-based molecular glue derivatives and their uses

Abstract

Molecular glue derivatives or their tautomers, meso-isomers, racemates, enantiomers, diastereomers, and pharmaceutical salts, hydrates, solvates thereof, as well as methods for their use and preparation are provided.

Description

[Technical Field]

[0001] This invention claims priority from a prior patent application bearing patent application number 202310116140.4 and entitled "Dromide-based molecular glue derivatives and their uses," filed with the State Intellectual Property Office of China on February 15, 2023, the entire text of which is incorporated herein by reference.

[0002] The present invention belongs to the field of pharmaceutical technology, specifically to a dodamide-based molecular glue derivative and its use for antitumor purposes. [Background technology]

[0003] Domide compounds have long been used as clinical therapeutic agents in the fields of immunomodulation and antitumor. For example, thalidomide has long been used to treat leprosy and several skin diseases, such as discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and Behçet's syndrome. Pomalidomide and lenalidomide are commonly used in the treatment of multiple myeloma. Recent research has revealed that these domide molecules have a mechanism of action similar to "molecular glue," achieving therapeutic effects by degrading corresponding target proteins. Currently available domide small molecules suffer from problems such as high toxicity and poor efficacy. For example, thalidomide is the culprit behind the well-known "thalidomide disaster." Research into structural modifications of this type of domide compound has become increasingly widespread. Among them, Orum Therapeutics obtained Smol006 through structural modifications of this type of domide compound, which was then combined with antibody-coupled delivery technology to obtain the antibody-drug conjugate ORM-5029. This antibody-drug conjugate exhibited very good antitumor activity and good safety profile. However, during the research process, it was discovered that Smol006 only had moderate activity, and that it was not sufficient as an active ingredient of antibody-drug conjugates for tumors with relatively low receptor expression, so there is a strong need to develop a compound with higher activity. Summary of the Invention

[0004] The present invention provides a domide-based molecular glue derivative that has superior antitumor effects and is safer.

[0005] The present invention provides a compound having the structure shown in formula (I) or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof: [ka] Among them, A is H, D, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 selected from halogenated alkyl groups, B is H, D, halogen, -NH2, -NO2, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 selected from halogenated alkyl groups, W is selected from -C(=O)- or -CH2-; L a is an alkylene group chain of 1 to 4 carbons, wherein each alkylene group is independently optionally substituted with -NH-, -O-, -C(=O)-, -C(=NH)-, -C(=S)-, -CF2-, -S(=O)-, -S(=O)2-, -C(-OH)H-, -C(NH2)H-, or -C(=NC≡N)-; x is selected from integers of 0 to 4, for example, 0, 1, 2, 3, or 4; y is selected from integers of 0 to 4, for example, 0, 1, 2, 3, or 4; z is selected from integers of 0 to 4, for example, 0, 1, 2, 3, or 4; [ka] is C 6-14 selected from an aryl group, a 5- to 6-membered heteroaryl group, and a 3- to 18-membered cycloalkyl group; R a and R bare H, D, halogen, -OH, -CN, -NO2, -NH2, and C, respectively. 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy group, -R c , -OR c , -CH(R c )OH, -CHCH(R c )OH, -NH(R c ), independently selected from R c is H, a 3- to 8-membered cycloalkyl group, C 6-14 Aryl group, benzyl group, C 1-6 alkyl groups, L b is an optionally substituted C 1-20 (For example, C 1-18 , C 1-16 , C 1-14 , C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 3-12 , C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 ) alkylene groups, wherein each alkylene group is independently selected from -CR e R f -, -O-, -S-, -NR d optionally substituted with -, a 3- to 8-membered cycloalkylene group, or a 3- to 8-membered heterocyclylene; R d is H, C 1-12 Alkyl group, 3-8 membered cycloalkyl group, benzyl group, C 6-14 Aryl group, 5-6 membered heteroaryl ring, C 1-12 selected from an alkoxycarbonyl group, -Boc, -Cbz, -Fmoc, an acetyl group, and a trifluoroacetyl group; R e and R fare H and C, respectively. 1-12 Alkyl group, 3-8 membered cycloalkyl group, benzyl group, C 6-14 independently selected from an aryl group, a 5- to 6-membered heteroaryl group, P is selected from -H, and when the atom linked to P is a nitrogen atom, P may be selected from a linear or branched aliphatic oxycarbonyl group having 1 to 12 carbon atoms, -Boc, -Cbz, -Fmoc, a formyl group, an acetyl group, or a trifluoroacetyl group; and when the atom linked to P is an oxygen atom, P may be selected from an acetyl group, a trifluoroacetyl group, a trimethylsilyl group, a dimethyl tert-butylsilyl group, or a diphenyl tert-butylsilyl group.

[0006] In some embodiments of the present invention, A is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, and pentafluoroethyl.

[0007] In some embodiments of the present invention, B is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, pentafluoroethyl, amino, and nitro.

[0008] In some embodiments of the present invention, W is selected from -CH2-.

[0009] In some embodiments of the present invention, L a is an alkylene chain of 1 to 4 carbons, wherein each alkylene group is independently optionally substituted with -NH-, -C(=O)-, -C(=S)-, or -CF2-; and Q1 is selected from phenyl, naphthyl, pyridinyl, pyrazolyl, furanyl, thiazolyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0010] In some embodiments of the present invention, R a and R brespectively represent hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, amino group, methyl group, ethyl group, n-propyl group, isopropyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, pentafluoroethyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, trifluoromethoxy group, difluoromethoxy group, fluoromethoxy group, pentafluoroethoxy group, hydroxy group, -R c , -OR c , -CH(R c )OH, -CHCH(R c )OH, or -NH(R c ), among which R c is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, methyl, ethyl, n-propyl, and isopropyl.

[0011] In some embodiments of the present invention, L b is an optionally substituted C 1-20 (For example, C 1-18 , C 1-16 , C 1-14 , C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 3-12 , C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 ) alkylene groups, wherein each alkylene group is independently selected from -CR e R f -, -O-, -S-, -NR d It may be substituted with a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group, a piperidinylene group, a tetrahydropyranylene group, a pyrrolidinylene group, or a tetrahydrofuranylene group.

[0012] In some embodiments of the present invention, R d is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazolyl, thiazolyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, -Boc, -Cbz, -Fmoc, acetyl, and trifluoroacetyl.

[0013] In some embodiments of the present invention, R e and R f are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazolyl, and thiazolyl.

[0014] In some embodiments of the present invention, P is selected from -H; when the atom linked to P is a nitrogen atom, P may be selected from a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, -Boc, -Cbz, -Fmoc, a formyl group, an acetyl group, or a trifluoroacetyl group; and when the atom linked to P is an oxygen atom, P may be selected from an acetyl group, a trifluoroacetyl group, a trimethylsilyl group, a dimethyl tert-butylsilyl group, or a diphenyl tert-butylsilyl group.

[0015] In some embodiments of the present invention, there is provided a compound having the structure shown in formula (I-1) or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, and pharmaceutical salt, hydrate, solvate thereof: [ka] wherein U is selected from -NH-, -CH2-, and -CF2-; R1 is hydrogen, halogen, C 1-6 Alkyl group, C 1-6selected from halogenated alkyl groups and 3- to 8-membered cycloalkyl groups, X1 and X2 are each independently selected from —O—, —S—, and a bond; X3 is selected from -N(R7)- and a bond; L1 and L2 are bond and -C, respectively. 1-6 Alkyl group -, -C 1-6 Alkyl group -CH(R3)-C 1-6 Alkyl group -, -C(R3)(R4)-C 1-6 Alkyl group -, -C 1-6 Alkyl group -3 to 8-membered cycloalkyl group-C 1-6 Alkyl group -, -3 to 8-membered cycloalkyl group -C 1-6 Alkyl group -, -C 1-6 alkyl group-3-8-membered heterocyclyl group-C 1-6 Alkyl group -, -3 to 8-membered heterocyclyl group -C 1-6 alkyl group, R3 and R4 are H and C, respectively. 1-6 Alkyl group, C 6-14 are independently selected from an aryl group and a 3- to 8-membered cycloalkyl group, or R3 and R4 together with the carbon atom connected thereto form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group; R2 is H, an optionally substituted substituent: C 1-6 Alkyl group, 3- to 16-membered cycloalkyl group, 3- to 16-membered heterocyclyl group, -C 1-6 Alkyl group -C(R5)(R6)-C 1-6 Alkyl group -, -C 1-6 alkyl group -C(R5)(R6)-; R5 and R6 are H and C, respectively. 1-6 Alkyl group, C 6-14 are independently selected from an aryl group and a 3- to 8-membered cycloalkyl group, or R5 and R6 together with the carbon atom connected thereto form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered heterocyclyl group; R7 is H, an optionally substituted substituent: C 1-6selected from an alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, or -N(R7)(R2) together form a 3- to 16-membered heterocyclyl group; Among these, the optionally substituted substituents include —OH, C 1-6 Alkyl group, (R8)(R9)NH-, 3- to 8-membered heterocyclyl group, C 1-6 selected from an alkyloxycarbonyl group (e.g., a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group), a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc); R8 and R9 are H and C, respectively. 1-6 Alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, C 6-14 independently selected from an aryl group and a benzyl group; The heteroatoms of the heterocyclyl group are selected from O, S and N.

[0016] In some embodiments of the present invention, R1 is hydrogen, fluorine, chlorine, bromine, iodine, C 1-3 Alkyl group, C 1-3 It is selected from halogenated alkyl groups and 3- to 6-membered cycloalkyl groups.

[0017] In some embodiments of the present invention, L1 and L2 are each a bond, -C 1-3 Alkyl group -, -C 1-3 Alkyl group -CH(R3)-C 1-3 Alkyl group -, -C(R3)(R4)-C 1-3 Alkyl group -, -C 1-3 Alkyl group - 3 to 6-membered cycloalkyl group -C 1-3 Alkyl group -, -3 to 6-membered cycloalkyl group -C 1-3 Alkyl group -, -C 1-3 Alkyl group-5-6 membered heterocyclyl group-C 1-3 Alkyl group -, -5-6 membered heterocyclyl group -C 1-3 alkyl groups independently selected from:

[0018] In some embodiments of the present invention, R3 and R4 are each H, C 1-3 R3 and R4 are independently selected from an alkyl group, a phenyl group, and a 3- to 6-membered cycloalkyl group, or R3 and R4 together with the carbon atom connected thereto form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group.

[0019] In some embodiments of the present invention, R2 is H, an optionally substituted substituent: C 1-3 Alkyl groups, 3- to 8-membered monocyclic cycloalkyl groups, 6- to 14-membered spirocyclic cycloalkyl groups, 5- to 14-membered fused-ring cycloalkyl groups, 5- to 14-membered bridged-ring cycloalkyl groups, 3- to 8-membered monocyclic heterocyclyl groups, 6- to 14-membered spirocyclic heterocyclyl groups, 5- to 14-membered fused-ring heterocyclyl groups, 5- to 14-membered bridged-ring heterocyclyl groups, -C 1-3 Alkyl group -C(R5)(R6)-C 1-3 Alkyl group -, -C 1-3 The alkyl group is selected from -C(R5)(R6)-.

[0020] In some embodiments of the present invention, R5 and R6 are each H, C 1-3 R5 and R6 are independently selected from an alkyl group, a phenyl group, and a 3- to 6-membered cycloalkyl group, or R5 and R6 together with the carbon atom connected thereto form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group.

[0021] In some embodiments of the present invention, R7 is H, an optionally substituted substituent: C 1-3 It is selected from an alkyl group, a 3- to 6-membered cycloalkyl group, and a 5- to 6-membered heterocyclyl group, or -N(R7)(R2) together form a 3- to 8-membered monocyclic heterocyclyl group, a 6- to 14-membered spirocyclic heterocyclyl group, a 5- to 14-membered fused-ring heterocyclyl group, or a 5- to 14-membered bridged-ring heterocyclyl group.

[0022] In some embodiments of the present invention, the optionally substituted substituents are OH—, C 1-3Alkyl group, (R8)(R9)NH-, 5-6 membered heterocyclyl group, C 1-3 It is selected from alkyloxycarbonyl groups.

[0023] In some embodiments of the present invention, R8 and R9 are each H, C 1-3 It is independently selected from an alkyl group, a 3- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclyl group, a phenyl group, and a benzyl group.

[0024] In some embodiments of the present invention, R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] In some embodiments of the present invention, L1 and L2 are each a bond, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, a tert-butylene group, an n-pentylene group, an n-hexylene group, -methyl-C(R3)(R4)-methyl-, -methyl-C(R3)(R4)-ethyl-, -methyl-C(R3)(R4)-propyl-, -ethyl-C(R3)(R4)-ethyl-, -propyl-C(R3)(R4)-ethyl-, -propyl-C(R3)(R4)-propyl-, -C(R3)(R4)-methyl-, -C(R3)(R4)-ethyl-, or -C(R3)(R4). -propyl group, -C(R3)(R4)-butyl group, -C(R3)(R4)-pentyl group, -C 1-3 Alkyl group-Cyclopropyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group -Cyclobutyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group-Cyclopentyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group -Cyclohexyl group-C 1-3 Alkyl group -, -C1-3 Alkyl group -Cyclopropyl group-, -C 1-3 Alkyl group -Cyclobutyl group-, -C 1-3 Alkyl group -Cyclopentyl group-, -C 1-3 Alkyl group -Cyclohexyl group-, -C 1-3 Alkyl group-Tetrahydropyranyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group-Piperidinyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group-Tetrahydrofuranyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group-pyrrolidinyl group-C 1-3 Alkyl group -, -C 1-3 Alkyl group - tetrahydropyranyl group, -C 1-3 Alkyl group - piperidinyl group, -C 1-3 Alkyl group -Tetrahydrofuranyl group-, -C 1-3 Independently selected from alkyl groups and pyrrolidinyl groups.

[0026] In some embodiments of the present invention, R3 and R4 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or R3 and R4 together with the carbon atoms connected thereto form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, or pyrrolidinyl group.

[0027] In some embodiments of the invention, R2 is H, optionally substituted substituents: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -methyl-C(R5)(R6)-methyl-, -methyl-C(R5)(R6)-ethyl-, -methyl-C(R5)(R6)-propyl-, -ethyl-C(R5)(R6)-ethyl- , -propyl group-C(R5)(R6)-ethyl group-, -propyl group-C(R5)(R6)-propyl group-, -C(R5)(R6)-methyl group-, -C(R5)(R6)-ethyl group-, -C(R5)(R6)-propyl group-, -C(R5)(R6)-butyl group-, -C(R5)(R6)-pentyl group-, azetidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, phenyl group, [ka] Selected from.

[0028] In some embodiments of the present invention, R5 and R6 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; or R5 and R6 together with the carbon atoms connected thereto form a cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydrothiophenyl group.

[0029] In some embodiments of the invention, R7 is selected from H, optionally substituted substituents: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, or -N(R7)(R2) is [ka] Form.

[0030] In some embodiments of the present invention, the optionally substituted substituents are selected from OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (R8)(R9)N-, azetidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tert-butoxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), and sulfonic acid.

[0031] In some embodiments of the present invention, R8 and R9 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, phenyl, and benzyl.

[0032] In some embodiments of the invention, R2 is H, optionally substituted substituents: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -methyl-C(R5)(R6)-methyl-, -methyl-C(R5)(R6)-ethyl-, -methyl-C(R 5) (R6)-propyl group, -ethyl group, -C(R5)(R6)-ethyl group, -propyl group, -C(R5)(R6)-ethyl group, -propyl group, -C(R5)(R6)-propyl group, -C(R5)(R6)-methyl group, -C(R5)(R6)-ethyl group, -C(R5)(R6)-propyl group, -C(R5)(R6)-butyl group, -C(R5)(R6)-pentyl group, phenyl group, [ka] TIFF2026506684000007.tif180169 Selected from.

[0033] In some embodiments of the present invention, R2 is hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, CH3NH-, a cyclopropyl group, a cyclohexyl group, a phenyl group, [ka] Selected from.

[0034] In some embodiments of the invention, R2 is [ka] Selected from.

[0035] In some embodiments of the present invention, L1 and L2 are each a bond, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, a tert-butylene group, an n-pentylene group, an isopentylene group, a neopentylene group, an n-hexylene group, a 2-methylpentylene group, a 3-methylpentylene group, [ka] are independently selected from

[0036] In some embodiments of the present invention, L1 and L2 are each a bond, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, a tert-butylene group, an n-pentylene group, an isopentylene group, a neopentylene group, an n-hexylene group, a 2-methylpentylene group, a 3-methylpentylene group, [ka] are independently selected from

[0037] In some embodiments of the present invention, L1 and L2 are each a bond, [ka] are independently selected from

[0038] In the present invention, [ka] have the same meaning and represent a bond.

[0039] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-2): [ka] wherein R2 is defined as in formula (I-1), and m and n are each independently selected from integers of 0 to 6, for example, 0, 1, 2, 3, 4, 5, and 6.

[0040] In some embodiments of the present invention, R2 is selected from optionally substituted 3- to 16-membered heterocyclyl groups, wherein the heteroatom of said heterocyclyl group is selected from nitrogen.

[0041] In some embodiments of the present invention, R2 is selected from the group consisting of optionally substituted 3- to 8-membered monocyclic heterocyclyl groups, 6- to 14-membered spirocyclic heterocyclyl groups, 5- to 14-membered fused-ring heterocyclyl groups, and 5- to 14-membered bridged-ring heterocyclyl groups, wherein the heteroatom of said heterocyclyl groups is selected from nitrogen.

[0042] In some embodiments of the present invention, R2 is selected from optionally substituted 5-6 membered monocyclic heterocyclyl groups.

[0043] In some embodiments of the present invention, R2 is an optionally substituted substituent: an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, [ka] Selected from.

[0044] In some embodiments of the invention, R2 is an optionally substituted substituent: [ka] Selected from.

[0045] In some embodiments of the present invention, the optionally substituted substituents are H, C 1-3 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3It is selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc).

[0046] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-3): [ka] wherein m and n are independently selected from integers of 0 to 6, for example, 0, 1, 2, 3, 4, 5, and 6. In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-4):

[0047] [ka] Among them, the definitions of L1, X2, and R2 are the same as those in formula (I-1).

[0048] In some embodiments of the invention, L1 is [ka] Selected from.

[0049] In some embodiments of the invention, R2 is an optionally substituted substituent: [ka] Selected from.

[0050] In some embodiments of the invention, the optionally substituted substituent is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3It is selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc).

[0051] In some embodiments of the invention, X2 is selected from -O-, -S-.

[0052] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-5): [ka] Among these, the definitions of L1 and R2 are the same as in formula (I-1).

[0053] In some embodiments of the invention, L1 is [ka] Selected from.

[0054] In some embodiments of the invention, R2 is [ka] Selected from.

[0055] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-6): [ka] Among them, the definitions of L1, L2, and R2 are the same as in formula (I-1).

[0056] In some embodiments of the present invention, L1 and L2 each represent: [ka] are independently selected from

[0057] In some embodiments of the invention, R2 is [ka] Selected from.

[0058] In some embodiments of the present invention, L1 is selected from a methylene group.

[0059] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-7): [ka] Among them, the definitions of L1, R2, and R7 are the same as in formula (I-1).

[0060] In some embodiments of the present invention, L1 is -C 1-6 alkyl groups.

[0061] In some embodiments of the present invention, L1 is selected from a methylene group, an ethylene group, an n-propylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group.

[0062] In some embodiments of the invention, R2 is [ka] Selected from.

[0063] In some embodiments of the present invention, R7 is H, a methyl group, [ka] Selected from.

[0064] In some embodiments of the present invention, R2 and R7 together with the N to which they are attached [ka] Form.

[0065] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-8): [ka] Among these, the definitions of L1 and R2 are the same as in formula (I-1).

[0066] In some embodiments of the present invention, L1 is -C 1-6 alkyl groups.

[0067] In some embodiments of the present invention, L1 is selected from a methylene group, an ethylene group, an n-propylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group.

[0068] In some embodiments of the invention, R2 is an optionally substituted substituent: [ka] Selected from.

[0069] In some embodiments of the invention, the optionally substituted substituent is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 It is selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc).

[0070] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-9): [ka] Among these, the definitions of X1, X2, L1, R2, and U are the same as those in formula (I-1).

[0071] In some embodiments of the present invention, X1 and X2 are selected from -O-.

[0072] In some embodiments of the present invention, L1 is -C 1-6 alkyl groups.

[0073] In some embodiments of the present invention, L1 is selected from a methylene group, an ethylene group, an n-propylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group.

[0074] In some embodiments of the present invention, R2 is selected from optionally substituted piperidinyl groups.

[0075] In some embodiments of the invention, R2 is an optionally substituted substituent: [ka] Selected from.

[0076] In some embodiments of the invention, the optionally substituted substituent is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 It is selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc).

[0077] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-10): [ka] Among these, the definitions of L1, R2, and U are the same as those in formula (I-1).

[0078] In some embodiments of the present invention, U is selected from -NH-.

[0079] In some embodiments of the present invention, L1 is -C 1-6 alkyl groups.

[0080] In some embodiments of the present invention, L1 is selected from a methylene group, an ethylene group, an n-propylene group, an n-butylene group, an n-pentylene group, and an n-hexylene group.

[0081] In some embodiments of the present invention, R2 is an optionally substituted substituent: an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, [ka] Selected from.

[0082] In some embodiments of the invention, R2 is an optionally substituted substituent: [ka] Selected from.

[0083] In some embodiments of the present invention, the optionally substituted substituents are H, C 1-3 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3It is selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc).

[0084] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-11): [ka] Among them, R 10 is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc); m and n are each independently selected from integers of 0 to 6, for example, 0, 1, 2, 3, 4, 5, and 6.

[0085] In some embodiments of the present invention, the compound having the structure shown in formula (I-1) has the structure shown in formula (I-12): [ka] Among them, R 10 is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 selected from an alkyloxycarbonyl group, a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc); m and n are each independently selected from integers of 0 to 6, for example, 0, 1, 2, 3, 4, 5, and 6.

[0086] In the present invention, [ka] have the same meaning and represent a bond.

[0087] In some embodiments of the present invention, there is provided a compound having the following structure: or a tautomer, meso form, racemic form, enantiomer, diastereomer, and pharmaceutical salt, hydrate, or solvate thereof:

[0088] [ka] TIFF2026506684000042.tif255169 TIFF2026506684000043.tif250169 TIFF2026506684000044.tif250169 TIFF2026506684000045.tif104169

[0089] In some embodiments, the present invention provides use of a compound of Formula (I-1) to Formula (I-12) and the above table, or a tautomer, meso form, racemate, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating cancer.

[0090] In some embodiments, the cancer comprises liver cancer, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), stomach cancer, esophageal cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, hematological tumors or glioblastoma multiforme, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), cervical cancer, uterine cancer, endometrial cancer, salivary gland cancer, glioma, neuroblastoma, sarcoma, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, etc. The above cancers are preferably cancers associated with the abnormal expression of HER2, Claudin 18.2, DLL3, and BCMA, and more preferably, cancers associated with the abnormal expression of HER2 include lung cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer, endometrial cancer, gastric cancer, and prostate cancer, cancers associated with the abnormal expression of DLL3 include lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and cancers associated with the abnormal expression of BCMA include lymphoma (multiple myeloma).

[0091] In some embodiments, the present invention provides use of a compound of Formula (I-1) to Formula (I-12) and the Tables above, or a tautomer, meso form, racemate, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof, for treating cancer.

[0092] In some embodiments, the cancer comprises liver cancer, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), stomach cancer, esophageal cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, hematological tumors or glioblastoma multiforme, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), cervical cancer, uterine cancer, endometrial cancer, salivary gland cancer, glioma, neuroblastoma, sarcoma, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, etc. The above cancers are preferably cancers associated with the abnormal expression of HER2, Claudin 18.2, DLL3, and BCMA, and more preferably, cancers associated with the abnormal expression of HER2 include lung cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer, endometrial cancer, gastric cancer, and prostate cancer, cancers associated with the abnormal expression of DLL3 include lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and cancers associated with the abnormal expression of BCMA include lymphoma (multiple myeloma).

[0093] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula (I-1) to Formula (I-12) and the Tables above, or a tautomer, meso form, racemate, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable adjuvants.

[0094] In some embodiments, the present invention provides an antibody-drug conjugate of the following formula (II), and pharmaceutical salts, hydrates, solvates, stereoisomers, or isotopically labeled compounds thereof: [ka] Among them, Ab is selected from an antibody or antigen-binding fragment; L is a linker moiety, one end of which is linked to Ab and the other end of which is linked to a biologically active molecule D; D is a structure formed by linking the compound represented by formula (I) to L, d is selected from integers or decimals of 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7, or 8; When d is a decimal number, it refers to the average number of linker-drug molecules conjugated per antibody unit.

[0095] In some embodiments of the present invention, D is a structure formed by linking a compound represented by formulae (I-1) to (I-12) to L, and more preferably D is a structure formed by linking the above compounds B1 to B96 to L, preferably via a nitrogen atom, more preferably via a nitrogen atom on R2 or linked to R2, for example: [ka] and Among them, the wavy line indicates the linkage between D and L.

[0096] In some embodiments, the Ab is selected from antibodies or antigen-binding fragments thereof that target HER2, DLL3, Claudin18.2, or BCMA.

[0097] In some embodiments, the Ab is selected from Trastuzumab (heavy chain and light chain combination: SEQ ID NOs: 1 and 2), or Pertuzumab (heavy chain and light chain combination: SEQ ID NOs: 3 and 4), SYM003 (heavy chain and light chain combination: SEQ ID NOs: 5 and 6), SYM004 (heavy chain and light chain combination: SEQ ID NOs: 7 and 8), or Belantamab (heavy chain and light chain combination: SEQ ID NOs: 9 and 10).

[0098] In some embodiments, -L- is selected from -S-L'-TC-, where S is an active functional group for linking to an antibody, L' is a spacing linking fragment or is absent, T is an optionally present functional group that triggers cleavage of the linker, and C is an optionally present autolytic spacing fragment.

[0099] In some embodiments, S is optionally formed from an Sr group that reacts with an antibody or antigen-binding fragment Ab. Sr preferably includes a sulfhydryl-reactive group, an amino-reactive group, a carboxy-reactive group, a disulfide bond crosslinking group, or the like. For antibodies incorporating unnatural amino acids, it may include a click chemistry reactive group such as a ketone, hydrazine or hydrazide, azide, an alkyne such as a ring-strained alkyne, a cyclopropene, or a diene. The antibody Ab binding site may include any suitable amino acid residue or N297 glycosylation linkage of the CH2 domain, such as fucose, galactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and sialic acid (SA) introduced by glycoengineering. The conjugation reaction may involve chemical or enzymatic reactions, such as the transfer of an amine-containing drug linker or reactive spacer to a deglycosylated antibody using transglutaminase (MTGase).

[0100] For example, when Sr comprises a methylsulfonylpyrimidinyl group or a maleimide group, S comprises the following fragment attached to an antibody: [ka] Among them, the left wavy line indicates the binding site with the antibody moiety, and the right wavy line indicates the binding site with the remaining part of Sr or L' (T if L' is absent).

[0101] In some embodiments, Sr is an optional binding fragment S L Further includes S L is an optionally substituted C 1-10 Alkylene group, alkenylene group or alkynylene group, C 6-12 Arylene group or C 3-12 Cycloalkylene group, C 2-11 Heteroarylene group or C 2-11 heterocyclylene groups or combinations thereof, and optionally spaced by O, CO, NH or combinations thereof, preferably S L contains an alkynyl group or a polyethylene glycol fragment, more preferably S Lincludes a cyclohexyl group, a phenyl group, a triazolyl group, a piperidinyl group, or a piperazinyl group.

[0102] In some embodiments, L' comprises a hydrophilically modified fragment such as a polyethylene glycol fragment, and in some other embodiments, L' comprises an amino acid residue having a tertiary amine or quaternary ammonium group in the side chain.

[0103] In some embodiments, T is a peptide fragment, a bivalent peptide group comprising 1 to 8 (specifically 1, 2, 3, 4, 5, 6, 7, or 8) optionally substituted natural or unnatural amino acid residues in L- or D-form, each of which may be homologous or different, including the following amino acid residues: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), and the like. ), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, demethylpyrrolysine, or analogs of the above amino acids, such as, for example, -ValCit-, -CitVal-, -AlaAla-, - AlaCit-, -CitAla-, -AsnCit-, -CitAsn-, -CitCit-, -ValGlu-, -GluVal-, -SerCit-, -CitSer-, -LysCit-, -CitLys-, -AspCit-, -CitAsp-, -AlaVal- , -ValAla-, -PheAla-, -AlaPhe-, -PheLys-, -LysPhe-, -ValLys-, -LysVal-, -AlaLys-, -LysAla-, -PheCit-, -CitPhe-, -LeuCit-, -CitLeu-, -IleCi t-, -CitIle-, -PheArg-, -ArgPhe-, -CitTrp-, -TrpCit-, -AlaAlaAla-, -PhePheLys-, -LysPhePhe-, -DPhePheLys-, -DLysPhePhe-, -GlyPheLys-, -L ysPheGly-, -GlyPheLeuGly-, -GlyLeuPheGly-, -GluValCit-, -AlaLeuAlaLeu-, -GlyGlyGly-, -GlyGlyGlyGly-, -GlyPheValGly-, -GlyValPheGly-,-GlyGlyPheGly-, -GlyGlyValGly-.

[0104] In further embodiments, L' is located at either end of the peptide fragment T, or between any two amino acids, or replaces any one amino acid.

[0105] In some embodiments, S, L', T, C and D are linked together by any functional group, preferably an amide bond in which the N atom is optionally substituted with a methyl group.

[0106] In some embodiments, Sr is selected from Sr1 to Sr11. [ka]

[0107] In some embodiments, L' is selected from L'1 to L'7. [ka]

[0108] In some embodiments, T is selected from T1 to T11. [ka]

[0109] In some embodiments, C is selected from C1 and C2. [ka]

[0110] In some embodiments of the present invention, Formula (II) has a structure shown in Formula (II-a1) or Formula (II-a2): [ka] Among them, Ab, SL , L', C, D and d have the same meanings as above.

[0111] In some embodiments of the present invention, Formula (II) is a structure represented by Formula (II-b1) to Formula (II-b4): [ka] wherein L' is absent, T is a peptide fragment, C is an autolytic spacing fragment, and the remaining groups have the same meanings as above.

[0112] In some embodiments of the present invention, formula (II) has a structure represented by formulas (II-c1) to (II-c5). [ka]

[0113] In some embodiments of the present invention, the Ab is selected from Trastuzumab (heavy chain and light chain combination: SEQ ID NOs: 1 and 2), or Pertuzumab (heavy chain and light chain combination: SEQ ID NOs: 3 and 4), SYM003 (heavy chain and light chain combination: SEQ ID NOs: 5 and 6), SYM004 (heavy chain and light chain combination: SEQ ID NOs: 7 and 8), Belantamab (heavy chain and light chain combination: SEQ ID NOs: 9 and 10).

[0114] In this case, d is selected from integers or decimals of 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7, and 8.

[0115] When d is a decimal number, it refers to the average number of linker-drug molecules conjugated per antibody unit.

[0116] The present invention provides a compound of formula (III): [ka] Among them, Sr, L', T, C and D have the same definitions as above.

[0117] In some embodiments, the present invention provides compounds of formula (III-a1) and (III-a2): [ka] wherein Sr, L', T, C, m, and n have the same definitions as above, and preferably, Sr contains a maleimide group or a methylsulfonylpyrimidinyl group, L' is absent, T is a peptide fragment, and C is [ka] is.

[0118] In some embodiments, the present invention provides compounds of formulae (III-b1) to (III-b5): [ka]

[0119] The present invention further provides the use of a compound of formula I in the manufacture of an antibody drug conjugate (ADC).

[0120] In the present invention, the antibody is linked to the compound of formula (III) by a coupling method commonly used in the art, such as lysine coupling, inter-heavy chain reductive disulfide bond coupling, and directed coupling (Beck A, Reichert JM. Antibody-drug conjugates: Present and future; MAbs, 2014, 6:15-17; McCombs JR, Owen S C. Antibody drug conjugates: design and selection of linker, payload, and conjugation chemistry. The AAPS journal, 2015, 17:339-351). In the present invention, the antibody is preferably linked by inter-heavy chain reductive disulfide bond coupling, i.e., by reaction with a thiol group (sulfur atom of a cysteine ​​residue) formed by reduction of one or more of the inter-heavy chain disulfide bond sites (two sites between heavy chains, two sites between heavy and light chains).

[0121] Furthermore, the present invention provides a pharmaceutical composition comprising the antibody-drug conjugate according to the present invention and a pharmaceutical salt, hydrate, solvate, stereoisomer, or isotope-labeled compound thereof, which further comprises pharmaceutically acceptable adjuvants and carriers.

[0122] Furthermore, the present invention provides the use of the antibody-drug conjugate according to the present invention and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof in the manufacture of a medicament for treating cancer.

[0123] In some embodiments, the cancer is selected from the group consisting of liver cancer, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), stomach cancer, esophageal cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, hematological tumors or glioblastoma multiforme, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), cervical cancer, uterine cancer, endometrial cancer, salivary gland cancer, glioma, neuroblastoma, sarcoma, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, The cancers include leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, etc., and the above cancers are preferably cancers associated with the abnormal expression of HER2, Claudin 18.2, DLL3, and BCMA. More preferably, cancers associated with the abnormal expression of HER2 include lung cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer, endometrial cancer, gastric cancer, and prostate cancer, cancers associated with the abnormal expression of DLL3 include lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and cancers associated with the abnormal expression of BCMA include lymphoma (multiple myeloma).

[0124] In some embodiments, the present invention provides the use of an antibody-drug conjugate according to the present invention and pharmaceutical salts, hydrates, solvates, stereoisomers, or isotopically labeled compounds thereof for treating cancer.

[0125] In some embodiments, the cancer is selected from the group consisting of liver cancer, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), stomach cancer, esophageal cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, hematological tumors or glioblastoma multiforme, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), cervical cancer, uterine cancer, endometrial cancer, salivary gland cancer, glioma, neuroblastoma, sarcoma, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, The cancers include leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, etc., and the above cancers are preferably cancers associated with the abnormal expression of HER2, Claudin 18.2, DLL3, and BCMA. More preferably, cancers associated with the abnormal expression of HER2 include lung cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer, endometrial cancer, gastric cancer, and prostate cancer, cancers associated with the abnormal expression of DLL3 include lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and cancers associated with the abnormal expression of BCMA include lymphoma (multiple myeloma).

[0126] The dodamide-based molecular glue compounds of the present invention have superior efficacy, such as superior cellular activity and superior tumor-suppressing effect, compared to prior art compounds such as Orum Therapeutics' Smol006. The compounds of the present invention are useful for producing antibody-drug conjugates (ADCs), and the produced ADCs also have superior efficacy, such as superior cellular activity and superior tumor-suppressing effect.

[0127] Abbreviations and Definitions Unless otherwise specified, the following terms used in this application have the following meanings.

[0128] When a trade name is used in this application, unless otherwise specified, the trade name includes the ingredient combination, generic drug, and active drug ingredient of the product that the trade name represents.

[0129] Unless otherwise specified, the term "antibody-drug conjugate" refers to an antibody (e.g., a monoclonal antibody) or antibody fragment linked to a biologically active cytotoxic drug via a stable chemical linker compound.

[0130] Unless otherwise specified, the term "linker-drug compound" refers to the structure of the portion of an "antibody-drug conjugate" that consists of a linker compound and a drug compound.

[0131] The linker-drug compound of the present invention is linked to the antibody by a coupling method commonly used in the art, such as lysine coupling, inter-light / heavy chain reductive disulfide bond coupling, and directed coupling (Beck A, Reichert JM. Antibody-drug conjugates: Present and future; MAbs, 2014, 6:15-17; McCombs JR, Owen S C. Antibody drug conjugates: design and selection of linker, payload, and conjugation chemistry. The AAPS journal, 2015, 17:339-351). In the present invention, the linker-drug compound is preferably linked by inter-light / heavy chain reductive disulfide bond coupling, i.e., by reaction with a thiol group (sulfur atom of a cysteine ​​residue) formed by reduction of one or more of the inter-light / heavy chain disulfide bond sites (two sites between heavy chains, two sites between heavy and light chains).

[0132] The term "tautomer" refers to isomers with different energies that can be converted into one another via a low energy barrier. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called proton-transition tautomers) include tautomers that interconvert via proton transition, e.g., ketone-enol isomerization and imine-enamine isomerization. Valence tautomers include tautomers that interconvert via recombination of bonding electrons.

[0133] The compounds of the present invention can exist in isotopically labeled or enriched forms, and contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the largest number of atoms found in nature. The isotopes can be radioactive or non-radioactive. Isotopes commonly used as isotopic labels include hydrogen isotopes. 2 H and 3 H, carbon isotope 13 C and 14 C, chlorine isotope 35 Cl and 37 Cl, fluorine isotopes 18 F, an iodine isotope 123 I and 125 I, nitrogen isotope 13 N and 15 N, oxygen isotopes 15 O. 17 O and 18 O and sulfur isotopes 35 These isotopically labeled compounds can be used to study the distribution of medicinal molecules in tissues. 2 H and 13 C is more widely applied because it is easy to label and detect. Some heavy isotopes, e.g., deuterium ( 2 Substitution of H can improve metabolic stability and extend half-life, thereby achieving the goal of reducing dosage, thereby providing therapeutic advantages. Isotopically labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just as non-isotopically labeled compounds are synthesized. This application includes various deuterated forms. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. In addition to commercially available deuterated molecular blocks, deuterated products can be prepared using commercially available deuterated starting materials or synthesized using conventional techniques using deuterated reagents, including, but not limited to, deuterated water, deuterated acetone, deuterated methanol, deuterated acetonitrile, deuterated borane, sodium deuterated borohydride, and lithium aluminum deuterated hydride.

[0134] The terms "solvate" and "solvate" refer to a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). Such physical associations include hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be isolated. The solvent molecules in a solvate may exist in an ordered and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" covers solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are known in the art.

[0135] The term "heteroatom" refers to, namely, nitrogen, oxygen, sulfur, and halogen atoms. The term "alkyl group" refers to a monovalent saturated aliphatic hydrocarbon group, including straight- or branched-chain groups of 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., a C alkyl group), more preferably 1 to 8 carbon atoms (a C alkyl group), and even more preferably 1 to 6 carbon atoms (i.e., a C alkyl group). For example, a "C alkyl group" refers to an alkyl group having 1 to 6 carbon atoms in the carbon chain (e.g., 1, 2, 3, 4, 5, or 6), and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like.

[0136] The terms "-alkyl group-" or "alkylene group" refer to a saturated straight or branched chain divalent hydrocarbon group. For example, a C1-C8 alkylene group refers to a straight or branched chain alkylene group having from 1 to 8 carbon atoms.

[0137] The term "alkoxy group" refers to an -O-alkyl group, where the definition of the alkyl group is the same as above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically, 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a 1-methylpropoxy group, a 2-methylpropoxy group, a tert-butoxy group, a pentyloxy group, a 1-methylbutoxy group, a 2-methylbutoxy group, a 3-methylbutoxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group, a 2,2-dimethylpropoxy group, and a 1-ethylpropoxy group.

[0138] The term "halogen" or "halo" refers to F, Cl, Br, I.

[0139] The term "halogenated alkyl group" refers to an alkyl group, as defined above, in which one, two, or more hydrogen atoms or all hydrogen atoms have been replaced with halogen. Representative examples of halogenated alkyl groups include CCl, CHCl, CHCl, CF, CHF, CHF, CBr, CHBr, CHBr, CI, CHI, CHI, CHCF, CFCF, and the like.

[0140] The term "aryl group" or "aromatic ring group" refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl group" may be used interchangeably with the term "aromatic ring group." Illustrative examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, or pyrenyl groups.

[0141] The term "heteroaryl group" or "heteroaromatic ring group" refers to an aromatic monocyclic or polycyclic ring system containing a 5- to 14-membered structure, or preferably a 5- to 10-membered structure, or preferably a 5- to 8-membered structure, more preferably a 5- to 6-membered structure, in which one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, with the number of heteroatoms preferably being one, two or three. Illustrative examples of heteroaryl groups include furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, and benzothiophenyl. groups, benzopyridyl groups, benzopyrimidinyl groups, benzopyrazinyl groups, benzimidazolyl groups, benzophthalazinyl groups, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl and the like.

[0142] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, spirocyclic, or fused ring. Preferably, it contains 3 to 16 carbon atoms (i.e., a C3-16 cycloalkyl group), more preferably 3 to 12 carbon atoms (a C3-12 cycloalkyl group), and even more preferably 3 to 8 carbon atoms (a C3-8 cycloalkyl group), 3 to 6 carbon atoms (a C3-6 cycloalkyl group), or 5 to 6 carbon atoms (a C5-6 cycloalkyl group). Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, 2-ethylcyclopentyl, dimethylcyclobutyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0143] The term "bridged cyclic" refers to a polycyclic aliphatic hydrocarbon group in which two carbon rings share two or more carbon atoms, and the bridged cyclic ring contains 4 to 20 carbon atoms, preferably 4 to 10 carbon atoms (including 4, 5, 6, 7, 8, 9, or 10 carbon atoms). Non-limiting examples of bridged rings include: [ka] Includes:

[0144] The term "spirocyclic" refers to an alicyclic hydrocarbon group in which two carbon rings in the molecule share one carbon atom, and the spirocyclic ring contains 5 to 20 carbon atoms, preferably 5 to 11 carbon atoms (including 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms). Non-limiting examples of spirocyclic rings include: [ka] Includes:

[0145] The term "fused ring" refers to an alicyclic hydrocarbon group in which two carbon rings in the molecule share two carbon atoms, and the fused ring contains 5 to 20 carbon atoms, preferably 5 to 11 carbon atoms (including 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms). Non-limiting examples of fused rings include: [ka] Includes:

[0146] The term "-cycloalkyl group-" or "cycloalkylene group" refers to a "cycloalkyl group" that is bonded to two substituents.

[0147] The term "heterocyclyl group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3 to 20 ring atoms, of which 1, 2, 3, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3 to 12 ring atoms (3- to 12-membered heterocyclyl groups), more preferably 3 to 10 ring atoms (3- to 10-membered heterocyclyl groups), or 3 to 8 ring atoms (3- to 8-membered heterocyclyl groups), or 3 to 6 ring atoms (3- to 6-membered heterocyclyl groups), or 4 to 6 ring atoms (4- to 6-membered heterocyclyl groups), or 5 to 6 ring atoms (5- to 6-membered heterocyclyl groups). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Illustrative examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups. A "heterocyclyl group" can be monocyclic (a "monocyclic heterocyclyl group") or one of a fused (a "fused-ring heterocyclyl group" or "heterofused-ring"), bridged (a "heterobridged-ring" or "bridged-ring heterocyclyl group"), or spiro-fused (a "heterospirocyclic" or "spirocyclic heterocyclyl group") ring system, such as a bicyclic system (a "bicyclic heterocyclyl group"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl group" further includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclic groups, where the point of attachment is on the carbocyclic or heterocyclyl ring, or "heterocyclyl group" further includes ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, or cycloalkyl groups as defined above are fused with one or more heteroaryl groups, where the point of attachment is on the heterocyclyl ring or cycloalkyl ring, and in such cases the number of members of the heterocyclyl ring system is the number of atoms in the fused ring.In some embodiments, each instance of a heterocyclyl group can be independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl group") or substituted with one or more substituents (a "substituted heterocyclyl group"). Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thiocanyl groups.Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrodibenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolyl, etc.

[0148] Unless otherwise specified, a "heterocycloalkyl group" refers to a monocyclic, saturated "heterocyclyl group" or "heterocycle" as defined above, in which the ring atoms are defined as above, i.e., 3 to 20 ring atoms (a "3- to 20-membered heterocycloalkyl group"), and the number of heteroatoms is 1 to 4 (1, 2, 3, or 4), preferably 1 to 3 (1, 2, or 3), and each heteroatom is independently selected from N, O, and S. Preferably, it contains 3 to 12 ring atoms ("3-12-membered heterocycloalkyl group"), more preferably 3 to 10 ring atoms ("3-10-membered heterocycloalkyl group"), even more preferably 3 to 8 ring atoms ("3-8-membered heterocycloalkyl group"), even more preferably 4 to 7 ring atoms ("4-7-membered heterocycloalkyl group"), even more preferably 5 to 10 ring atoms ("5-10-membered heterocycloalkyl group"), and even more preferably 5 to 6 ring atoms ("5-6-membered heterocycloalkyl group"). In some embodiments, each instance of a heterocycloalkyl group can independently be optionally substituted, e.g., unsubstituted ("unsubstituted heterocycloalkyl group") or substituted with one or more substituents ("substituted heterocycloalkyl group"). The above "heterocyclyl group" or "heterocycle" moiety represents some exemplary "heterocycloalkyl groups," and includes, but is not limited to, aziridinyl group, oxiranyl group, thiiranyl group, azetidinyl group, oxetanyl group, thietanyl group, tetrahydrofuranyl group, oxanyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, oxathiolanyl group, oxazolidinyl group, dioxanyl group, dithianyl group, thiazolidinyl group, pyrrolidinyl group, pyrazolidinyl group, and imidazolinidine.

[0149] Non-limiting examples of "spirocyclic heterocyclyl groups" include: [ka] Includes:

[0150] Non-limiting examples of "fused ring heterocyclyl groups" include: [ka] Includes:

[0151] The terms "-heterocyclyl-" or "heterocyclylene" refer to a "heterocyclyl" group that is linked to two substituents.

[0152] The term "derivative" refers to a compound formed by replacing an atom or atomic group in a parent compound molecule with another atom or atomic group, and the compound is called a derivative of the parent compound.

[0153] The term "pharmaceutical salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a drug, drug-linker, or antibody-linker-drug conjugate). The compound may contain at least one amino, imino, hydroxy, or carboxy group and may thereby form an addition salt with a corresponding acid or base. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogensulfate, phosphate, acid phosphate (-H2PO4), phosphite, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, potassium salt, sodium salt, ammonium salt, calcium salt, and the like. Furthermore, pharmaceutically acceptable salts have more than one charged atom in their structure. Of these, multiple charged atoms are some examples of pharmaceutically acceptable salts, and they may have multiple counter atoms. For example, pharmaceutically acceptable salts have one or more charged atoms and / or one or more counter atoms.

[0154] The term "tumor" refers to a new organism formed when certain cells in a local tissue lose normal control over their growth at the genetic level under the action of various carcinogenic factors, resulting in clonal abnormal proliferation. DETAILED DESCRIPTION OF THE INVENTION

[0155] The present application will be further illustrated by the following examples, but the scope of the present application is not limited to these examples. In the following examples, experimental methods for which specific conditions are not specified generally follow conventional conditions or conditions suggested by the manufacturer. Unless otherwise specified, all percentages, proportions, ratios, or parts are by weight.

[0156] Example 1: Synthesis of compound Smol006 [ka]

[0157] Smol006 can be obtained by referring to the synthesis method of the same compound in patent WO2021198965A1. LC-MS (ESI): (M+H) + Calculated value 528.2, experimental value 528.3.

[0158] Example 2: Synthesis of compounds B19 to B24 [ka]

[0159] Compound 1 (49.686 mmol) was dissolved in THF (120 mL). Sodium hydride (99.372 mmol, 60%) was added under nitrogen gas in an ice bath and stirred for half an hour. Allyl bromide (99.372 mmol) was added to the reaction mixture under nitrogen gas. After 2 hours, the reaction progress was monitored by TLC. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution in an ice bath. The mixture was extracted with methyl tert-butyl ether and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 2 (33.15 mmol, yield: 66%). LC-MS (ESI): (M+H-Boc) + Calculated value 142.2, experimental value 142.3.

[0160] Under nitrogen gas conditions, a tetrahydrofuran solution of 9-BBN (79.56 mL, 39.7788 mmol, 0.5 mmol / mL) was added to a THF solution of compound 2 (33.149 mmol) in an ice bath, and the temperature was raised to 80°C to carry out the reaction. After reacting for 2 hours, the progress of the reaction was monitored by TLC. After the reaction was completed, the temperature was returned to room temperature, and the reaction solution containing compound 3 was used directly in the next reaction.

[0161] To the solution of compound 3 under nitrogen gas protection, DMF (100 mL) and an aqueous solution (30 mL) of potassium phosphate (41.436 mmol) were added and stirred for 10 minutes. Under nitrogen gas protection, 3-chloro-4-bromoaniline (33.149 mmol) and Pd(dppf)Cl2 (3.3149 mmol) were added and the reaction was continued under nitrogen gas protection at 90 °C for 3 hours. The reaction progress was monitored by TLC and LCMS. After complete consumption of the starting materials, the mixture was cooled to room temperature, extracted with ethyl acetate and saturated ammonium chloride solution, filtered to remove insoluble matter, and the organic phase was re-extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified twice using a silica gel column to give compound 4 (13.82 mmol, 42% yield). LC-MS (ESI): (M+H-Boc). + Calculated value 269.1, experimental value 269.1.

[0162] General synthesis method for target compounds [ka]

[0163] Compound 4 (13.5538 mmol) was dissolved in dichloromethane (90 mL), and DIPEA (3.5 g, 27.1076 mmol) and phenyl chloroformate (16.264 mmol) were added sequentially to the solution. The mixture was stirred at room temperature. After 30 minutes, the reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column to give compound 5 (12.07 mmol, 89% yield). LC-MS (ESI): (M+H-Boc) + Calculated value 389.2, experimental value 389.2.

[0164] Compound 5 (10.225 mmol) was dissolved in DMF (80 mL), compound 6 (11.247 mmol) was added, and the solid was dispersed in the solution using ultrasound. DIPEA (40.9 mmol) was then added, and the mixture was heated to 50 °C. After 3 hours, the reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound A19 (9.637 mmol, 94% yield). LC-MS (ESI): (M+H-Boc) + Calculated 568.2, experimental 568.4. HRMS (ESI): (M+Na) + Calculated value 690.2665, experimental value 690.2607. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.75 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.51 (s, 1H), 7.44 (dd, J = 7.9, 1.5 Hz, 1H), 7.19 - 7.11 (m, 2H), 6.79 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 - 4.37 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 3.70 - 3.33 (m, 4H), 3.29 - 3.21 (m, 2H), 3.16 - 2.97 (m, 1H), 2.96 - 2.87 (m, 1H), 2.69 - 2.56 (m, 3H), 2.38 (qd, J = 13.1, 4.4 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.86 - 1.68 (m, 3H), 1.67 - 1.58 (m, 1H), 1.54 - 1.42 (m, 1H), 1.37 (s, 9H), 1.30 (t, J = 5.8 Hz, 1H).

[0165] Compound A19 (2.7986 mmol) was dissolved in dichloromethane (19 mL). A solution of hydrogen chloride in ethyl acetate (44 mmol, 11 mL, 4 mmol / mL) was added dropwise to the solution in an ice bath. A large amount of solid was produced by the addition of the solution. After 2 hours, the reaction progress was monitored by TLC and LCMS. After the reaction was complete, the solvent was removed under reduced pressure at low temperature and dried in vacuo to give compound B19 (2.647 mmol, 94% yield). LC-MS (ESI): (M+H) + Calculated 568.2, experimental 568.3. HRMS (ESI): (M+H) + Calculated value 568.2321, experimental value 568.2340. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.16 (s, 1H), 9.09 - 8.88 (m, 1H), 8.67 - 8.38 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.51 (s, 1H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.05 (t, J = 6.1 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 - 4.36 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 3.61 (dt, J = 6.5, 3.4 Hz, 1H), 3.56 - 3.47 (m, 1H), 3.42 - 3.34 (m, 1H), 3.19 - 3.10 (m, 1H), 3.00 - 2.86 (m, 4H), 2.71 - 2.63 (m, 2H), 2.63 - 2.54 (m, 1H), 2.38 (qd, J = 13.1, 4.3 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.87 - 1.69 (m, 4H), 1.69 - 1.52 (m, 2H).

[0166] Compounds A20 to A24 and B20 to B24 were obtained by the same preparation method as for compounds A19 and B19, except that the starting material was replaced with the corresponding Boc-protected piperidin-3-yl alkyl alcohol from compound 1, respectively.

[0167] [Table 1]

[0168] Example 3: Synthesis of Compounds B1 to B6 [ka]

[0169] Compound 7 (4 mmol) and compound 8 (6 mmol) were dissolved in DMF (20 mL), cesium carbonate (8 mmol) was added, and the mixture was stirred overnight at 60 °C under nitrogen gas protection. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using a silica gel column to give compound 9 (3.44 mmol, yield: 86%). LC-MS (ESI): (M+H) + Calculated value 371.1, experimental value 371.2.

[0170] Compound 9 (3 mmol) was dispersed in water (30 mL), B2(OH)4 (15 mmol) was added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 10 (2.34 mmol, 78% yield). LC-MS (ESI): (M+H) + Calculated value 341.2, experimental value 341.2.

[0171] Referring to the method of Example 2, compound 4 was replaced with compound 10 to obtain compound A2. LC-MS (ESI): (M+H) + Calculated value 640.2, experimental value 640.4.

[0172] Referring to the method of Example 2, compound 4 was replaced with compound 10 to obtain compound B2. LC-MS (ESI): (M+H) + Calculated value 540.2, experimental value 540.5.

[0173] Using the same preparation method as for compounds A2 and B2, the starting material was replaced with the corresponding Boc-protected piperidin-3-yl alkyl alcohol from compound 8, to obtain compounds A1, A3 to A6, and B1, B3 to B6.

[0174] [Table 2]

[0175] Example 4: Synthesis of compounds B7 to B12 [ka]

[0176] Compound 11 (4 mmol) was dissolved in DCM (10 mL), and phosphorus tribromide (8 mmol) was added and stirred under nitrogen gas. After 2 hours, the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 12 (2.84 mmol, yield: 71%).

[0177] Compound 13 (5.0 mmol) was dissolved in DMF (10 mL), and under nitrogen gas protection, sodium hydride (5 mmol, 60%) was added in an ice bath and stirred for half an hour. Compound 12 (2.5 mmol) in DMF (5 mL) was added to the reaction system and stirred for 3 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column to give compound 14 (2.15 mmol, yield: 86%). LC-MS (ESI): (M+H) + Calculated value 399.2, experimental value 399.3.

[0178] Compound 14 (2 mmol) was dispersed in water (5 mL), B2(OH)4 (10 mmol) was added, and the mixture was heated to 100 °C under nitrogen protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 15 (1.74 mmol, 87% yield). LC-MS (ESI): (M+H) + Calculated value 369.2, experimental value 369.3.

[0179] Referring to the method of Example 2, compound 4 was replaced with compound 15 to obtain compound A9. LC-MS (ESI): (M+H) + Calculated value 668.2, experimental value 668.5.

[0180] Referring to the method of Example 2, compound 4 was replaced with compound 15 to obtain compound B9. LC-MS (ESI): (M+H) + Calculated value 568.2, experimental value 568.6.

[0181] Using the same preparation method as for compounds A9 and B9, compounds A7 to A8, A10 to A12, B7 to B8, and B10 to B12 were obtained by replacing the starting material from compound 13 with the corresponding Boc-protected piperidin-3-yl alkyl alcohol, respectively.

[0182] [Table 3]

[0183] Example 5: Synthesis of compounds B13 to B18 [ka]

[0184] Compound 16 (4.638 mmol) was dissolved in THF (10 mL). Borane-tetrahydrofuran solution (13.5 mL, 1.0 mmol / mL, 13.5 mmol) was added under nitrogen protection in an ice bath and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was returned to room temperature and quenched by adding methanol dropwise in an ice bath. Extraction was performed with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 17 (4.524 mmol). LC-MS (ESI): (M+H) + Calculated value 202.0, experimental value 202.1.

[0185] Compound 17 (1 mmol) was dispersed in water (5 mL), B2(OH)4 (5 mmol) was added, and the mixture was stirred at 100 °C under nitrogen gas protection. The reaction progress was monitored by TLC and LCMS. After the reaction was completed, the mixture was returned to room temperature and extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 18 (0.92 mmol, yield: 92%). LC-MS (ESI): (M+H) + Calculated value 172.0, experimental value 172.1.

[0186] Compound 18 (0.5 mmol) was dissolved in DMF (5 mL). Under nitrogen gas protection, sodium hydride (0.5 mmol, 60%) was added in an ice bath and stirred for half an hour. Compound 19 (0.5 mmol) in DMF (2 mL) was added and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 20 (0.16 mmol, 32% yield). LC-MS (ESI): (M+H) + Calculated value 355.2, experimental value 355.2.

[0187] Referring to the method of Example 2, compound 4 was replaced with compound 20 to obtain compound A13. LC-MS (ESI): (M+H) + Calculated value 654.2, experimental value 654.5.

[0188] Referring to the method of Example 2, compound 4 was replaced with compound 20 to obtain compound B13. LC-MS (ESI): (M+H) + Calculated value 554.2, experimental value 554.4.

[0189] Compounds A14 to A18 and B14 to B18 were obtained by the same preparation method as for compounds A13 and B13, except that the starting material was replaced by the corresponding Boc-protected piperidin-3-yl alkyl alcohol from compound 13, respectively.

[0190] [Table 4]

[0191] Example 6: Synthesis of Compounds B25 to B42 [ka]

[0192] Compound 21 (10 mmol), cuprous iodide (1 mmol), triethylamine (5 mL), and Pd(PPh3)2Cl2 (0.5 mmol) were dissolved in THF (20 mL). Under nitrogen gas protection, 3-butyn-1-ol (0.757 mL, 10 mmol) was added to the reaction mixture, which was then heated to 60 °C and stirred. After 4 hours, the reaction progress was monitored by TLC and LCMS. Upon completion, the solids in the reaction mixture were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 22 (8.9 mmol, 89% yield). LC-MS (ESI): (M+H) + Calculated value 226.0, experimental value 226.0.

[0193] Compound 22 (8 mmol) was dissolved in THF (20 mL), and under nitrogen gas protection, platinum dioxide (0.125 g) was added. The atmosphere was replaced with hydrogen, and the mixture was stirred. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, diatomaceous earth was added, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified using a silica gel column to give compound 23 (7.36 mmol, yield: 92%). LC-MS (ESI): (M+H) + Calculated value 200.1, experimental value 200.1.

[0194] Compound 23 (5 mmol) was dissolved in DMF (50 mL). Under nitrogen gas protection, sodium hydride (5 mmol, 60%) was added in an ice bath and stirred for half an hour. Compound 24 (5 mmol) in DMF (10 mL) was added and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 25 (1.49 mmol, 30% yield). LC-MS (ESI): (M+H) + Calculated value 453.3, experimental value 453.5.

[0195] Referring to the method of Example 2, compound 4 was replaced with compound 25 to obtain compound A30. LC-MS (ESI): (M+H) + Calculated value 752.3, experimental value 752.6.

[0196] Referring to the method of Example 2, compound 4 was replaced with compound 25 to obtain compound B30. LC-MS (ESI): (M+H) + Calculated value 652.3, experimental value 652.6.

[0197] Using the same preparation method as for compounds A30 and B30, the starting material was replaced by 4-pentyn-1-ol or 6-hexyn-1-ol from 3-butyn-1-ol, and by the corresponding Boc- and Ts-protected piperidin-3-yl alkyl alcohol from compound 24, to obtain compounds A25 to A29, A31 to A42, B25 to B29, and B31 to B42.

[0198] [Table 5]

[0199] Example 7: Synthesis of compounds B43 to B54 [ka] TIFF2026506684000078.tif66169

[0200] Compound 26 (20 mmol) was dissolved in dichloromethane (50 mL), and bromoethanol (21 mmol) was added to the reaction mixture. The mixture was then incubated overnight at 45°C under nitrogen gas protection. The reaction was monitored by TLC and LCMS. After completion, the mixture was cooled to room temperature, and ethyl acetate (200 mL) was added. The mixture was stirred for 2 hours. The mixture was then placed in an ice bath and stirred for 3 hours. The solid was collected by filtration and washed with ethyl acetate to give compound 27 (17.41 mmol, 87% yield). LC-MS (ESI): (M+H) + Calculated value 146.1, experimental value 146.1.

[0201] The hydrobromide salt of compound 27 (17.41 mmol) was dissolved in methanol (40 mL), TEA (18 mmol) and BocO (18 mmol) were added, and the reaction was stirred. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 28 (16.89 mmol, yield: 97%). LC-MS (ESI): (M+H) + Calculated value 246.2, experimental value 246.4.

[0202] Compound 28 (16.89 mmol) was dissolved in DCM (50 mL), DIPEA (34 mmol) and TsCl (34 mmol) were added to the reaction mixture, and the mixture was stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 29 (14.69 mmol, 87% yield). LC-MS (ESI): (M+H) + Calculated value 400.2, experimental value 400.3.

[0203] Compound 18 (2 mmol) was dissolved in DMF (10 mL), and under nitrogen gas protection, sodium hydride (2 mmol, 60%) was added in an ice bath. The mixture was stirred for half an hour. Compound 29 (2 mmol) in DMF (2 mL) was added and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 30 (0.46 mmol, 23% yield). LC-MS (ESI): (M+H) + Calculated value 399.2, experimental value 399.4.

[0204] Referring to the method of Example 2, compound 4 was replaced with compound 30 to obtain compound A48. LC-MS (ESI): (M+H) + Calculated value 698.2, experimental value 698.4.

[0205] Referring to the method of Example 2, compound 4 was replaced with compound 30 to obtain compound B48. LC-MS (ESI): (M+H) + Calculated value 598.2, experimental value 598.4.

[0206] By referring to the synthetic procedures and methods of compounds A48 and B48, compounds 26 and 18 were substituted with different primary amines and alcohols to obtain compounds A43 to A47, A49 to A54, B43 to B47, and B49 to B54.

[0207] [Table 6]

[0208] Example 8: Synthesis of compounds B55 to B72 [ka] TIFF2026506684000081.tif225169

[0209] Compound 31 (5 mmol) was dissolved in DMF (20 mL), and sodium hydride (10 mmol, 60%) was added in an ice bath under nitrogen gas conditions and stirred for half an hour. Allyl bromide (10 mmol) was added to the reaction mixture under nitrogen gas conditions. After 2 hours, the reaction progress was monitored by TLC. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution in an ice bath. The mixture was extracted with methyl tert-butyl ether and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 32 (4.3 mmol, yield: 86%). LC-MS (ESI): (M+H) + Calculated value 216.2, experimental value 216.4.

[0210] Under nitrogen gas conditions, a solution of 9-BBN in tetrahydrofuran (3.0 mL, 1.5 mmol, 0.5 mmol / mL) was added to a solution of compound 32 (1.0 mmol) in tetrahydrofuran in an ice bath, and the temperature was raised to 80°C to carry out the reaction. After reacting overnight, the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was returned to room temperature, and the reaction mixture containing compound 33 was used directly in the next reaction.

[0211] Under nitrogen gas protection, DMF (10 mL) and an aqueous solution (3 mL) of potassium phosphate (1.25 mmol) were added to the solution of 33 and stirred for 10 minutes. Under nitrogen gas protection, 3-chloro-4-bromoaniline (1.0 mmol) and Pd(dppf)Cl2 (0.1 mmol) were added. The mixture was heated to 90 °C and reacted overnight. The reaction progress was monitored by TLC and LCMS. After complete consumption of the starting materials, the mixture was cooled to room temperature and extracted with ethyl acetate and saturated ammonium chloride solution. The insoluble matter was removed by filtration. The organic phase was re-extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 34 (0.43 mmol, 43% yield). LC-MS (ESI): (M+H) + Calculated value 342.2, experimental value 342.4.

[0212] Referring to the method of Example 2, compound 4 was replaced with compound 34 to obtain compound A59. LC-MS (ESI): (M+H) + Calculated 642.2, experimental 642.4. HRMS (ESI): (M+Na) + Calculated value 664.2508, experimental value 664.2509. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.77 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.51 (s, 1H), 7.47 - 7.41 (m, 1H), 7.20 - 7.10 (m, 2H), 6.80 (t, J = 6.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.50 - 4.37 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 3.45 (t, J = 5.6 Hz, 2H), 3.38 (t, J = 6.2 Hz, 2H), 3.31 - 3.29 (m, 2H), 2.98 - 2.86 (m, 1H), 2.86 - 2.74 (m, 3H), 2.69 - 2.55 (m, 3H), 2.44 - 2.32 (m, 1H), 2.05 - 1.94 (m, 1H), 1.80 - 1.66 (m, 2H), 1.38 (s, 9H).

[0213] The method of Example 2 was used as a reference, compound 4 was replaced with compound 34, and compound B59 was obtained. LC-MS(ESI):(M+H) + The calculated value is 542.2, and the calculated value is 542.4. HRMS(ESI):(M+H) + The calculated value is 542.2165 and the calculated value is 542.2174. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.35 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.52 - 7.51 (m, 1H), 7.45 - 7.44 (m, 1H), 7.20 - 7.15 (m, 3H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 - 4.36 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 3.63 (t, J = 5.2 Hz, 2H), 3.44 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 5.2 Hz, 2H), 2.98 - 2.83 (m, 1H), 2.71 - 2.63 (m, 2H), 2.63 - 2.56 (m, 1H), 2.55 (s, 3H), 2.44 - 2.32 (m, 1H), 2.07 - 1.93 (m, 1H), 1.84 - 1.76 (m, 2H).

[0214] By referring to the synthetic procedures and methods of compounds A59 and B59, compound 31 is replaced with different alcohols to obtain A55 to A72 and B55 to B72.

[0215] [Table 7]

[0216] Example 9: Synthesis of compounds B73 to B75 [ka]

[0217] Compound 35 (5 mmol) was dissolved in THF (20 mL), DIPEA (10 mmol) and TsCl (10 mmol) were added, and the mixture was stirred overnight. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 36 (3.7 mmol, 74% yield). LC-MS (ESI): (M+H) + Calculated value 396.1, experimental value 396.4.

[0218] Compound 36 (1 mmol) was dissolved in methanol (10 mL), compound 37 (1.1 mmol) was added, and the reaction was stirred. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction solution containing compound 38 was used directly in the next reaction. LC-MS (ESI): (M+H) + Calculated value 315.1, experimental value 315.3.

[0219] To the reaction mixture of compound 38, BocO (2.0 mmol) was added and the reaction was stirred. After 2 hours, the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column to give compound 39 (0.84 mmol, yield: 84%). LC-MS (ESI): (M+H) + Calculated value 415.1, experimental value 415.3.

[0220] Compound 39 (0.5 mmol) was dispersed in water (5 mL), B2(OH)4 (5 mmol) was added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 40 (0.355 mmol, 71% yield). LC-MS (ESI): (M+H) + Calculated value 385.2, experimental value 385.3.

[0221] Referring to the method of Example 2, compound 4 was replaced with compound 40 to obtain compound A75. LC-MS (ESI): (M+H) + Calculated value 684.2, experimental value 684.5.

[0222] Referring to the method of Example 2, compound 4 was replaced with compound 40 to obtain compound B75. LC-MS (ESI): (M+H) + Calculated value 584.2, experimental value 584.5.

[0223] By referring to the synthesis procedures and methods of compounds A75 and B75, compounds 35 and 37 are substituted with different alcohols and thiols to obtain A73-A74 and B73-B74.

[0224] [Table 8]

[0225] Example 10: Synthesis of compounds B76 to B78 [ka]

[0226] Compound 41 (5 mmol) and compound 42 (5 mmol) were dissolved in DMF (10 mL), DIPEA (15 mmol) and HATU (6 mmol) were added, and the mixture was stirred overnight. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium carbonate solution. The organic phase was collected and extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 43 (3.95 mmol, 79% yield). LC-MS (ESI): (M+H) + Calculated value 254.2, experimental value 254.3.

[0227] Compound 43 (3.95 mmol) was dissolved in THF (20 mL), and LiAlH4 (16 mmol) was added in an ice bath under nitrogen gas protection, followed by stirring at 60 °C. After 4 hours, the reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was returned to room temperature and quenched by adding aqueous sodium hydroxide in an ice bath. The quenched solution was stirred for 2 hours, and the reaction mixture containing compound 44 was used in the next reaction without further treatment. LC-MS (ESI): (M+H) + Calculated value 212.2, experimental value 212.2.

[0228] To the reaction mixture of compound 44, BocO (5 mmol) was added and the mixture was stirred. After 2 hours, the reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 45 (3.47 mmol, 88% yield). LC-MS (ESI): (M+H) + Calculated value 312.2, experimental value 312.3.

[0229] Compound 45 (1.0 mmol) was dissolved in 3-chloro-4-fluoronitrobenzene (1.5 mmol) and DMF (5 mL), and cesium carbonate (2.0 mmol) was added. The mixture was stirred overnight at 60°C under nitrogen gas protection. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 46 (0.76 mmol, yield: 76%). LC-MS (ESI): (M+H) + Calculated value 467.2, experimental value 467.4.

[0230] Compound 46 (0.76 mmol) was dispersed in water (5 mL), B2(OH)4 (5 mmol) was added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 47 (0.68 mmol, 89% yield). LC-MS (ESI): (M+H) + Calculated value 437.2, experimental value 437.4.

[0231] Referring to the method of Example 2, compound 4 was replaced with compound 47 to obtain compound A76. LC-MS (ESI): (M+H) + Calculated value 736.3, experimental value 736.6.

[0232] Referring to the method of Example 2, compound 4 was replaced with compound 47 to obtain compound B76. LC-MS (ESI): (M+H) + Calculated value 636.3, experimental value 636.5.

[0233] By referring to the synthetic procedures and methods of compounds A76 and B76, compounds 41 and 42 are substituted with different amines and carboxylic acid esters to obtain compounds A77 to A78 and B77 to B78.

[0234] [Table 9]

[0235] Example 11: Synthesis of compounds B79 to B81 [ka]

[0236] Compound 48 (5 mmol) and compound 49 (5 mmol) were dissolved in DMF (10 mL), DIPEA (15 mmol) and HATU (6 mmol) were added, and the mixture was stirred overnight. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium carbonate solution. The organic phase was collected and extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 50 (3.85 mmol, 77% yield). LC-MS (ESI): (M+H) + Calculated value 242.2, experimental value 242.4.

[0237] Compound 50 (3.85 mmol) was dissolved in THF (20 mL), and LiAlH4 (16 mmol) was added in an ice bath under nitrogen gas protection, followed by stirring at 60 °C. After 4 hours, the reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was returned to room temperature and quenched by adding aqueous sodium hydroxide in an ice bath. The quenched solution was stirred for 3 hours, and the reaction mixture containing compound 51 was used in the next reaction without further treatment. LC-MS (ESI): (M+H) + Calculated value 200.2, experimental value 200.2.

[0238] To the reaction mixture of compound 51, BocO (5 mmol) was added and the mixture was stirred. After 2 hours, the reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic layer was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give compound 52 (3.28 mmol, 85% yield). LC-MS (ESI): (M+H) + Calculated value 300.2, experimental value 300.5.

[0239] Compound 52 (1.0 mmol) was dissolved in DMF (5 mmol), and under nitrogen gas protection, sodium hydride (1.5 mmol, 60%) was added in an ice bath and stirred for half an hour. Compound 12 (1.5 mmol) in DMF (2 mL) was added to the reaction mixture and stirred for 3 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column to give compound 53 (0.95 mmol, yield: 95%). LC-MS (ESI): (M+H) + Calculated value 469.2, experimental value 469.4.

[0240] Compound 53 (0.95 mmol) was dispersed in water (5 mL), B2(OH)4 (5 mmol) was added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 54 (0.76 mmol, 80% yield). LC-MS (ESI): (M+H) + Calculated value 439.3, experimental value 439.5.

[0241] Referring to the method of Example 2, compound 4 was replaced with compound 54 to obtain compound A80. LC-MS (ESI): (M+H) + Calculated value 738.3, experimental value 738.6.

[0242] Referring to the method of Example 2, compound 4 was replaced with compound 54 to obtain compound B80. LC-MS (ESI): (M+H) + Calculated value 638.3, experimental value 638.5.

[0243] By referring to the synthetic procedures and methods of compounds A80 and B80, compounds 48 and 49 can be substituted with different amines and carboxylic acid esters to obtain A79 to A81, B79, and B81.

[0244] [Table 10]

[0245] Example 12: Synthesis of Compounds B82 to B86 [ka]

[0246] Compound 55 (5 mmol) was dissolved in DCM (10 mL), TsCl (10 mmol) and DIPEA (10 mmol) were added, and the mixture was stirred overnight. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column to give compound 56 (3.9 mmol, 78% yield). LC-MS (ESI): (M+H) + Calculated value 356.0, experimental value 356.1.

[0247] Compound 56 (2 mmol) and compound 57 (2.2 mmol) were dissolved in CH3CN (10 mL), DIPEA (4 mmol) was added, and the mixture was stirred at 80 °C under nitrogen gas protection. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 58 (1.52 mmol, 76% yield). LC-MS (ESI): (M+H) + Calculated value 398.2, experimental value 398.4.

[0248] Compound 58 (1.52 mmol) was dispersed in water (10 mL), B2(OH)4 (10 mmol) was added, and the mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 59 (1.26 mmol, 83% yield). LC-MS (ESI): (M+H) + Calculated value 368.2, experimental value 368.4.

[0249] Referring to the method of Example 2, compound 4 was replaced with compound 59 to obtain compound A84. LC-MS (ESI): (M+H) + Calculated value 667.2, experimental value 667.4.

[0250] Referring to the method of Example 2, compound 4 was replaced with compound 59 to obtain compound B84. LC-MS (ESI): (M+H) + Calculated value 567.2, experimental value 567.4.

[0251] By referring to the synthetic procedures and methods of compounds A84 and B84, compounds 55 and 57 were substituted with different alcohols and amines to obtain A82 to A83, A85 to A86, B82 to B83, and B85 to B86.

[0252] [Table 11]

[0253] Example 13: Synthesis of compounds B87 to B90 [ka]

[0254] Under nitrogen gas conditions, a solution of 9-BBN in tetrahydrofuran (15 mmol, 30 mL, 0.5 mmol / mL) was added to a solution of compound 60 (10 mmol) in tetrahydrofuran in an ice bath, and the mixture was heated to 80°C and stirred to carry out the reaction. After reacting overnight, the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was returned to room temperature, and the reaction solution containing compound 61 was used directly in the next reaction.

[0255] Under nitrogen gas protection, DMF (100 mL) and an aqueous solution (30 mL) of potassium phosphate (12.5 mmol) were added to the reaction mixture containing compound 61 and stirred for 10 minutes. Under nitrogen gas protection, 3-chloro-4-nitrobenzene (10 mmol) and Pd(dppf)Cl2 (1 mmol) were added. The mixture was heated to 90 °C and reacted overnight. The reaction progress was monitored by TLC and LCMS. After complete consumption of the starting materials, the mixture was returned to room temperature and extracted with ethyl acetate and saturated ammonium chloride solution. The insoluble matter was removed by filtration. The organic phase was re-extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 62 (7.59 mmol, 76% yield). LC-MS (ESI): (M+H) + Calculated value 216.0, experimental value 217.1.

[0256] Compound 62 was dissolved in DCM (2 mmol), and phosphorus tribromide (4 mmol) was added in an ice bath. The reaction was carried out under nitrogen gas protection. After 4 hours, the progress of the reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction was quenched by adding water in an ice bath, and extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to obtain compound 63 (1.48 mmol, yield: 74%).

[0257] Compound 63 (1.48 mmol) was dissolved in ethyl acetate (10 mL), triphenylphosphine (1.6 mmol) was added, and the reaction was carried out at room temperature under nitrogen gas protection. After 2 hours, the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solid was collected by filtration, washed with ethyl acetate, and dried under vacuum to give compound 64 (1.42 mmol, yield: 96%). LC-MS (ESI): M + Calculated value: 460.1, experimental value: 460.3.

[0258] Compound 64 (1.42 mmol) was dissolved in THF (20 mL) and t-BuOK (1.5 mmol) was added under nitrogen gas protection in an ice bath. After half an hour, a solution of compound 65 (1.5 mmol) in THF (5 mL) was added and the reaction was stirred under nitrogen gas protection. After 2 hours, the reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution in an ice bath, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 66 (1.25 mmol, 88% yield). LC-MS (ESI): (M+H) + Calculated value 411.2, experimental value 411.3.

[0259] Compound 66 (0.5 mmol) was dissolved in THF (5 mL), platinum dioxide (50 mg) was added under nitrogen gas protection, and the atmosphere was replaced with hydrogen. The reaction was stirred for 2 hours. After 2 hours, the reaction progress was monitored by TLC and LCMS. Upon completion, diatomaceous earth was added and the mixture was filtered to remove solids. The filtrate was concentrated under reduced pressure, and the residue was purified using a silica gel column to give compound 67 (0.44 mmol, 88% yield). LC-MS (ESI): (M+H) + Calculated value 383.2, experimental value 383.3.

[0260] Referring to the method of Example 2, compound 4 was replaced with compound 67 to obtain compound A87. LC-MS (ESI): (M+H) + Calculated value 682.2, experimental value 682.5.

[0261] Referring to the method of Example 2, compound 4 was replaced with compound 67 to obtain compound B87. LC-MS (ESI): (M+H) + Calculated value 582.2, experimental value 582.5.

[0262] Referring to the synthetic procedures and methods of compounds A87 and B87, compound 65 was replaced with different ketones to obtain A88 to A90 and B88 to B90.

[0263] [Table 12]

[0264] Example 14: Synthesis of compounds B91 to B93 [ka]

[0265] Compound 1 (3.0 mmol) and compound 68 (6.0 mmol) were dissolved in DMF (5 mL), and the reaction mixture was stirred under nitrogen gas protection in an ice bath with sodium hydride (6 mmol, 60%). After 4 hours, the reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution in an ice bath, and extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 69 (0.9345 mmol, yield: 31%). LC-MS (ESI): (M+H) + Calculated value: 360.2, experimental value: 360.3.

[0266] Compound 69 (0.9345 mmol) was dissolved in a mixture of DMF (4 mL) and water (1 mL), potassium fluoride (4.673 mmol) was added, and the mixture was stirred overnight at 80°C under nitrogen gas. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified using a silica gel column to give compound 70 (0.7288 mmol, 77.99%). LC-MS (ESI): (M+H) + Calculated value 245.2, experimental value 245.3.

[0267] Compound 70 (0.7288 mmol) was dissolved in 3-chloro-4-fluoronitrobenzene (1.45 mmol) and DMF (4 mL), and cesium carbonate (2.90 mmol) was added. The mixture was stirred overnight at 60°C under nitrogen gas protection. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate and saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 71 (0.6175 mmol, yield: 85%). LC-MS (ESI): (M+H) + Calculated value 401.1, experimental value 401.2.

[0268] Compound 71 (0.5723 mmol) was dissolved in DMF (5 mL), B2(OH)4 (11.445 mmol) and 4,4'-bipyridine (0.005723 mmol) were added. After stirring for 10 minutes, the reaction progress was monitored by TLC and LCMS. Upon completion, the reaction was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound 72 (0.5323 mmol, yield: 93%). LC-MS (ESI): (M+H) + Calculated value 371.2, experimental value 371.3.

[0269] Referring to the method of Example 2, compound 4 was replaced with compound 72 to obtain compound A91. LC-MS (ESI): (M+H) + Calculated 670.2, experimental 670.5. HRMS (ESI): (M+Na) + Calculated value 692.2458, experimental value 692.2459. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.62 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 2.6 Hz, 1H), 7.51 (s, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.18 (dd, J = 8.9, 2.6 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.74 (t, J = 6.1 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 - 4.36 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 4.08 (t, J = 4.7 Hz, 2H), 3.83 - 3.69 (m, 2H), 3.53 (s, 1H), 3.41 (dt, J = 7.5, 3.8 Hz, 1H), 3.30 - 2.99 (m, 3H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.00 (ddd, J = 7.2, 4.7, 2.2 Hz, 1H), 1.83 (s, 1H), 1.50 (d, J = 24.3 Hz, 1H), 1.37 (s, 9H), 1.29 (td, J = 8.7, 4.3 Hz, 1H).

[0270] Referring to the method of Example 2, compound 4 was replaced with compound 72 to obtain compound B91. LC-MS (ESI): (M+H) + Calculated 570.2, experimental 570.5. HRMS (ESI): (M+H) + Calculated value 570.2114, experimental value 570.2138. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.00 (s, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.20 (dd, J = 8.9, 2.6 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.97 (t, J = 6.1 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 - 4.36 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 4.18 - 4.06 (m, 2H), 3.90 - 3.79 (m, 2H), 3.79 - 3.71 (m, 1H), 3.23 - 3.09 (m, 1H), 3.08 - 2.84 (m, 4H), 2.65 - 2.55 (m, 1H), 2.46 - 2.30 (m, 1H), 2.05 - 1.95 (m, 1H), 1.88 - 1.74 (m, 2H), 1.74 - 1.50 (m, 2H).

[0271] By referring to the synthetic procedures and methods of compounds A91 and B91, compound 1 is replaced with different alcohols to obtain A92 to A93 and B92 to B93.

[0272] [Table 13]

[0273] Example 17: Preparation of antibody drug conjugates (ADCs) of compounds of the invention

[0274] [ka] B19 (0.1 mmol) was dissolved in DMF (2 mL), Linker-01 (0.11 mmol) was added to the solution, and DIPEA (0.3 mmol) was added dropwise. The mixture was stirred and allowed to react. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound LD01 (0.068 mmol, 68%). LC-MS (ESI): (M+H) + Calculated value 1166.5, experimental value 1167.0.

[0275] [ka] Smol006 (0.1 mmol) was dissolved in DMF (2 mL), Linker-01 (0.11 mmol) was added, and DIPEA (0.3 mmol) was added dropwise. The reaction was stirred and allowed to proceed. The reaction progress was monitored by TLC and LCMS. Upon completion, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound LD09 (0.063 mmol, 63%). LC-MS (ESI): (M+H) + Calculated value 1126.5, experimental value 1127.0.

[0276] [ka] B19 (0.1 mmol) was dissolved in DMF (2 mL), Linker-04 (0.11 mmol) was added, and DIPEA (0.3 mmol) was added dropwise. The mixture was stirred and reacted. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound LD02 (0.085 mmol, 85%). LC-MS (ESI): (M+H) + Calculated value 1080.4, experimental value 1080.9.

[0277] [ka] B63 (0.1 mmol) was dissolved in DMF (2 mL), Linker-04 (0.11 mmol) was added, and DIPEA (0.3 mmol) was added dropwise. The mixture was stirred and reacted. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound LD06 (0.083 mmol, 83%). LC-MS (ESI): (M+H) + Calculated value 1052.4, experimental value 1052.7.

[0278] [ka] B19 (0.1 mmol) was dissolved in DMF (2 mL), Linker-02 (0.11 mmol) was added, and DIPEA (0.3 mmol) was added dropwise. The mixture was stirred and reacted. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to give compound LD07 (0.053 mmol, 53%). LC-MS (ESI): (M+H) + Calculated value 1631.6, experimental value 1632.0.

[0279] [ka] B19 (0.1 mmol) was dissolved in DMF (2 mL), Linker-03 (0.11 mmol) was added to the solution, and DIPEA (0.3 mmol) was added dropwise. The mixture was stirred and reacted. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column to obtain compound LD08-a (0.075 mmol, 75%). LC-MS (ESI): (M+2H) 2+ Calculated value 1030.0, experimental value 1030.3.

[0280] LD08-a (0.075 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mmol) was added dropwise to the solution, followed by stirring. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the solvent was removed under reduced pressure, the mixture was dissolved, ethyl acetate was added, and the mixture was extracted with pure water. The aqueous phase was collected and lyophilized to give compound LD08 (0.061 mmol, 81%). LC-MS (ESI): (M+H) + Calculated value 1802.8, experimental value 1803.2.

[0281] The following Linker-drugs were obtained by using a method similar to that of the above LD01 and LD09, but replacing the raw materials.

[0282] [Table 14]

[0283] ADC manufacturing: Typical procedure: The antibody sample was diluted to approximately 10 mg / mL in an appropriate buffer (matching the sample buffer). An appropriate amount of reducing agent, TCEP, was added. The number of equivalents was adjusted according to the target DAR. For a target DAR of 8, 8-10 equivalents were added, and for a target DAR of 4, 2-3 equivalents were added. The pH was then adjusted to 7-7.4 with Tris buffer and reduced for 1-1.5 hours at room temperature. The intermediate state of antibody reduction was monitored by CE-SDS. If antibody reduction was sufficient, an appropriate amount of saturated citric acid solution was added to adjust the pH to approximately 6.5. An excess amount of linker drug in DMSO was then added so that the linker drug equivalents were 15-20 times the antibody equivalents. The coupling reaction was carried out at room temperature for approximately 30 minutes. After coupling was complete, the reaction mixture was filtered, followed by ultrafiltration using a centrifugal concentration tube to remove excess linker drug and other small molecule impurities. After the purification was completed, the obtained sample was subjected to DAR measurement by hydrophobic chromatography or ultraviolet spectrophotometry.

[0284] An example of the preparation of an ADC is as follows.

[0285] ADC01-01-8: The antibody trastuzumab was diluted to 10 mg / mL in phosphate buffer and 8 equivalents of the reducing agent TCEP were added. The pH was adjusted to 7-7.4 with Tris buffer and reduced at room temperature for 1.5 hours, resulting in the reduction of the antibody interchain disulfide bonds to sulfhydryl groups. The intermediate state of antibody reduction was monitored by CE-SDS. If the antibody reduction was sufficient, an appropriate amount of saturated citric acid solution was added to adjust the pH to approximately 6.5, and then 20 equivalents of LD01 in DMSO were added and the coupling reaction was carried out at room temperature for 30 minutes. After coupling was complete, the reaction mixture was filtered, followed by ultrafiltration using a centrifugal concentration tube to remove excess linker drug and other small molecule impurities. After purification, the resulting sample was subjected to DAR measurement by hydrophobic chromatography or UV spectrophotometry.

[0286] ADC01-01-4: The antibody trastuzumab was diluted to 10 mg / mL in phosphate buffer and 2.2 equivalents of the reducing agent TCEP were added. The pH was adjusted to 7-7.4 with Tris buffer and reduced for 1 hour at room temperature, resulting in the reduction of the antibody interchain disulfide bonds to sulfhydryl groups. The intermediate state of antibody reduction was monitored by CE-SDS. If antibody reduction was sufficient, an appropriate amount of saturated citric acid solution was added to adjust the pH to approximately 6.5, followed by the addition of 15 equivalents of LD01 in DMSO, and the coupling reaction was carried out at room temperature for approximately 30 minutes. After coupling was complete, the reaction mixture was filtered, followed by ultrafiltration using a centrifugal concentration tube to remove excess linker drug and other small molecule impurities. After purification, the resulting sample was subjected to DAR measurement by hydrophobic chromatography or UV spectrophotometry.

[0287] The amino acid sequences of the antibodies used are as follows:

[0288] HER2 SYM001 (Trastuzumab) >Heavy chain (SEQ ID NO: 1) EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK > Light chain (SEQ ID NO: 2) DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0289] SYM007 (Pertuzumab) Heavy chain (SEQ ID NO: 3) EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG > Light chain (SEQ ID NO: 4) DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0290] Claudin 18.2 SYM003 >Heavy chain (SEQ ID NO: 5) EVQLSESGGALVQPGESLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSSLSGSGRSTYYAASIKGRFTISRDNSKNTLYLQMSSLRAEDTAIYYCAKSLSYYHYYFDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >Light chain (SEQ ID NO: 6) DIQLTQSPSFLSASVGDRVPITCRASQDISNYLAWYQQKPGKAPKLLIYSASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFASYHCQQVKTYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0291] DLL3 SYM004 >Heavy chain (SEQ ID NO: 7) QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG >Light chain (SEQ ID NO: 8) EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0292] BCMA SYM008 (Belantamab) >Heavy chain (SEQ ID NO: 9) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVL DNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGK >Light chain (SEQ ID NO: 10) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0293] The antibody-drug conjugates obtained are as shown in the table below.

[0294] [Table 15]

[0295] Test Example 1: In vitro antitumor activity of the molecular glue compound of the present invention Various tumor cells were commercially available and used to evaluate the antitumor inhibitory activity of the compounds of the present invention. Each tumor cell was cultured to a cell density of 80% to 90%. When the cell activity measured with trypan blue was 90% or higher, the cells were plated. After cell density optimization, 100 μL of cell suspension was added to BeyoGold™ HL-60, SK-BR-3 at a cell density of 3000 / well, Romas at a cell density of 6000 / well, NCI-H929 at a cell density of 4000 / well, and NCI-H82 at a cell density of 5000 / well. TM The cells were seeded into a 96-well ultra-low-adsorption black, clear-bottom plate (product number: FULA965-24pcs) and cultured overnight until the adherent cells attached and the cells requiring aggregate growth were aggregated. The next day, 50 μL of medium was aspirated from the 96-well plate, and the compound diluted with the corresponding medium was added. The highest concentration was 1 μM, and the compound was diluted 5-fold with a gradient of DMSO. The final DMSO concentration was 1‰. The compound was then added to the cell culture plate awaiting measurement. The plate was then cultured for 96 hours in a 37°C, 5% carbon dioxide incubator. Before measurement, CellTiter-Lumi TM The luminescence-based cell activity measurement reagent was equilibrated to room temperature in the dark, and then CellTiter-Lumi was added to each well of a 96-well plate. TM 50 μL of cell activity assay reagent (product number: C0065XL) was added, and the mixture was placed on a shaker and shaken at 300 rpm for 10 minutes in the dark to fully lyse the cells. After sufficient incubation, the fluorescence intensity was measured using a multifunctional fluorescence microplate reader, and the cell inhibition rate was determined based on the fluorescence intensity. Cell activity curves were generated using Graphpad Prism 8.0, and IC50 values ​​were calculated. Using the above method, activity tests were conducted on the compounds of the present invention, and the test results for several compounds are shown in Table 1.

[0296] [Table 16]

[0297] The above results demonstrate that the compounds of the present invention have higher cellular activity than Smol006 in cells of different indications, and have greater applicability.

[0298] Test Example 2: Verification of GSPT1 protein degradation by the compounds of the present invention This experiment was used to evaluate compound targeting. HEK293T cells were modified with CRISPR gene editing to add a HiBiT protein tag to the N-terminus of the endogenous GSPT1 protein, creating a HiBiT-GSPT1 HEK293T stable transfectant cell line. HiBiT-GSPT1 HEK293T cells were cultured in DMEM containing 10% FBS and 1% PenStrep. When the cell density reached 80%-90%, the cells were digested with trypsin, dissociated into individual cells, and resuspended in the corresponding medium. The cells were counted using a Cell Countess (NanoEnTek, Cat. EVE-MC2) and assayed for cell viability using trypan blue to ensure viability was above 90%. Cells were plated into 384-well plates (Corning, Cat. 3764) at 10,000 cells per well in 40 μL of cell suspension. The cells were then warmed to 37°C and incubated overnight in a 5% CO2 incubator. The next day, compounds to be tested were added to the 384-well plates at a maximum concentration of 30 μM, diluted 5-fold, and incubated at 1‰ DMSO for 24 h in a 5% CO2 incubator. The Nano-Glo HiBiT reagent was allowed to equilibrate to room temperature before testing. The LgBiT protein was diluted 1:100 with Nano-Glo HiBiT Lytic buffer, and the Nano-Glo@HiBiT Lytic primer was diluted 1:50 to the appropriate volume. The cell culture plate was equilibrated at room temperature for 10 minutes, and 40 μL of Nano-Glo HiBiT Lytic assay reagent was added to each well. The plate was then shaken in the dark at 300 rpm for 3 minutes on a microplate shaker. After sufficient reaction, the fluorescence values ​​were read using a BMG PHERASTAR FS (BMG LRBTECH, Cat. PHERAstar FSX) and the DC50 values ​​were calculated using GraphPad Prism 8.0.

[0299] [Table 17]

[0300] The above results demonstrate that the compounds of the present invention, after derivatization, do not affect their ability to degrade GSPT1 protein, and their antitumor mechanism of action is still to catalyze the degradation of GSPT1 protein in cells.

[0301] Test Example 3: Activity verification of the compound of the present invention in a cell line highly expressing efflux pump proteins Three types of cells used to evaluate the activity of the compounds of the present invention against cell lines highly expressing efflux pump proteins were all purchased from Nanjing Kebai Biology, and all cells were obtained from ATCC (American Type Culture Collection). Each tumor cell was cultured to a cell density of 80% to 90%, and the cell viability was measured using trypan blue to confirm that the cell viability was 90% or higher before plating. After optimizing the cell density, 75 μL of each cell suspension from the three types of cells (SNU-5, HCT-15, and AsPc-1) (3000 / well) was added to BeyoGold TM Cells were seeded into ultra-low-binding black, clear-bottom 96-well plates (product number: FULA965-24pcs) and incubated overnight in a CO2 cell incubator at 37°C. The next day, after cells had adhered to the plate, 75 μL of compound diluted in the corresponding medium was added to the plate. The maximum concentration was 1 μM, and the compound was diluted five-fold. The final DMSO concentration was 1‰. The cells were then cultured in a 37°C, 5% CO2 incubator for 96 hours. The CellTiter-Lumi™ luminescent cell activity assay reagent was allowed to equilibrate to room temperature in the dark before assay. Then, 50 μL of CellTiter-Lumi™ (product number: C0065XL) cell activity assay reagent was added to each well of the 96-well plate and shaken at 300 rpm for 10 minutes in the dark to fully lyse the cells. After sufficient reaction, the chemiluminescence intensity was measured using a multi-function microplate reader, and the cell activity inhibition rate was tested based on the chemiluminescence intensity. The cell activity curve was generated using Graphpad Prism 8.0, and the IC50 value was calculated. The results are shown in Table 3.

[0302] [Table 18]

[0303] The above results demonstrate that the compounds of the present invention have higher cellular activity than Smol006 in cells highly expressing different efflux pump proteins, and therefore have greater applicability. Test Example 4: Evaluation of metabolic stability of the compounds of the present invention in liver microsomes

[0304] 1. Test Method The target substances B61, B63, and B19 were incubated in duplicate with mouse, rat, dog, monkey, and human liver microsomes (final system concentration: 0.5 mg / mL). The final concentration of primer in the incubation system was 1 μM, and the incubation time was 60 minutes. Samples were taken at 0, 5, 15, 30, and 60 minutes, and the reaction was stopped with iced acetonitrile containing an internal standard (testosterone-d3, concentration: 10 ng / mL). Verapamil was used as a positive control. The samples were analyzed by LC-MS / MS to determine the concentrations of B61, B63, and B19 and calculate the percent remaining. The natural logarithm of the percent remaining was linearly fitted against time to determine the elimination rate constant (k). The half-life (t1 / 2), intrinsic clearance (CLint, in vitro), and hepatic clearance (CLhb) were calculated according to the following equations: t1 / 2 = 0.693 / k CLint, in vitro = k × incubation volume (mL) / liver microsome content (mg) × (microsomes (mg) / liver weight (g)) × (liver weight (g) / body weight (kg)) CLhb=hepatic blood flow mL / min / kg×CLint, in vitro / (hepatic blood flow mL / min / kg+ CLint, in vitro) Criteria: CLhb has low clearance when hepatic blood flow is less than 20% and high clearance when hepatic blood flow is greater than 80%.

[0305] 2.Results The intrinsic clearance of B61 in human, monkey, dog, rat, and mouse liver microsomes was 7.03, 13.7, 11.8, 19.8, and 32.2 mL / min / kg, respectively.

[0306] The intrinsic clearance of B63 in human, monkey, and rat liver microsomes was 0.190, 0.257, and 1.39 mL / min / kg, respectively. B63 was hardly cleared in humans, monkeys, dogs, rats, and mice, and the percentage of primer remaining after 60 min of incubation was 98.8%, 101%, 103%, 94.9%, and 102%, respectively.

[0307] The intrinsic clearance of B19 in human, monkey, rat, and mouse liver microsomes was 5.80, 11.3, 6.55, and 17.0 mL / min / kg, respectively. It was barely cleared in dogs and mice, with the remaining percentage of primer after 60 min of incubation being 118% and 92.8%, respectively.

[0308] The results of metabolic stability of B61, B63, and B19 in mouse, rat, dog, monkey, and human liver microsomes are shown in Table 4 below.

[0309] [Table 19]

[0310] Test Example 5: In vitro antitumor activity of the ADC of the present invention Tumor cell lines from various tumor sources were commercially available. All cells were obtained from ATCC (American Type Culture Collection) and used to evaluate the antitumor inhibitory activity of the ADCs of the present invention. Various tumor cells were cultured to a cell density of 80% to 90%. When the cell activity measured with trypan blue was 90% or higher, plating was performed. Different cell lines were optimized to a density of 3000 to 5000 cells / well, and 75 μL of the cell suspension was added to each BeyoGold™ 10000-100000-cell suspension. TMCells were plated onto ultra-low-binding black, clear-bottom 96-well plates (Beyotime, product number: FULA965-24pcs) and cultured overnight. After the cells had attached, the following day, ADC samples diluted in the corresponding medium were added. The ADC samples to be assayed, diluted 5-fold with a maximum concentration of 100 nM, were then added to the cell culture plate. The plates were cultured for 6 days in a 37°C, 5% CO2 incubator. Before assay, the CellTiter-Lumi™ luminescent cell activity assay reagent was equilibrated to room temperature in the dark. Then, 50 μL of CellTiter-Lumi™ (Beyotime, product number: C0065XL) cell activity assay reagent was added to each well of the 96-well plate. The plates were then placed on a shaker at 300 rpm for 10 minutes in the dark to fully lyse the cells. After sufficient reaction, the fluorescence intensity was measured using a multifunctional fluorescence microplate reader, and the cell inhibition rate was tested based on the fluorescence intensity. The cell activity curve was generated using Graphpad Prism 8.0, and the IC50 value was calculated. The activity data of each ADC sample in different tumor cell lines are shown in the table below.

[0311] [Table 20]

[0312] The ADC samples obtained by applying the small molecule compounds of the present invention as payloads have high activity in tumor cells for various indications, and therefore show great prospects for application.

Claims

1. A compound having the structure shown in formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, and pharmaceutical salt, hydrate, solvate thereof, 【Chemistry 1】 Among them, A is H, D, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 selected from halogenated alkyl groups, B is H, D, halogen, -NH 2 , -NO 2 , C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 selected from halogenated alkyl groups, W is -C(=O)- or -CH 2 -Selected from L a is a 1 to 4 carbon alkylene group chain, wherein each alkylene group is independently -NH-, -O-, -C(=O)-, -C(=NH)-, -C(=S)-, -CF 2 -, -S(=O)-, -S(=O) 2 -, -C(-OH)H-, -C(NH 2 ) may be substituted by H-, -C(=NC≡N)-, x is selected from the integers 0 to 4, for example 0, 1, 2, 3, 4; y is selected from the integers 0 to 4, e.g., 0, 1, 2, 3, 4; z is selected from the integers 0 to 4, for example, 0, 1, 2, 3, or 4; 【Chemistry 2】 is C 6-14 selected from an aryl group, a 5- to 6-membered heteroaryl group, and a 3- to 18-membered cycloalkyl group; R a and R b are H, D, halogen, -OH, -CN, and -NO, respectively. 2 , -NH 2 , C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy group, -R c , -OR c , -CH(R c )OH, -CH 2 CH (R c ) OH, -NH(R c ) independently selected from R c is H, a 3- to 8-membered cycloalkyl group, C 6-14 Aryl group, benzyl group, C 1-6 alkyl groups, L b is an optionally substituted C 1-20 (For example, C 1-18 , C 1-16 , C 1-14 , C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 3-12 , C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 ) alkylene groups, wherein each alkylene group is independently selected from -CR e R f -, -O-, -S-, -NR d -, a 3- to 8-membered cycloalkylene group, or a 3- to 8-membered heterocyclylene; R d is H, C 1-12 Alkyl group, 3- to 8-membered cycloalkyl group, benzyl group, C 6-14 Aryl groups, 5- to 6-membered heteroaryl rings, C 1-12 selected from an alkoxycarbonyl group, -Boc, -Cbz, -Fmoc, an acetyl group, and a trifluoroacetyl group; R e and R f are H and C, respectively. 1-12 Alkyl group, 3- to 8-membered cycloalkyl group, benzyl group, C 6-14 independently selected from an aryl group, a 5- to 6-membered heteroaryl group, P is selected from -H, and when the atom linked to P is a nitrogen atom, P may be selected from a linear or branched aliphatic oxycarbonyl group having 1 to 12 carbon atoms, -Boc, -Cbz, -Fmoc, a formyl group, an acetyl group, or a trifluoroacetyl group; when the atom linked to P is an oxygen atom, P may be selected from an acetyl group, a trifluoroacetyl group, a trimethylsilyl group, a dimethyl tert-butylsilyl group, or a diphenyl tert-butylsilyl group; A compound having the structure shown in formula (I) or its tautomers, meso-isomers, racemates, enantiomers, diastereomers, and pharmaceutical salts, hydrates, and solvates thereof.

2. A compound having a structure represented by formula (I-1) or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer thereof, and a pharmaceutical salt, hydrate, or solvate thereof, 【Transformation 3】 Among them, U is -NH-, -CH 2 -, -CF 2 -Selected from R 1 is hydrogen, halogen, C 1-6 Alkyl group, C 1-6 selected from halogenated alkyl groups and 3- to 8-membered cycloalkyl groups; X 1 , X 2 are each independently selected from —O—, —S—, and a bond; X 3 is -N(R 7 ) -, bond, L 1 , L 2 are bond, -C 1-6 Alkyl group -, -C 1-6 Alkyl group -CH(R 3 )-C 1-6 Alkyl group -, -C(R 3 ) (R 4 )-C 1-6 Alkyl group -, -C 1-6 Alkyl group-3 to 8-membered cycloalkyl group-C 1-6 Alkyl group, 3- to 8-membered cycloalkyl group, C 1-6 Alkyl group -, -C 1-6 alkyl group-3 to 8-membered heterocyclyl group-C 1-6 Alkyl group -, -3 to 8-membered heterocyclyl group -C 1-6 alkyl group, R 3 , R 4 are H and C, respectively. 1-6 Alkyl group, C 6-14 independently selected from an aryl group, a 3- to 8-membered cycloalkyl group, or R 3 and R 4 together with the carbon atom to which it is attached form a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, R 2 is H, an optionally substituted substituent: C 1-6 Alkyl group, 3- to 16-membered cycloalkyl group, 3- to 16-membered heterocyclyl group, -C 1-6 Alkyl group -C(R 5 ) (R 6 )-C 1-6 Alkyl group -, -C 1-6 Alkyl group -C(R 5 ) (R 6 ) - selected from R 5 , R 6 are H and C, respectively. 1-6 Alkyl group, C 6-14 independently selected from an aryl group, a 3- to 8-membered cycloalkyl group, or R 5 and R 6 together with the carbon atom to which it is attached form a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, R 7 is H, an optionally substituted substituent: C 1-6 alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, or -N(R 7 ) (R 2 ) form a 3- to 16-membered heterocyclyl group; wherein the optionally substituted substituents are —OH, C 1-6 Alkyl group, (R 8 ) (R 9 ) NH-, 3- to 8-membered heterocyclyl group, C 1-6 selected from an alkyloxycarbonyl group (e.g., a tert-butoxycarbonyl group (Boc), a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group), a benzyloxycarbonyl group (Cbz), a fluorenylmethyloxycarbonyl group (Fmoc), and an allyloxycarbonyl group (Alloc); R 8 , R 9 are H and C, respectively. 1-6 Alkyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-14 independently selected from an aryl group and a benzyl group; The heteroatoms of the heterocyclyl group are selected from O, S, and N. A compound having the structure represented by formula (I-1) or its tautomer, meso form, racemic form, enantiomer, diastereomer, and pharmaceutical salt, hydrate, and solvate thereof.

3. Formula (I-1) has a structure represented by formula (I-2) to formula (I-11), 【Chemistry 4】 【change】 Among them, U and X 1 , X 2 , L 1 , L 2 , R 2 , R 7 is defined as in formula (I-1), R 10 is C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 alkyloxycarbonyl group, tert-butoxycarbonyl group (Boc), methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group), benzyloxycarbonyl group (Cbz), fluorenylmethyloxycarbonyl group (Fmoc), and allyloxycarbonyl group (Alloc); m and n are each independently selected from integers of 0 to 6, e.g., 0, 1, 2, 3, 4, 5, or 6; A compound having a structure represented by formula (I-1) according to claim 2, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof.

4. R 2 is selected from optionally substituted substituents: 3- to 8-membered monocyclic heterocyclyl groups, 6- to 14-membered spirocyclic heterocyclyl groups, 5- to 14-membered fused-ring heterocyclyl groups, and 5- to 14-membered bridged-ring heterocyclyl groups, wherein the heteroatoms of said heterocyclyl groups are selected from nitrogen; A compound having a structure represented by formula (I-1) to formula (I-11) according to claim 2 or 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof.

5. R 2 is an optionally substituted substituent: azetidinyl group, pyrrolidinyl group, piperidinyl group, 【Transformation 5】 Selected from Among them, 【Transformation 6】 represents a bond, A compound having a structure represented by formula (I-1) to formula (I-11) according to claim 2 or 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof.

6. L 1 , L 2 are methylene groups, 【Transformation 7】 are independently selected from R 2 is an optionally substituted substituent: 【Transformation 8】 Selected from R 7 is H, a methyl group, 【Chemistry 9】 Selected from or R 2 and R 7 together with the N connected to it, 【Chemistry 10】 Forming The optionally substituted substituents are H, C 1-3 Alkyl group, C 1-6 Alkyloxycarbonyl groups (e.g., C 1-3 alkyloxycarbonyl group, tert-butoxycarbonyl group (Boc), methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group), benzyloxycarbonyl group (Cbz), fluorenylmethyloxycarbonyl group (Fmoc), and allyloxycarbonyl group (Alloc); Among them, 【Chemistry 11】 represents a bond, A compound having a structure represented by formula (I-1) to formula (I-11) according to claim 2 or 3, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof.

7. A compound having the structure shown in formula (I) or formula (I-1) according to claim 1 or 2, or a tautomer, meso form, racemic form, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof, having the following structure: 【Chemistry 12】 【change】 【change】 【change】 【change】

8. An antibody-drug conjugate represented by the following formula (II) and a pharmaceutical salt, hydrate, solvate, stereoisomer or isotope-labeled compound thereof: 【Chemistry 13】 Among them, Ab is selected from an antibody or antigen-binding fragment; L is a linker moiety, one end of which is linked to Ab and the other end of which is linked to a biologically active molecule D; D is a structure formed by linking the compound represented by formula (I) according to claim 1 to L, d is an integer or decimal number selected from 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7, or 8; When d is a decimal, it refers to the average number of linker-drug molecules conjugated per antibody unit. An antibody-drug conjugate of formula (II) and pharmaceutical salts, hydrates, solvates, stereoisomers or isotopically labeled compounds thereof.

9. D is a structure formed by linking the compound represented by formula (I-1) according to claim 2 or formula (I-2) to formula (I-12) according to claim 3 to L, and more preferably D is a structure formed by linking the compound B1 to B96 according to claim 7 to L, preferably linked to L via a nitrogen atom, and more preferably R 2 Above or R 2 and pharmaceutical salts, hydrates, solvates, stereoisomers, or isotope-labeled compounds thereof according to claim 8, wherein

10. The Ab is selected from antibodies or antigen-binding fragments thereof that target HER2, DLL3, Claudin18.2, and BCMA; The antibody-drug conjugate according to claim 8, and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

11. -L- is selected from -S-L'-TC-, in which S is an active functional group for linking to an antibody, L' is a spacing linking fragment or a chemical bond, T is an optional functional group that triggers cleavage of the linker, and C is an optional autolytic spacing fragment; The antibody-drug conjugate according to claim 8, and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

12. S is optionally formed from an Sr group that reacts with an antibody or antigen-binding fragment Ab, and Sr preferably comprises a sulfhydryl-reactive group, an amino-reactive group, a carboxy-reactive group, a disulfide bond cross-linking group, or the like. The antibody incorporating the unnatural amino acid may comprise a click chemistry reactive group such as a ketone, a hydrazine or hydrazide, an azide, an alkyne such as a ring-strained alkyne, a cyclopropene, or a diene. Preferably, Sr comprises a methylsulfonylpyrimidinyl group or a maleimide group; Preferably, Sr is an optional binding fragment S L Further includes S L is an optionally substituted C 1-10 Alkylene group, alkenylene group or alkynylene group, C 6-12 Arylene group or C 3-12 Cycloalkylene group, C 2-11 Heteroarylene group or C 2-11 heterocyclylene groups or combinations thereof, and optionally spaced by O, CO, NH or combinations thereof, more preferably S L contains an alkynyl group or a polyethylene glycol fragment, more preferably S L contains a cyclohexyl group, a phenyl group, a triazolyl group, a piperidinyl group, or a piperazinyl group, The antibody-drug conjugate according to claim 11, and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

13. The antibody-drug conjugate and pharmaceutical salts, hydrates, solvates, stereoisomers, or isotope-labeled compounds thereof of claim 11, wherein L' comprises a hydrophilically modified fragment such as a polyethylene glycol fragment or a polysarcosine fragment, or L' comprises an amino acid residue having a tertiary amine or a quaternary ammonium group in the side chain.

14. T is a peptide fragment, a bivalent peptide group comprising 1 to 8 (specifically 1, 2, 3, 4, 5, 6, 7, or 8) optionally substituted natural or unnatural amino acid residues in L- or D-form, each of which may be homologous or different, and which are selected from the following amino acid residues: alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), and methionine (Met). , asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), norvaline (Nva), norleucine (Nle), selenocysteine ​​(Sec), pyrrolysine (Pyl), homoserine, homocysteine, demethylpyrrolysine, or analogs of the above amino acids, for example, -ValCit-, -CitVal-, -AlaAla-, -AlaCit-, -CitAla la-, -AsnCit-, -CitAsn-, -CitCit-, -ValGlu-, -GluVal-, -SerCit-, -CitSer-, -LysCit-, -CitLys-, -AspCit-, -CitAsp-, -AlaVal-, -ValAla-, -Ph eAla-, -AlaPhe-, -PheLys-, -LysPhe-, -ValLys-, -LysVal-, -AlaLys-, -LysAla-, -PheCit-, -CitPhe-, -LeuCit-, -CitLeu-, -IleCit-, -CitIle-, -P heArg-, -ArgPhe-, -CitTrp-, -TrpCit-, -AlaAlaAla-, -PhePheLys-, -LysPhePhe-, -DPhePheLys-, -DLysPhePhe-, -GlyPheLys-, -LysPheGly-, -Gly PheLeuGly-, -GlyLeuPheGly-, -GluValCit-, -AlaLeuAlaLeu-, -GlyGlyGly-, -GlyGlyGlyGly-, -GlyPheValGly-, -GlyValPheGly-, -GlyGlyPheGly-,-GlyGlyValGly-, Preferably, L' is located at either end of the peptide fragment T, or between any two amino acids, or replaces any one amino acid. The antibody-drug conjugate according to claim 11, and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

14. The formula (II) is a structure represented by formula (II-a1) or formula (II-a2), 【Chemistry 14】 Among them, Ab, S L , L', T, C, D and d have the same meanings as in claim 12; Preferably, formula (II) is a structure represented by formula (II-b1) to formula (II-b4), 【Chemistry 15】 More preferably, formula (II) has a structure represented by formulas (II-c1) to (II-c5): 【Chemistry 16】 The antibody-drug conjugate according to claim 12, and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

15. The Ab is selected from Trastuzumab (heavy chain and light chain combination: SEQ ID NOs: 1 and 2), Pertuzumab (heavy chain and light chain combination: SEQ ID NOs: 3 and 4), SYM003 (heavy chain and light chain combination: SEQ ID NOs: 5 and 6), SYM004 (heavy chain and light chain combination: SEQ ID NOs: 7 and 8), and Belantamab (heavy chain and light chain combination: SEQ ID NOs: 9 and 10), The antibody-drug conjugate of formula (II) according to claim 8 and pharmaceutical salts, hydrates, solvates, stereoisomers or isotope-labeled compounds thereof.

16. Use of the compound according to any one of claims 1 to 7, or a tautomer, meso form, racemate, enantiomer, diastereomer, or pharmaceutical salt, hydrate, or solvate thereof, or the antibody-drug conjugate according to any one of claims 8 to 15, or a pharmaceutical salt, hydrate, solvate, stereoisomer, or isotope-labeled compound thereof, in the manufacture of a medicament for treating cancer.

17. The cancers include liver cancer, kidney cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), stomach cancer, esophageal cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, hematological tumors or glioblastoma multiforme, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), cervical cancer, uterine cancer, endometrial cancer, salivary gland cancer, glioma, neuroblastoma, sarcoma, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, , chronic lymphocytic leukemia), bone cancer, skin cancer, and thyroid cancer, preferably cancers associated with abnormal expression of HER2, Claudin 18.2, DLL3, and BCMA, more preferably cancers associated with abnormal expression of HER2 include lung cancer, breast cancer (e.g., ductal carcinoma), ovarian cancer, endometrial cancer, gastric cancer, and prostate cancer, cancers associated with abnormal expression of DLL3 include lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and cancers associated with abnormal expression of BCMA include lymphoma (multiple myeloma).

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a tautomer, meso form, racemate, enantiomer, or diastereomer thereof, and a pharmaceutical salt, hydrate, or solvate thereof, or the antibody-drug conjugate according to any one of claims 8 to 15, and a pharmaceutical salt, hydrate, solvate, stereoisomer, or isotope-labeled compound thereof, and one or more pharmaceutically acceptable adjuvants.

19. A compound of formula (III), 【Chemistry 17】 wherein the definitions of Sr, L', T, C and D are the same as those in claim 8; Preferably, the compound of formula (III) has the structure shown in formula (III-a): [Chemistry 18] wherein m and n are each independently selected from integers of 0 to 6, e.g., 0, 1, 2, 3, 4, 5, and 6; Preferably, Sr comprises a maleimide group or a methylsulfonylpyrimidinyl group, L' is absent, T is a peptide fragment, and C is 【Chemistry 19】 and More preferably, the compound of formula (III) is a compound of formula (III-b1) to (III-b5), 【Chemistry 20】 A compound of formula (III).

20. 10. Use of a compound of formula (I) according to claim 1 in the manufacture of an antibody-drug conjugate.

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