "heterocycloalkyl," which may refer to a stable, non-aromatic 3- to 7-membered monocyclic alkyl ring structure, a fused 7- to 10-membered bicyclic heterocyclic ring structure, or a bridged 6- to 10-membered bicyclic heterocyclic ring structure. These structures also contain one or more heteroatoms in addition to carbon atoms, which may be selected from the group consisting of oxygen, sulfur, and nitrogen. For example, they contain 1 to 4 heteroatoms as defined above. Heterocycloalkyls may be substituted or unsubstituted. Aliphatic heterocyclyls may be substituted or unsubstituted.

[0029] In this application, the terms "aliphatic heterocyclylene" and "heterocyclylene" are used interchangeably, and the term "aliphatic heterocyclylene" generally refers to a group having a residue derived from an aliphatic heterocycle by removing two hydrogen atoms from carbon atoms of the ring. The aliphatic heterocyclylene may be substituted or unsubstituted.

[0030] In this application, in describing cyclic structures such as cycloalkyl, cycloalkylene, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, and heteroarylene, prefixes (e.g., C 3 ~C 20 , C 3 ~C 7 Or C 5 ~C 6) is generally intended to refer to the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, "C 5 ~C 6 The term "heterocyclyl" refers to a heterocyclyl group having 5 or 6 ring atoms. 5 ~C 10 The term "heteroaryl" refers to a heteroaryl group having from 5 to 10 ring atoms.

[0031] In this application, the term "ring atom" or "ring atom" generally refers to an atom included in a ring structure. For example, a ring atom may be a carbon atom of a benzene ring or a nitrogen atom of a pyridine ring. When a hydrogen atom is connected to a ring atom, the ring atom may be substituted or unsubstituted.

[0032] In this application, the term "independently" generally means that the variable applies in each case, regardless of the presence or absence of variables with the same or different definitions in the same compound. For example, the variable may refer to the type or number of substituents in a compound, the type of atom in a compound, etc. For example, when R occurs twice in a compound and R is defined as "independently carbon or nitrogen", both R may be carbon, both R may be nitrogen, or one R may be carbon and the other R may be nitrogen.

[0033] In this application, the term "optional" or "optionally" generally means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl" means that alkyl may, but need not, be present, and that the description includes cases where the heterocyclyl group is substituted or unsubstituted with an alkyl.

[0034] In this application, the term "substituted" generally means that one or more hydrogen atoms in a group, for example up to 5 (e.g., 1 to 3) hydrogen atoms, are each independently replaced with the corresponding number of substituents. Substituents are present only at their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0035] When substituted, substituents on an "optionally substituted" group include, but are not limited to, the following groups: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyl ester, lower formylamino, cyano, halogen, hydroxy, The group may include one or more substituents, either alone or in combination, independently selected from the group consisting of amino, lower alkylamino, arylamino, acylamino, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, nitrile, CF3, cycloalkyl, pyridinyl, thiophene, furanyl, lower carbamate, halophenyl, hydroxyphenyl, haloalkyl, and hydroxyalkyl, or a series of specifically specified groups. Two substituents may be linked together to form a 5-, 6-, or 7-membered aromatic or non-aromatic carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms, for example, methylenedioxy or ethylenedioxy. Optionally substituted groups may be incompletely substituted (e.g., -CH 2 CH 3 ), full substitutions (e.g., -CF 2 CF3 ), one substitution (-CH 2 CH 2 F), or any level of substitution between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ). When a substituent is recited without any qualification as to substitution, both substituted and unsubstituted forms are included. When a substituent is referred to as "substituted", the substituted form is specifically intended. In addition, a different set of optional substituents for a particular moiety can be defined as needed; in such cases, the optional substitutions will be as defined and will often immediately follow the phrase "optionally substituted with". The term "lower" in reference to an organic group or compound means a compound or group having up to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may be branched or unbranched. Lower alkyl represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl.

[0036] In this application, the term “zero or more (e.g., zero or one or more, zero or one, or zero) methylene units are replaced” generally refers to when a structure contains one or more methylene units, one or more of the methylene units may not be replaced, or one or more groups that are not methylene (e.g., —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —C(O)O—, —NH—, —O—, —S—, —SO—, —SO 2 -, -PH-, -P(=O)H-, -NHSO 2 -, -SO 2 NH-, -C(=S)-, -C(=NH)-, -N=N-, -C=N-, -N=C- or -C(=N 2 -) may be substituted.

[0037] In this application, terms such as "alkyl", "alkenyl" and "cycloalkyl" are used to refer to any group, group, or group that is, as known to those skilled in the art, 1 ~C 4 Alkyl, C 3 ~C7 Cycloalkoxy and C 1 ~C 4 It may be preceded by a notation indicating the number of atoms present in the group under certain circumstances, such as alkylcarbonylamino, and the subscript following the "C" indicates the number of carbon atoms present in the group. For example, C 3 Alkyl refers to an alkyl group containing 3 carbon atoms (e.g., n-propyl, or isopropyl); 1~10 In the formula: wherein the group members may contain any number of carbon atoms in the range of 1 to 10.

[0038] One or more hydrogen atoms in the group, for example up to 5 (for example, 1 to 3) hydrogen atoms, are each independently replaced with the corresponding number of substituents. Substituents are present only at their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, when an amino or hydroxyl having free hydrogen is bonded to a carbon atom having an unsaturated (for example, olefinic) bond, it may become unstable.

[0039] In this application, the term "compound" generally refers to a substance having two or more different elements. For example, the compounds disclosed herein can be organic compounds. For example, the compounds disclosed herein can be compounds with a molecular weight of 500 or less, compounds with a molecular weight of 1000 or less, compounds with a molecular weight of 1000 or more, compounds with a molecular weight of 10,000 or more, or compounds with a molecular weight of 100,000 or more. In this application, a compound can also refer to a compound that includes a linkage by a chemical bond, for example, a compound in which one or more molecules with a molecular weight of 1000 or less are linked to a biopolymer by a chemical bond, and the biopolymer can be a polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compounds disclosed herein can include a compound in which a protein is linked to one or more molecules with a molecular weight of 1000 or less, a compound in which a protein is linked to one or more molecules with a molecular weight of 10,000 or less, and a compound in which a protein is linked to one or more molecules with a molecular weight of 100,000 or less.

[0040] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. In addition, sterile fixed oils may be commonly used as a solvent or suspending medium. For example, any blend of fixed oils may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0041] In this application, the compounds of this application include their tautomers, mesomers, racemates, enantiomers and / or diastereoisomers. In this application, the term "diastereoisomer" generally refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers may have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. In this application, the terms "tautomer" and "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that can be converted into each other by crossing a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some bond electrons. In this application, the term "mesomer" generally means that the molecule contains an asymmetric atom, but has a total optical rotation of zero due to the presence of symmetry factors. The terms "racemate" or "racemic mixture" refer to a composition of equimolar amounts of two enantiomeric substances.

[0042] In this application, certain atoms of the compounds of this application may exist in two or more isotopic forms. For example, hydrogen is present in protium ( 1 H), deuterium ( 2 H), tritium ( 3H), and carbon occurs as three different isotopes ( 12 C. 13 C and 14 Examples of isotopes that can be incorporated into the compounds of the present application include: 15 N, 18 O. 17 O. 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125 I, or similar isotopes. Thus, the compounds of the present application may be enriched with one or more of these isotopes compared to the natural abundance of these isotopes. Such isotopically enriched compounds may be used for a variety of purposes, as known to those of skill in the art. For example, deuterium ( 2 Substitution with heavier isotopes such as deuterium (H) may offer certain therapeutic advantages, possibly due to their greater metabolic stability. 2 The natural abundance of hydrogen (H) is about 0.015%. Thus, about 1 out of every 6500 hydrogen atoms is a deuterium atom. Thus, the deuterium abundance at one or more sites (in some cases) in the deuterium-containing compounds of the present invention is greater than 0.015%. Unless otherwise indicated, structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds having the same structure as the structures of this application except that a hydrogen atom is replaced with deuterium or tritium, or a carbon atom is replaced with carbon-13 or carbon-14, are within the scope of this application.

[0043] In this application, "isomers" generally refer to different compounds that have the same molecular formula. "Stereoisomers" generally refer to isomers that differ only in the way the atoms are arranged in space. In this application, the term "isomer" includes all geometric and stereoisomers. For example, "isomers" include cis and trans isomers of geometric double bonds (also called E and Z isomers); R and S-enantiomers; diastereoisomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof as falling within the scope of this disclosure.

[0044] In this application, "enantiomer" generally refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds of unknown absolute configuration are specified as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate the plane of polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereoisomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R)- or (S)-. The chemical compounds, pharmaceutical compositions and methods of the present application are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthesizers or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0045] In this application, the term "enantiomeric purity" generally refers to the relative amount, expressed as a percentage, of the presence of a particular enantiomer relative to the other enantiomer. For example, when a compound that can potentially have an (R)- or (S)-isomeric configuration exists as a racemic mixture, the enantiomeric purity is about 50% for either the (R)- or (S)-isomer. When the compound has a predominance of one isomer over the other, e.g., 80% (S)- and 20% (R), the enantiomeric purity of the compound for the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined by several methods known in the art, including, but not limited to, chromatography using a chiral support, polarimetry of the rotation of polarized light, nuclear magnetic resonance spectroscopy using a chiral shift reagent (including, but not limited to, lanthanide-containing chiral complexes or pircl alcohol), or derivatization of the compound using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0046] In this application, the term "tautomer" generally refers to a class of isomers that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). "Tautomerization" includes prototropic tautomerization or proton shift tautomerization, which are considered subsets of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton with a change in bond order. The exact ratio of tautomers depends on several factors, such as temperature, solvent, and pH. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerization (i.e., the reaction that provides the tautomeric pair) can be catalyzed by an acid or base, or can occur with or without the action of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(different)enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0047] In this application, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs, and other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The pharmaceutical composition can facilitate administration to the living body, thereby facilitating the absorption of the active ingredient and exerting its biological activity. For the preparation of conventional pharmaceutical compositions, the Chinese Pharmacopoeia can be referred to.

[0048] In this application, the term "pharmaceutical acceptable salt" generally refers to a salt of a compound or ligand-drug conjugate of the application, or a salt of a compound described herein. Such salts can be safe and / or effective when used in mammals and have the required biological activity, and the antibody-antibody drug conjugate compounds of the application can form salts with acids, and non-limiting examples of pharmaceutical acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrophosphate, dihydrophosphate, salicylate, hydrocitrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0049] In this application, the terms "immunoconjugate", "conjugate", "antibody-drug conjugate" or "ADC" generally refer to a compound or derivative thereof linked to a protein, such as a cell binding agent (e.g., an anti-TNF-α antibody or fragment thereof), and are defined by the following general formula: (SM-LQ)nA, where SM is a group derived from a small molecule glucocorticoid receptor agonist (e.g., a glucocorticoid), L is a linker, Q is a heterobifunctional group, a heterotrifunctional group, or is absent, A is a protein (e.g., an antibody or antigen-binding fragment thereof, an anti-TNF protein, an anti-TNF-α antibody or fragment thereof, a soluble receptor, or a soluble TNF receptor), and n is 1-10. Immunoconjugates may also be defined in the reverse order by the following general formula: A-(QL-SM)n.

[0050] In this application, the term "linker" generally refers to any chemical moiety capable of linking a protein (e.g., an antibody, an antibody fragment (e.g., an antigen-binding fragment), or a functional equivalent) to a glucocorticoid. The linker may be susceptible to cleavage (a "cleavable linker"), thereby facilitating release of the glucocorticoid. For example, such a cleavable linker may be susceptible to acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage under conditions under which the glucocorticoid and / or antibody retain activity. Alternatively, the linker may be substantially resistant to cleavage (a "non-cleavable linker").

[0051] In this application, the term "drug antibody ratio" or "DAR" refers to the number of SMs (i.e., groups derived from a small molecule glucocorticoid receptor agonist (e.g., a glucocorticoid)) linked to A (i.e., a protein, e.g., an antibody or antigen-binding fragment thereof, an anti-TNF protein, an anti-TNF-α antibody or fragment thereof, a soluble receptor, or a soluble TNF receptor). Thus, for an immunoconjugate having the general formula (SM-LQ)nA, the DAR is defined by the variable "n."

[0052] When referring to a compound having the formula (SM-LQ)nA that represents an individual immunoconjugate, the DAR generally refers to the number of SMs linked to an individual A (e.g., n is an integer from 1 to 10).

[0053] When referring to a compound having the formula (SM-LQ)nA that represents multiple immunoconjugates, the DAR generally refers to the average number of SMs linked to an A (e.g., n is an integer or fractional number from 1 to 10). Thus, as an example, a compound having the formula (SM-LQ)nA that includes a first immunoconjugate having 3 SMs per A and a second immunoconjugate having 4 SMs per A has a DAR (i.e., "n") of 3.5.

[0054] In the present application, non-cleavable linker generally refers to any chemical moiety that can link glucocorticoid to antibody in a stable covalent manner and does not fall into the categories listed above for cleavable linker.Thus, non-cleavable linker is substantially resistant to acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage and disulfide bond cleavage.Furthermore, non-cleavable refers to the ability of the chemical bond in or adjacent to the linker to withstand cleavage induced by acid, photolabile cleavage agents, peptidases, esterases, or chemical or physiological compounds that cleave disulfide bonds under conditions that do not cause the glucocorticoid and / or antibody to lose their activity.

[0055] Some cleavable linkers are cleaved by peptidases ("peptidase-cleavable linkers"). Only certain peptides are readily cleaved inside and outside the cell. See, for example, Trout et al., Proc. Natl. Acad. Sci. USA, 626-629 (1982) and Umemoto et al., Int. J. Cancer, 677-684 (1989). Furthermore, peptides are composed of α-amino acid units and peptide bonds, which are chemically amide bonds between the carboxylic acid of one amino acid and the amino group of a second amino acid. Other amide bonds (e.g., the bond between a carboxylic acid and the α-amino acid group of lysine) are understood to be non-peptide bonds and are considered to be non-cleavable.

[0056] Some linkers are cleaved by esterases ("esterase-cleavable linkers"). Only certain esters can be cleaved by esterases present inside and outside the cell. Esters are formed by the condensation of a carboxylic acid with an alcohol. Simple esters are esters made with simple alcohols (e.g., aliphatic alcohols) as well as small cyclic and small aromatic alcohols.

[0057] In some embodiments, the cleavable linker component may comprise a peptide comprising 1-10 amino acid residues. In these embodiments, the peptide allows for cleavage of the linker by a protease, thereby facilitating release of the glucocorticoid upon exposure to intracellular proteases, such as lysosomal enzymes (Doronina et al., (2003) Nat. Biotechnol. 21:778-784). Exemplary peptides include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, alanine-alanine (ala-ala), valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).

[0058] Peptides may include naturally occurring and / or non-natural amino acid residues. The term "naturally occurring amino acid" generally refers to Ala, Asp, Cys, Glu, Phe, Gly, His, He, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, Thr, Val, Trp, and Tyr. Non-limiting examples of "non-natural amino acids" (i.e., amino acids that do not occur naturally) include homoserine, homoarginine, citrulline, phenylglycine, taurine, iodotyrosine, selenocysteine, norleucine ("Nle"), norvaline ("Nva"), β-alanine, L- or D-naphthalenine, ornithine ("Orn"), and the like. Peptides can be designed and optimized for enzymatic cleavage by specific enzymes (e.g., tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases).

[0059] Amino acids may also include D-forms of natural and unnatural amino acids. "D-" refers to an amino acid having a "D" (dextrorotatory) configuration, as opposed to the configuration in naturally occurring ("L-") amino acids. Natural and unnatural amino acids are either commercially available (Sigma Chemical Co. or Advanced Chemtech) or can be synthesized using methods known in the art.

[0060] In this application, the term "pharmaceutical acceptable carrier" generally refers to a carrier for providing therapeutic agents such as antibodies or polypeptides, genes, and other therapeutic agents. This term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without causing undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, poly(amino acids), amino acid copolymers, lipid aggregates, and inactivated virus particles. Such carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol, and ethanol. Auxiliary substances such as wetting or emulsifying agents, or pH buffering substances, can also be present in these carriers.

[0061] In this application, the term "anti-TNFα protein" generally refers to a protein capable of (i) binding to TNFα and (ii) inhibiting the binding of soluble TNF-α to cell surface TNF receptors (p55 and / or p75) and / or lysing cells expressing surface TNFα or TNFα receptors in vitro in the presence of complement. Anti-TNFα proteins include, for example, anti-TNF antibodies or antigen-binding fragments thereof (e.g., adalimumab or infliximab) and soluble TNF receptors (e.g., etanercept).

[0062] In this application, the term "antibody" generally refers to an immunoglobulin reactive to a specific protein or peptide or fragment thereof. The antibody may be of any class of antibody, including but not limited to IgG, IgA, IgM, IgD, and IgE, and of any subclass (e.g., IgG1, IgG2, IgG3, and IgG4). The antibody may have a heavy chain constant region selected from the group consisting of, for example, IgG1, IgG2, IgG3, and IgG4. The antibody may also have a light chain selected from the group consisting of, for example, kappa (κ) and lambda (λ). The antibody of this application may be derived from any species. The term "antibody" may include intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing antibodies, and any other modified immunoglobulin molecule, so long as the antibody exhibits the desired biological activity.

[0063] In this application, the term "antigen-binding fragment" generally refers to a portion of an antibody molecule that contains amino acids involved in the specific binding of the antibody to an antigen. The portion of the antigen that is specifically recognized and bound by an antibody is referred to as the "epitope" above. As described above, an antigen-binding domain may typically include an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it does not necessarily have to include both. For example, an Fd fragment has two VH regions and typically retains some of the antigen-binding function of the intact antigen-binding domain. Examples of antigen-binding fragments of antibodies include: (1) a Fab fragment, a monovalent fragment having the VL, VH, constant light chain (CL) and CH1 domains; (2) a F(ab')2 fragment, a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment having two VH and CH1 domains; (4) a Fv fragment having the VL and VH domains of a single arm of an antibody; (5) a dAb fragment having a VH domain (Ward et al., "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli", Nature 341:544-546 (1989), which is incorporated herein by reference in its entirety); (6) isolated complementarity determining regions (CDRs); (7) single chain Fv (scFv), e.g., derived from an scFV-library.The two domains of the Fv fragment, VL and VH, are encoded by separate genes but can be linked by recombinant methods using a synthetic linker that allows the VL and VH regions to be prepared as a single protein chain that pairs to form a monovalent molecule (called single-chain Fv (scFv)) (see, for example, Huston et al., “Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli”, Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)); (8) VHH for the variable antigen-binding domain of heavy chain antibodies from the Camelidae family (camel, dromedary, llama, alpaca, etc.) (Nguyen VK et al., 2000, The EMBO Journal, 19, 921-930; Muyldermans S., 2001, J. Immunol. 2001, 144: 111-112; (See reviews in Biotechnol., 74, 277-302 and Vanl and Schoot P. et al., 2011, Antiviral Research 92, 389-407.) VHHs are also called nanobodies (Nbs).

[0064] In this application, the term "variable region" or "variable domain" generally refers to the domain of the heavy or light chain of an antibody that is involved in binding the antibody to an antigen. In this application, the term "variable" generally means that certain portions of the sequence of the variable domain of an antibody vary widely, resulting in the binding and specificity of various particular antibodies to their particular antigens. The variability is not uniformly distributed throughout the variable region of an antibody. It is concentrated in three segments (LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3) in each of the light and heavy chain variable regions, called the complementarity determining regions (CDRs) or hypervariable regions (HVRs). The more highly conserved parts of the variable domain are called the framework (FR). Each naturally occurring heavy and light chain variable domain contains four FRs (H-FR1, H-FR2, H-FR3, H-FR4, L-FR1, L-FR2, L-FR3, and L-FR4) in a mainly β-sheet configuration. The FRs are connected by three CDR structural loop regions. The CDRs in each chain are held in close proximity by the FR regions and, together with the CDRs from the other chain, form the antigen-binding site of antibodies.

[0065] There are various methods in the art that allow encoding the variable regions of an antibody or splitting the CDRs of an antibody. Examples of such methods are the Kabat numbering scheme and definition rules, which are based on sequence variability (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, Md. (1991)), the Chothia numbering scheme and definition rules, which are based on the location of structural loop regions (A1-see Lazikani et al., J Mol Biol 273:927-48, 1997), the IMGT numbering scheme and definition rules, which are based on the alignment of amino acid sequences of germline V genes (efranc et al.), and the Honneger numbering scheme (AHo's), Martin numbering scheme, Gelfand numbering scheme, etc. (Mathieu Dondelinger et al., Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface / Residue Definition, Front. Immunol., October 2001). (See 16,2018).

[0066] In this application, the term "percent sequence identity" generally refers to the number of identical amino acid matches ("hits") of two or more aligned amino acid sequences compared to the number of amino acid residues that make up the full length of the amino acid sequences. In other words, alignment can be used to determine the percentage of amino acid residues that are the same for two or more sequences (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity) when comparing and aligning sequences to obtain maximum agreement (as measured using sequence comparison algorithms known in the art) or when manually aligned and visually inspected. Thus, the sequences compared to determine sequence identity may differ by one or more substitutions, additions or deletions of amino acids. Suitable programs for aligning protein sequences are known to those skilled in the art. Percent sequence identity of protein sequences can be determined, for example, using programs such as CLUSTALW, Clustal Omega, FASTA or BLAST, for example using the NCBI BLAST algorithm (Altschul SF, et al., (1997), Nucleic Acids Res. 25:3389-3402).

[0067] In this application, the term "antibody analog" is generally used in the broadest sense, specifically encompassing molecules that specifically bind to a target molecule with a monospecificity and that are structurally distinct from a natural antibody. For example, in the context of describing an anti-PD-1 antibody or an anti-PD-L1 antibody, the term "antibody analog" refers to an antibody that contains a segment that has substantial identity to a portion of its amino acid sequence and has at least one of the following properties: (1) specific binding to PD-1 or PD-L1 under appropriate binding conditions, and (2) the ability to inhibit at least one biological activity of PD-1 or PD-L1. Typically, an antibody analog contains conservative amino acid substitutions (or insertions or deletions) relative to the natural sequence. Analogs are typically at least 20 or 25 amino acids in length, at least 50, 60, 70, 80, 90, 100, 150, or 200 amino acids in length or longer, and generally can be as long as a full-length heavy or light chain of an antibody. Some examples include antibody analogs with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 substitutions compared to the germline amino acid sequence.

[0068] In this application, the term "effective amount" or "therapeutically effective amount" generally refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use described below, including but not limited to the treatment of a disease. The therapeutically effective amount may vary depending on the intended use (in vivo or in vitro); or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, and can be easily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells (e.g., platelet adhesion and / or cell migration). The specific dose will vary depending, for example, on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered.

[0069] In this application, the term "in vivo" generally refers to events that take place inside a subject's body.

[0070] In this application, the term "in vitro" generally refers to events that occur outside of a subject's body. For example, in vitro assays include any assay that is performed outside of a subject. In vitro assays include cell-based assays that use live or dead cells. In vitro assays also include cell-free assays that do not use intact cells.

[0071] In this application, the terms "treatment" and "treating" generally refer to a method of achieving a beneficial or desired result, including but not limited to a therapeutic benefit. Therapeutic benefit includes, but is not limited to, eradicating, inhibiting, reducing, or reversing the underlying disease being treated. In addition, therapeutic benefit is achieved by eradicating, inhibiting, reducing, or reversing one or more physiological symptoms associated with the underlying disease, and thus, although improvement is observed in the patient, the patient may still suffer from the underlying disease.

[0072] In this application, the terms "prevention" and "preventing" generally refer to a method of achieving a beneficial or desired result, including but not limited to a prophylactic benefit. For the purposes of a prophylactic benefit, the pharmaceutical composition can be administered to a patient who is at risk of developing a particular disease, or who reports having one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been obtained.

[0073] In this application, the term "subject" or "patient" generally refers to humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly)) and / or other primates (e.g., cynomolgus or rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys.

[0074] In this application, the term "about" or "approximately" generally refers to the margin of error of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" generally means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" generally means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0075] In this application, the term "comprise" and variations thereof, including "comprises," "comprising," and other forms, generally means the inclusion of other components, elements, integers, steps, etc. [Brief description of the drawings]

[0076] [Figure 1a] Figure 1 shows the inhibitory effect of the drug conjugate of the present invention on R848-induced release of IFNα, TNFα, IL-6 and IL-8 from human peripheral blood mononuclear cells: 1a: R848-induced IFNα release from PBMC, 1b: R848-induced TNFα release from PBMC, 1c: R848-induced IL6 release from PBMC, 1d: R848-induced IL8 release from PBMC. [Figure 1b] Figure 1 shows the inhibitory effect of the drug conjugate of the present invention on R848-induced release of IFNα, TNFα, IL-6 and IL-8 from human peripheral blood mononuclear cells: 1a: R848-induced IFNα release from PBMC, 1b: R848-induced TNFα release from PBMC, 1c: R848-induced IL6 release from PBMC, 1d: R848-induced IL8 release from PBMC. [Figure 1c]Figure 1 shows the inhibitory effect of the drug conjugate of the present invention on R848-induced release of IFNα, TNFα, IL-6 and IL-8 from human peripheral blood mononuclear cells: 1a: R848-induced IFNα release from PBMC, 1b: R848-induced TNFα release from PBMC, 1c: R848-induced IL6 release from PBMC, 1d: R848-induced IL8 release from PBMC. [Figure 1d] Figure 1 shows the inhibitory effect of the drug conjugate of the present invention on R848-induced release of IFNα, TNFα, IL-6 and IL-8 from human peripheral blood mononuclear cells: 1a: R848-induced IFNα release from PBMC, 1b: R848-induced TNFα release from PBMC, 1c: R848-induced IL6 release from PBMC, 1d: R848-induced IL8 release from PBMC.

[0077] [Diagram 2] FIG. 1 shows the measurement of biological activity in a fluorescein isothiocyanate (FITC)-induced delayed-type IV hypersensitivity mouse model.

[0078] [Figure 3a] Figure 3 shows arthritis scores for bovine type II collagen mixed adjuvant induced DBA / 1 mouse arthritis model: 3a: arthritis score; 3b: AUC of arthritis score. [Figure 3b] Figure 3 shows arthritis scores for bovine type II collagen mixed adjuvant induced DBA / 1 mouse arthritis model: 3a: arthritis score; 3b: AUC of arthritis score. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; A1 is a substituted benzene ring; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy, each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0080] In certain embodiments, the compound of formula I, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; A1 is a substituted benzene ring; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O)2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is 0 or 1; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6alkoxy, each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy].

[0081] In certain preferred embodiments of the present invention, certain groups in the compounds of formula (I), (Ia), (Ib) and (Ic) or pharma- ceutically acceptable salts thereof are defined as follows, and groups not mentioned are as described in any one of the embodiments of this application (abbreviated as "in certain embodiments").

[0082] In certain embodiments, X is -O-, -S-, or -NH-.

[0083] In certain embodiments, CR 4 R 5 The units are each independently unsubstituted or replaced by a group selected from the group consisting of -O-, -S-, and -C(=O)-.

[0084] In certain embodiments, R 4 and R 5 taken together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl.

[0085] In certain embodiments, R 4 and R 5 are independently hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 4 and R 5 When contains a methylene unit, R 4 and R 5 Each methylene unit is independently unsubstituted or R 4 and R 5 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0086] In certain embodiments, R 4 and R 5 are each independently hydrogen, protium, deuterium, tritium, a halogen, an optionally substituted -C(=O)H, an optionally substituted -OH, an optionally substituted -SH, an optionally substituted -NH 2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 4 and R 5 When contains a methylene unit, R 4 and R 5 Each methylene unit is independently unsubstituted or R 4 and R 5 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0087] In certain embodiments, R 4 and R 5 are each independently H, F, Cl, -OH, -NH 2 and C 1 ~C 6 alkyl, or R 4 and R 5 Together, C 3 ~C 6 cycloalkyl or 3- to 6-membered heterocyclyl; n is selected from the group consisting of 1, 2 and 3, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0088] In certain embodiments, (CR 4 R 5 )n -, each independently, -CH 2 -, -CH 2 CH 2 -, [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0089] In certain embodiments, Y 1 is absent or is protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0090] In certain embodiments, Y 1 is absent or is protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 1 ~C6 alkoxy; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0091] In certain embodiments, Y 1 is absent or is selected from hydroxy, sulfhydryl, amino, and optionally substituted C 1 ~C 6 alkyl.

[0092] For example, A1 (structural unit [ka] )teeth, [ka] may be selected from the group consisting of:

[0093] In certain embodiments, R 1 , R 2 and R 3 are independently hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 , R 2 and R 3 When contains a methylene unit, R 1 , R 2 and R 3 Each methylene unit is independently unsubstituted or R 1 , R 2 and R 3 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0094] In certain embodiments, R 1 and R 2 are each independently H, F, Cl, Br, and optionally substituted C 1 ~C 6 alkyl.

[0095] For example, R 1 and R 2 may each independently be selected from the group consisting of H, F, Cl, Br, and optionally substituted methyl.

[0096] In certain embodiments, R 3 is hydrogen, optionally substituted -OH, optionally substituted -SH and optionally substituted C 1~C 6 alkyl.

[0097] In certain embodiments, R 3 When is optionally substituted methyl, R 3 is R 31 is replaced by R 31 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 31 When contains a methylene unit, R 31 Each methylene unit is independently unsubstituted or R 31 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0098] In certain embodiments, R 31is selected from the group consisting of hydrogen, halogen, optionally substituted —OH, and optionally substituted —SH.

[0099] In certain embodiments, R 31 is optionally substituted -OH, R 31 is R 311 is replaced by R 311 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 311 When contains a methylene unit, R 311 Each methylene unit is independently unsubstituted or R 311 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0100] In certain embodiments, R 311is hydrogen, optionally substituted -P(=O)H 2 , optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 2 ~C 9 heterocyclylene; R 311 When contains a methylene unit, R 311 Each methylene unit is independently unsubstituted or R 311 Each methylene unit is independently -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H 2 -, optionally substituted -NH-; the substituents being protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -N + (R) 3 , -PHR, -P(R) 2 , -P(=O)R 2 , -OP(=O)R 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy, each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0101] In certain embodiments, R 311 is optionally substituted hydrogen, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] is selected from the group consisting of:

[0102] In certain embodiments, R 3 is optionally substituted -OH, R 3 is R 32 is replaced by R 32 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 32 When contains a methylene unit, R 32 Each methylene unit is independently unsubstituted or R 32 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0103] In certain embodiments, R 32 is hydrogen and optionally substituted C 1 ~C 6 alkyl.

[0104] In certain embodiments, R 32 is optionally substituted methyl or optionally substituted ethyl, R 32 is R 321 is replaced by R 321 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 321 When contains a methylene unit, R 321 Each methylene unit is independently unsubstituted or R 321 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0105] In certain embodiments, R 321 is hydrogen, halogen, -CN and optionally substituted C 1 ~C 6 alkyl.

[0106] In certain embodiments, R 321 is selected from the group consisting of hydrogen, F, Cl, —CN, and optionally substituted methyl.

[0107] In certain embodiments, R 3 When is optionally substituted -SH, R 3 is R 33 is replaced by R 33 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 33 When contains a methylene unit, R 33 Each methylene unit is independently unsubstituted or R 33 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0108] In certain embodiments, R 33 is hydrogen and optionally substituted C 1 ~C 6 alkyl.

[0109] In certain embodiments, R 33 is optionally substituted methyl.

[0110] In certain embodiments, R 33 When is optionally substituted methyl, R 33 is R 331 is replaced by R 331are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 331 When contains a methylene unit, R 331 Each methylene unit is independently unsubstituted or R 331 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0111] In certain embodiments, R 331 is selected from the group consisting of hydrogen, chlorine, fluorine and -CN.

[0112] For example, R 3 is an optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted -OH, optionally substituted -OCH 3 , optionally substituted -OCH 2 F, optionally substituted -OCH 2 Cl, optionally substituted -OCH 2 CN, optionally substituted -OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 and optionally substituted -SCH 2 CN.

[0113] In certain embodiments, R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R 3 But -CH 2 Cl, -CH 2 SH, -CH 2 OH, [ka] -OCH 3 , -OCH 2 F, -OCH 2 Cl, -OCH 2 CN, -OCH 2 CH 3 , -SH, -SCH 2 F, -SCH 2 Cl, -SCH 2 CF 3 and -SCH 2 CN, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0114] In certain embodiments, R 1 and R 2are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen; R 3 is CH 2 OH, -SCH 2 F, [ka] is selected from the group consisting of:

[0115] In certain embodiments, B is absent or optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 3 ~C 8 Heterocyclyl, optionally substituted C 6 ~C 10 Aryl and optionally substituted C 5 ~C 10 heteroaryl, and the substituents are selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0116] In certain embodiments, B is optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of: 1 is selected from the group consisting of N and optionally substituted CH.

[0117] In certain embodiments, X 1 When is optionally substituted -CH, X 1 is R 6 is replaced by R 6 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 6 When contains a methylene unit, R 6 Each methylene unit is independently unsubstituted or R 6 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0118] In certain embodiments, R 6 is selected from the group consisting of hydrogen and optionally substituted --OH.

[0119] In certain embodiments, R 6 is optionally substituted —OH, R 6 is R 61 is replaced by R 61 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 61 When contains a methylene unit, R 61 Each methylene unit is independently unsubstituted or R 61 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0120] In certain embodiments, R 61 is H and optionally substituted C 1 ~C 6 alkyl.

[0121] In certain embodiments, X 1 is CH, C(-O-CH 3 ) and N.

[0122] In certain embodiments, B is Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of: 2 and X 3 are each independently selected from the group consisting of O, S, and optionally substituted NH.

[0123] In certain embodiments, X 2 and X 3 When is optionally substituted NH, X 2 Or X 3 is R 7 is replaced by R 7 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 7 When contains a methylene unit, R 7 Each methylene unit is independently unsubstituted or R 7 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0124] In certain embodiments, R 7 is hydrogen and optionally substituted C 1 ~C 6 alkyl; R7 When contains a methylene unit, R 7 Each methylene unit is independently unsubstituted or R 7 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0125] In certain embodiments, R 7 is optionally substituted C 1 ~C 6 When it is alkyl, R 7 is R 71 is replaced by R 71 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 71 When contains a methylene unit, R 71 Each methylene unit is independently unsubstituted or R 71Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0126] In certain embodiments, R 71 is H and optionally substituted C 1 ~C 6 alkyl.

[0127] In certain embodiments, X 2 Or X 3 NH, N(CH 3 ), O and S.

[0128] For example, B: Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] and the substituents can be selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 Each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6alkoxy.

[0129] In certain embodiments, B is [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0130] In certain embodiments, W is absent or W is -S(=O)-, -S(=O) 2 -, -O-, -S-, optionally substituted -NHC(=O)-, optionally substituted -C(=O)NH-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene; when W contains methylene units, each methylene unit of W is independently unsubstituted or each methylene unit of W is independently selected from the group consisting of -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0131] In certain embodiments, W is optionally substituted C 1 ~C 6When W is alkylene, W is R 8 is replaced by R 8 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 8 When contains a methylene unit, R 8 Each methylene unit is independently unsubstituted or R 8 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0132] In certain embodiments, R 8 is hydrogen, ═O, optionally substituted C 1 ~C 6 It is selected from the group consisting of alkyl and optionally substituted cycloalkyl.

[0133] In certain embodiments, R 8is optionally substituted methyl.

[0134] In certain embodiments, R 8 When is optionally substituted methyl, R 8 is R 81 is replaced by R 81 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0135] In certain embodiments, R 81 is selected from the group consisting of halogen and optionally substituted cycloalkyl.

[0136] In certain embodiments, R 81 is selected from the group consisting of F and optionally substituted cyclopropyl.

[0137] In certain embodiments, W is absent or W is -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -CH 2 NHC(=O)-, optionally substituted -NHC(=O)CH 2 -, optionally substituted -C(=O)NH-, optionally substituted -NH-, optionally substituted -CH=CH-, [ka] Optionally substituted C 1 ~C 6 Alkylene, optionally substituted -OCH 2 -, optionally substituted -CH 2 O-, optionally substituted -SCH 2 -, optionally substituted -CH 2 S-, optionally substituted -NHC(=O)-, optionally substituted -C(=O)CH 2 -, optionally substituted -CH 2 NH-, optionally substituted -NHCH 2 -, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of:

[0138] For example, W is absent or W is [ka] is selected from the group consisting of:

[0139] In certain embodiments, W is absent or [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0140] In another example, B may be absent, or [ka] may be selected from the group consisting of: W may be absent or may be [ka] may be selected from the group consisting of: A1 is, [ka] may be selected from the group consisting of:

[0141] In certain embodiments, [ka] [In the formula, X is selected from the group consisting of -O-, -S-, and -NH-; R 4 and R 5 are each independently H, F, Cl, -OH, or -NH 2 and C 1 ~C 6 selected from the group consisting of alkyl; N is selected from the group consisting of 1, 2 and 3; Y 1 is absent or is hydroxy, sulfhydryl, amino and C 1 ~C 6 selected from the group consisting of alkyl; R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R 3 is -CH2 Cl, -CH 2 SH, -CH 2 OH, [ka] -OCH 3 , -OCH 2 F, -OCH 2 Cl, -OCH 2 CN, -OCH 2 CH 3 , -SH, -SCH 2 F, -SCH 2 Cl, -SCH 2 CF 3 and -SCH 2 CN], or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0142] For example, a compound of formula I has the following structure: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

[0143] In another aspect, the present invention provides a compound of the formula [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0144] In another aspect, the present application relates to a compound of formula IIa or IIb: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; A2 is a substituted benzene ring; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Y 2 is selected from the group consisting of -O-, -S- and -NR-; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0145] In certain embodiments, the wavy line in formula IIa or IIb [ka] is an X group or Y 2 It represents that the ligand is directly linked via a group or is linked to the ligand via a linker fragment.

[0146] In certain preferred embodiments of the present invention, certain groups in the compounds of formula (IIa) and (IIb) or pharma- ceutically acceptable salts thereof are defined as follows, and groups not mentioned are as described in any one of the embodiments of this application (abbreviated as "certain embodiments").

[0147] In certain embodiments, CR 4 R 5The units are each independently unsubstituted or replaced by a group selected from the group consisting of -O-, -S-, and -C(=O)-.

[0148] In certain embodiments, R 4 and R 5 taken together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl. For example, R 4 and R 5 can be taken together to form cyclopropyl or cyclobutyl.

[0149] In certain embodiments, R 4 and R 5 are independently hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 4 and R 5 When contains a methylene unit, R 4 and R 5 Each methylene unit is independently unsubstituted or R 4 and R 5 Each methylene unit is independently -S(=O)-, -S(=O) 2and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0150] In certain embodiments, R 4 and R 5 are each independently hydrogen, protium, deuterium, tritium, a halogen, an optionally substituted -C(=O)H, an optionally substituted -OH, an optionally substituted -SH, an optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 4 and R 5 When contains a methylene unit, R 4 and R 5 Each methylene unit is independently unsubstituted or R 4 and R 5 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0151] In certain embodiments, R 4 and R 5 are each independently H, F, Cl, -OH, -NH 2 and C 1 ~C 6 n is selected from the group consisting of 1, 2 and 3, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0152] In certain embodiments, Y 1 are protium, deuterium, tritium, halogens, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0153] In certain embodiments, Y 1 are protium, deuterium, tritium, halogens, -OR, -SR, -NHR, -N(R) 2 , optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 1 ~C 6alkoxy; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0154] In certain embodiments, Y 1 is not present or -OR, -SR, -N(R) 2 and optionally substituted C 1 ~C 6 alkyl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, C 1 ~C 6 Alkyl and C 1 ~C 6 alkoxy.

[0155] In certain embodiments, Y 1 is absent or is hydroxy, sulfhydryl, amino, and C 1 ~C 6 alkyl.

[0156] In certain embodiments, Y 2 includes -NR-; each R is hydrogen, protium, deuterium, tritium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0157] For example, A2 (structural unit [ka] )teeth, [ka] [ka] may be selected from the group consisting of:

[0158] In certain embodiments, R 1 , R 2 and R 3 are independently hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 , R 2 and R 3 When contains a methylene unit, R 1 , R 2 and R 3 Each methylene unit is independently unsubstituted or R 1 , R 2 and R 3 Each methylene unit is independently -S(=O)-, -S(=O) 2and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0159] In certain embodiments, R 1 and R 2 are each independently H, F, Cl, Br, and optionally substituted C 1 ~C 6 alkyl.

[0160] In certain embodiments, R 1 and R 2 are each independently selected from the group consisting of H, F, Cl, Br, and optionally substituted methyl.

[0161] In certain embodiments, R 3 is hydrogen, optionally substituted -OH, optionally substituted -SH and optionally substituted C 1 ~C 6 alkyl.

[0162] In certain embodiments, R 3 When is optionally substituted methyl, R 3 is R 31 is replaced by R 31 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2, optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 31 When contains a methylene unit, R 31 Each methylene unit is independently unsubstituted or R 31 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0163] In certain embodiments, R 31 is selected from the group consisting of hydrogen, halogen, optionally substituted —OH, and optionally substituted —SH.

[0164] In certain embodiments, R 31 is optionally substituted —OH, R 31 is R 311 is replaced by R 311 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2, optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 311 When contains a methylene unit, R 311 Each methylene unit is independently unsubstituted or R 311 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0165] In certain embodiments, R 311 is hydrogen, optionally substituted -P(=O)H 2 , optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 2 ~C 9 heterocyclylene; R 311 When contains a methylene unit, R 311 Each methylene unit is independently unsubstituted or R 311 Each methylene unit is independently -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H2 -, optionally substituted -NH-; the substituents being protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -N + (R) 3 , -PHR, -P(R) 2 , -P(=O)R 2 , -OP(=O)R 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy, each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0166] In certain embodiments, R 311 is optionally substituted hydrogen, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] is selected from the group consisting of:

[0167] In certain embodiments, R 3 is optionally substituted —OH, R 3 is R 32 is replaced by R 32 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 32 When contains a methylene unit, R 32 Each methylene unit is independently unsubstituted or R 32 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0168] In certain embodiments, R 32 is hydrogen and optionally substituted C 1 ~C 6 alkyl.

[0169] In certain embodiments, R 32 is optionally substituted methyl or optionally substituted ethyl, R 32 is R 321 is replaced by R 321 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 321 When contains a methylene unit, R 321 Each methylene unit is independently unsubstituted or R 321 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0170] In certain embodiments, R 321 is hydrogen, halogen, -CN and optionally substituted C 1 ~C 6 alkyl.

[0171] In certain embodiments, R 321 is selected from the group consisting of hydrogen, F, Cl, —CN, and optionally substituted methyl.

[0172] In certain embodiments, R 3 When is optionally substituted -SH, R 3 is R 33 is replaced by R 33 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 33 When contains a methylene unit, R 33 Each methylene unit is independently unsubstituted or R 33 Each methylene unit is independently -S(=O)-, -S(=O) 2and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0173] In certain embodiments, R 33 is hydrogen and optionally substituted C 1 ~C 6 alkyl.

[0174] In certain embodiments, R 33 is optionally substituted methyl or optionally substituted ethyl, R 33 is R 331 is replaced by R 331 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 331 When contains a methylene unit, R 331 Each methylene unit is independently unsubstituted or R 331 Each methylene unit is independently -S(=O)-, -S(=O)2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0175] In certain embodiments, R 331 is selected from the group consisting of hydrogen, chlorine, fluorine and -CN.

[0176] For example, R 3 is an optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted -OH, optionally substituted -OCH 3 , optionally substituted -OCH 2 F, optionally substituted -OCH 2 Cl, optionally substituted -OCH 2 CN, optionally substituted -OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 and optionally substituted -SCH 2 CN.

[0177] In certain embodiments, R 3 But -CH 2 Cl, -CH 2 SH, -CH 2 OH, [ka] -OCH 3 , -OCH 2 F, -OCH 2 Cl, -OCH 2 CN, -OCH 2 CH 3 , -SH, -SCH 2 F, -SCH 2 Cl, -SCH 2 CF 3and -SCH 2 CN, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0178] In certain embodiments, R 1 and R 2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen; R 3 is CH 2 OH, -SCH 2 F, [ka] is selected from the group consisting of:

[0179] In certain embodiments, B is absent or optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 3 ~C 8 Heterocyclyl, optionally substituted C 6 ~C 10 Aryl and optionally substituted C 5 ~C 10 heteroaryl, and the substituents are selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O)2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0180] In certain embodiments, B is optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of: 1 is selected from the group consisting of N and optionally substituted CH.

[0181] In certain embodiments, X 1 When is optionally substituted -CH, X 1 is R 6 is replaced by R6 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 6 When contains a methylene unit, R 6 Each methylene unit is independently unsubstituted or R 6 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0182] In certain embodiments, R 6 is selected from the group consisting of hydrogen and optionally substituted --OH.

[0183] In certain embodiments, R 6 is optionally substituted —OH, R 6 is R 61 is replaced by R 61are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 61 When contains a methylene unit, R 61 Each methylene unit is independently unsubstituted or R 61 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0184] In certain embodiments, R 61 is H and optionally substituted C 1 ~C 6 alkyl.

[0185] In certain embodiments, X 1 is CH, C(-O-CH 3 ) and N.

[0186] In certain embodiments, B is optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of: 2 and X 3 are each independently selected from the group consisting of O, S, and optionally substituted NH.

[0187] In certain embodiments, X 2 and X 3 When is optionally substituted NH, X 2 Or X 3 is R 7 is replaced by R 7 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 7 When contains a methylene unit, R 7 Each methylene unit is independently unsubstituted or R 7 Each methylene unit is independently -S(=O)-, -S(=O) 2and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0188] In certain embodiments, R 7 is hydrogen and optionally substituted C 1 ~C 6 alkyl.

[0189] In certain embodiments, R 7 is optionally substituted C 1 ~C 6 When it is alkyl, R 7 is R 71 is replaced by R 71 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 71 When contains a methylene unit, R 71 Each methylene unit is independently unsubstituted or R 71Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0190] In certain embodiments, R 71 is H and optionally substituted C 1 ~C 6 alkyl.

[0191] In certain embodiments, X 2 Or X 3 NH, N(CH 3 ), O and S.

[0192] In certain embodiments, B is Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] and the substituents are selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 Each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6alkoxy.

[0193] In certain embodiments, B is [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0194] In certain embodiments, W is absent or W is -S(=O)-, -S(=O) 2 -, -O-, -S-, -NHC(=O)-, -C(=O)NH-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene; when W contains methylene units, each methylene unit of W is independently unsubstituted or each methylene unit of W is independently selected from the group consisting of -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0195] In certain embodiments, W is optionally substituted C 1 ~C 6 When W is alkylene, W is R 8is replaced by R 8 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 8 When contains a methylene unit, R 8 Each methylene unit is independently unsubstituted or R 8 Each methylene unit is independently -S(=O)-, -S(=O) 2 and optionally substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene.

[0196] In certain embodiments, R 8 is hydrogen, ═O, optionally substituted C 1 ~C 6 It is selected from the group consisting of alkyl and optionally substituted cycloalkyl.

[0197] In certain embodiments, R 8 is optionally substituted methyl.

[0198] In certain embodiments, R 8 When is optionally substituted methyl, R 8 is R 81 is replaced by R 81 are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, =O, =S, optionally substituted -S(=O)H, optionally substituted -S(=O) 2 H, optionally substituted -C(=O)H, optionally substituted -OH, optionally substituted -SH, optionally substituted -PH 2 , optionally substituted -P(=O)H 2 , optionally substituted -NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0199] In certain embodiments, R 81 is selected from the group consisting of halogen and optionally substituted cycloalkyl.

[0200] In certain embodiments, R 81 is selected from the group consisting of F and optionally substituted cyclopropyl.

[0201] In certain embodiments, W is absent or W is -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -CH 2 NHC(=O)-, optionally substituted -NHC(=O)CH 2 -, optionally substituted -C(=O)NH-, optionally substituted -NH-, optionally substituted -CH=CH-, [ka] Optionally substituted C 1 ~C 6 Alkylene, optionally substituted -OCH 2 -, optionally substituted -CH 2 O-, optionally substituted -SCH 2 -, optionally substituted -CH 2 S-, optionally substituted -NHC(=O)-, optionally substituted -COCH 2 -, optionally substituted -CH 2 NH-, optionally substituted -NHCH 2 -, optionally substituted -CH(CH 3 )-, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] is selected from the group consisting of:

[0202] For example, W is absent or W is [ka] is selected from the group consisting of:

[0203] In certain embodiments, W is absent or [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0204] For example, B may be absent, or [ka] may be selected from the group consisting of: W may be absent or may be [ka] may be selected from the group consisting of: A2 is, [ka] [ka] may be selected from the group consisting of:

[0205] In certain embodiments, [ka] [In the formula, X is selected from the group consisting of -O-, -S-, and -NH-; R 4 and R 5 are each independently H, F, Cl, -OH, or -NH 2 and C 1 ~C 6 selected from the group consisting of alkyl; N is selected from the group consisting of 1, 2 and 3; Y 1 is absent or is hydroxy, sulfhydryl, amino and C 1 ~C 6 selected from the group consisting of alkyl; R 1 and R 2are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R 3 is -CH 2 Cl, -CH 2 SH, -CH 2 OH, [ka] -OCH 3 , -OCH 2 F, -OCH 2 Cl, -OCH 2 CN, -OCH 2 CH 3 , -SH, -SCH 2 F, -SCH 2 Cl, -SCH 2 CF 3 and -SCH 2 CN], or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0206] In certain embodiments, [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0207] In certain embodiments, the compound of formula IIa or IIb, or a tautomer, mesomeric, racemic, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, further comprises a trigger fragment (Tr), which has the following structure: [ka] [Wherein Tr has the following structure: [ka] selected from the group consisting of; R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Y 2 is selected from the group consisting of -O-, -S- and -NR-; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2, -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy].

[0208] For example, R 1 and R 2 may each independently be selected from the group consisting of H, F, Cl, Br, and optionally substituted methyl.

[0209] For example, R 3 is an optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted -OH, optionally substituted -OCH 3 , optionally substituted -OCH2 F, optionally substituted -OCH 2 Cl, optionally substituted -OCH 2 CN, optionally substituted -OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 and optionally substituted -SCH 2 CN.

[0210] For example, B: Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] and the substituents are selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 Each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy.

[0211] For example, W is absent or W is [ka] is selected from the group consisting of:

[0212] In certain embodiments, the linker fragment is 1 Fragment, L 2 Fragment and / or L 3 The compound includes a fragment having the following structure: [ka] [In the formula, Tr is absent or is any group; L 3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units; R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1is any group, and m is any integer from 0 to 4; Y 2 is selected from the group consisting of -O-, -S- and -NR-; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy].

[0213] In certain preferred embodiments of the present invention, certain groups in the compounds of formula (IVa) and (IVb) or pharma- ceutically acceptable salts thereof are defined as follows, and groups not mentioned are as described in any one of the embodiments of this application (abbreviated as "in certain embodiments").

[0214] In certain embodiments, L 3 is selected from the group consisting of dipeptides, tripeptides and tetrapeptides.

[0215] In certain embodiments, the dipeptide is selected from the group consisting of GA, GG, AG, EG, EA, GE, DG, DA, GD, VC, VA, AA, and VK.

[0216] In certain embodiments, the tripeptide is selected from the group consisting of EAG, EGG, GEG, GEA, DAG, DGG, GDG, GDA, GGA, GAG, GFG, AAG, AAA, VAG, VCG and VKG.

[0217] In certain embodiments, the tetrapeptide is selected from the group consisting of GGFG, GGAG, GGGG, GEGG, GEAG, GDGG, GDAG, AAAG and EAGG.

[0218] In certain embodiments, L 3are glycine-glycine-phenylalanine-glycine (GGGG), alanine-alanine-alanine-glycine (AAAG), glycine-glycine-glycine-glycine (GGGG), valine-alanine-glycine (VAG), valine-citrulline-glycine (VCG), alanine-alanine-glycine (AAG), alanine-alanine-alanine (AAA), valine-alanine (VA), valine-citrulline (VC), alanine-alanine (AA), glutamic acid-alanine The amino acid is selected from the group consisting of valine-lysine-glycine (EAGG), glycine-glutamic acid-alanine-glycine (GEAG), glycine-glutamic acid-glycine-glycine (GEGG), glutamic acid-glycine-glycine (EGG), glutamic acid-alanine-glycine (EAG), valine-lysine-glycine (VKG), glycine-glutamic acid-glycine (GEG), glutamic acid-alanine (EA), glutamic acid-glycine (EG) and glycine-glutamic acid.

[0219] In certain embodiments, L 2 does not exist.

[0220] In certain embodiments, L 2 may or may not contain branched PEG or linear PEG.

[0221] In certain embodiments, L 2 When does not contain PEG, L 2 teeth, [ka] is selected from the group consisting of:

[0222] In certain embodiments, L 2 When contains a linear PEG chain, L 2 teeth, [ka] and p is an integer of 1 to 20.

[0223] In certain embodiments, L 2 When contains a linear PEG chain, L 2 is selected from the group consisting of: [Table 2] In certain embodiments, L 2 When contains PEG branch chains, L 2 teeth, [ka] [ka] and q is selected from the group consisting of:

[0224] In certain embodiments, L 2 When contains PEG branch chains, L 2 teeth, [Table 3-1] [Table 3-2] [Table 3-3] is selected from the group consisting of:

[0225] In certain embodiments, L 1 When is coupled to a sulfhydryl of the ligand, L 1 teeth, [ka] R L1a , R L1b and R L1c are independently hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, alkyl, alkenyl, alkynyl, aralkyl, heterocyclyl, aryl, and heteroaryl.

[0226] In certain embodiments, R L1a , R L1b and R L1c are each independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted aryl, and optionally substituted benzyl.

[0227] In certain embodiments, L 1 When is coupled to the ligand via an amino group, L 1 teeth, [ka] is selected from the group consisting of:

[0228] In certain embodiments, L 1 When is coupled via click chemistry, L 1 teeth, [ka] is selected from the group consisting of:

[0229] For example, a compound of formula IVa or IVb has the following structure: [Table 4-1] [Table 4-2] [Table 4-3]

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

[0230] In certain embodiments, the compound of formula IVa or IVb is [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0231] In certain embodiments, the compound of the invention further comprises a linker fragment, wherein the compound of formula IIa or IIb can be coupled to a ligand via a linker fragment, and the compound has the following structure: [ka] [In the formula, Tr is absent or is any group; L 3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units; L in formulae IVa-1 and IVb-1 1 is the connected form; R 1 , R 2 , R 3 , R 4 , R 5 , B., W., C.R. 4 R 5 , n, X, Y 1 and Y 2 are each as described in any embodiment of the present invention; Wavy lines in the general formula [ka] L 1 or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0232] In certain embodiments, the structural unit -Tr-L 3 -L 2 -L 1 -but, [ka] or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, is provided.

[0233] In another aspect, the present application provides a conjugate comprising the compound described above, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0234] In certain embodiments, the conjugate comprises a ligand-drug conjugate. For example, the conjugate may comprise an antibody-drug conjugate.

[0235] In certain embodiments, the ligand comprises an antibody or an antigen-binding fragment thereof.

[0236] In certain embodiments, the antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, and a polyclonal antibody.

[0237] In certain embodiments, the antigen-binding fragment is selected from the group consisting of a Fab, Fab', F(ab')2, Fv, scFv, diabody, Fd, dAb, VHH, maxibody, and complementarity determining region (CDR) fragment.

[0238] In certain embodiments, the ligand is selected from the group consisting of AXL, BAFFR, BCMA, BCR list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD163, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, cluster of differentiation 40 (CD40), CD44, CD 45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2, CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1 / 2, CXCR4, CXCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HHLA2, HLA class II, HVEM, ICOSLG, IFNAR, type I interferon receptor subunit (I FNAR1), IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, Integrin, LAG3 , LIFR, MAG / Siglec-4 (sialic acid-binding immunoglobulin-like lectin-4), MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, OX40 (CD134), PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1 (sialic acid-binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Si Specifically binds to an antigen selected from the group consisting of glec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, TCR-list component / associated, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, tumor necrosis factor alpha (TNFα), TROY, TSLPR, TYRO, VLDLR, VSIG4, IL2R-y, and VTCN1.

[0239] In certain embodiments, the ligand specifically binds to TNFα, CD40 and / or IFNAR1.

[0240] In certain embodiments, the ligand is selected from the group consisting of an anti-TNFα antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, and an anti-IFNAR1 antibody or antigen-binding fragment thereof. In certain embodiments, the ligand is selected from the group consisting of an anti-TNFα antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, an anti-BDCA2 antibody or antigen-binding fragment thereof, and an anti-IFNAR1 antibody or antigen-binding fragment thereof.

[0241] For example, the ligand may be selected from the group consisting of an anti-TNFα monoclonal antibody, an anti-CD40 monoclonal antibody, and an anti-IFNAR1 monoclonal antibody.

[0242] The present disclosure also provides an immunoconjugate comprising a glucocorticoid receptor agonist linked to an anti-TNFα protein. In certain embodiments, the anti-TNFα protein is an antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-TNFα protein is an antibody or an antigen-binding fragment thereof that binds to TNFα (e.g., soluble TNFα and / or membrane-bound TNFα). In certain embodiments, the anti-TNFα protein is a soluble TNF receptor protein, e.g., a soluble TNF receptor protein fused to a heavy chain constant domain or a fragment thereof (e.g., Fc). In some embodiments, the anti-TNFα protein (e.g., an anti-TNF antibody, antigen-binding fragment thereof, or a soluble TNF receptor) can bind and internalize TNFα on a cell surface. For example, U.S. Patent Application Publication No. 2014 / 0294813 (incorporated herein by reference in its entirety) discloses an anti-TNF protein that exhibits internalization upon binding to human TNF on a cell surface. In certain embodiments, the antibody or antigen-binding fragment thereof binds to human and / or mouse TNF-α. Antibodies and antigen-binding fragments that bind to TNF-α are known in the art.

[0243] Anti-TNF-α antibodies and antigen-binding fragments thereof include, for example, adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, golimumab, and anti-mouse TNFα mIgG2a. Other anti-TNF-α antibodies and antigen-binding fragments are provided, for example, in WO 2013 / 087912, WO 2014 / 152247, and WO 2015 / 073884, each of which is incorporated herein by reference in its entirety.

[0244] Adalimumab is described in U.S. Patent No. 6,258,562, which is incorporated herein by reference in its entirety. Infliximab is described in U.S. Patent No. 5,656,272, which is incorporated herein by reference in its entirety. Certolizumab pegol is described in WO 01 / 94585, which is incorporated herein by reference in its entirety. Afelimomab (also known as MAK195) is described in Vincent, Int. J. Clin. Pract. 54:190-193 (2000), which is incorporated herein by reference in its entirety. Ozoralizumab (also known as ATN-103) is a nanobody. It contains three heavy chain variable regions fused by GlySer linkers. Variable regions 1 and 3 are identical, and ozoralizumab does not contain a heavy chain. Ozolarizumab is described in WO 2012 / 131053, which is incorporated herein by reference in its entirety. Placlumab (also known as CEP-37247) is a domain consisting of a VL-pCH1-CH2-CH3 or [V-κ]2-Fc dimer, and is described in Gay et al., Mabs 2:625-638 (2010), which is incorporated herein by reference in its entirety. Golimumab (also known as CNTO 148) is described in WO 2013 / 087912, and sequences are provided in GenBank: DI496971.1 and GenBank DI 496970.1, each of which is incorporated herein by reference in its entirety. Anti-mouse TNFα mIgG2a is described in McRae BL et al., J Crohn Colitis 10(1):69-76 (2016), each of which is incorporated by reference in its entirety.

[0245] The anti-TNF-α antibodies and antigen-binding fragments thereof also include antibodies and antigen-binding fragments thereof that competitively inhibit the binding of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab to TNF-α. The anti-TNF-α antibodies and antigen-binding fragments thereof also include antibodies and antigen-binding fragments thereof that bind to the same TNF-α epitope as adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab.

[0246] In certain embodiments, the anti-TNF-α antibody or antigen-binding fragment thereof competitively inhibits the binding of adalimumab to TNF-α. In certain embodiments, the anti-TNF-α antibody or antigen-binding fragment thereof binds to the same TNF-α epitope as adalimumab. In certain embodiments, the anti-TNF-α antibody or antigen-binding fragment thereof is adalimumab or an antigen-binding fragment thereof. In certain embodiments, the anti-TNF-α antibody or antigen-binding fragment thereof is adalimumab.

[0247] In certain embodiments, the anti-TNF-α antibody or antigen-binding fragment thereof comprises the sequence, e.g., the complementarity determining regions (CDRs), variable heavy domain (VH), and / or variable light domain (VL), of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab.

[0248] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region (VH), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the HCDR1, HCDR2 and HCDR3, respectively, of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0249] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain variable region of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0250] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain, wherein the heavy chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0251] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody light chain variable region (VL), wherein the light chain variable region comprises an LCDR1, LCDR2 and LCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the LCDR1, LCDR2 and LCDR3, respectively, of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0252] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein the light chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain variable region of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0253] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody light chain, wherein the light chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain of the following molecules: adalimumab, infliximab, afelimomab or golimumab.

[0254] In certain embodiments, the present application provides an antibody or antigen-binding fragment thereof that can specifically bind to TNF-α and comprises the Chothia VL CDRs of the VL of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab. In certain aspects, provided herein is an antibody or antigen-binding fragment thereof that can specifically bind to TNF-α and comprises the Chothia VH CDRs of the VH of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab. In certain aspects, provided herein is an antibody or antigen-binding fragment thereof that specifically binds TNF-α and comprises a Chothia VL CDR of the VL of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab, and a Chothia VH CDR of the VH of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placlumab, or golimumab.

[0255] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region (VH), wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the HCDR1, HCDR2, and HCDR3, respectively, of the following molecules: adalimumab, infliximab, afelimomab, golimumab, or anti-mouse TNFα mIgG2a 8c11.

[0256] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain variable region of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0257] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain, wherein the heavy chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0258] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody light chain variable region (VL), wherein the light chain variable region comprises an LCDR1, LCDR2 and LCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the LCDR1, LCDR2 and LCDR3, respectively, of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0259] For example, an anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3, and these CDRs have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, respectively, of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0260] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein the light chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain variable region of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0261] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity, respectively, to the light chain variable region of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0262] In certain embodiments, the anti-TNFα antibody or antigen-binding fragment thereof comprises a light chain of the antibody, wherein the light chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0263] For example, an anti-TNFα antibody or antigen-binding fragment thereof includes an antibody heavy chain and a light chain, wherein the heavy chain and the light chain have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity, respectively, to the light chain of the following molecules: adalimumab, infliximab, afelimomab, golimumab or anti-mouse TNFα mIgG2a 8c11.

[0264] The sequences of exemplary anti-TNF-α antibodies or antigen-binding fragments thereof are provided in Tables 1-2. [Table 5] [Table 6]

[0265] In one embodiment, the antibody or antigen-binding fragment thereof is an antagonist antibody or antigen-binding fragment thereof that causes a decrease in CD40 activity or function compared to the CD40 activity or function in the absence of the antibody or antigen-binding fragment thereof. In a particular embodiment, the antibody or antigen-binding fragment thereof is substantially free of agonist activity, i.e., the antibody or antigen-binding fragment thereof does not cause an increase in the amount of CD40 activity or function compared to the CD40 activity or function in the absence of the antibody or antigen-binding fragment thereof. In certain embodiments, the anti-CD40 antibody is a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, or an antigen-binding fragment thereof.

[0266] In certain embodiments, the anti-CD40 antibody is iscalimab (CFZ533) (Novartis; described in U.S. Pat. Nos. 8,828,396 and 9,221,913); the anti-CD40 antibody is lucatumumab (Novartis; described in U.S. Pat. No. 8,277,810); antibodies 5D12, 3A8, 3C6, or humanized antibodies thereof (Novartis; described in U.S. Pat. No. 5,874,082); antibody 15B8 (Novartis; described in U.S. Pat. No. 7,445,780); antibody 4D11 (Kyowa Hakko Kirin; described in U.S. Pat. No. 7,193,064); teneliximab (Bristol Myers Squibb; described in U.S. Patent No. 6,051,228); antibody PG102 (PanGenetics; described in U.S. Patent No. 8,669,352); antibody 2C10 (Primatope; U.S. Patent Application No. 20140093497); anti-CD40 antibodies described in U.S. Patent Nos. 8,591,900 and 8,778,345 (Boehringer Ingelheim); anti-CD40 antibodies described in U.S. Patent No. 5,801,227 (Amgen); or APX005 (Boehringer Ingelheim; described in U.S. Patent Application No. 20120301488).

[0267] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody, the heavy chain variable region comprising an HCDR1, HCDR2, and HCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the HCDR1, HCDR2, and HCDR3, respectively, of the following molecule: iscalimab (CFZ533).

[0268] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain variable region of the following molecule: iscalimab (CFZ533).

[0269] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises an antibody heavy chain, wherein the heavy chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain of the following molecule: iscalimab (CFZ533).

[0270] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises an antibody light chain variable region (VL), wherein the light chain variable region comprises an LCDR1, an LCDR2, and an LCDR3 that have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity, respectively, to the LCDR1, LCDR2, and LCDR3 of the following molecule: iscalimab (CFZ533).

[0271] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein the light chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain variable region of the following molecule: iscalimab (CFZ533).

[0272] In certain embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises an antibody light chain, wherein the light chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain of the following molecule: iscalimab (CFZ533).

[0273] The sequences of exemplary anti-CD40 antibodies or antigen-binding fragments thereof are provided in Table 3. [Table 7]

[0274] In one embodiment, the antibody of the present invention is specific for (i.e., specifically binds to) IFNAR1. Such antibodies are also referred to herein as "anti-IFNAR1 antibodies of the present invention." In another embodiment, the antibody of the present invention is specific for human IFNAR1. In another embodiment, the anti-IFNAR1 antibody of the present invention may cross-react with IFNAR1 of species other than human, or with IFNAR1 of other proteins structurally related to human IFNAR1 (e.g., human IFNAR1 homologs). In other embodiments, the anti-IFNAR1 antibody of the present invention may be specific only for human IFNAR1 and does not show species or other types of cross-reactivity.

[0275] Selected sequences of anti-IFNAR1 antibodies can be found in U.S. Patent No. 5,235,038 and U.S. Patent Application No. 5,919,453. The entire contents of U.S. Patent Nos. 10,831,459, 10 / 182,058, 11,157,494, and 11,521,102 are incorporated herein by reference in their entirety for all purposes.

[0276] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises an antibody heavy chain variable region (VH), the heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, each of which have at least about 80% sequence identity to the HCDR1, HCDR2, and HCDR3, respectively, of the following molecule: anifrolumab (MEDI-546).

[0277] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody, wherein the heavy chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain variable region of the following molecule: anifrolumab (MEDI-546).

[0278] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises an antibody heavy chain, wherein the heavy chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the heavy chain of the following molecule: anifrolumab (MEDI-546).

[0279] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises an antibody light chain variable region (VL), the light chain variable region comprising LCDR1, LCDR2 and LCDR3, each of which have at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the LCDR1, LCDR2 and LCDR3, respectively, of the following molecule: anifrolumab (MEDI-546).

[0280] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody, wherein the light chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain variable region of the following molecule: anifrolumab (MEDI-546).

[0281] In certain embodiments, the anti-IFNAR1 antibody or antigen-binding fragment thereof comprises a light chain of the antibody, wherein the light chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the light chain of the following molecule: anifrolumab (MEDI-546).

[0282] The sequences of exemplary anti-IFNAR1 antibodies or antigen-binding fragments thereof are provided in Table 4. [Table 8]

[0283] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of an antibody having at least about 80% sequence identity to the heavy chain variable region of the following molecule: ritifilimab (BIIB059). In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain variable region of an antibody having at least about 80% sequence identity to the light chain variable region of the following molecule: ritifilimab (BIIB059).

[0284] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises an antibody heavy chain, which has at least about 80% sequence identity to the heavy chain of the following molecule: ritifilimab (BIIB059). In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises an antibody light chain, which has at least about 80% sequence identity to the light chain of the following molecule: ritifilimab (BIIB059).

[0285] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) of an antibody, wherein the heavy chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the heavy chain variable region of the following molecule: ritifilimab (BIIB059).

[0286] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) of the antibody, wherein the light chain variable region has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the light chain variable region of the following molecule: ritifilimab (BIIB059).

[0287] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises an antibody heavy chain, wherein the heavy chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the heavy chain of the following molecule: ritifilimab (BIIB059).

[0288] In certain embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof comprises an antibody light chain, wherein the light chain has at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% sequence identity to the light chain of the following molecule: ritifilimab (BIIB059).

[0289] The sequences of exemplary anti-BDCA2 antibodies or antigen-binding fragments thereof are provided in Table 5. [Table 9]

[0290] The present application also encompasses variants and equivalents that are substantially homologous to the anti-TNF-α, anti-CD40 or anti-IFNAR1 antibodies described herein. Such variants and equivalents may include, for example, conservative substitution mutations (i.e., replacement of one or more amino acids with similar amino acids). For example, conservative substitution refers to the substitution of one amino acid for another amino acid of the same class, such as the substitution of an acidic amino acid for another acidic amino acid, a basic amino acid for another basic amino acid, or a neutral amino acid for another neutral amino acid. The purpose of conservative amino acid substitution is well known in the art. The antibody may be a recombinant, natural or synthetic polypeptide of an antibody. It is understood in the art that some amino acid sequences of the present application may be altered without significantly affecting the structure or function of the protein. Thus, the present application further includes variants of the polypeptides that exhibit significant activity or include regions of the antibody. Such variants include deletions, insertions, inversions, repeats and type substitutions.

[0291] In certain embodiments, the ligand is selected from the group consisting of adalimumab, iscalimab (CFZ533), anifrolumab (MEDI-546), infliximab, afelimomab, golimumab, anti-mouse TNFα mIgG2a 8c11, ritifilimab (BIIB059), and derivatives and biosimilars thereof.

[0292] For example, the ligand is selected from the group consisting of adalimumab, iscalimab (CFZ533) and anifrolumab (MEDI-546).

[0293] In certain embodiments, the ligand-drug conjugate has the following structure: [ka] [In the formula, Ab represents a ligand capable of binding to a target, including but not limited to antibodies and antigen-binding fragments thereof; N a-I is any number between 1 and 10; Tr is absent or is any group; L 3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units; R 1 , R 2 , R 3 , R 4 and R 5 are each independently any group; B is absent or any group; W is absent or any group; CR 4 R 5 The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) 2 -, -C(=O)-, -C=C and [ka] and R is replaced by a group selected from the group consisting of 4 and R 5 can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl, and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of -O-, -S-, and -NR-; Y 1 is any group, and m is any integer from 0 to 4; Y 2 is selected from the group consisting of -O-, -S- and -NR-; Substituents include protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 alkoxy].

[0294] The term "ligand" generally refers to any molecule that can specifically bind and / or reactively bind to or form a complex with a target molecule, such as a receptor, substrate, antigenic determinant, or other binding site on a target cell or tissue. Examples of ligands include antibodies and fragments thereof (e.g., monoclonal antibodies or fragments thereof), enzymes (e.g., fibrinolytic enzymes), biological response modifiers (e.g., interleukins, interferons, erythropoietin, or colony stimulating factors), peptide hormones and antigen-binding fragments thereof, polysaccharides, lipids, oligonucleotides, polynucleotides, synthetic molecules, inorganic molecules, organic molecules, and any combination thereof.

[0295] The term "target" or "target molecule" can include a wide variety of substances and molecules, ranging from simple molecules to complex targets. Target molecules can be proteins, nucleic acids, lipids, carbohydrates, or any other molecules that can be recognized by a polypeptide domain. For example, target molecules can include compounds (i.e., non-biological compounds, e.g., organic molecules, inorganic molecules, or molecules having organic and inorganic atoms, but excluding polynucleotides and proteins), mixtures of compounds, arrays of spatially localized compounds, biopolymers, phage peptide display libraries, polysome peptide display libraries, extracts made from biological materials (e.g., bacteria, plants, fungi, or animal (e.g., mammalian) cells or tissues), proteins, toxins, peptide hormones, cells, viruses, and the like. Other target molecules include, for example, whole cells, whole tissues, mixtures of related or unrelated proteins, mixtures of virus or bacterial strains, and the like.

[0296] The term "specifically binds" or "specific" generally refers to a measurable and reproducible interaction, such as binding between a target and an antibody, that can determine the presence of the target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds to a target (which may be an epitope) may be an antibody that binds to the target with higher affinity, avidity, more readily, and / or for a longer period of time than it binds to other targets. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved in proteins of different species. In certain embodiments, specific binding may include, but need not be, exclusive binding.

[0297] Coupling unit L 1 The structure of L may vary before and after coupling to the ligand, i.e. 1 The structure may vary in the linker-payload structure (e.g., Formula IVa or Formula IVb) and the drug-ligand conjugate structure (e.g., Formula Va or Formula Vb), and such variations may be readily determined by one of ordinary skill in the art.

[0298] For example, L 1 When is coupled to a ligand via a sulfhydryl, L 1 The structural changes are as follows: [Table 10-1] [Table 10-2] where the sulfhydryl may be from the Ligand, R L1a , R L1b and R L1c are independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl; for example, R L1a , R L1b and R L1c may each independently be selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted aryl, and optionally substituted benzyl.

[0299] For example, L 1 When is coupled to the ligand via an amino group, L 1 The structural changes are as follows: [Table 11] In the formula, the amino may be derived from the ligand.

[0300] For example, L 1 When is coupled to a ligand via click chemistry, L 1 The structural changes are as follows: [Table 12] .

[0301] For example, R 1 and R 2 may each independently be selected from the group consisting of H, F, Cl, Br, and optionally substituted methyl.

[0302] For example, R 3 is an optionally substituted -CH 2 Cl, optionally substituted -CH 2 SH, optionally substituted -CH 2 OH, optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted -OH, optionally substituted -OCH 3 , optionally substituted -OCH 2 F, optionally substituted -OCH 2 Cl, optionally substituted -OCH 2 CN, optionally substituted -OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted -SCH 2 F, optionally substituted -SCH 2 Cl, optionally substituted -SCH 2 CF 3 and optionally substituted -SCH 2 CN.

[0303] For example, B: Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] Optionally substituted [ka] and optionally substituted [ka] and the substituents are selected from the group consisting of protium, deuterium, tritium, halogen, -CN, =O, =N-OH, =N-OR, =NR, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR 2 , -OC(O)NHR, -OC(O)NR 2 , -SR, -S(O)R, -S(O) 2 R, -NHR, -N(R) 2 , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) 2 NHR, -S(O) 2 N(R) 2 , -NHS(O) 2 NR 2 , -NRS(O) 2 NR 2 , -NHS(O) 2 R, -NRS(O) 2 R, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 Each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6alkoxy.

[0304] For example, W is absent or W is [ka] is selected from the group consisting of:

[0305] For example, the conjugate may have the structure: [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9] [Table 13-10] [Table 13-11] [Table 13-12] [Table 13-13]

Table 13-14

Table 13-15

Table 13-16

Table 13-17

Table 13-18

Table 13-19

Table 13-20

Table 13-21

Table 13-22

Table 13-23

Table 13-24

Table 13-25

Table 13-26

Table 13-27

Table 13-28

Table 13-29

Table 13-30

Table 13-31

Table 13-32

Table 13-33

Table 13-34

Table 13-35

Table 13-36

Table 13-37

Table 13-38

Table 13-39

Table 13-40

Table 13-41

Table 13-42

Table 13-43

Table 13-44

Table 13-45

Table 13-46

[0306] In certain embodiments, for the conjugates of the present invention, the ligand-drug conjugate has the following structure: [ka] [In the formula, Ab represents a ligand capable of binding to a target, preferably an antibody or an antigen-binding fragment thereof; N a-Iis any number between 1 and 10; X is selected from the group consisting of -O-, -S-, and -NH-; R 4 and R 5 are each independently H, F, Cl, -OH, or -NH 2 and C 1 ~C 6 selected from the group consisting of alkyl; N is selected from the group consisting of 1, 2 and 3; Y 1 is absent or is hydroxy, sulfhydryl, amino and C 1 ~C 6 selected from the group consisting of alkyl; R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; R 3 is -CH 2 Cl, -CH 2 SH, -CH 2 OH, [ka] -OCH 3 , -OCH 2 F, -OCH 2 Cl, -OCH 2 CN, -OCH 2 CH 3 , -SH, -SCH 2 F, -SCH 2 Cl, -SCH 2 CF 3 and -SCH 2 CN.

[0307] In certain embodiments, the conjugate of the invention has the following structure: [ka] [ka] [In the formula, N a-Iis any number from 1 to 10, and Ab is selected from an antibody or an antigen-binding fragment thereof.

[0308] In certain embodiments, the conjugate of the invention has the following structure: [ka] [ka] [ka] [ka] [In the formula, N a-I is any number from 1 to 10.

[0309] In certain embodiments, the active metabolites of the conjugates include the compounds described above.

[0310] In another aspect, the present application provides a pharmaceutical composition comprising the compound as described above, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or mixtures thereof, or pharma- ceutically acceptable salts thereof, and / or a conjugate as described above, and optionally a pharma- ceutically acceptable carrier.

[0311] In another aspect, the present application provides a method of affecting immune system function comprising administering to a subject a compound as described above, or a tautomer, mesomeric, racemic, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, a conjugate as described above, and / or a pharmaceutical composition as described above.

[0312] In certain embodiments, affecting immune system function includes affecting immune cell function.

[0313] In certain embodiments, the immune cells are selected from the group consisting of granulocytes and agranulocytes.

[0314] In certain embodiments, the immune cells are selected from the group consisting of neutrophils, eosinophils, and basophils.

[0315] In certain embodiments, the immune cells are selected from the group consisting of lymphocytes and phagocytes.

[0316] In certain embodiments, the immune cell is selected from the group consisting of a B cell, a T cell, a natural killer cell, a monocyte, a macrophage, a mast cell, and a dendritic cell.

[0317] In another aspect, the present application provides the use of the above compound, or a tautomer, mesomeric, racemic, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, said conjugate, and / or said pharmaceutical composition, for the manufacture of a medicament for the prevention and / or treatment of a disease and / or condition.

[0318] In certain embodiments, the disease and / or condition comprises a disease and / or condition associated with glucocorticoid receptor signaling.

[0319] In certain embodiments, the disease and / or condition is selected from the group consisting of a proliferative disease and / or condition, a metabolic disease and / or condition, an inflammatory disease and / or condition, and a neurodegenerative disease and / or condition.

[0320] In certain embodiments, the disease and / or condition is selected from the group consisting of systemic autoimmune diseases and / or conditions, blood system-related diseases and / or conditions, neuromuscular system-related diseases and / or conditions, digestive system-related diseases and / or conditions, urinary system-related diseases and / or conditions, endocrine system-related diseases and / or conditions, skin and muscular system-related diseases and / or conditions, and respiratory system-related diseases and / or conditions.

[0321] In certain embodiments, the disease and / or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, ankylosing spondylitis, Wegener's granulomatosis, and systemic sclerosis.

[0322] In certain embodiments, the disease and / or condition is selected from the group consisting of autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and vasculitis.

[0323] In certain embodiments, the disease and / or condition is selected from the group consisting of multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome.

[0324] In certain embodiments, the disease and / or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, autoimmune liver disease, and atrophic gastritis.

[0325] In certain embodiments, the disease and / or condition is selected from the group consisting of IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, Goodpasture's syndrome, and lupus nephritis.

[0326] In certain embodiments, the disease and / or condition is selected from the group consisting of type I diabetes, Graves' disease, Hashimoto's thyroiditis, primary adrenal cortical atrophy, and chronic thyroiditis.

[0327] In certain embodiments, the disease and / or condition is selected from the group consisting of psoriasis, pemphigus vulgaris, cutaneous lupus erythematosus, dermatomyositis, and polymyalgia rheumatica.

[0328] In certain embodiments, the disease and / or condition is asthma.

[0329] In another aspect, the present application provides a method for preventing and / or treating a disease and / or condition comprising administering to a subject in need thereof a compound as defined above, or a tautomer, mesomeric, racemic, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharma- ceutically acceptable salt thereof, a conjugate as defined above, and / or a pharmaceutical composition as defined above.

[0330] In certain embodiments, the disease and / or condition comprises a disease and / or condition associated with glucocorticoid receptor signaling.

[0331] In certain embodiments, the disease and / or condition is selected from the group consisting of a proliferative disease and / or condition, a metabolic disease and / or condition, an inflammatory disease and / or condition, and a neurodegenerative disease and / or condition.

[0332] In certain embodiments, the disease and / or condition is selected from the group consisting of systemic autoimmune diseases and / or conditions, blood system-related diseases and / or conditions, neuromuscular system-related diseases and / or conditions, digestive system-related diseases and / or conditions, urinary system-related diseases and / or conditions, endocrine system-related diseases and / or conditions, skin and muscular system-related diseases and / or conditions, and respiratory system-related diseases and / or conditions.

[0333] In certain embodiments, the disease and / or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, ankylosing spondylitis, Wegener's granulomatosis, and systemic sclerosis.

[0334] In certain embodiments, the disease and / or condition is selected from the group consisting of autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, and vasculitis.

[0335] In certain embodiments, the disease and / or condition is selected from the group consisting of multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome.

[0336] In certain embodiments, the disease and / or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, autoimmune liver disease, and atrophic gastritis.

[0337] In certain embodiments, the disease and / or condition is selected from the group consisting of IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, Goodpasture's syndrome, and lupus nephritis.

[0338] In certain embodiments, the disease and / or condition is selected from the group consisting of type I diabetes, Graves' disease, Hashimoto's thyroiditis, primary adrenal cortical atrophy, and chronic thyroiditis.

[0339] In certain embodiments, the disease and / or condition is selected from the group consisting of psoriasis, pemphigus vulgaris, cutaneous lupus erythematosus, dermatomyositis, and polymyalgia rheumatica.

[0340] In certain embodiments, the disease and / or condition is asthma. Without being bound by any theory, the following examples are intended only to illustrate the compounds, methods of preparation, uses, etc. of the present application, and are not intended to limit the scope of the present application. EXAMPLES

[0341] In this application: Reagents that provide bromination conditions include, but are not limited to, aqueous bromine, N-bromosuccinimide, dibromohydantoin, phosphorus tribromide, liquid bromine / triphenylphosphine, hydrobromic acid, and carbon tetrabromide. Titanium catalysts include, but are not limited to, tetraisopropyl titanate, triisopropoxytitanium chloride, titanium tetrachloride, and methyl triisopropoxytitanium. Palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, tris(dibenzylideneacetone)dipalladium, bis(acetonitrile)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II] dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II] dichloride dichloromethane complex, bis(benzonitrile)palladium chloride, 1,4-butylenebis(diphenylphosphine)-palladium dichloride, allylpalladium chloride dimer, and allyl(cyclopentadienyl)palladium(II). Boric acid dimers include bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bis(hexyleneglycolato)diboron, bis(catecholato)diboron, bis(diisopropyl-L-tartrate glycolato)diboron, bis[(-)pinanediol]diborate, bis[(1S,2S,3R,5S-pinanediolato]diboron, tetramethyldiborane, bis(N,N,N',N'-tetramethyl-D-tartramidate)diboron, and tetrahydroxydiborane. These include, but are not limited to, boron, bis(N,N,N',N'-tetramethyl-L-tartramidate)diboron, bis(diisopropyl-D-tartrate glycolato)diboron, bis(diethyl-D-tartrate glycolato)diboron, bis(2,4-dimethyl-2,4-pentanediol)borate, bis(diethyl-L-tartrate glycolato)diboron, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylboronic acid. Metallic copper salts include, but are not limited to, copper sulfate, copper sulfate pentahydrate, cuprous sulfate, cupric chloride, cuprous chloride, cupric carbonate, cupric phosphate, cupric acetate and their hydrates, cupric oxalate, cupric fluoroborate and their hydrates, cupric methoxide, cupric tartrate, copper formate, cuprous iodide, copper(II) trifluoroacetate, copper(II) trifluoromethanesulfonate, copper carbonate, cupric bromide, cuprous bromide, and cuprous oxide. The ligand may be selected from any of the ligands commonly used in the Ullmann reaction, including, but not limited to, L-proline, tyrosine, phenylalanine, 1,10-phenanthroline, N,N'-dimethylethylenediamine, ethylene glycol, 1,1'-binaphthyl 2,2'-diol, ethyl 2-cyclohexanonecarboxylate, and salicylaldehyde hydrazone. Condensing agents include 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphine, and ester, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Reagents that provide basic conditions include organic and inorganic bases, organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, piperidine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and the like, and inorganic bases include, but are not limited to, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, sodium phosphate, and potassium phosphate. Reagents that provide acidic conditions include protic acids and Lewis acids, protic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, and Lewis acids include, but are not limited to, boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, stannic chloride, and ferric chloride. Hydrogenation conditions include, but are not limited to, Pb / C / hydrogen, Pt / C / hydrogen, palladium chloride / hydrogen, Raney nickel / hydrogen, palladium hydroxide on carbon / hydrogen, and palladium hydroxide / hydrogen. Reagents that provide oxidizing conditions include, but are not limited to, Dess-Martin periodinane, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate. Reagents that provide reducing conditions include, but are not limited to, sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. Reagents that provide oxidizing conditions include, but are not limited to, Dess-Martin periodinane, hydrogen peroxide, sodium chlorite, sodium hypochlorite, and potassium perchlorate.

[0342] In addition, in this application, The structures of the compounds are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was performed using a Quantum-I NMR spectrometer with deuterated dimethylsulfoxide (DMSO-D), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard, and chemical shifts are given in units of 10_6 (ppm).

[0343] MS is performed using an Angilent 6230 ESI-TOF mass spectrometer (manufacturer: Agilent, type c: 6230).

[0344] UPLC is performed using a Waters Acquity UPLC SQD liquid chromatograph mass spectrometer (Poroshell 120 EC-C18, 2.1 mm x 50 mm, 1.9 μm column).

[0345] HPLC is performed using an Agilent 1260 high performance liquid chromatograph (TOSOH G3000 SW SEC column).

[0346] The UV is measured using a Thermo Nanodrop 2000 spectrophotometer.

[0347] Enzyme-linked immunoassays are performed using an EnVision microplate reader (PerkinElmer).

[0348] As thin layer chromatography silica gel plate, Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is adopted. The specification adopted by TLC is 0.15-0.20mm, and the specification adopted by thin layer chromatography for product separation and purification is 0.4-0.5mm.

[0349] Yantai Yellow Sea silica gel, 200-300 mesh, is commonly used as a support in column chromatography.

[0350] Known starting materials of the present application can be synthesized using or according to methods known in the art or can be purchased from companies such as ABCR GMBH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., and Darui Chemicals.

[0351] In the examples, all reactions are carried out under an argon or nitrogen atmosphere unless otherwise noted.

[0352] By argon or nitrogen atmosphere it is meant that the reaction flask is connected to a balloon containing about 1 L of argon or nitrogen.

[0353] By hydrogen atmosphere it is meant that the reaction flask is connected to a balloon containing approximately 1 L of hydrogen.

[0354] In the examples, unless otherwise specified, the solutions in the reactions are aqueous solutions.

[0355] In the examples, unless otherwise specified, the reaction temperature is room temperature, which is the optimal reaction temperature and is in the range of 20°C to 30°C.

[0356] The eluent system for column chromatography and the developer system for thin-layer chromatography used to purify compounds include A: dichloromethane and isopropanol system, B: dichloromethane and methanol system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the different polarities of the compounds, and can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.

[0357] Some of the compounds of the present disclosure are characterized by TOF-LC / MS. TOF-LC / MS analysis is performed using an Agilent 6230 Time-of-Flight Mass Spectrometer and an Agilent 1290-Infinity Ultra Performance Liquid Chromatograph.

[0358] An exemplary preparation route of the present application is as follows: Preparation of payload and linker-payload Preparation Route 1 [ka] Step 1: Introducing a bromine atom into the benzene ring of a compound of general formula (P1) under optional bromination conditions; Step 2: reacting a compound of general formula (P2) with boronic acid dimer under optional palladium reagent catalyzed conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y1) under optional palladium reagent catalysis conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Removal of the protecting group PG from compounds of general formula (P5) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P6).

[0359] In the above process, PG can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Ring B is an optionally substituted aryl or heteroaryl; -B(OR) 2 is two R's linked together to form C 1 ~C 6 Alkyl, aryl, heteroaryl, carboxy or acyloxyC 1 ~C 6 boronate monomers capable of forming heterocyclic, heterobridged or heterospirocyclic rings, optionally substituted with alkyl; X is chlorine, bromine or iodine; Each R is hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; R, R 1 , R 2 and R 3 represents R, R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 2 [ka]

[0360] Step 1: reacting a compound of general formula (Y1) with a compound of general formula (P1) under optional metal copper salt catalyzed conditions and optional ligand and optional basic conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional oxidation conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Removal of the protecting group PG from compounds of general formula (P5) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P6).

[0361] In the above process, PG can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 3 [ka]

[0362] Step 1: subjecting a compound of general formula (P1) to a carbonyl insertion reaction under optional palladium reagent catalyzed conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional bromination conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y1) under optional basic conditions to obtain a compound of general formula (P5); Step 5: reacting a compound of general formula (P5) under optional reducing conditions to obtain a compound of general formula (P6); Step 6: reacting a compound of general formula (P6) under optional oxidation conditions to obtain a compound of general formula (P7); Step 7: reacting a compound of general formula (P7) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P8); Step 8: Removal of the protecting group PG from compounds of general formula (P8) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P9).

[0363] In the above process, PG 1 and P.G. 2 may be a common protecting group for a hydroxy or ester group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; R is optionally substituted C 1 ~C 6 may be alkyl; Ring B is an optionally substituted aryl or heteroaryl; R, R 1 , R 2 and R 3 represents R, R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 4 [ka]

[0364] Step 1: Introducing a bromine atom to the methyl of a compound of general formula (P1) under optional bromination conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) with a compound of general formula (Y1) under optional palladium reagent catalysis conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P4); Step 4: Removal of the protecting group PG from compounds of general formula (P4) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P5).

[0365] In the above process, PG 1 can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 5 [ka]

[0366] Step 1: reacting a compound of general formula (P1) under optional reducing conditions to obtain a compound of general formula (P2); Step 2: Adding a protecting group PG to a compound of general formula (P2) under optional acidic or basic conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y1) under optional basic conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) under optional reducing conditions to obtain a compound of general formula (P5); Step 5: reacting a compound of general formula (P5) under optional oxidation conditions to obtain a compound of general formula (P6); Step 6: reacting a compound of general formula (P6) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P7); Step 7: Removal of the protecting group PG from compounds of general formula (P7) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P8).

[0367] In the above process, Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; PG 1 and P.G. 2 can be a common hydroxy or hydroxy protecting group; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 6 [ka]

[0368] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional condensation conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional oxidation conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Reacting a compound of general formula (P5) under optional reducing conditions gives a compound of general formula (P6).

[0369] In the above process, PG 1 and P.G. 2may be a common protecting group for a hydroxy or ester group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 7 [ka]

[0370] Step 1: introducing a nitro group into the benzene ring of a compound of general formula (P1) under nitration conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) with boronic acid dimer under optional palladium reagent catalyzed conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y1) under optional palladium reagent catalysis conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: reacting a compound of general formula (P5) under optional hydrogenation conditions to obtain a compound of general formula (P6); Step 6: Removal of the protecting group PG from compounds of general formula (P6) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P7).

[0371] In the above process, PG can be a common hydroxy protecting group; -B(OR) 2 is two R's linked together to form C 1 ~C 6 Alkyl, aryl, heteroaryl, carboxy or acyloxyC 1 ~C 6 boronate monomers capable of forming heterocyclic, heterobridged or heterospirocyclic rings, optionally substituted with alkyl; Each R is hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Line 8 [ka]

[0372] Step 1: introducing a nitro group into the benzene ring of a compound of general formula (P1) under nitration conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) with an ethyl Grignard reagent under optional titanium catalyzed conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P2) with boronic acid dimer under optional palladium reagent catalyzed conditions to obtain a compound of general formula (P3); Step 4: reacting a compound of general formula (P3) with a compound of general formula (Y1) under optional palladium reagent catalysis conditions to obtain a compound of general formula (P4); Step 5: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 6: Reduction of the nitro group of a compound of general formula (P5) under optional hydrogenation conditions, followed by separation by preparative HPLC, gives a compound of general formula (P6).

[0373] In the above process, Ring B is an optionally substituted aryl or heteroaryl; -B(OR) 2 is two R's linked together to form C 1 ~C 6 Alkyl, aryl, heteroaryl, carboxy or acyloxyC 1 ~C 6 boronate monomers capable of forming heterocyclic, heterobridged or heterospirocyclic rings, optionally substituted with alkyl; Each R is hydrogen, protium, deuterium, tritium, oxygen, hydroxyl, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 9 [ka]

[0374] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional basic conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional oxidation conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Removal of the protecting group PG from compounds of general formula (P5) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P6).

[0375] In the above process, PG can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 10 [ka]

[0376] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional palladium catalysis conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional oxidation conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Removal of the protecting group PG from compounds of general formula (P5) under optional acidic or basic conditions, followed by separation by preparative HPLC, gives compounds of general formula (P6).

[0377] In the above process, X is NR or -O-, and R is optionally substituted C 1 ~C 6 is alkyl; PG can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; Ring B is an optionally substituted aryl or heteroaryl; R 1 , R 2 and R 3represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 11 [ka]

[0378] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional condensation conditions to obtain a compound of general formula (P2); Step 2: reacting a compound of general formula (P2) under optional reducing conditions to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) under optional oxidation conditions to obtain a compound of general formula (P4); Step 4: reacting a compound of general formula (P4) with a compound of general formula (Y2) under optional acidic or basic conditions to obtain a compound of general formula (P5); Step 5: Reaction of a compound of general formula (P5) under optional reducing conditions, followed by separation by preparative HPLC, gives a compound of general formula (P6).

[0379] In the above process, PG can be a common hydroxy protecting group; Y is hydrogen, protium, deuterium, tritium, halogen, -OR, -SR, -NHR, -N(R) 2 , -PHR, -P(R) 2 , -P(=O)HR, -P(=O)R 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C 1 ~C 6Alkyl, C 1 ~C 6 Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 ~C 6 Alkyl and halogenated C 1 ~C 6 independently selected from the group consisting of alkoxy; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as: Preparation Route 12 [ka]

[0380] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional condensation conditions to obtain a compound of general formula (P2); Step 2: optionally under acidic or basic conditions, a protecting group PG is reacted with a compound of general formula (P2) 1 to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y2) under optional condensation conditions to obtain a compound of general formula (P4); Step 4: Protecting group PG from compound of general formula (P4) under optional acidic or basic conditions 1 to obtain a compound of general formula (P5); Step 5: reacting a compound of general formula (P5) with a compound of general formula (Y3) under optional condensation conditions to obtain a compound of general formula (P6); Step 6: Protecting group PG from compound of general formula (P6) under optional acidic or basic conditions 1 to obtain a compound of general formula (P7); Step 7: Compounds of general formula (P7) are reacted with compounds of general formula (Y3) under optional condensation conditions, followed by separation by preparative HPLC to give compounds of general formula (P8).

[0381] In the above process, Ring B is an optionally substituted aryl or heteroaryl; W is absent or any group; X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -or [ka] and; Y 1 is hydrogen, hydroxy, fluoro, chloro, methyl, hydroxy or methoxy; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (II), formula (III) or formula (IV) of the present application. 1 , R 2 and R 3 It may be defined as: LG 1 , L.G. 2 , L.G. 3 and L.G. 4 can be a common hydroxy or carboxy of an activated ester; PG 1 , P.G. 2 and P.G. 3 can be a common amino protecting group; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as:

[0382] Tr is absent or is any group; L 3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units. Preparation Route 13 [ka]

[0383] Step 1: A compound of general formula (P1) is reacted with a compound of general formula (Y1) under optional condensation conditions, followed by separation by preparative HPLC to give a compound of general formula (P2).

[0384] In the above process, Ring B is an optionally substituted aryl or heteroaryl; W is absent or any group; X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -or [ka] and; Y is -O-, -S- or -NH-; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as:

[0385] LG 1 can be a common hydroxy or carboxy of an activated ester; Tr is absent or is any group; L3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units. Preparation Route 14 [ka]

[0386] Step 1: reacting a compound of general formula (P1) with a compound of general formula (Y1) under optional condensation conditions to obtain a compound of general formula (P2); Step 2: optionally under acidic or basic conditions, a protecting group PG is reacted with a compound of general formula (P2) 1 to obtain a compound of general formula (P3); Step 3: reacting a compound of general formula (P3) with a compound of general formula (Y2) under optional condensation conditions to obtain a compound of general formula (P4); Step 4: Protecting group PG from compound of general formula (P4) under optional acidic or basic conditions 1 to obtain a compound of general formula (P5); Step 5: Compounds of general formula (P5) are reacted with compounds of general formula (Y3) under optional condensation conditions, followed by separation by preparative HPLC to give compounds of general formula (P6).

[0387] In the above process, Ring B is an optionally substituted aryl or heteroaryl; W is absent or any group; X is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -or [ka] and; Y is -O-, -S- or -NH-; LG 1 , L.G.2 and L.G. 3 can be a common hydroxy or carboxy of an activated ester; PG 1 , P.G. 2 and P.G. 3 can be a common amino protecting group; R 1 , R 2 and R 3 represents R in any one of formula (I), formula (IIa), formula (IIb), formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) of the present application. 1 , R 2 and R 3 It can be defined as:

[0388] Tr is absent or is any group; L 3 is selected from a polypeptide fragment; L 2 is absent or selected from a linker fragment; L 1 is selected from coupling units. II. Preparation of Antibody-Drug Conjugates (ADCs) Preparation Route 15 [ka]

[0389] reacting a ligand Ab with a compound of any one of formula (IVa) or formula (IVb) in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least one free sulfhydryl (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (IC) or formula (II-C) can be a sulfhydryl derived from Ab; Tr, L 1 , L 2 and L 3 In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 1 , L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It can be defined as: L 1x is L coupled to a sulfhydryl. 1 represents the structure after coupling to; The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above. Preparation Route 16 [ka]

[0390] In step 1, a ligand Ab is reacted with a compound of any one of formula (IVa) or formula (IVb) in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least one free sulfhydryl (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (Va) or formula (Vb) can be a sulfhydryl derived from Ab; In step 2, a compound of either formula (Va) or formula (Vb) is incubated in an alkaline buffer at a selected temperature for a selected time to obtain another compound of either formula (Va) or formula (Vb) of the present application; Tr, L 2 and L 3 In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It may be defined as: The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above; the selected temperature may be between 5° C. and 60° C.; and the incubation time may be between 0 hours and 72 hours. Preparation Route 17 [ka]

[0391] reacting a ligand Ab with a compound of either formula (IVa) or formula (IVb) having groups capable of coupling to two sulfhydryls in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least two free sulfhydryls (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (Va) or formula (Vb) can be a sulfhydryl derived from Ab; Tr, L 1 , L 2 and L 3In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 1 , L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It can be defined as: L 1y is L coupled to two sulfhydryls. 1 represents the structure after coupling to; A compound of formula (Va) or formula (Vb) having groups capable of coupling to two sulfhydryls is [ka] and R L1a , R L1b and R L1c are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, arcyl, heterocyclyl, aryl, and heteroaryl; The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above. Preparation Route 18 [ka]

[0392] reacting a ligand Ab with a compound of either formula (IVa) or formula (IVb) having groups capable of coupling to two sulfhydryls in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least one free sulfhydryl (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (Va) or formula (Vb) can be a sulfhydryl derived from Ab; Tr, L 1 , L 2 and L 3 In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 1, L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It can be defined as: L 1x is L coupled to a sulfhydryl. 1 represents the structure after coupling to; The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above. Preparation Route 19 [ka]

[0393] In step 1, a ligand Ab is reacted with a compound of any one of formula (IVa) or formula (IVb) in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least one free sulfhydryl (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (Va) or formula (Vb) can be a sulfhydryl derived from Ab; In step 2, a compound of either formula (Va) or formula (Vb) is incubated in an alkaline buffer at a selected temperature for a selected time to obtain another compound of either formula (Va) or formula (Vb) of the present application; Tr, L 2 and L 3 In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It may be defined as: The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above; the selected temperature may be between 5° C. and 60° C.; and the incubation time may be between 0 hours and 72 hours. Preparation Route 20 [ka]

[0394] reacting a ligand Ab with a compound of either formula (IVa) or formula (IVb) having groups capable of coupling to two sulfhydryls in an acidic, neutral or alkaline buffer to obtain a compound of formula (Va) or formula (Vb); Ab is a ligand containing at least two free sulfhydryls (-SH), which can be obtained by reducing the ligand using a reducing agent; the reducing agent includes, but is not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, the disulfide bond (-SS-) between the ligand chains can be reduced to form a free sulfhydryl; the S atom in the compound of formula (Va) or formula (Vb) can be a sulfhydryl derived from Ab; Tr, L 1 , L 2 and L 3In any one of the compounds of formula (IVa) or formula (IVb) of the present application, Tr, L 1 , L 2 and L 3 Ab and N a-I In any one of the compounds of formula (Va) or formula (Vb) of the present application, Ab and N a-I It can be defined as: L 1y is L coupled to two sulfhydryls. 1 represents the structure after coupling to; A compound of formula (Va) or formula (Vb) having groups capable of coupling to two sulfhydryls is [ka] and R L1a , R L1b and R L1c are hydrogen, protium, deuterium, tritium, halogens, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, arcyl, heterocyclyl, aryl, and heteroaryl; The buffer is selected from the group consisting of the following buffers having a pH between 2 and 12: citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, phosphoric acid-potassium phosphate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, succinic acid-sodium succinate buffer, acetic acid-sodium acetate buffer, boric acid-borax buffer, boric acid-potassium borate buffer, borax-sodium hydroxide buffer, histidine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, arginine-hydrochloric acid buffer, sodium bicarbonate-sodium carbonate buffer, potassium bicarbonate-potassium carbonate buffer, Tris-hydrochloric acid buffer, aqueous ammonia-ammonium chloride buffer, sodium barbiturate-hydrochloric acid buffer, borax-sodium carbonate buffer, boric acid-potassium chloride buffer, and combinations of two or more of the above. Example 1 compound 1 [ka]

[0395] Step 1 Compound 1A (500 mg, 3.67 mmol) was dissolved in dichloromethane (10 mL), then DIEA (1.42 g, 10.99 mmol) was added, and TBSCl (830 mg, 5.51 mmol) in dichloromethane (5 mL) was added to the above reaction solution, and stirred for 17 hours overnight. After the reaction was detected to be complete by TLC (PE / EA=20 / 1), the reaction solution was directly dried by rotary evaporation under reduced pressure and subjected to column chromatography (PE:EA=100:0-100:1) to obtain a milky white oily liquid 1B (800 mg, yield: 87%).

[0396] Step 2 Compound 1B (125 mg, 0.50 mmol) and compound 1C (188 mg, 0.50 mmol) were added and dissolved in ultra-dry acetonitrile (8 mL), the reaction solution was purged with nitrogen, cooled to 0 ° C, and a mixture of methanesulfonic acid (48 mg, 0.50 mmol) and MeCN (2 mL) was added by syringe, and stirred overnight for 16 hours. After the reaction was detected to be complete by TLC (PE / EA = 3 / 1), sodium bicarbonate was added to the reaction solution, filtered, and dried by rotary evaporation to obtain the crude product, which was then purified by preparative chromatography to obtain compound 1 (62 mg, yield: 25%) as a white powder and 1S (7 mg, yield: 3%) as a white powder, respectively.

[0397] Compound 1: MS-ESI: m / z 495.3[M+H] + .

[0398] 1 H NMR (400MHz, DMSO-d 6 )δ 7.41(d,J=8.1Hz,2H),7.34-7.28(m,3H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H) ,5.43(s,1H),4.93(d,J=4.9Hz,1H),4.79(brs,1H),4.52(d,J=19.5Hz,1H),4.48(s, 2H),4.34-4.25(m,1H),4.19(d,J=19.5Hz,1H),2.61-2.52(m,1H),2.35-2.27(m,1H) ,2.19-1.98(m,2H),1.84-1.58(m,5H),1.39(s,3H),1.13-0.95(m,2H),0.87(s,3H).

[0399] Compound 1S: MS-ESI: m / z 495.3[M+H] + .

[0400] 1 H NMR (400MHz, DMSO-d 6)δ 7.35-7.27(m,3H),7.22(d,J=8.1Hz,2H),6.17(dd,J=10.1,1.9Hz,1H),6.09(s,1H),5.95( s,1H),5.30(d,J=6.8Hz,1H),4.81-4.76(m,1H),4.48(s,2H),4.30(s,1H),4.25(d,J=19.2H) z,1H),4.01(d,J=19.2Hz,1H),2.59-2.53(m,1H),2.36-2.28(m,1H),2.12-1.97(m,2H),1. 90-1.69(m,5H),1.39(s,3H),1.26-1.13(m,1H),1.06(dd,J=11.0,3.4Hz,1H),0.89(s,3H). compound 2 [ka]

[0401] Step 1 Compound 2A (5.0 g, 25.4 mmol) and imidazole (2.59 g, 38.0 mmol) were dissolved in dichloromethane (50 mL), then TBSCl (4.9 g, 32.5 mmol) was added, and the reaction solution was reacted at 25 ° C for 2 hours. After the reaction was detected to be complete by TLC, 100 mL of water was added to the reaction solution, and extracted twice with 100 mL of dichloromethane (× 2), and the dichloromethane was combined, dried over anhydrous sodium sulfate, and dried by rotary evaporation, and the residue was directly stirred with silica gel and subjected to column chromatography (PE:EA = 20:1) to obtain a yellow solid 2B (3 g, yield: 38%). MS-ESI: m / z 312.2 [M + H] + .

[0402] Step 2: Compound 2B (1.0 g, 3.2 mmol) was dissolved in THF (10 mL) and the reaction solution was purified by N 2 After purging with 10 ... 3 / THF (6.4 mL, 6.4 mmol) was added and the reaction was detected to be complete after 17 h by LCMS. The reaction solution was added to methanol (40 mL) (kept in an ice bath at 0° C.) and diluted with BH 3After quenching, the mixture was dried by rotary evaporation to give a colorless oil 2C (500 mg, yield: 52%). MS-ESI: m / z 298.1 [M+H] + .

[0403] Step 3 Compound 2C (500 mg, 1.68 mmol) was dissolved in dichloromethane (8 mL), the reaction solution was cooled to 0 °C, Dess-Martin reagent (1.43 g, 3.36 mmol) was added, and the reaction was allowed to proceed for 1.5 h. After the reaction was detected to be complete by LCMS, the reaction solution was diluted with water (100 mL), extracted twice with ethyl acetate (100 mL + 50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and dried by rotary evaporation to give a white solid 2D (250 mg, yield: 50%). MS-ESI: m / z 296.0 [M + H] + .

[0404] Step 4 Compound 2D (100 mg, 0.34 mmol), Compound 1C (127 mg, 0.34 mmol) and MgSO 4 (250 mg, 2.08 mmol) was dissolved in acetonitrile (10 mL), the reaction solution was cooled to 0 °C, purged with nitrogen, trifluoromethanesulfonic acid (150 mg, 1.0 mmol) was added, and after the addition was completed, it was kept in ice bath for 2 h. After the reaction was detected to be complete by LCMS, the reaction solution was directly filtered, and the filter cake was rinsed with acetonitrile three times. The mother liquor was concentrated by rotary evaporation and subjected to column chromatography (DCM:MeOH=30:1) to obtain a white solid 2E (100 mg, yield: 55%). MS-ESI: m / z 540.0 [M+H] + .

[0405] Step 5: Compound 2E (100 mg, 0.18 mmol) and iron powder (100 mg, 1.8 mmol) were added to ethanol (4 mL) and NH 4 Cl (96 mg, 1.8 mmol) was dissolved in water and added to ethanol, and the reaction solution was diluted with N 2The mixture was purged with 0.5 mL of ethyl acetate and heated to 60° C. for 2 h. After the reaction was completed by LCMS, the reaction solution was filtered through Celite and the filter cake was rinsed with ethanol three times. The mother liquor was concentrated by rotary evaporation, subjected to preparative chromatography, and lyophilized to obtain white solid powder 2 (40 mg, yield: 42%) and white solid powder 2S (5 mg, yield: 5%), respectively.

[0406] Compound 2: MS-ESI: m / z 532.2 [M+Na] + .

[0407] 1 H NMR (400MHz, DMSO-d 6 )δ 7.32(d,J=10.1Hz,1H),7.20(d,J=7.7Hz,1H),6.94(s,1H),6.89(d,J=7.7Hz,1H),6.16(dd,J=10.1,1.9H z,1H),5.93(s,1H),5.34(s,1H),4.95-4.89(m,1H),4.80(brs,1H),4.49(d,J=19.4Hz,1H),4.44(s,2H),4 .33-4.27(m,1H),4.18(d,J=19.4Hz,1H),2.62-2.52(m,1H),2.35-2.28(m,1H),2.19-2.07(m,1H),2.07-1 .99(m,1H),1.80-1.60(m,5H),1.40(s,3H),1.15-1.02(m,1H),0.99(dd,J=11.2,3.6Hz,1H),0.86(s,3H).

[0408] Compound 2S: MS-ESI: m / z 532.3 [M+Na] + .

[0409] 1 H NMR (400MHz, DMSO-d 6)δ 7.32(d,J=10.1Hz,1H),7.15-7.09(m,1H),6.70(s,1H),6.63(d,J=7.6Hz,1H),6.17(dd,J=1 0.0,1.9Hz,1H),5.99(s,1H),5.94(s,1H),5.25(d,J=6.8Hz,1H),4.78(brs,1H),4.40(s,2H) ,4.33-4.22(m,2H),4.02(d,J=19.2Hz,1H),2.60-2.53(m,1H),2.36-2.28(m,1H),2.11-1.9 7(m,2H),1.90-1.69(m,5H),1.39(s,3H),1.26-1.13(m,1H),1.09-1.02(m,1H),0.88(s,3H). compound 3 [ka]

[0410] Step 1: Compound 3A (6.58 g, 33.08 mmol, 1.0 equiv.) and compound 3B (5.03 g, 33.08 mmol, 1.0 equiv.) were placed in a 250 mL three-neck flask and diluted with THF (50 mL), water (5 mL), and K 2 CO 3 (13.71 g, 99.24 mmol, 3.0 equiv.) was added to the reaction solution under a nitrogen atmosphere, and Pd(dppf)Cl 2 (1.21 g, 1.65 mmol, 0.05 equiv.) was added, purged with nitrogen three times, heated to reflux at 80 °C, and stirred for 3-4 h. After the reaction was detected to be complete by TLC (PE / EA = 5 / 1), the reaction solution was cooled to room temperature, filtered, and the filtrate was poured into 300 mL of water and extracted with EA (200 mL). The organic phase was washed with water (100 mL × 3), washed once with saturated NaCl, and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated by rotary evaporation, and the residue was stirred with silica gel and subjected to column chromatography (PE / EA=7 / 1) to give the product, which was concentrated by rotary evaporation to give a white solid 3C (2.5 g, yield: 33%).

[0411] Step 2 Compound 1D (3 g, 7.97 mmol, 1.0 equivalent), compound 3C (1.8 g, 7.97 mmol, 1.0 equivalent) and MgSO 4 (2.88 g, 23.91 mmol, 3.0 equiv.) was placed in a 100 mL three-neck flask, acetonitrile (30 mL) was added, trifluoromethanesulfonic acid (1.2 g, 7.97 mmol, 1.0 equiv.) was added in an ice-water bath under a nitrogen atmosphere, the temperature was raised to room temperature, and the reaction was allowed to proceed for 2 hours after the addition was complete. After the completion of the reaction was detected by TLC (PE / EA=3 / 1), the reaction solution was filtered, the filtrate was concentrated by rotary evaporation, and the residue was stirred with silica gel and subjected to column chromatography (PE / EA=2 / 1) to obtain the product, which was concentrated by rotary evaporation to obtain a white solid 3 (3.7 g, yield: 79%).

[0412] MS-ESI: m / z 585.3[M+H] + .

[0413] 1 H NMR (400MHz, DMSO-d 6 )δ 7.36(d,J=7.8Hz,2H),7.30(d,J=10.1Hz,1H),7.24(d,J=7.7Hz,2H),7.20(d,J=7.5Hz,1H),7.15(s,1H),7.11(d,J =7.6Hz,1H),7.07(d,J=7.6Hz,1H),6.16(dd,J=10.1,1.9Hz,1H),5.92(s,1H),5.39(s,1H),4.91(d,J=4.8Hz,1H), 4.78(brs,1H),4.49(d,J=19.4Hz,1H),4.43(s,2H),4.32-4.25(m,1H),4.17(d,J=19.5Hz,1H),3.90(s,2H),2.59- 2.51(m,1H),2.35-2.26(m,1H),2.18-1.95(m,2H),1.82-1.56(m,5H),1.39(s,3H),1.11-0.96(m,4H),0.85(s,3H). compound 4 [ka]

[0414] Step 1 Compound 4A (500mg, 2.51mmol) in THF / H 2 Compound 4B (573 mg, 3.77 mmol) and K 2 CO 3 (1.04 g, 7.53 mmol) was added. The reaction solution was purged with nitrogen, and then Pd(dppf)Cl 2 (367 mg, 0.50 mmol) was added, heated to 80° C. under nitrogen atmosphere, and reacted for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography (PE / EA=1:0-3:1) to obtain a yellow solid 4C (270 mg, yield: 48%).

[0415] Step 2: Compound 4C (150 mg, 0.66 mmol) was dissolved in MeCN (10 mL), and then compound 1C (250 mg, 0.66 mmol) and MgSO 4 (160 mg, 1.32 mmol) was added, and trifluoromethanesulfonic acid (299 mg, 1.99 mmol) was added under nitrogen atmosphere at 0° C. The reaction solution was reacted at 0° C. for 1 hour, diluted with water (20 mL), extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with brine (10 mL), dried, and concentrated by rotary evaporation to obtain the crude product, which was subjected to preparative chromatography to obtain white powdery solid 4 (120 mg, yield: 31%) and white powdery solid 4S (13 mg, yield: 3%), respectively.

[0416] Compound 4: MS-ESI: m / z 585.4[M+H] + .

[0417] 1 H NMR (400MHz, DMSO-d 6)δ 7.35(d,J=8.0Hz,2H),7.30(d,J=10.1Hz,1H),7.24-7.16(m,4H),7.14(d,J=8.1Hz,2H),6.16(d d,J=10.1,1.9Hz,1H),5.92(s,1H),5.38(s,1H),4.90(d,J=4.8Hz,1H),4.48(d,J=19.4Hz,1H), 4.42(s,2H),4.31-4.25(m,1H),4.16(d,J=19.4Hz,1H),3.89(s,2H),2.59-2.52(m,1H),2.36-2 .25(m,1H),2.18-1.96(m,2H),1.82-1.55(m,5H),1.38(s,3H),1.10-0.94(m,2H),0.85(s,3H).

[0418] Compound 4S: MS-ESI: m / z 585.3[M+H] + .

[0419] 1 H NMR(400MHz,クロロホルム-d)δ 7.31-7.26(m,3H),7.21-7.11(m,6H),6.31(dd,J=10.1,1.9Hz,1H),6.08(s,2H),5.43 -5.38(m,1H),4.65(s,2H),4.52-4.45(m,1H),4.27(d,J=19.9Hz,1H),4.05(d,J=19.9 Hz,1H),3.95(s,2H),2.66-2.54(m,1H),2.23-2.07(m,3H),1.95-1.83(m,2H),1.80-1 .68(m,1H),1.63(dd,J=14.1,2.6Hz,1H),1.46(s,3H),1.31-1.13(m,2H),0.99(s,3H). Compound 5

change

[0420] Step 1 Compound 5A (50 g, 216 mmol, 1.0 eq.) and imidazole (22 g, 323 mmol, 1.5 eq.) were added to a 2 L three-neck flask, and the reaction mixture was dissolved in dichloromethane (700 mL), followed by slow addition of TBSCl (44 g, 292 mmol, 1.35 eq.). After complete consumption of the starting material was detected by TLC (PE / EA=9 / 1), the reaction solution was cooled to room temperature, filtered, and diluted with dichloromethane (100 mL) and H. 2 The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 5B (65 g, yield: 87%).

[0421] Step 2 Compound 5B (60 g, 173 mmol, 1.0 equiv.), bis(pinacolato)diboron (44 g, 173 mmol, 1.0 equiv.), Pd(dppf)Cl 2 (6.3 g, 8.6 mmol, 0.05 equiv.) and potassium acetate (51 g, 520 mmol, 3.0 equiv.) were added to a 2 L three-neck flask, and the reaction mixture was dissolved in dioxane (1 L) and N 2 The reaction solution was stirred at 110° C. for 12 hours under atmospheric conditions. After the completion of the reaction was detected by TLC (PE:EA=9:1), the reaction solution was cooled to room temperature, filtered, and diluted with ethyl acetate (1 L) and H 2 It was extracted twice with O (1 L), and the organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 5C (60 g, yield: 88%).

[0422] Step 3 Compound 5C (30 g, 76 mmol, 1.0 equivalent), compound 5D (15.2 g, 76 mmol, 1 equivalent) and Pd(dppf)Cl 2 (3 g, 4 mmol, 0.05 equiv.) was added to a 1 L three-neck flask and dissolved in dioxane (600 mL) and water (60 mL) under a nitrogen atmosphere. 2 CO 3(74 g, 228 mmol, 3.0 equiv.) was added and the reaction solution was reacted at 110° C. for 2 hours. After the reaction was completed as detected by TLC (PE:EA=9:1), the reaction solution was cooled to room temperature, filtered, and diluted with ethyl acetate (1 L) and H 2 The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 5E (20 g, yield: 68%).

[0423] Step 4 Compound 5E (2.0g, 5.2mmol, 1.0eq), Compound 1C (1.96g, 5.2mmol, 1.0eq) and MgSO 4 (1.88 g, 15.6 mmol, 3.0 equiv.) was added to a 250 mL three-neck flask, acetonitrile (50 mL) was added to the reaction mixture, cooled to -20 °C with dry ice and ethanol, trifluoromethanesulfonic acid (2.34 g, 15.6 mmol, 3.0 equiv.) was slowly added, and stirred at 0 °C for 2 h. After the completion of the reaction was detected by TLC (PE:EA = 1:1), sodium bicarbonate solution was added to adjust the pH to 7-8, acetonitrile was removed by rotary evaporation, and the reaction solution was extracted and slurried with PE:EA = 3:1 to obtain the crude product of compound 5F (3.2 g, yield: 98%), which was used directly in the next step. MS-ESI: m / z 630.1 [M + H] + .

[0424] Step 5: Compound 5F (3.2 g, 5.08 mmol, 1 equivalent) and Fe (2.84 g, 50.8 mmol, 10 equivalents) were placed in a 250 mL three-neck flask, ethanol (80 mL) was added, and NH 4Cl (2.72 g, 50.8 mmol, 10 equiv.) was dissolved in water (80 mL) and then placed in a three-neck flask, and the reaction solution was reacted at 60 °C for 2 h. After the completion of the reaction was detected by TLC (DCM:MOH=10:1), ethanol was removed by evaporation under reduced pressure, and aqueous sodium bicarbonate was added to adjust the pH to 8. The reaction solution was extracted twice with 80 mL of dichloromethane and water, and the organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a yellow solid (2.6 g) as a crude product, of which 400 mg was subjected to reverse phase column chromatography to obtain compound 5 (43.9 mg, purity: ≧95%).

[0425] MS-ESI: m / z 600.1 [M+H] + .

[0426] 1 H NMR (400MHz, DMSO-d 6 )δ 7.38(d,J=8.0Hz,2H),7.31(d,J=10.1Hz,1H),7.24(d,J=7.9Hz,2H),6.96(s,1H),6.90(s,1H),6.76(s, 1H),6.16(dd,J=10.1,1.8Hz,1H),5.93(s,1H),5.40(s,1H),4.92(d,J=4.8Hz,1H),4.79(brs,1H),4.49( d,J=19.4Hz,1H),4.43(s,2H),4.32-4.26(m,1H),4.17(d,J=19.5Hz,1H),3.90(s,2H),2.62-2.52(m,1H) ),2.36-2.26(m,1H),2.18-1.97(m,2H),1.81-1.55(m,5H),1.39(s,3H),1.10-0.94(m,2H),0.86(s,3H). compound 6 [ka]

[0427] Step 1 Compound 6A (10 g, 43.1 mmol) was dissolved in dichloromethane (100 mL), then DIEA (16.7 g, 129.3 mmol) was added, and TBSCl (9.7 g, 64.6 mmol) in dichloromethane (100 mL) was added to the above reaction solution, which was then stirred overnight for 3 days. After the reaction was detected to be complete by TLC (PE / EA=40 / 1), the reaction solution was directly dried by rotary evaporation under reduced pressure and subjected to column chromatography with pure petroleum ether to obtain pale yellow oily liquid 6B (12.0 g, yield: 80%).

[0428] Step 2 Compound 6B (1 g, 2.89 mmol), bis(pinacolato)diboron (883 mg, 3.48 mmol), KOAc (853 mg, 8.69 mmol) and Pd(dppf)Cl 2 (212 mg, 0.29 mmol) was added to 1,4-dioxane (10 mL), the reaction was purged with nitrogen, heated (110 °C), and stirred overnight for 17 h. After the reaction was complete as detected by TLC (PE:EA = 40:1), the reaction solution was directly dried by rotary evaporation, and the residue was directly stirred with silica gel and subjected to column chromatography (petroleum ether: ethyl acetate = 50:1) to give a pale yellow oily liquid 6C (183 mg, yield: 16%). MS-ESI: m / z 394.3 [M+H] + .

[0429] Step 3 Compound 6C (180 mg, 0.46 mmol), Pd(dppf)Cl2 (33.5 mg, 0.046 mmol), compound 5D (90.6 mg, 0.46 mg), Cs2CO3 (298 mg, 0.92 mmol), 1,4-dioxane (8 mL) and water (2 mL) were added, and the reaction solution was purged with N2, heated (110 °C), and stirred overnight (20 h). After the reaction was detected to be complete by TLC (PE / EA = 10 / 1), the reaction solution was directly dried by rotary evaporation, and the residue was directly stirred with silica gel and subjected to column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain a pale yellow oily liquid 6D (95.8 mg, yield: 54%). MS-ESI: m / z 386.1 [M + H] + .

[0430] Step 4: Compound 6D (500 mg, 1.30 mmol), compound 1C (488 mg, 1.30 mmol), MeCN (10 mL) and MgSO4 (930 mg, 7.73 mmol) were added to a three-neck flask, and the reaction solution was purified with N 2 The mixture was purged with 0.05% water, cooled to 0° C., and trifluoromethanesulfonic acid (585 mg, 3.90 mmol) was added via a constant pressure dropping funnel and stirred (3 h). After the reaction was detected to be complete by TLC (DCM / MeOH=10 / 1), the reaction solution was directly dried by rotary evaporation, and the residue was directly stirred with silica gel and subjected to column chromatography (dichloromethane:MeOH=50:1) to obtain a white solid 6E (300 mg, yield: 37%); MS-ESI: m / z 630.1 [M+H] + .

[0431] Step 5: Compound 6E (4 g, 6.35 mmol) and ethanol (100 mL) were added to a one-neck flask, and iron powder (2.36 g, 42.1 mmol) and NH 4 Cl (3.4 g, 63.6 mmol) was dissolved in water (40 mL) and then added to the one-neck flask, and the reaction solution was purged with N2, heated to 60 °C, and stirred (2 h). TLC (dichloromethane / CH 3 After the reaction was completed by detection with NaHCO 3 The pH was adjusted to 7-8 by adding an aqueous solution, the reaction solution was stirred for 10 minutes and filtered, the filtrate was concentrated by rotary evaporation, the residue was dissolved by adding dichloromethane, stirred and subjected to column chromatography (dichloromethane:methanol=30:1) to obtain a white powdery solid 6 (3.5 g, yield: 92%), 50 mg of which was subjected to preparative thin layer chromatography, filtered, the filtrate was concentrated by rotary evaporation, acetonitrile and water (purified water) were added to the residue, and the product 6 was obtained by lyophilization (38 mg, purity: 90.08%).

[0432] MS-ESI: m / z 622.3 [M+Na] + .

[0433] 1H NMR (400MHz, DMSO-d 6 )δ 7.35(d,J=8.0Hz,2H),7.30(d,J=10.2Hz,1H),7.22-7.16(m,2H),6.93(d,J=7.6Hz,1H),6.45-6.40(m,1H),6 .40-6.34(m,1H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),5.14-5.04(m,1H),4.98-4.83(m,3 H),4.78(d,J=3.4Hz,1H),4.54-4.45(m,1H),4.34-4.26(m,3H),4.22-4.12(m,1H),3.75(s,2H),2.60-2.53( m,1H),2.36-2.26(m,1H),2.17-1.96(m,2H),1.81-1.60(m,5H),1.39(s,3H),1.09-0.97(m,2H),0.85(s,3H). compound 7 [ka]

[0434] Step 1 Compound 7A (65 g, 280 mmol, 1.0 eq.) and imidazole (29 g, 420 mmol, 1.5 eq.) were added to a 2 L three-neck flask, and the reaction mixture was dissolved in dichloromethane (700 mL), followed by slow addition of TBSCl (59 g, 392 mmol, 1.35 eq.). After complete consumption of the starting material was detected by TLC (PE / EA=9 / 1), the reaction solution was cooled to room temperature, filtered, and diluted with dichloromethane (100 mL) and H. 2 The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 7B (80 g, yield: 82%).

[0435] Step 2 Compound 7B (70 g, 203 mmol, 1.0 equiv.), bis(pinacolato)diboron (51 g, 203 mmol, 1.0 equiv.), Pd(dppf)Cl 2(7.4 g, 10.1 mmol, 0.05 equiv.) and potassium acetate (60 g, 609 mmol, 3.0 equiv.) were added to a 2 L three-neck flask, and the reaction mixture was dissolved in dioxane (1 L) and N 2 The reaction solution was stirred at 110° C. for 12 hours under atmospheric conditions. After the completion of the reaction was detected by TLC (PE:EA=10:1), the reaction solution was cooled to room temperature, filtered, and diluted with ethyl acetate (1 L) and H 2 It was extracted twice with O (1 L), and the organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 7C (60 g, yield: 75%).

[0436] Step 3 Compound 7C (15 g, 38 mmol, 1.0 equivalent), compound 5D (7.6 g, 38 mmol, 1 equivalent) and Pd(dppf)Cl 2 (1.4 g, 1.9 mmol, 0.05 equiv.) was placed in a 1 L three-neck flask, dioxane (600 mL) was added, and Cs 2 CO 3 (37 g, 114 mmol, 3.0 equiv.) was dissolved in water (50 mL), and the reaction solution was reacted at 110° C. for 2 hours under a nitrogen atmosphere. After the completion of the reaction was detected by TLC (PE:EA=10:1), the reaction solution was cooled to room temperature, filtered, and diluted with ethyl acetate (1 L) and H 2 The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, stirred with silica gel, and purified by normal phase column chromatography (PE:EA=10:1) to give a white solid 7D (10 g, yield: 68%).

[0437] Step 4 Compound 7D (1 g, 2.6 mmol, 1.0 eq.), Compound 1C (0.98 g, 2.6 mmol, 1.0 eq.) and MgSO 4(0.94 g, 7.8 mmol, 3.0 equiv) was added to a 250 mL three-neck flask, acetonitrile (50 mL) was added to the reaction mixture, cooled to -20 °C with dry ice and ethanol, trifluoromethanesulfonic acid (1.17 g, 7.8 mmol, 3.0 equiv) was slowly added, and stirred at 0 °C for 2 h. After the completion of the reaction was detected by TLC (dichloromethane:MeOH = 10:1), sodium bicarbonate solution was added to adjust the pH to 7-8, acetonitrile was removed by rotary evaporation, the reaction solution was extracted, and slurried with PE:EA = 3:1 to obtain compound 7E (1.4 g, yield: 86%). MS-ESI: m / z 630.1 [M + H] + .

[0438] Step 5: Compound 7E (200 mg, 0.317 mmol, 1 equivalent) and iron powder (177 mg, 3.17 mmol, 10 equivalents) were placed in a 25 mL three-neck flask, ethanol (6 mL) was added, and NH 4 Cl (170 mg, 3.17 mmol, 10 equiv) was dissolved in water (6 mL) and then placed in a three-neck flask, and the reaction solution was reacted at 60° C. for 2 hours. After the completion of the reaction was detected by TLC (DCM:MeOH=10:1), ethanol was removed by evaporation under reduced pressure, and aqueous sodium bicarbonate was added to adjust the pH to 8. The reaction solution was extracted twice with 80 mL of dichloromethane and water, and the organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to obtain a yellow solid (200 mg), which was subjected to reverse phase column chromatography to obtain compound 7 (42.6 mg, yield: 22%).

[0439] MS-ESI: m / z 600.8[M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d 6)δ 7.36(d,J=8.0Hz,2H),7.31(d,J=10.1Hz,1H),7.22(d,J=7.9Hz,2H),7.20-7.14(m,1H),7.07(d,J=8.0Hz ,1H),6.98(d,J=8.0Hz,1H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=4.7Hz,1H) ,4.79(s,1H),4.54-4.45(m,3H),4.31-4.26(m,1H),4.17(d,J=19.5Hz,1H),3.87(s,2H),2.60-2.53(m,1 H),2.36-2.26(m,1H),2.18-1.96(m,2H),1.81-1.54(m,5H),1.39(s,3H),1.12-0.94(m,2H),0.86(s,3H). compound 8 [ka]

[0441] Step 1 Compound 3 (2 g, 3.42 mmol, 1.0 eq.) and compound 8A (2.52 g, 6.84 mmol, 2.0 eq.) were placed in a reaction flask, the reaction mixture was dissolved in THF (30 mL), and TsOH (0.63 g, 3.66 mmol, 1.07 eq.) was added in an ice-water bath under a nitrogen atmosphere, and the mixture was reacted at 5-10 °C for 30-40 min. After the completion of the reaction was detected by TLC (PE / EA=1 / 2), the reaction solution was added to water, the product was extracted with EA (100 mL), the organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the residue was stirred with silica gel and subjected to column chromatography (PE / EA=2 / 1) to obtain the product, which was concentrated by rotary evaporation to obtain a white solid 8B (2.3 g, yield: 75%). MS-ESI: m / z 893.4 [M+H] + .

[0442] Step 2 Compound 8B (2 g, 2.24 mmol) was dissolved in DCM (20 mL), and DEA (6 mL) was added dropwise to the reaction solution in an ice-water bath under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at room temperature for 2 hours. After the reaction was detected to be complete by TLC (PE / EA=1 / 2), the reaction solution was concentrated by rotary evaporation, extracted three times with DCM, subjected to reverse phase column chromatography, and lyophilized to obtain an off-white solid 8C (600 mg, yield: 40%). MS-ESI: m / z 671.3 [M+H] + .

[0443] Step 3 Compound 8C (300 mg, 0.447 mmol, 1.0 equiv) and compound 8D (230 mg, 0.492 mmol, 1.1 equiv) were added to a reaction flask, the reaction solution was dissolved in DMF (3.5 mL), DIEA (173 mg, 1.341 mmol, 3.0 equiv) was added in an ice-water bath under nitrogen atmosphere, then HATU (221 mg, 0.581 mmol, 1.3 equiv) in 1 mL of DMF was added dropwise, and then stirred at 0-5 °C for 30 min after the addition was complete. After the reaction was detected to be complete by LC-MS, the reaction solution was poured into ice water, and EA (100 mL) was added to extract the product. The organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give a yellow solid 8E (430 mg, yield: 86%). MS-ESI: m / z 1119.4[M+H] + .

[0444] Step 4: Compound 8E (300 mg, 0.268 mmol, 1 equivalent) and Pd(PPh 3 ) 4 (62 mg, 0.0536 mmol, 0.2 equiv.) and N-methylmorpholine (452 ​​mg, 4.47 mmol, 16.7 equiv.) were added to the reaction flask, and the reaction mixture was reacted at room temperature under nitrogen atmosphere for 1 h. After the reaction was detected to be complete by TLC, the reaction solution was directly purified by reverse phase column chromatography to obtain a white solid 8F (210 mg, yield: 72%). MS-ESI: m / z 1079.3 [M+H] + .

[0445] Step 5 Under nitrogen atmosphere, compound 8F (200 mg, 0.185 mmol) was dissolved in DCM (2.4 mL), and DEA (0.8 mL) was added dropwise to the reaction solution in an ice-water bath. After the addition was completed, the reaction solution was heated at room temperature for 2 hours. After the reaction was detected to be complete by LCMS, the reaction solution was directly extracted and washed three times with PE (60 mL x 3), and the product precipitated and adhered to the wall of the bottle, which was dissolved in acetonitrile (3 mL) and purified by reverse phase column chromatography to obtain a white solid 8G (62 mg, yield: 39%). MS-ESI: m / z 857.6 [M+H] + .

[0446] Step 6 Compound 8G (60 mg, 0.07 mmol, 1.0 equivalent) was dissolved in THF (3 mL), the reaction solution was dissolved in water (0.6 mL), TEA (414 mg, 4.1 mmol, 58 equivalent) was added in an ice-water bath, and after stirring for 1 minute, bromoacetyl bromide (113 mg, 0.56 mmol, 8.0 equivalent) was added, and the mixture was stirred at 0 to 5 ° C for 5 minutes. The reaction was detected to be complete by LC-MS, and the reaction solution was stored with dry ice and ethanol, subjected to preparative chromatography, and then freeze-dried to obtain a white solid 8 (11 mg, yield: 16%).

[0447] MS-ESI: m / z 977.3[M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d 6)δ 8.62(t,J=6.6Hz,1H),8.47(t,J=5.6Hz,1H),8.24(t,J=5.9Hz,1H),8.18 (d,J=7.7Hz,1H),7.40-7.34(m,2H),7.31(d,J=10.1Hz,1H),7.27-7.20( m,3H),7.16(brs,1H),7.14-7.07(m,2H),6.16(dd,J=10.1,1.9Hz,1H),5 .93(s,1H),5.39(s,1H),4.91(d,J=5.1Hz,1H),4.77(brs,1H),4.65-4.55 (m,2H),4.49(d,J=19.4Hz,1H),4.39(s,2H),4.33-4.25(m,2H),4.17(d, J=19.5Hz,1H),3.94-3.89(m,4H),3.80(d,J=5.6Hz,2H),3.72(d,J=5.8Hz ,2H),2.57-2.52(m,2H),2.30-2.24(m,2H),2.18-2.06(m,1H),2.06-1.8 9(m,2H),1.83-1.59(m,6H),1.39(s,3H),1.12-0.97(m,2H),0.85(s,3H). compound 9 [ka]

[0449] Step 1 Compound 4 (2.4 g, 4.1 mmol, 1.0 eq.) and compound 8A (4.5 g, 12.3 mmol, 3.0 eq.) were placed in a reaction flask, the reaction mixture was dissolved in THF (30 mL), and TsOH (1.1 g, 6.6 mmol, 1.6 eq.) was added in an ice-water bath under a nitrogen atmosphere, and the mixture was reacted at 5-10 °C for 30-40 min. After the completion of the reaction was detected by TLC (PE / EA=1 / 2), the reaction solution was added to water, the product was extracted with EA (100 mL), the organic phase was washed with water (50 mL x 3), dried with anhydrous sodium sulfate, concentrated, and the residue was stirred with silica gel and subjected to column chromatography (PE / EA=2 / 1) to obtain the product, which was concentrated by rotary evaporation to obtain a white solid 9A (1.5 g, yield: 41%). MS-ESI: m / z 893.4 [M+H] + .

[0450] Step 2 Compound 9A (1.3 g, 1.46 mmol) was dissolved in DCM (13 mL), and DEA (2.6 mL) was added dropwise to the reaction solution in an ice-water bath under a nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at room temperature for 2 hours. After the reaction was detected to be complete by TLC (PE / EA=1 / 2), the reaction solution was concentrated by rotary evaporation, extracted three times with DCM, subjected to reverse phase column chromatography, and lyophilized to obtain an off-white solid 9B (350 mg, yield: 36%). MS-ESI: m / z 670.8 [M+H] + .

[0451] Step 3 Compound 9B (350 mg, 0.52 mmol, 1.0 equiv.) and compound 8D (243 mg, 0.52 mmol, 1.0 equiv.) were added to the reaction flask, the reaction solution was dissolved in DMF (3.5 mL), DIEA (168 mg, 1.3 mmol, 2.5 equiv.) was added in an ice-water bath under nitrogen atmosphere, HATU (240 mg, 0.63 mmol, 1.21 equiv.) in 1 mL of DMF was added dropwise, and after the addition was completed, the mixture was stirred at 0-5 °C for 30 min. After the reaction was detected to be complete by LC-MS, the reaction solution was poured into ice water, EA (100 mL) was added, and the product was extracted. The organic phase was washed with water (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give a foamy yellow solid 9C (600 mg). The yield was not calculated because the crude product exceeded the theoretical amount. MS-ESI: m / z 1119.4[M+H] + .

[0452] Step 4: Compound 9C (400 mg, 0.35 mmol, 1.0 equivalent) and Pd(PPh 3 ) 4 (82 mg, 0.071 mmol, 0.2 equiv.) and N-methylmorpholine (353 mg, 3.5 mmol, 10.0 equiv.) were added to the reaction flask, and the reaction mixture was reacted at room temperature under nitrogen atmosphere for 1 h. After the completion of the reaction was detected by LC-MS, the reaction solution was directly purified by reverse phase column chromatography to obtain a white solid 9D (150 mg, yield: 39%). MS-ESI: m / z 1079.4 [M+H] + .

[0453] Step 5: Under nitrogen atmosphere, compound 9D (150 mg, 0.14 mmol) was dissolved in DCM (1.5 mL), and DEA (0.3 mL) was added dropwise to the reaction solution in an ice-water bath. After the addition was completed, the reaction solution was heated at room temperature for 2 hours. After the reaction was detected to be complete by LCMS, the reaction solution was directly concentrated by rotary evaporation, extracted with DCM three times, and purified by reverse phase column chromatography to obtain a white solid 9E (60 mg, yield: 50%). MS-ESI: m / z 857.4 [M+H] + .

[0454] Step 6 Compound 9E (50 mg, 0.058 mmol, 1.0 equiv.) was dissolved in THF (3 mL), and the reaction solution was dissolved by adding 3 drops of water. TEA (117 mg, 1.16 mmol, 20.0 equiv.) was added in an ice-water bath and stirred for 1 min. Bromoacetyl bromide (93 mg, 0.46 mmol, 8.0 equiv.) was added and stirred for 5 min at 0-5 °C. The reaction was detected to be complete by LC-MS, and the reaction solution was stored on dry ice, subjected to preparative chromatography, and freeze-dried to obtain a white solid 9 (11 mg, yield: 19%). MS-ESI: m / z 977.3[M+H] + .

[0455] 1 H NMR (400MHz, DMSO-d 6)δ 8.62(t,J=6.6Hz,1H),8.49(t,J=5.6Hz,1H),8.26(t,J=5.8Hz,1H),8.19(d,J=7.5Hz,1H),7.36(d,J=7.9Hz,2H),7.30(d,J=10.1Hz,1H),7 .26-7.14(m,6H),6.16(dd,J=10.1,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=4.9Hz,1H),4.79(brs,1H),4.61-4.54(m,2H),4.49(d ,J=19.4Hz,1H),4.37(s,2H),4.32-4.24(m,2H),4.16(d,J=19.4Hz,1H),3.95-3.88(m,4H),3.79(d,J=5.5Hz,2H),3.72(d,J=5.8Hz,2H),2 .58-2.52(m,2H),2.30-2.24(m,2H),2.17-2.05(m,1H),2.05-1.89(m ,2H),1.82-1.58(m,6H),1.39(s,3H),1.11-0.96(m,2H),0.85(s,3H). compound 10 [ka]

[0456] Step 1 Compound 5 (1.9 g, 3.21 mmol, 1.0 eq.), compound 8D (1.5 g, 3.21 mmol, 1.0 eq.) and HATU (1.6 g, 4.24 mmol, 1.3 eq.) were added to a 100 mL three-neck flask, the reaction mixture was dissolved in 45 mL of DMF, and 2,6-lutidine (1.4 g, 12.72 mmol, 4.0 eq.) was added slowly. After the starting material was completely consumed as detected by LCMS, the reaction solution was slowly dripped into water (300 mL) and filtered to obtain the product, which was dried under vacuum by oil pump to obtain a yellow solid 10A (3.3 g, yield: 94%). MS-ESI: m / z 1048.4 [M+H] + .

[0457] Step 2: Compound 10A (1.8 g, 1.72 mmol, 1.0 equivalent) and Pd(PPh 3 ) 4(392 mg, 0.34 mmol, 0.2 equiv) was added to a 50 mL three-neck flask, and the reaction mixture was dissolved in dichloromethane (30 mL), and under nitrogen atmosphere, N-methylmorpholine (868 mg, 8.6 mmol, 5.0 equiv) was slowly added and reacted for 0.5 h. After the reaction was detected to be complete by LCMS, diethylamine (6 mL) was slowly added to the three-neck flask and stirred at room temperature for 1 h. After the reaction was detected to be complete by LCMS, DMF (20 mL) was added to the reaction solution and subjected to rotary evaporation under vacuum at room temperature until 20 mL of solvent remained, then rotary evaporation was stopped, and the residue was subjected to reverse phase column chromatography (ACN 30%-70% in water) and lyophilized to obtain a pale yellow solid 10B (455 mg, yield: 34%).

[0458] Step 3 Compound 10B (150 mg, 0.19 mmol, 1.0 eq) was dissolved in THF (5 mL) and water (0.2 mL), triethylamine (190 mg, 1.9 mmol, 10 eq) was added, and the reaction solution was cooled to 0° C. in an ice-water bath. Bromoacetyl bromide (153 mg, 0.76 mmol, 4.0 eq) was dissolved in 1 mL of THF, and the resulting solution was slowly added to the above reaction solution and reacted at 0° C. for 15 minutes. After the completion of the reaction was detected by LCMS, the reaction solution was subjected to preparative chromatography to obtain a white solid 10 (20 mg, yield: 12%).

[0459] MS-ESI: m / z 906.3[M+H] + .

[0460] 1 H NMR (400MHz, DMSO-d 6)δ 9.87(s,1H),8.52(s,1H),8.22(d,J=7.6Hz,1H),7.43(s,1H),7.38(d,J=7.9Hz,2H),7.31(d,J=9.7Hz,2H),7.23(d,J=7.9 Hz,2H),6.87(s,1H),6.16(d,J=10.3Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.1Hz,1H),4.78(s,1H),4.49(d,J=19.2 Hz,1H),4.41(s,2H),4.39-4.32(m,1H),4.29(s,1H),4.17(d,J=19.5Hz,1H),3.93(s,2H),3.88(s,2H),3.82-3.77(m,2H) ,2.59-2.53(m,1H),2.35-2.21(m,4H),2.04-1.92(m,2H),1.84-1.63(m,6H),1.39(s,3H),1.09-0.99(m,2H),0.86(s,3H). compound 11 [ka]

[0461] Step 1 Compound 6 (300 mg, 0.5 mmol, 1.0 eq.), compound 8D (233 mg, 0.5 mmol, 1.0 eq.) and HATU (228 mg, 0.6 mmol, 1.2 eq.) were added to a 25 mL three-neck flask, the reaction mixture was dissolved in DMF (5 mL), and 2,6-lutidine (150 mg, 1.4 mmol, 2.8 eq.) was added slowly. After the starting material was completely consumed as detected by LCMS, the reaction solution was slowly dripped into water (100 mL) and filtered to obtain the product, which was dried under vacuum by oil pump to obtain a yellow solid 11A (450 mg, yield: 86%). MS-ESI: m / z 1048.4 [M+H] + .

[0462] Step 2: Compound 11A (450 mg, 0.43 mmol, 1.0 equiv.) and Pd(PPh 3 ) 4(92 mg, 0.08 mmol, 0.2 equiv) was added to a 50 mL three-neck flask, the reaction mixture was dissolved in THF (10 mL), and N-methylmorpholine (200 mg, 1.98 mmol, 4.6 equiv) was slowly added to the reaction solution under nitrogen atmosphere and reacted for 0.5 h. After the reaction was detected to be complete by LCMS, the reaction solution was subjected to reverse phase column chromatography (ACN 30%-70% in water) and lyophilized to obtain a pale yellow solid 11B (250 mg, yield: 58%). MS-ESI: m / z 1008.3 [M+H] + .

[0463] Step 3 Compound 11B (250 mg, 0.25 mmol) was added to a 25 mL three-neck flask, and the reaction mixture was dissolved in DCM (10 mL). Diethylamine (2 mL) was added to the reaction solution under nitrogen atmosphere and reacted for 0.5 hours. After the completion of the reaction was detected by LCMS, the reaction solution was subjected to reverse phase column chromatography (ACN in water 20% to 50%) and lyophilized to obtain a pale yellow solid 11C (130 mg, yield: 67%). MS-ESI: m / z 786.4 [M+H] + .

[0464] Step 4 Compound 11C (120 mg, 0.153 mmol, 1.0 eq) was dissolved in THF (5 mL) and water (0.2 mL), triethylamine (155 mg, 1.53 mmol, 10.0 eq) was added, and the reaction solution was cooled to 0° C. in an ice-water bath. Bromoacetyl bromide (123 mg, 0.61 mmol, 4.0 eq) was dissolved in 1 mL of THF, and the resulting solution was slowly added to the above reaction solution and reacted at 0° C. for 15 minutes. After the completion of the reaction was detected by LCMS, the reaction solution was subjected to preparative HPLC to obtain white solid 11 (12.2 mg, yield: 9%).

[0465] MS-ESI: m / z 906.3[M+H] + .

[0466] 1 H NMR (400MHz, DMSO-d 6)δ 9.51(s,1H),8.58-8.45(m,1H),8.37(d,J=7.6Hz,1H),7.51-7.46(m,1H),7.40-7.34(m,2H),7.31(d,J=10.0Hz,1H),7.28- 7.19(m,3H),7.01-6.94(m,1H),6.16(dd,J=10.0,1.9Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.0Hz,1H),4.77(brs,1H) ),4.49(d,J=19.5Hz,1H),4.42(d,J=3.7Hz,1H),4.39-4.32(m,1H),4.29(brs,1H),4.17(d,J=19.5Hz,1H),3.98-3.77(m,6H) ),2.60-2.52(m,2H),2.34-2.28(m,2H),2.18-1.96(m,3H),1.88-1.55(m,6H),1.39(s,3H),1.13-0.98(m,2H),0.85(s,3H). compound 12 [ka]

[0467] Step 1: Compound 4C (10.0 g, 44.2 mmol) in DCM (70 mL) was added with TEA (8.94 g, 88.39 mmol, 12.30 mL), the reaction solution was cooled to 0° C., MsCl (6.08 g, 53.0 mmol, 4.10 mL) was added, and the mixture was stirred at 25° C. for 12 h. After the starting material was completely consumed as detected by LCMS, the reaction solution was diluted with DCM (50 mL), quenched with water (200 mL), and extracted with DCM (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), and diluted with anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C. and filtered, and the filtrate was concentrated by rotary evaporation to give compound 12A (8.60 g, crude) as a yellow oil.

[0468] Step 2: Compound 12A (8.60 g, 31.58 mmol) in DMF (51.6 mL) was added with thioglycolic acid (7.21 g, 63.15 mmol) and stirred at 25° C. for 5 hours. After TLC (PE / EA=5:1) showed that the starting material was completely consumed, water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated saline, then washed with 5% LiCl aqueous solution, and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated by rotary evaporation to give compound 12B (5.75 g, yield: 57.82%, purity: 90.2%) as a brown oil. MS-ESI: m / z 285.2 [M+H] + .

[0469] Step 3: Compound 12B (12.0 g, 42.2 mmol) was dissolved in methanol (240 mL) and the reaction solution was added with K 2 CO 3 (8.75 g, 63.3 mmol) was added and stirred at 20° C. for 3 h. After complete consumption of the starting material was detected by LCMS, the reaction solution was poured into DCM (240 mL) and 0.5 M HCl (100 mL) was added, followed by liquid separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to give an off-white solid 12C (10.0 g, yield: 97.7%). MS-ESI: m / z 483.2 [M+H] + .

[0470] Step 4 Compound 12C (9.00 g, 37.1 mmol), compound 1C (13.9 g, 37.1 mmol) and anhydrous magnesium sulfate (13.4 g, 111 mmol) were added to acetonitrile (270 mL), and TfOH (16.7 g, 111 mmol, 9.84 mL) was added dropwise at 0° C. After the dropwise addition was completed, the reaction solution was warmed to 20° C. and stirred for 3 hours. After the starting material was completely consumed as detected by LCMS, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (100 mL×2). The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated to give off-white solid 12D (15.0 g, yield: 33.6%). MS-ESI: m / z 1199.4 [M+H] + .

[0471] Step 5 Compound 12D (290 mg, crude) was added to DMF (4 mL), followed by DL-dithiothreitol (200 mg, 1.30 mmol), and the reaction solution was reacted at room temperature under nitrogen atmosphere for 16 hours. After the reaction was detected to be complete by LCMS, the reaction solution was directly subjected to preparative HPLC to obtain white powdery solid 12 (20 mg, yield: 13.8%). MS-ESI: m / z 601.2 [M+H] + .

[0472] 1H NMR(400MHz,DMSO)δ 7.37(d,J=8.1Hz,2H),7.31(d,J=10.1Hz,1H),7.23(dd,J=8.1,3.3Hz,4H),7.14(d,J=8.0Hz,2H ),6.16(dd,J=10.1,1.7Hz,1H),5.93(s,1H),5.39(s,1H),4.91(d,J=5.0Hz,1H),4.78(s,1H),4 .49(d,J=19.4Hz,1H),4.29(s,1H),4.17(d,J=19.5Hz,1H),3.88(d,J=11.3Hz,2H),3.67(d,J=7 .6Hz,2H),2.77(t,J=7.6Hz,1H),2.50-2.55(m,1H),2.45-2.25(m,1H),2.25-2.05(m,2H),1.80 - 1.53(m,5H),1.38(s,3H),1.14 - 0.94(m,2H),0.86(s,3H). compound 13 [ka]

[0473] Step 1 Compound 12 (7.00 g, 11.6 mmol) and compound 8A (4.29 g, 11.6 mmol) were added to DMF (49.0 mL), and TfOH (3.50 g, 23.3 mmol, 2.06 mL) was added to the reaction solution, which was stirred at 25° C. for 16 hours. After the starting material was completely consumed as detected by LCMS, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (100 mL×3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 13A as a yellow oil (15.0 g, crude product was not calculated yield). MS-ESI: m / z 909.3 [M+H] + .

[0474] Step 2 Compound 13A (15.0 g, 16.5 mmol) was added to acetonitrile (105 mL), and diethylamine (6.03 g, 82.5 mmol, 8.50 mL) was added to the reaction solution, and the mixture was stirred at 25° C. for 16 hours. After the starting material was completely consumed by LCMS, the reaction solution was slurried with acetonitrile (20.0 mL), filtered, and the resulting filter cake was sucked dry, and the crude product was subjected to preparative reverse phase chromatography (water:acetonitrile=25%-55%, 20 min) and lyophilized to obtain compound 13B as a white solid (0.900 g, yield: 7.94%). MS-ESI: m / z 687.3 [M+H] + .

[0475] Step 3 Compound 13B (500 mg, 727 μmol) and compound 8D (526 mg, 1.09 mmol) were added to DMF (5 mL), and HATU (830 mg, 2.18 mmol) and 2,6-lutidine (56.0 mg, 1.46 mmol, 169 μL) were added to the reaction solution, followed by stirring at 20° C. for 3 hours. After LCMS showed that the starting material was completely consumed, the reaction solution was dried under vacuum to obtain a crude product (550 mg), of which 250 mg was subjected to preparative reverse phase chromatography to obtain compound 13C (100 mg, yield: 26.2%) as a white solid. MS-ESI: m / z 1151.4 [M+H] + .

[0476] Step 4 Compound 13C (50.0 mg, 43.4 μmol) was added to acetonitrile (1 mL), and diethylamine (15.8 mg, 217 μmol, 22.3 μL) was added to the reaction solution, followed by stirring at 25° C. for 6 hours. After complete consumption of the starting material was detected by LCMS, the reaction solution was concentrated by rotary evaporation and slurried with methyl tert-butyl ether (3.00 mL) to give compound 13D as a yellow solid (40.0 mg, yield: 99.1%). MS-ESI: m / z 929.2 [M+H] + .

[0477] Step 5 EEDQ (31.9 mg, 129 μmol) and bromoacetic acid (11.3 mg, 81.8 μmol) were dissolved in DMF (0.8 mL), and the reaction solution was stirred at room temperature for 1 hour, after which compound 13D (40.0 mg, 43.0 μmol) was added and stirred at 25° C. for 2 hours. After the starting material was completely consumed as detected by LCMS, the reaction solution was concentrated by rotary evaporation to obtain compound 13E as a yellow solid (the crude product was used directly in the next step). MS-ESI: m / z 1049.2 [M+H] + .

[0478] Step 6 Compound 13E (45.0 mg, 42.8 μmol) was dissolved in DCM (1.50 mL), and trifluoroacetic acid (770 mg, 6.75 mmol, 500 μL) was added to the reaction solution and stirred at 25° C. for 1 h. After the starting material was completely consumed as detected by LCMS, the reaction solution was concentrated by rotary evaporation, and then the crude product was purified by preparative reverse phase chromatography to obtain compound 13 (3.06 mg, yield: 7.18%) as a yellow solid. MS-ESI: m / z 993.2 [M+H] + .

[0479] 1 HNMR (400MHz, DMSO-d 6)δ 7.83(br d,1H,J=7.6Hz),7.63(br d,1H,J=7.2Hz),7.4(m,2H),7.26(br d,2H,J=8.0Hz),7.16(br d,1H,J=7.6Hz),4.92(br s,1H),4.48(br s,1H),4.30(br s,2H),4.1-4.3(m,2H),4.02(br d,1H,J=13.6Hz),3.92(br d,2H,J=8.4Hz),3.81(br d,2H,J=5.2Hz),3.74(br s,3H),3.63(br s,2H),2.91(s,2H),2.75(br s,1H),2.3-2.4(m,2H),2.27(br s,2H),2.1-2.1(m,1H),2.02(br s,1H),1.92(br s,1H),1.77(br s,3H),1.3-1.5(m,8H),1.25(s,2H),1.18(br d,1H,J=7.2Hz),1.02(br s,1H),0.8-1.0(m,2H). Compound 14, reference compound P1: [ka]

[0480] It was synthesized according to the reference patent China Patent No. 109476699(A). Compound 15 (reference compound LP1): [ka]

[0481] It was synthesized according to the reference patent China Patent No. 111465399(A). Compound 16, reference compound LP2: [ka]

[0482] It was synthesized according to the reference patent China Patent No. 111417410(A). Example 2

[0483] In this application, 20 mM histidine aqueous buffer (pH=5.5) was obtained by adjusting the pH of 20 mM histidine aqueous solution to 5.5 with HOAc. Stock solution 1: 10 mM EDTA buffer, pH=4.7; Stock solution 2: 800 mM sodium citrate aqueous buffer, pH=8.4; Stock solution 3: 500 mM urea aqueous solution; Stock solution 4: 10 mM tris(2-carboxyethyl)phosphine aqueous solution.

[0484] The protein purity of the ADC in this application was determined by SEC method, the parameters of which are given below. [Table 14]

[0485] The DAR value of the ADC in this application can be detected by LC-MS method. The experimental procedure was as follows: 75.0 μL of 8.0 mol / L guanidine hydrochloride (Gdn-HCl), 5.0 μL of 1.0 mol / L Tris-HCl, and 2.0 μL of 1 mol / L DTT were added to a solution containing 40.0 μg of ADC sample. The solution was diluted to 100.0 μL with ultrapure water, mixed well, and incubated at 22° C. for 30 minutes. The drug / antibody ratio (DAR) was then analyzed using LC-MS. The LC parameters are shown below. [Table 15]

[0486] The MS parameters are shown below. [Table 16]

[0487] The DAR value of the ADC in the present application can also be detected by the HIC method, and the parameters are shown below. [Table 17]

[0488] Mouse anti-TNFα mIgG2a 8c11: light chain amino acid sequence is shown as SEQ ID NO: 31, heavy chain amino acid sequence is shown as SEQ ID NO: 32, prepared with reference to WO2015191783(A2).

[0489] Antibody Adalimumab (Humira): the light chain amino acid sequence is shown as SEQ ID NO:9 and the heavy chain amino acid sequence is shown as SEQ ID NO:10, and was prepared with reference to US Pat. No. 6,090,382(A).

[0490] Antibody Ritifilimab (BIIB059): the light chain amino acid sequence is shown as SEQ ID NO: 42, and the heavy chain amino acid sequence is shown as SEQ ID NO: 37, and was prepared with reference to China Patent No. 105452295(B).

[0491] Antibody iscalimab: the light chain amino acid sequence is shown as SEQ ID NO: 19, and the heavy chain amino acid sequence is shown as SEQ ID NO: 20, prepared with reference to China Patent No. 105949314(B). 2.1 Conjugate 1 (8c11-Conjugate 1) [ka]

[0492] The prepared tris(2-carboxyethyl)phosphine aqueous solution (10 mM, 0.054 mL, 0.54 nmol) was added to anti-mouse TNFα mIgG2a 8c11 in aqueous PB buffer (0.05 M PBS buffer, pH = 6.5; 2.5 mL, 9.96 mg / mL, 0.168 nmol) at 37 ° C., the reaction solution was placed in a water bath shaker and shaken at 37 ° C. for 3 hours to react, after which the reaction was stopped. The reaction solution was cooled to 25 ° C. in a water bath and diluted to 5.0 mg / mL, and 2.0 mL of the solution was taken out and used in the next step.

[0493] Compound IV-1 (1.67 mg, 2.02 nmol) was dissolved in 0.10 mL of DMA, and the resulting solution was added to the above solution (2.0 mL), placed in a water bath shaker, shaken, and reacted at 25° C. for 3 hours, after which the reaction was stopped. The reaction solution was desalted and purified through a Sephadex G25 gel column (eluent: 0.05 M PBS buffer (pH 6.5) containing 0.001 M EDTA) to obtain the exemplary product of formula (Va) in PBS buffer (5.0 mg / mL, 1.1 mL).

[0494] The pH value of the PBS buffer of ADC was adjusted to 9 with 1 M Tris buffer, the resulting solution was incubated at 37° C. for 24 hours, and the pH was adjusted to 6.5 with 1 mol / L citrate buffer to obtain conjugate 1 (3.3 mg / mL, 5.5 mL). a-I can be detected by LC-MS. 2.2 Conjugate 2 (8c11-Conjugate 2) [ka]

[0495] The prepared tris(2-carboxyethyl)phosphine aqueous solution (10 mM, 0.054 mL, 0.54 nmol) was added to the antibody 8c11 in aqueous PB buffer (0.05 M PBS buffer, pH = 6.5; 2.5 mL, 9.96 mg / mL, 0.168 nmol) at 37 ° C., the reaction solution was placed in a water bath shaker and shaken at 37 ° C. for 3 hours to react, after which the reaction was stopped. The reaction solution was cooled to 25 ° C. in a water bath and diluted to 5.0 mg / mL, and 2.0 mL of the solution was taken out and used in the next step.

[0496] Compound IV-12 (1.67 mg, 2.02 nmol) was dissolved in 0.10 mL of DMA, and the resulting solution was added to the above solution (2.0 mL), placed in a water bath shaker, shaken, and reacted at 25° C. for 3 hours, after which the reaction was stopped. The reaction solution was desalted and purified with a Sephadex G25 gel column (eluent: 0.05 M histidine buffer (pH 5.5) containing 0.001 M EDTA) to obtain conjugate 2 (5.0 mg / mL, 1.1 mL).

[0497] N a-I can be detected by LC-MS. 2.3 Conjugate 3 (8c11-Conjugate 3) [ka]

[0498] The prepared tris(2-carboxyethyl)phosphine aqueous solution (10 mM, 0.054 mL, 0.54 nmol) was added to the antibody 8c11 in aqueous PB buffer (0.05 M PBS buffer, pH = 6.5; 2.5 mL, 9.96 mg / mL, 0.168 nmol) at 37 ° C., the reaction solution was placed in a water bath shaker and shaken at 37 ° C. for 3 hours to react, after which the reaction was stopped. The reaction solution was cooled to 25 ° C. in a water bath and diluted to 5.0 mg / mL, and 2.0 mL of the solution was taken out and used in the next step.

[0499] Compound IV-11 (1.67 mg, 2.02 nmol) was dissolved in 0.10 mL of DMA, and the resulting solution was added to the above solution (2.0 mL), placed in a water bath shaker, shaken, and reacted at 25° C. for 3 hours, after which the reaction was stopped. The reaction solution was desalted and purified with a Sephadex G25 gel column (eluent: 0.05 M histidine buffer (pH 5.5) containing 0.001 M EDTA) to obtain conjugate 3 (5.3 mg / mL, 1.5 mL).

[0500] N a-I can be detected by LC-MS. 2.4 Conjugate 4 (8c11-Conjugate 4) [ka]

[0501] The prepared tris(2-carboxyethyl)phosphine aqueous solution (10 mM, 0.054 mL, 0.54 nmol) was added to the antibody 8c11 in aqueous PB buffer (0.05 M PBS buffer, pH = 6.5; 2.5 mL, ...

Claims

1. Formula I: 【Chemical 1】 [In the formula, R 1 and R 2 are each independently selected from the group consisting of H, F, Cl, Br, and optionally substituted C 1 -C 6 alkyl; R 3 is optionally substituted —CH 2 Cl, optionally substituted —CH 2 SH, optionally substituted —CH 2 OH, optionally substituted —CH 2 OH, 【Chemistry 2】 Optionally substituted 【Chemistry 3】 Optionally substituted 【Chemistry 4】 Optionally substituted 【Chemistry 5】 Optionally substituted 【Chemistry 6】 Optionally substituted 【Chemistry 7】 Optionally substituted 【Chemistry 8】 Optionally substituted 【Chemistry 9】 Optionally substituted 【Chemistry 10】 Optionally substituted 【Chemistry 11】 Optionally substituted 【Chemistry 12】 Optionally substituted 【Chemistry 13】 Optionally substituted 【Chemistry 14】 selected from the group consisting of optionally substituted —OH, optionally substituted —OCH 3 , optionally substituted —OCH 2 F, optionally substituted —OCH 2 Cl, optionally substituted —OCH 2 CN, optionally substituted —OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted —SCH 2 F, optionally substituted —SCH 2 Cl, optionally substituted —SCH 2 CF 3 , and optionally substituted —SCH 2 CN; R 4 and R 5 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted —C(═O)H, optionally substituted —OH, optionally substituted —SH, optionally substituted —NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; when R 4 and R 5 contain methylene units, said methylene units of R 4 and R 5 are each independently unsubstituted or said methylene units of R 4 and R 5 are each independently —S(═O)—, —S(═O) 2 substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene; B is optionally substituted 【Chemistry 15】 Optionally substituted 【Chemistry 16】 and optionally substituted 【Chemistry 17】 X 1 is selected from the group consisting of CH, C(—O—CH 3 ) and N; W is absent or is selected from the group consisting of: -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -CH 2 NHC(=O)-, optionally substituted -NHC(=O)CH 2 -, optionally substituted -C(=O)NH-, optionally substituted -NH-, optionally substituted -CH=CH-, 【Chemistry 18】 Optionally substituted C 1 -C 6 alkylene, optionally substituted —OCH 2 —, optionally substituted —CH 2 O—, optionally substituted —SCH 2 —, optionally substituted —CH 2 S—, optionally substituted —NHC(═O)—, optionally substituted —C(═O)CH 2 —, optionally substituted —CH 2 NH—, optionally substituted —NHCH 2 —, optionally substituted 【Chemistry 19】 Optionally substituted 【Chemistry 20】 Optionally substituted 【Chemical 21】 Optionally substituted 【Chemical 22】 and optionally substituted 【Chemical 23】 selected from the group consisting of: A1 is a substituted benzene ring; CR ４ R ５ The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) ２ -, -C(=O)-, -C=C and 【Chemistry 24】 and R is replaced by a group selected from the group consisting of ４ and R ５ can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is —O—, —S—, or —NH—; Y 1 is absent or selected from the group consisting of protium, deuterium, tritium, halogen, —OR, —SR, —NHR, —N(R) 2 , optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy; each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C 1 -C 6 alkyl, and halogenated C 1 -C 6 alkoxy, and m is any integer from 0 to 1; Substituents include protium, deuterium, tritium, halogen, —CN, ═O, ═N—OH, ═N—OR, ═N—R, —OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)NHR, and —C(O)NR. ２ , -OC(O)NHR, -OC(O)NR ２ , -SR, -S(O)R, -S(O) ２ R, -NHR, -N(R) ２ , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) ２ NHR, -S(O) ２ N (R) ２ , -NHS(O) ２ NR ２ , -NRS(O) ２ NR ２ , -NHS(O) ２ R, -NRS(O) ２ R.C. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy, and each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, hydroxy, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. 【Request 2】 【Chemical 25】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , CR 4 R 5 , B, W, A1, X, Y 1 , n and m are as defined in claim 1], or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. CR ４ R ５ 3. The compound according to any one of claims 1 to 2, wherein each unit is independently unsubstituted or substituted with a group selected from the group consisting of -O-, -S- and -C(=O)-, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

4. R ４ and R ５ are each independently H, F, Cl, —OH, or —NH ２ and C １ ~C ６ alkyl, or R ４ and R ５ Together, C ３ ~C ６ cycloalkyl or 3- to 6-membered heterocyclyl; n is selected from the group consisting of 1, 2 and 3, preferably (CR ４ R ５ ) ｎ - is independently -CH ２ -, 【Chemical Formula 26】 10. The compound of claim 1, selected from the group consisting of: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. Y １ is absent or is hydroxy, sulfhydryl, amino, and optionally substituted C １ ~C ６ 3. The compound according to claim 1, wherein the compound is selected from the group consisting of alkyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

6. 【Catalog 27】 but, 【Chemical 28】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. R １ and R ２ are each independently selected from the group consisting of H, F, Cl, Br and optionally substituted methyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

8. R ３ But -CH ２ Cl, —CH ２ SH, -CH ２ OH, 【Chemical 29】 -OCH ３ , -OCH ２ F, -OCH ２ Cl, —OCH ２ CN, -OCH ２ CH ３ , -SH, -SCH ２ F, -SCH ２ Cl, -SCH ２ CF ３ and -SCH ２ CN, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

9. B, 【Chemistry 30】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

10. W is absent or W is 【Chemical 31】 and preferably W is absent or W is selected from the group consisting of: 【Chemical 32】 2. The compound of claim 1, wherein:

11. 【Chemical 33】 [In the formula, X is selected from the group consisting of —O—, —S—, and —NH—; R ４ and R ５ are each independently H, F, Cl, —OH, or —NH ２ and C １ ~C ６ selected from the group consisting of alkyl; n is selected from the group consisting of 1, 2 and 3; Y １ is absent or is hydroxy, sulfhydryl, amino and C １ ~C ６ selected from the group consisting of alkyl; R １ and R ２ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and methyl; R ３ is -CH ２ Cl, —CH ２ SH, -CH ２ OH, 【Chemical Formula 34】 -OCH ３ , -OCH ２ F, -OCH ２ Cl, —OCH ２ CN, -OCH ２ CH ３ , -SH, -SCH ２ F, -SCH ２ Cl, -SCH ２ CF ３ and -SCH ２ CN, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

12. The following structure: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 and preferably a compound of the formula: 【Chemical 35】 10. The compound of claim 1, selected from the group consisting of: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

13. Formula IVa or IVb: 【Chemical 36】 [In the formula, R １ and R ２ are each independently selected from H, F, Cl, Br and optionally substituted C １ ~C ６ selected from the group consisting of alkyl; R 3 is optionally substituted —CH 2 Cl, optionally substituted —CH 2 SH, optionally substituted —CH 2 OH, optionally substituted —CH 2 OH; 【Chemical 37】 Optionally substituted 【Chemical Formula 38】 Optionally substituted 【Chemical 39】 Optionally substituted 【Chemistry 40】 Optionally substituted 【Chemistry 41】 Optionally substituted 【Chemistry 42】 Optionally substituted 【Chemistry 43】 Optionally substituted 【Chemical 44】 Optionally substituted 【Chemistry 45】 Optionally substituted 【Chemistry 46】 selected from the group consisting of optionally substituted —OH, optionally substituted —OCH 3 , optionally substituted —OCH 2 F, optionally substituted —OCH 2 Cl, optionally substituted —OCH 2 CN, optionally substituted —OCH 2 CH 3 , optionally substituted sulfhydryl, optionally substituted —SCH 2 F, optionally substituted —SCH 2 Cl, optionally substituted —SCH 2 CF 3 , and optionally substituted —SCH 2 CN; R 4 and R 5 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted —C(═O)H, optionally substituted —OH, optionally substituted —SH, optionally substituted —NH 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; when R 4 and R 5 contain methylene units, said methylene units of R 4 and R 5 are each independently unsubstituted or said methylene units of R 4 and R 5 are each independently —S(═O)—, —S(═O) 2 substituted with a group selected from the group consisting of -, -O-, -S-, -C(=O)-, optionally substituted -PH-, optionally substituted -P(=O)H-, optionally substituted -NH-, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, and optionally substituted heteroarylene; B is optionally substituted 【Chemistry 47】 Optionally substituted 【Chemistry 48】 and optionally substituted 【Chemistry 49】 X 1 is selected from the group consisting of CH, C(—O—CH 3 ) and N; W is absent or is selected from the group consisting of: -S(=O)-, -S(=O) 2 -, -O-, -S-, -C(=O)-, optionally substituted -CH 2 NHC(=O)-, optionally substituted -NHC(=O)CH 2 -, optionally substituted -C(=O)NH-, optionally substituted -NH-, optionally substituted -CH=CH-, 【Chemistry 50】 Optionally substituted C 1 -C 6 alkylene, optionally substituted —OCH 2 —, optionally substituted —CH 2 O—, optionally substituted —SCH 2 —, optionally substituted —CH 2 S—, optionally substituted —NHC(═O)—, optionally substituted —COCH 2 —, optionally substituted —CH 2 NH—, optionally substituted —NHCH 2 —, optionally substituted —CH(CH 3 )—, optionally substituted 【Chemistry 51】 Optionally substituted 【Chemistry 52】 Optionally substituted 【Chemistry 53】 Optionally substituted 【Chemical 54】 and optionally substituted 【Chemistry 55】 selected from the group consisting of: CR ４ R ５ The units are each independently unsubstituted or -O-, -S-, -NR-, -S(O)-, -S(O) ２ -, -C(=O)-, -C=C and 【Chemical Formula 56】 and R is replaced by a group selected from the group consisting of ４ and R ５ can be taken together to form optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted bridged cyclyl, optionally substituted bridged heterocyclyl, optionally substituted spirocyclyl and optionally substituted spiroheterocyclyl, where n is any integer from 1 to 20; X is selected from the group consisting of —O—, —S—, and —NR—; Y 1 is absent or selected from the group consisting of -OR, -SR, -N(R) 2 and optionally substituted C 1 -C 6 alkyl; each R is independently selected from the group consisting of hydrogen, protium, deuterium, tritium, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and m is any integer from 0 to 4; Y ２ is selected from the group consisting of —O—, —S—, and —NR—; Substituents include protium, deuterium, tritium, halogen, —CN, ═O, ═N—OH, ═N—OR, ═N—R, —OR, —C(O)R, —C(O)OR, —OC(O)R, —OC(O)OR, —C(O)NHR, and —C(O)NR. ２ , -OC(O)NHR, -OC(O)NR ２ , -SR, -S(O)R, -S(O) ２ R, -NHR, -N(R) ２ , -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, -S(O) ２ NHR, -S(O) ２ N (R) ２ , -NHS(O) ２ NR ２ , -NRS(O) ２ NR ２ , -NHS(O) ２ R, -NRS(O) ２ R.C. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ alkoxy; each R is selected from the group consisting of hydrogen, protium, deuterium, tritium, oxygen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogenated C １ ~C ６ Alkyl and halogenated C １ ~C ６ independently selected from the group consisting of alkoxy; Tr is absent or is any group; L 3 is selected from polypeptide fragments; L2 is absent or selected from a linker fragment; L 1 is selected from coupling units; or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

14. R ４ and R ５ are each independently H, F, Cl, —OH, or —NH ２ and C １ ~C ６ 14. The compound of formula IVa or IVb according to claim 13, wherein n is selected from the group consisting of alkyl; and n is selected from the group consisting of 1, 2 and 3, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

15. Y １ is absent or hydroxy, sulfhydryl, amino, and C １ ~C ６ 14. A compound of formula IVa or IVb according to claim 13, wherein the compound is selected from the group consisting of alkyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

16. 【Catalog 57】 but, 【Chemistry 58】 【Chemical Formula 59】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

17. R １ and R ２ are each independently selected from the group consisting of H, F, Cl, Br and optionally substituted methyl, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

18. R ３ But -CH ２ Cl, —CH ２ SH, -CH ２ OH, 【Chemistry 60】 -OCH ３ , -OCH ２ F, -OCH ２ Cl, —OCH ２ CN, -OCH ２ CH ３ , -SH, -SCH ２ F, -SCH ２ Cl, -SCH ２ CF ３ and -SCH ２ CN, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

19. B, 【Hua 61】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

20. W is absent or W is 【Hua 62】 and preferably W is absent or W is selected from the group consisting of: 【Chemistry 63】 14. A compound of formula IVa or IVb according to claim 13, wherein: or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

21. The compound of formula IVa or IVb according to claim 13, 19 or 20. [In the formula, X is selected from the group consisting of —O—, —S—, and —NH—; R ４ and R ５ are each independently H, F, Cl, —OH, or —NH ２ and C １ ~C ６ selected from the group consisting of alkyl; n is selected from the group consisting of 1, 2 and 3; Y １ is absent or is hydroxy, sulfhydryl, amino and C １ ~C ６ selected from the group consisting of alkyl; R １ and R ２ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and methyl; R ３ is -CH ２ Cl, —CH ２ SH, -CH ２ OH, 【Hua 64】 -OCH ３ , -OCH ２ F, -OCH ２ Cl, —OCH ２ CN, -OCH ２ CH ３ , -SH, -SCH ２ F, -SCH ２ Cl, -SCH ２ CF ３ and -SCH ２ CN, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

22. Tr is absent or has the following structure: 【Chemistry 65】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

23. L ３ is selected from the group consisting of dipeptides, tripeptides, and tetrapeptides; the dipeptide is selected from the group consisting of GA, GG, AG, EG, EA, GE, DG, DA, GD, VC, VA, AA, and VK; the tripeptide is selected from the group consisting of EAG, EGG, GEG, GEA, DAG, DGG, GDG, GDA, GGA, GAG, GFG, AAG, AAA, VAG, VCG and VKG; The tetrapeptide is selected from the group consisting of GGFG, GGAG, GGGG, GEAG, GDGG, GDAG, AAAG and EAGG, preferably L ３ However, glycine-glycine-phenylalanine-glycine (GGGF), alanine-alanine-alanine-glycine (AAAG), glycine-glycine-glycine-glycine (GGGG), valine-alanine-glycine (VAG), valine-citrulline-glycine (VCG), alanine-alanine-glycine (AAG), alanine-alanine-alanine (AAA), valine-alanine (VA), valine-citrulline (VC), alanine-alanine (AA), glutamic acid-alanine-glycine-glycine (EAGG), glycine-glutamic acid-alanine-glycine (GEAG), Glycine 14. A compound of formula IVa or IVb according to claim 13 selected from the group consisting of lysine-glutamic acid-glycine-glycine (GEGG), glutamic acid-glycine-glycine (EGG), glutamic acid-alanine-glycine (EAG), valine-lysine-glycine (VKG), glycine-glutamic acid-glycine (GEG), glutamic acid-alanine (EA), glutamic acid-glycine (EG) and glycine-glutamic acid, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

24. L ２ does not exist or L ２ may or may not contain PEG branched chains or PEG linear chains, preferably (1) L ２ When does not contain PEG, L ２ teeth, 【Hua 66】 selected from the group consisting of: (2) L ２ When L contains the linear PEG chain, ２ teeth, 【Chemical Formula 67】 wherein p is any integer from 1 to 20; (3) L ２ When L contains the PEG branch chain, ２ teeth, 【Chemistry 68】 【Chemical Formula 69】 wherein q is selected from the group consisting of any integer from 1 to 30, preferably (1) L ２ When L contains the linear PEG chain, ２ teeth, 【Table 2】 (2) L ２ When L contains the PEG branch chain, ２ teeth, 【Table 3-1】 【Table 3-2】 【Table 3-3】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

25. (1) L １ is coupled to the ligand via a sulfhydryl, L １ teeth, 【Chemistry 70】 [In the formula, R Ｌ１ａ , R Ｌ１ｂ and R Ｌ１ｃ are each independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted aryl, and optionally substituted benzyl; (2) L １ is coupled to the ligand via an amino group; １ teeth, 【Chemical 71】 selected from the group consisting of: (3) L １ is coupled via click chemistry, L １ teeth, 【Chemical 72】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

26. The compound of formula IVa or IVb has the following structure: 【Table 4-1】 【Table 4-2】 【Table 4-3】 【Table 4-4】 【Table 4-5】 【Table 4-6】 【Table 4-7】 【Table 4-8】 【Table 4-9】 【Table 4-10】 【Table 4-11】 【Table 4-12】 【Table 4-13】 【Table 4-14】 【Table 4-15】 【Table 4-16】 and preferably the compound of formula IVa or IVb has the following structure: 【Chemical 73】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

27. A ligand-drug conjugate, wherein the ligand-drug conjugate has the following structure: 【Chemical 74】 [In the formula, Ab represents a ligand capable of binding to a target, and N a-I is any number from 1 to 10; Tr is as defined in claim 22; L ３ is as claimed in claim 23; L ２ is as claimed in claim 24; L １ is selected from coupling units; L in Formulas Va and Vb １ is the linkage form; R １ , R ２ , R ３ , R ４ , R ５ , B.W., C.R. ４ R ５ , n, X, Y １ and Y ２ or a pharmaceutically acceptable salt thereof.

28. The structural unit -Tr-L ３ -L ２ -L １ -but, 【Chemistry 75】 or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

29. the ligand comprises an antibody or an antigen-binding fragment thereof; Preferably, the antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, and a polyclonal antibody; and the antigen-binding fragment is selected from the group consisting of a Fab, a Fab', a F(ab')2, a Fv, a scFv, a diabody, a Fd, a dAb, a VHH, a maxibody, and a complementarity-determining region (CDR) fragment; Preferably, the ligand is selected from the group consisting of an anti-TNFα antibody or antigen-binding fragment thereof, an anti-CD40 antibody or antigen-binding fragment thereof, and an anti-IFNAR1 antibody or antigen-binding fragment thereof; 28. The ligand-drug conjugate of claim 27, wherein the ligand is preferably selected from the group consisting of adalimumab, iscalimab (CFZ533), anifrolumab (MEDI-546), infliximab, afelimomab, golimumab, BIIB059, 8c11, and derivatives and biosimilars thereof.

30. L １ When L is coupled to Ab via a sulfhydryl, １ has the following structure: 【Chemical 76】 and R Ｌ１ｃ is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted aryl; L １ When is coupled to Ab via an amino, L １ has the following structure: 【Chemical Formula 77】 selected from the group consisting of: L １ When is coupled to Ab via click chemistry, L １ has the following structure: 【Chemical 78】 28. The ligand-drug conjugate of claim 27, selected from the group consisting of:

31. The ligand-drug conjugate of claim 31, wherein the ligand-drug conjugate has the following structure: 【Table 5-1】 【Table 5-2】 【Table 5-3】 【Table 5-4】 【Table 5-5】 【Table 5-6】 【Table 5-7】 【Table 5-8】 【Table 5-9】 【Table 5-10】 【Table 5-11】 【Table 5-12】 【Table 5-13】 【Table 5-14】 【Table 5-15】 【Table 5-16】 【Table 5-17】 【Table 5-18】 【Table 5-19】 【Table 5-20】 【Table 5-21】 【Table 5-22】 【Table 5-23】 【Table 5-24】 【Table 5-25】 【Table 5-26】 【Table 5-27】 【Table 5-28】 【Table 5-29】 【Table 5-30】 【Table 5-31】 【Table 5-32】 【Table 5-33】 【Table 5-34】 【Table 5-35】 【Table 5-36】 【Table 5-37】 【Table 5-38】 【Table 5-39】 【Table 5-40】 【Table 5-41】 【Table 5-42】 【Table 5-43】 【Table 5-44】 【Table 5-45】 [In the formula, N ａ－Ｉ is any number from 1 to 10.

32. The ligand-drug conjugate has the following structure: 【Chemical 79】 [In the formula, Ab represents a ligand capable of binding to a target; N ａ－Ｉ is any number from 1 to 10; X is selected from the group consisting of —O—, —S—, and —NH—; R ４ and R ５ are each independently H, F, Cl, —OH, or —NH ２ and C １ ~C ６ selected from the group consisting of alkyl; n is selected from the group consisting of 1, 2 and 3; Y １ is absent or is hydroxy, sulfhydryl, amino and C １ ~C ６ selected from the group consisting of alkyl; R １ and R ２ are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and methyl; R ３ is -CH ２ Cl, —CH ２ SH, -CH ２ OH, 【Chemistry 80】 -OCH ３ , -OCH ２ F, -OCH ２ Cl, —OCH ２ CN, -OCH ２ CH ３ , -SH, -SCH ２ F, -SCH ２ Cl, -SCH ２ CF ３ and -SCH ２ CN, and preferably said ligand-drug conjugate has the following structure: 【Chemistry 81】 【Chemistry 82】 [In the formula, N ａ－Ｉ is any number from 1 to 10, and Ab is selected from an antibody or an antigen-binding fragment thereof.

33. A ligand-drug conjugate of the formula: 【Chemistry 83】 【Chemistry 84】 【Chemistry 85】 【Chemistry 86】 [In the formula, N ａ－Ｉ is any number from 1 to 10], or a tautomer, enantiomer or diastereoisomer thereof, or a mixture of these isomers, or a pharmaceutically acceptable salt or solvate thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 12, 13-15, 17-20 and 22-26, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a ligand-drug conjugate according to claim 27, and optionally a pharmaceutically acceptable carrier.

35. A method for affecting immune system function, comprising administering to a subject a compound according to any one of claims 1, 2, 12, 13-15, 17-20 and 22-26, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate according to any one of claims 27-33.

36. 35. A method of affecting immune system function comprising administering to a subject the pharmaceutical composition of claim 34.

37. Use of a compound according to any one of claims 1, 2, 12, 13-15, 17-20 and 22-26, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate according to any one of claims 27-33, in the preparation of a medicament for the prevention and / or treatment of diseases and / or conditions, including diseases and / or conditions associated with glucocorticoid receptor signaling, preferably wherein said disease and / or condition is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's disease, ...

10. The method of claim 1, wherein the patient is selected from the group consisting of: idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia and vasculitis, multiple sclerosis, myasthenia gravis and Guillain-Barré syndrome, ulcerative colitis, Crohn's disease, autoimmune diseases and atrophic gastritis, IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, Goodpasture's syndrome and lupus nephritis, type I diabetes, Graves' disease, Hashimoto's thyroiditis, primary adrenal atrophy and chronic thyroiditis, psoriasis, pemphigus vulgaris, lupus erythematosus, dermatomyositis and polymyalgia rheumatica, and asthma.

38. A pharmaceutical composition according to claim 34 for the manufacture of a medicament for the prevention and / or treatment of diseases and / or conditions, wherein said diseases and / or conditions include diseases and / or conditions associated with glucocorticoid receptor signaling, preferably said diseases and / or conditions include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, ankylosing spondylitis, Wegener's granulomatosis and systemic sclerosis, autoimmune hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, particular 2. The use of the present invention in a patient with a disease selected from the group consisting of: acute thrombocytopenia and vasculitis, multiple sclerosis, myasthenia gravis and Guillain-Barré syndrome, ulcerative colitis, Crohn's disease, autoimmune diseases and atrophic gastritis, IgA nephropathy, primary nephrotic syndrome, autoimmune glomerulonephritis, Goodpasture's syndrome and lupus nephritis, type I diabetes, Graves' disease, Hashimoto's thyroiditis, primary adrenal atrophy and chronic thyroiditis, psoriasis, pemphigus vulgaris, lupus erythematosus, dermatomyositis and polymyalgia rheumatica, and asthma.

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