An antitumor compound and its preparation method and application

Abstract

The present application relates to an anti-tumor compound, a preparation method and application thereof, and specifically to a compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and specifically to an anti-tumor compound and its preparation method and application. Background Art

[0002] Currently, cytotoxic small molecules used in antibody-drug conjugates (ADCs) can be camptothecin derivatives, which have anti-tumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody-drug conjugates (ADCs). However, further development of camptothecin derivatives and ADC drugs with better efficacy and / or safety is still needed. Summary of the Invention

[0003] The present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may have one or more effects selected from the following groups: (1) having inhibitory activity on the proliferation of tumor cells in vitro; (2) having targeted inhibition; (3) having plasma stability; (4) having an in vivo tumor-suppressing effect; (5) having a bystander killing effect; (6) having an anti-transporter transport ability; (7) having an in vivo tumor targeting ability; and (8) having good in vivo safety.

[0004] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a structure represented by formula (II-A):

[0005]

[0006] where X 1 For saturated C, the X 1 R n replace;

[0007] Ring A is selected from the following group: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or at least 1 substituent R 1a replace;

[0008] When ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[0009] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace;

[0010] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0011] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or at least 1 methylene unit is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0012] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0013] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L 1 0 or at least 1 methylene unit is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6)-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0014] Each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0015] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0016] m and n are each independently selected from an integer of at least 0, and p is an integer of at least 1.

[0017] On the one hand, the present application provides a general formula (II-E x ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0018]

[0019] where X 1 For saturated C, the X 1 R n replace;

[0020] Ring A is selected from the following group: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or at least 1 substituent R 1a replace;

[0021] When ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[0022] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace;

[0023] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0024] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or at least 1 methylene unit is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0025] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0026] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L1 0 or at least 1 methylene unit is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0027] Each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0028] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0029] m and n are each independently selected from an integer of at least 0, and p is an integer of at least 1.

[0030] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising formula (II-C x ) shows the structure:

[0031]

[0032] The L is -L a -L b -L c -;

[0033] The-L a -Selected from the following group:

[0034]

[0035] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp -, Z is -(C(R za )(R zb )) zn ;

[0036] where wn is selected from an integer at least 0,

[0037] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0038] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0039] wherein zn is selected from an integer of at least 0,

[0040] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(Rzx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0041] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cx replace;

[0042] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0043] Each R r , R ra , R rbEach is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0044] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0045] The-L c -Selected from the following group:

[0046]

[0047] where R L1 、R L2 Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0048] where X 1 For saturated C, the X 1 R n replace;

[0049] Ring A is selected from the following group: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or at least 1 substituent R 1a replace;

[0050] When ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[0051] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace;

[0052] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0053] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or at least 1 methylene unit is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0054] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0055] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L 1 0 or at least 1 methylene unit is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0056] Each R 1a , R 2a , R 3a , R 3b , R4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0057] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0058] m and n are each independently selected from an integer of at least 0, and p is an integer of at least 1.

[0059] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure represented by formula (II-Dx):

[0060]

[0061] Among them, Ab is the ligand, and the average number of connections N a An integer or decimal from 1 to 10;

[0062] The L is -L a -L b -L c -;

[0063] The-L a -Selected from the following group:

[0064]

[0065] Where W is -(C(R wa)(R wb )) wn -, Y is -(OCH2CH2) yn -O yp -, Z is -(C(R za )(R zb )) zn ;

[0066] where wn is selected from an integer at least 0,

[0067] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0068] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0069] wherein zn is selected from an integer of at least 0,

[0070] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0071] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cxreplace;

[0072] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0073] Each R r , R ra , R rb Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0074] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0075] The-L c -Selected from the following group:

[0076]

[0077] where R L1 、R L2Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0078] where X 1 For saturated C, the X 1 R n replace;

[0079] Ring A is selected from the following group: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or at least 1 substituent R 1a replace;

[0080] When ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[0081] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace;

[0082] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0083] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or at least 1 methylene unit is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0084] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0085] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L 1 0 or at least 1 methylene unit is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0086] Each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0087] Each of R, Ra , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0088] m and n are each independently selected from an integer of at least 0, and p is an integer of at least 1.

[0089] On the one hand, the present application provides a general formula (II-F x ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0090]

[0091] The L x For L ax -L b -L c -;

[0092] The L ax -Selected from the following group:

[0093]

[0094] where R hal is iodine or bromine;

[0095] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp -, Z is -(C(R za )(R zb )) zn ;

[0096] where wn is selected from an integer at least 0,

[0097] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx)-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0098] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0099] wherein zn is selected from an integer of at least 0,

[0100] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0101] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cx replace;

[0102] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0103] Each R r , R ra , R rb Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0104] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0105] The-L c -Selected from the following group:

[0106]

[0107] where R L1 、R L2 Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0108] where X 1 For saturated C, the X 1 R n replace;

[0109] Ring A is selected from the following group: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or at least 1 substituent R 1a replace;

[0110] When ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[0111] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace;

[0112] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0113] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or at least 1 methylene unit is each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0114] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0115] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L 1 0 or at least 1 methylene unit is each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0116] Each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0117] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0118] m and n are each independently selected from an integer of at least 0, and p is an integer of at least 1.

[0119] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the structure of the following group:

[0120]

[0121]

[0122] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a structure represented by formula (III-A):

[0123]

[0124] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0125] X is -L 1 -CH2-C(O)-;

[0126] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or at least 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0127] Each R 2 , R 3a , R 3b , R 4b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0128] Each of R, R a , R bEach is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0129] m is selected from an integer of at least 0, and n is selected from an integer of at least 1;

[0130] When R 1 When it is -O- or -HN-, L 1 At least one methylene unit of each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a , R 3b Not hydrogen at the same time.

[0131] In one aspect, the present application provides a compound represented by general formula (III-E) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0132]

[0133] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0134] X is -L 1 -CH2-C(O)-;

[0135] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or at least 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0136] Each R 2 , R 3a , R 3b , R 4b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0137] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0138] m is selected from an integer of at least 0, and n is selected from an integer of at least 1;

[0139] When R 1 When it is -O- or -HN-, L 1 At least one methylene unit of each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a , R 3b Not hydrogen at the same time.

[0140] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a structure represented by formula (III-C):

[0141]

[0142] The L is -L a -L b -L c -;

[0143] The-L a -Selected from the following group:

[0144]

[0145] Where W is -(C(R wa )(R wb )) wn-, Y is -(OCH2CH2) yn -O yp , Z is -(C(R za )(R zb )) zn ,;

[0146] where wn is selected from an integer at least 0,

[0147] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0148] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0149] wherein zn is selected from an integer of at least 0,

[0150] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0151] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cx replace;

[0152] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0153] Each R r , R ra , R rb Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0154] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0155] The-L c -Selected from the following group:

[0156]

[0157] where R L1 、R L2Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0158] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0159] X is -L 1 -CH2-C(O)-;

[0160] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or at least 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0161] Each R 2 , R 3a , R 3b , R 4b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0162] Each of R, R a , R bEach is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0163] m is selected from an integer of at least 0, and n is selected from an integer of at least 1;

[0164] When R 1 When it is -O- or -HN-, L 1 At least one methylene unit of each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a , R 3b Not hydrogen at the same time.

[0165] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the structure shown in formula (III-D):

[0166]

[0167] Among them, Ab is the ligand, and the average number of connections N a An integer or decimal from 1 to 10;

[0168] The L is -L a -L b -L c -;

[0169] The-L a -Selected from the following group:

[0170]

[0171] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , Z is -(C(R za )(R zb )) zn ,;

[0172] where wn is selected from an integer at least 0,

[0173] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0174] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0175] wherein zn is selected from an integer of at least 0,

[0176] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0177] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cx replace;

[0178] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SRr 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0179] Each R r , R ra , R rb Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0180] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0181] The-L c -Selected from the following group:

[0182]

[0183] where R L1 、R L2 Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0184] where R 1 Selected from the following group: -O-, -(R 2)N-,-P(=O)(R 2 )-, and -S-;

[0185] X is -L 1 -CH2-C(O)-;

[0186] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or at least 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0187] Each R 2 , R 3a , R 3b , R 4b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0188] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0189] m is selected from an integer of at least 0, and n is selected from an integer of at least 1;

[0190] When R 1 When it is -O- or -HN-, L 1 At least one methylene unit of each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a, R 3b Not hydrogen at the same time.

[0191] In one aspect, the present application provides a compound represented by the general formula (III-F) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0192]

[0193] The L x For L ax -L b -L c -;

[0194] The L ax -Selected from the following group:

[0195]

[0196] where R hal is iodine or bromine;

[0197] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , Z is -(C(R za )(R zb )) zn ,;

[0198] where wn is selected from an integer at least 0,

[0199] Zero or at least one methylene unit of W is independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0200] wherein yn is selected from an integer that is at least 0, and yp is 0 or 1;

[0201] wherein zn is selected from an integer of at least 0,

[0202] 0 or at least 1 methylene unit of Z is independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0203] -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted with at least one substituent R cx replace;

[0204] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or by R r Optionally substituted C 1-6 aliphatic groups;

[0205] Each Rr , R ra , R rb Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0206] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0207] The-L c -Selected from the following group:

[0208]

[0209] where R L1 、R L2 Each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0210] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0211] X is -L 1 -CH2-C(O)-;

[0212] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or at least 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0213] Each R 2 , R 3a , R 3b , R 4bEach is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[0214] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0215] m is selected from an integer of at least 0, and n is selected from an integer of at least 1;

[0216] When R 1 When it is -O- or -HN-, L 1 At least one methylene unit of each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a , R 3b Not hydrogen at the same time.

[0217] In one aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ligand drug conjugate comprises the structure of the following group:

[0218]

[0219] In one aspect, the present application provides a method for preparing the compound of the present application or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises reacting ligand Ab with a compound of formula (II-F) of the present application. x ) shows the structural contact.

[0220] On the one hand, the present application provides a method for preparing the compound of the present application or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises contacting the ligand Ab with the structure shown in formula (III-F) of the present application.

[0221] In one aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0222] On the one hand, the present application provides the use of a compound of the present application or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof and / or a pharmaceutical composition of the present application in the preparation of a medicament for treating and / or preventing tumors.

[0223] Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of this application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the drawings and specification of this application are merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0224] The specific features of the inventions of this application are set forth in the appended claims. The features and advantages of the inventions of this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows:

[0225] Figures 1-16 Shown are the in vivo tumor inhibition results of the compounds of the present application. DETAILED DESCRIPTION

[0226] The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0227] Definition of terms

[0228] In this application, the term "ligand" generally refers to a macromolecular compound that can recognize and bind to an antigen or receptor associated with a target cell. The function of the ligand can be to present the drug to the target cell population bound to the ligand. These ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells, receptors and / or antigens. In this application, the ligand can be represented by Ab. The ligand antigen forms a connection bond with the linker through a heteroatom on the ligand. It can be an antibody or an antigen-binding fragment thereof. The antibody can be selected from a chimeric antibody, a humanized antibody, a fully human antibody or a murine antibody; the antibody can be a monoclonal antibody. For example, the antibody can be an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 or EGFR. For example, the antibody can be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R , BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD14 7. CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45 , CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1 , CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DL L3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, F cRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6,IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP 14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, claudin 18.2, endothrin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein, or tissue factor.

[0229] In this application, the term "cytotoxic drug" generally refers to a toxic drug that has a strong chemical molecule that destroys the normal growth of tumor cells. Cytotoxic drugs can kill tumor cells at a sufficiently high concentration. The "cytotoxic drug" may include toxins, such as small molecule toxins or enzyme-active toxins of bacterial, fungal, plant or animal origin, radioactive isotopes (such as At 211 , I 131 , I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P 32or radioactive isotopes of Lu), toxic drugs, chemotherapeutic drugs, antibiotics and nucleolytic enzymes, for example, can be toxic drugs, including but not limited to camptothecin derivatives, for example, can be the camptothecin derivative exatecan (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]imidazo[1,2-b]quinoline-10,13(9H,15H)-dione).

[0230] In this application, the term "linker structure" generally refers to a chemical structure fragment or bond that is connected to a ligand at one end and to a cytotoxic drug at the other end. It can also be connected to a cytotoxic drug after being connected to other linkers. The direct or indirect connection to the ligand can refer to the group being directly connected to the ligand through a covalent bond, or it can be connected to the ligand through a linker structure. For example, the linker structure can be the -L described in this application. ax -L b -L c -and-or-L a -L b -L c For example, a chemical structure fragment or bond comprising an acid-labile linker structure (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker structure, a photolabile linker structure, a dimethyl linker structure, or a disulfide-containing linker structure can be used as the linker structure.

[0231] In this application, the term "optionally linked to other molecular moieties" generally means that the structure is not linked to any other chemical structure, or that the structure is linked to one or more other chemical structures (such as the ligands described in this application) that are different from the structure (for example, linked by a chemical bond or linked by a linker structure).

[0232] In this application, the term "ligand-drug conjugate" generally refers to a ligand linked to a biologically active cytotoxic drug via a stable linker. In this application, a "ligand-drug conjugate" may be an antibody-drug conjugate (ADC), which may be a monoclonal antibody or antibody fragment linked to a biologically active cytotoxic drug via a stable linker.

[0233] In this application, the term "antibody or its antigen-binding fragment" generally refers to immunological binding agents extending to all antibodies from all species, including dimers, trimers and multimers; bispecific antibodies; chimeric antibodies; fully human antibodies; humanized antibodies; recombinant and reconstructed antibodies and their fragments. The term "antibody or its fragment" can refer to any antibody-like molecule with an antigen-binding region, and the term includes small molecule fragments such as Fab', Fab, F(ab')2, single domain antibodies (DABs), Fv, scFv (single chain Fv), linear antibodies, diabodies, etc. The term "antigen-binding fragment" can refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. For example, a fragment of a full-length antibody can be used to perform the antigen-binding function of an antibody. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art. The antibodies may include: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-TROP2 antibody, anti-Claudin antibody One or more of 18.2 antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody or anti-Mesothelin antibody, for example, trastuzumab or pertuzumab.

[0234] In this application, the term "chimeric antibody" generally refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by the murine antibody. To create a chimeric antibody, a hybridoma that secretes a murine-specific monoclonal antibody can be established. The variable region genes can then be cloned from the murine hybridoma cells. The constant region genes of a human antibody can then be cloned as needed. The murine variable region genes and the human constant region genes can then be linked to form a chimeric gene, which is then inserted into an expression vector. The chimeric antibody molecule can then be expressed in either eukaryotic or prokaryotic systems.

[0235] In this application, the term "humanized antibody", also known as CDR-grafted antibody, generally refers to antibodies produced by transplanting mouse CDR sequences into human antibody variable region frameworks, i.e., different types of human germline antibody framework sequences. This can overcome the heterologous reactions induced by chimeric antibodies due to the large amount of mouse protein components they carry. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database.

[0236] In this application, the terms "fully human antibody", "fully human antibody" or "completely human antibody" are also called "fully human monoclonal antibody", and the variable region and constant region of the antibody can be both human, eliminating immunogenicity and toxic side effects. The development of monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies. The antibody or ligand described in this application can be a fully human monoclonal antibody. The relevant technologies for the preparation of fully human antibodies can be: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology (phagedisplay), transgenic mouse antibody preparation technology (transgenic mouse) and single B cell antibody preparation technology, etc.

[0237] In this application, the term "CDR" generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contributes to antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat EA et al. (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242), Chothia et al., "Canonical Structures For the Hypervariable Regions of Immunoglobulins," J. Mol. Biol. 196: 901 (1987); and MacCallum et al., "Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography," J. Mol. Biol. 262: 732 (1996)). As used in this application, the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 of the light chain variable domain (CDR L1, CDR L2, CDR L3 or L1, L2, L3), and CDR1, CDR2 and CDR3 of the heavy chain variable domain (CDR H1, CDR H2, CDR H3 or H1, H2, H3).

[0238] In this application, the term "methylene" generally refers to a residue derived from a group of one carbon atom by removing two hydrogen atoms. A methylene group may be substituted or unsubstituted, substituted or unsubstituted. The term "alkylene" generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which may be a straight-chain or branched group containing 1 to 20 carbon atoms, for example, an alkylene group containing 1 to 12 carbon atoms, for example, 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and 1,5-butylene (-CH2CH2CH2CH2CH2-), and the like. Alkylene may be substituted or unsubstituted, substituted or unsubstituted, for example, when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, for example, hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0239] In this application, the term "arylene" generally refers to a residue derived from two hydrogen atoms removed from the same carbon atom or two different carbon atoms of an aromatic ring. The term "aromatic ring" can refer to a 6- to 14-membered all-carbon monocyclic ring or a fused polycyclic ring (i.e., a ring sharing adjacent pairs of carbon atoms) with a conjugated π electron system, which can be 6- to 10-membered, such as benzene and naphthalene. The aromatic ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0240] As used herein, the term "heteroarylene" generally refers to a residue having two hydrogen atoms derived from the same or two different carbon atoms of a heteroaromatic ring. The term "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms can be selected from the group consisting of oxygen, sulfur, and nitrogen. A heteroaryl group can be 5 to 10-membered, and can be 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroarylene group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0241] In this application, the term "heterocyclylene" generally refers to a stable 3-7 membered monocyclic ring structure without aromaticity, a fused 7-10 membered bicyclic heterocyclic ring structure, or a bridged 6-10 membered bicyclic heterocyclic ring structure. These ring structures may be saturated or partially saturated. In addition to carbon atoms, these ring structures may contain one or more heteroatoms, wherein the heteroatoms may be selected from the following group: oxygen, sulfur, and nitrogen. For example, it may contain 1-4 heteroatoms as defined above. When used to refer to atoms in a heterocyclic ring structure, the term "nitrogen" may include nitrogen that has undergone substitution reactions. Heterocyclylene may be substituted or unsubstituted.

[0242] In this application, the term "carbocyclylene" generally refers to a residue derived from two carbon atoms, either identical or different, in a carbocyclic ring. The term "carbocycle" generally refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring having 3 to 20 carbon atoms, 3 to 12 carbon atoms, 3 to 10 carbon atoms, or 3 to 8 carbon atoms. Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane, and the like; polycyclic carbocycles may include spirocyclic, fused, and bridged carbocycles. Carbocyclylene may be substituted or unsubstituted.

[0243] As used herein, the term "partially unsaturated" generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules. The term "partially unsaturated" encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein. The term "unsaturated" refers to a moiety having one or more degrees of unsaturation.

[0244] In the present application, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine, for example, it can be fluorine or chlorine.

[0245] In this application, the term "aliphatic group" generally refers to a straight-chain, branched-chain, or cyclic hydrocarbon having 1 to 12 carbon atoms, which is either fully saturated or has one or more unsaturated units, provided the unsaturated units are not aromatic. For example, suitable aliphatic groups may include substituted or unsubstituted straight-chain, branched, or cyclic alkyl, alkenyl, alkynyl groups, and mixtures thereof; such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl groups. For example, aliphatic groups have 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0246] In this application, the term "optional" or "optionally" generally means that the subsequently described event or circumstance can but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group can but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0247] In this application, the term "substituted" generally refers to one or more hydrogen atoms in a group, for example up to 5, for example 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0248] In this application, the term 0 or more (e.g., 0 or at least 1, 0 or 1, 0) methylene units are "replaced" generally means that when the structure contains 1 or more methylene units, the one or more methylene units may be unsubstituted or replaced by one or more groups that are not methylene (e.g., -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -O-, -S-, -SO-, -SO2-, -PH-, -P(=O)H-, -NHSO2-, -SONH-, -C(=S)-, -C(=NH)-, -N=N-, -C=N-, -N=C- or -C(=N2)-).

[0249] One or more hydrogen atoms, for example up to 5, for example 1 to 3, in a group are independently replaced by a corresponding number of substituents. The substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0250] In this application, the term "compound" generally refers to a substance with two or more different elements. For example, the compound of the present application can be an organic compound, for example, the compound of the present application can be a compound with a molecular weight of less than 500, a compound with a molecular weight of less than 1000, a compound with a molecular weight of more than 1000, or a compound with a molecular weight of more than 10,000 or more than 100,000. In this application, a compound can also refer to a compound connected by chemical bonds, for example, it can be a compound in which one or more molecules with a molecular weight of less than 1000 are connected to a biomacromolecule through a chemical bond, and the biomacromolecule can be a polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compound of the present application can include a compound in which a protein is connected to one or more molecules with a molecular weight of less than 1000, a compound in which a protein is connected to one or more molecules with a molecular weight of less than 10,000, or a compound in which a protein is connected to one or more molecules with a molecular weight of less than 100,000.

[0251] Unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds identical to the structures described herein except for the replacement of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom by carbon-13 or carbon-14 are within the scope of this application.

[0252] As used herein, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to an organism, facilitating the absorption of the active ingredient and thereby exerting its biological activity. The preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.

[0253] In this application, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" generally refers to a salt of the compound or ligand-drug conjugate of the present application, or a salt of the compound described in the present application. Such salts may be safe and / or effective when used in mammals and may have the desired biological activity. The antibody-antibody drug conjugate compound of the present application may form a salt with an acid. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0254] In the present application, the term "solvate" or "solvate compound" generally refers to a pharmaceutically acceptable solvate formed by the ligand-drug conjugate compound of the present application and one or more solvent molecules. Non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0255] The term "drug loading" generally refers to the average number of cytotoxic drugs loaded on each ligand, and can also be expressed as the ratio of the amount of cytotoxic drug to the amount of antibody. The range of cytotoxic drug loading can be 0-12, for example, 1-10 cytotoxic drugs connected to each ligand (Ab). In the embodiment of the present application, the drug loading is expressed as N a , which can be exemplified by the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assay, and HPLC characterization can be used to identify the drug loading of each ADC molecule after the coupling reaction.

[0256] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as a solvent or suspending medium. For example, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0257] In this application, the term "comprising" generally refers to including the features specified but not excluding other elements. The terms "above" and "below" generally refer to including the number.

[0258] In this application, the term "about" generally refers to a variation within a range of 0.5%-10% above or below the specified value, for example, a variation within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value. Detailed Description of the Invention

[0260] In a first aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA):

[0261]

[0262] where R 1 Can be selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0263] L 2 It can be -(C(R 3a )(R 3b )) m -R, m can be selected from integers greater than 1;

[0264] Among them L 2 0 or more methylene units can be independently replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0265] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 1;

[0266] Among them L 10 or more methylene units can be independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0267] -Cy- can be selected from the following group: 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or each independently may be substituted by one or more substituents R 7 replace;

[0268] Each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R8 replace;

[0269] Each R 2 , R 7 , R 8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0270] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0271] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA):

[0272]

[0273] where R 1 Can be selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0274] L 2 It can be -(C(R 3a )(R 3b )) m -R, m can be selected from integers greater than 1;

[0275] Among them L 2 0 or more methylene units can be independently replaced by -Cy-, -N(R 4)C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0276] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 1;

[0277] Among them L 1 0 or more methylene units can be independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0278] -Cy- can be selected from the following group: 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or each independently may be substituted by one or more substituents R 7 replace;

[0279] Each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0280] Each R 2 , R 7 , R 8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0281] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0282] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA),

[0283] For example, where R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 Replace, each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 replace;

[0284] For example, where R 3a With R 5a Together with the atoms between them, they can form a ring B, which can be selected from the following groups: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or can be substituted by one or more substituents R 8 Replace, each R 3b , R 4 , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 replace;

[0285] For example, where R 4 With R 5a Together with the atoms between them, they can form a ring B, which can be selected from the following groups: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or can be substituted with one or more substituents R 8 Replace, each R 3a , R 3b , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 replace;

[0286] For example, where R 3a With R 6 Together with the atoms between them, they can form a ring B, which can be selected from the following groups: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or can be substituted by one or more substituents R 8 Replace, each R 3b , R 4 , R 5a , R 5b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 replace;

[0287] For example, where R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 Replace, each R 3a , R 3b , R5a , R 5b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them can form a ring B, said ring B can be selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclyl, wherein said ring B is unsubstituted or can be substituted by one or more substituents R 8 replace;

[0288] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA):

[0289]

[0290] where R 1 Can be -O-;

[0291] L 2 It can be -(C(R 3a )(R 3b )) m -R, m can be selected from integers from 1 to 3;

[0292] Among them L 2 0 methylene units can be replaced;

[0293] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers from 2 to 4;

[0294] Among them L 1 0, 1 or 2 methylene units may be replaced by -N(R 6 )C(O)-, -C(O)-, -OC(O)-, -NR 6 -, -O-, or -C(=S)- substitution;

[0295] Each R 3a , R 3b , R 5a , R 5b , R 6 Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a Together with the atoms between them, they can form Ring B, which can be selected from a 5-membered saturated heterocyclylene group, wherein the Ring B is unsubstituted,

[0296] R may be hydrogen or halogen.

[0297] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA):

[0298]

[0299] where R 1 Can be -O-;

[0300] L 2 It can be -(C(R 3a )(R 3b )) m -R, m can be selected from integers of 1 or 2;

[0301] Among them L 2 0 methylene units can be replaced;

[0302] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from an integer of 2 or 3;

[0303] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0304] Each R 3a , R 3b , R 5a , R 5b Each independently may be hydrogen, or R3a With R 5a Together with the atoms between them, they can form ring B, and the ring B can be selected from a 5-membered saturated heterocyclylene group having 1 nitrogen heteroatom, wherein the ring B is unsubstituted,

[0305] R may be hydrogen.

[0306] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (IA):

[0307]

[0308] where R 1 Can be -O-;

[0309] L 2 It can be -(C(R 3a )(R 3b )) m -R, m can be selected from integers of 1 or 2;

[0310] Among them L 2 0 methylene units can be replaced;

[0311] L 1 It can be -(C(R 5a )(R 5b ))2-;

[0312] Among them L 1 One methylene unit of can be replaced by -C(O)-;

[0313] Each R 3a , R 3b , R 5a , R 5b Each independently may be hydrogen, or R 3a With R 5a Together with the atoms between them, they can form ring B, and the ring B can be selected from a 5-membered saturated heterocyclylene group having 1 nitrogen heteroatom, wherein the ring B is unsubstituted,

[0314] R may be hydrogen.

[0315] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise the structure of the following group:

[0316]

[0317]

[0318] where R 1 It may be selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-.

[0319] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-A):

[0320]

[0321] where X 1 Can be selected from the following group: N, P, and saturated or unsaturated C, when X 1 When C can be saturated, the X 1 Can be R n Substitution; the ring A optionally connects the structure represented by the formula (II-A) to other molecular parts;

[0322] When X 1 When C is saturated, ring A may be selected from the following groups: 3- to 10-membered saturated or partially unsaturated heterocyclic groups, and 3- to 10-membered saturated or partially unsaturated carbocyclic groups, wherein the ring A may be substituted by 0 or more substituents R 1a replace;

[0323] Or, when X 1 When C is unsaturated, ring A may be selected from the following group: 6 to 10-membered aryl, 5 to 8-membered heteroaryl, 3 to 10-membered partially unsaturated heterocyclic group, and 3 to 10-membered partially unsaturated carbocyclic group, wherein the ring A may be 0 or more substituents R 1b replace;

[0324] Or, when X 1 When N or P is present, ring A may be selected from the following groups: 5- to 8-membered heteroaryl groups, and 3- to 10-membered saturated or partially unsaturated heterocyclic groups, wherein the ring A may be substituted by 0 or more substituents R 1c replace;

[0325] When ring A can be selected from the following group: 6 to 10-membered aryl, 5 to 8-membered heteroaryl, and 3 to 10-membered saturated or partially unsaturated carbocyclic group, said ring A can be substituted by p L 2 Substitute, the L 2 Cannot be R n ;

[0326] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A may be substituted by p L 2 substituted, or the ring A may contain q ring heteroatoms X 2 And the X 2 Used to connect the structure represented by formula (II-A) with other molecular parts;

[0327] X 2 may be selected from the group consisting of: N, and P;

[0328] L 2 Can be -R 2 -L 3 -, the R 2 Used to connect the structure represented by formula (II-A) with other molecular parts;

[0329] L 3 It can be -(C(R 3a )(R 3b )) m -, where L 3 When a methylene unit may be included, the L 3 The 0 or more methylene units of 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0330] R 2 Can be selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0331] L 1 It can be -(C(R 5a )(R 5b )) n -, where L 1 When a methylene unit may be included, the L 1 The 0 or more methylene units of 6)C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0332] Each R 1a , R 1b , R 1c , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0333] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0334] m and n can each independently be selected from integers of 0 or greater, and p and q can each independently be selected from integers of 1 or greater.

[0335] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0336]

[0337] X 1 It can be saturated C, the X 1 Can be R n replace;

[0338] Ring A may be selected from the following groups: a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and a 3- to 10-membered saturated or partially unsaturated carbocyclic group, wherein the ring A may be substituted by 0 or more substituents R 1a replace;

[0339] The ring A can be made of p L 2 Substitution, p can be selected from an integer greater than 1, the L 2 Cannot be R n ;

[0340] L 2 Can be -R 2 -L 3 -;

[0341] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0,

[0342] When L 3 When a methylene unit may be included, the L 3 The 0 or more methylene units of 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0343] R 2Can be selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0344] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0345] When L 1 When a methylene unit may be included, the L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0346] Each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0347] Each of R, R a , R bEach independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0348] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0349]

[0350] X 1 It can be saturated C, the X 1 Can be R n replace;

[0351] Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein the ring A may not be substituted or may be substituted with one or more substituents R 1a replace;

[0352] The ring A may contain q ring heteroatoms X 2 And the X 2 For direct or indirect connection to a ligand; q can be selected from an integer greater than 1, X 2 may be selected from the group consisting of: N, and P;

[0353] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0354] Among them L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6)-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0355] Each R 1a , R 5a , R 5b , R 6 , R n Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0356] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0357] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0358]

[0359] X 1 It can be unsaturated C;

[0360] Ring A may be selected from the following group: 6 to 10 membered aryl, 5 to 8 membered heteroaryl, 3 to 10 membered partially unsaturated heterocyclic group, and 3 to 10 membered partially unsaturated carbocyclic group, wherein the ring A is unsubstituted or may be substituted with one or more substituents R 1b replace;

[0361] The ring A can be made of p L 2 Substitution, p can be selected from integers greater than 1;

[0362] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0363] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0,

[0364] Among them L 3 The 0 or more methylene units of 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0365] R 2 Can be selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0366] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0367] Among them L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0368] Each R 1b , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0369] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0370] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0371]

[0372] X 1 It can be unsaturated C,

[0373] Ring A may be a 3- to 10-membered partially unsaturated heterocyclic group, wherein the ring A may be unsubstituted or may be substituted with one or more substituents R 1b replace;

[0374] The ring A may contain q ring heteroatoms X 2And the X 2 For direct or indirect connection to a ligand; q can be selected from an integer greater than 1, X 2 may be selected from the group consisting of: N, and P;

[0375] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0376] Among them L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0377] Each R 1b , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0378] Each of R, R a , R bEach independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0379] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0380]

[0381] X 1 Can be N or P;

[0382] Ring A may be selected from the following groups: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclic group, wherein the ring A may not be substituted or may be substituted with one or more substituents R 1c replace;

[0383] The ring A can be made of p L 2 Substitution, p can be selected from integers greater than 1;

[0384] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0385] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0,

[0386] Among them L 3 The 0 or more methylene units of 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4)-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0387] R 2 Can be selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[0388] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0389] Among them L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0390] Each R 1c , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0391] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0392] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0393]

[0394] X 1 Can be N or P;

[0395] Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein the ring A may not be substituted or may be substituted with one or more substituents R 1c replace;

[0396] The ring A may contain q ring heteroatoms X 2 And the X 2 For direct or indirect connection to a ligand; q can be selected from an integer greater than 1, X 2 may be selected from the group consisting of: N, and P;

[0397] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from integers greater than 0,

[0398] Among them L 1 The 0 or more methylene units of 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0399] Each R 1c , R 5a , R 5b , R 6 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0400] Each of R, R a , R b Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0401] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0402]

[0403] X 1 It can be saturated C, the X 1 Can be R n replace;

[0404] Ring A may be selected from the following groups: a 3- to 6-membered saturated heterocyclic group, and a 3- to 6-membered saturated or partially unsaturated carbocyclic group;

[0405] p can be 1, the L 2 Cannot be R n ;

[0406] L 2Can be -R 2 -L 3 -;

[0407] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers from 0 to 2, where 3 When a methylene unit may be included, the L 3 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0408] R 2 Can be selected from -O-;

[0409] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from 0 or 1;

[0410] When L 1 When a methylene unit may be included, the L 1 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0411] Each R 3a , R 3b , R 5a , R 5b , R n Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0412] Each R is independently hydrogen or halogen.

[0413] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0414]

[0415] X 1 It can be saturated C and the X 1 Connect R n , the R n It can be H;

[0416] Ring A may be selected from the following groups: a 5-membered saturated heterocyclic group having 1 nitrogen heteroatom, and a 4- to 6-membered saturated carbocyclic group;

[0417] The p may be 1;

[0418] L 2 Can be -R 2 -L 3 -, the L 3 Directly connected to the ring A;

[0419] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be 0 or 2;

[0420] R 2 Can be -O-;

[0421] L 1 It can be -C(O)-;

[0422] Each R 3a , R 3b Each independently may be hydrogen.

[0423] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0424]

[0425] X 1 It can be saturated C, the X 1 Can be R n replace;

[0426] Ring A may be a 3- to 6-membered saturated heterocyclic group;

[0427] The ring A may contain one ring-forming heteroatom N and the N is used to directly or indirectly connect to a ligand;

[0428] L 1 It can be -(C(R 5a )(R 5b )) n -, n can be selected from 0 or 1;

[0429] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0430] Each R 5a , R 5b , R n Each independently may be hydrogen, halogen or C which may be optionally substituted by R1-6 aliphatic groups;

[0431] Each R is independently hydrogen or halogen.

[0432] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0433]

[0434] X 1 It can be saturated C, the X 1 Can be replaced by H;

[0435] Ring A may be a 5-membered saturated heterocyclic group having 1 N heteroatom;

[0436] The ring A may contain one ring-forming heteroatom N and the N is used to directly or indirectly connect to a ligand;

[0437] L 1 It can be -C(O)-.

[0438] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0439]

[0440] X 1 It can be unsaturated C;

[0441] Ring A may be selected from the following group: 6-membered aryl, 5 to 8-membered heteroaryl, 3 to 10-membered partially unsaturated heterocyclic group, and 3 to 10-membered partially unsaturated carbocyclic group, wherein the ring A may be unsubstituted or may be independently substituted by 1 substituent R 1b replace;

[0442] The p may be 1;

[0443] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0444] L 3 Can be -C(R 3a )(R 3b )-;

[0445] R 2 Can be selected from -O-, -(R 2a )N-, or -S-;

[0446] L 1 Can be -C(R 5a )(R 5b )-;

[0447] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0448] Each R 1b , R 2a , R 3a , R 3b , R 5a , R 5b Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0449] Each R is independently hydrogen or halogen.

[0450] For example, the compound may comprise a structure represented by formula (II-Ax):

[0451] X 1 It can be unsaturated C;

[0452] Ring A may be selected from the following groups: 6-membered aryl, and 5- to 8-membered heteroaryl;

[0453] The p may be 1;

[0454] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0455] L 3 Can be -C(R 3a )(R 3b )-;

[0456] R 2 Can be selected from -O-, -(R 2a )N-, or -S-;

[0457] L 1 Can be -C(R 5a )(R 5b )-;

[0458] Among them L 10 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0459] Each R 2a , R 3a , R 3b , R 5a , R 5b Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0460] Each R is independently hydrogen or halogen.

[0461] For example, the compound may comprise a structure represented by formula (II-Ax):

[0462] X 1 It can be unsaturated C;

[0463] Ring A may be a 6-membered aryl group;

[0464] The p may be 1;

[0465] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0466] L 3 Can be -C(R 3a )(R 3b )-;

[0467] R 2 Can be -O-;

[0468] L 1 It can be -C(O)-;

[0469] Each R 3a , R 3b , R 5a , R 5b Each independently can be hydrogen or C 1-6 Aliphatic group.

[0470] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0471] X 1 It can be unsaturated C,

[0472] Ring A may be a 5-membered partially unsaturated heterocyclic group;

[0473] The ring A may contain one ring-forming heteroatom N and the N is used to directly or indirectly connect to a ligand;

[0474] L 1 Can be -C(R 5a )(R 5b ),

[0475] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0476] Each R 5a , R 5b Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0477] Each R can be independently hydrogen or halogen.

[0478] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ax):

[0479] X 1 Can be N;

[0480] Ring A may be a 6-membered saturated heterocyclic group;

[0481] The p may be 1;

[0482] L 2 Can be -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[0483] L 3 It can be -(C(R 3a )(R 3b )) m -, m can be 1 or 2,

[0484] Among them L 3 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0485] R 2 Can be selected from the following group: -O-, -(R 2a )N-, and -S-;

[0486] L 1 Can be -C(R 5a)(R 5b )-,

[0487] Among them L 1 One methylene unit of may be replaced by -C(O)- or -C(=S)-;

[0488] Each R 2a , R 3a , R 3b , R 5a , R 5b Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0489] Each R is independently hydrogen or halogen.

[0490] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-Ay):

[0491] X 1 Can be N,

[0492] Ring A may be a 5-membered partially unsaturated heterocyclic group;

[0493] The ring A may contain one ring-forming heteroatom N and the N is used to directly or indirectly connect to a ligand;

[0494] L 1 Can be -C(R 5a )(R 5b ),

[0495] Among them L 1 One or more methylene units may be replaced by -C(O)- or -C(=S)-;

[0496] Each R 5a , R 5b Each independently may be hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0497] Each R can be independently hydrogen or halogen.

[0498] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise the following group of structures:

[0499]

[0500]

[0501] where R 2 It may be selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-.

[0502] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0503]

[0504] where R 1 Can be selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[0505] X can be selected from the following group: -L 1 -C(R 1a )(R 1b )-C(O)-,-L 1 -C(R 1a )(R 1b )-C(S)-,-L 1 -L 0 -, and -L 3 -L 2 -;

[0506] L 1 It can be -(C(R 3a )(R 3b )) m -, where L 1 When a methylene unit may be included, the L 1 The 0 or more methylene units of each independently may be replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0507] L 0 Can be -C(R 2a )(R 2b )-, or L 0 It can be -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0508] L 2 Can be -C(R 5a )(R 5b )-, where L2 0 or 1 methylene unit can be replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-,

[0509] L 3 It can be -(C(R 7a )(R 7b )) n -, where L 3 The one or more methylene units are each independently replaced by -N(R 8 )C(O)-、-C(O)N(R 8 )-、-OC(O)-、-C(O)O-、-NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-、-P(=O)(R 8 )-、-N(R 8 )SO2-、-SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 The 0 or more methylene units can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- substituted;

[0510] Each R 1a , R 1b , R 2 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0511] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0512] m can be selected from an integer greater than 0, and n can be selected from an integer greater than 1;

[0513] When R 1 It can be -O- or -HN-, and X can be -L 1 -CH2-C(O)-, where L 1 When a methylene unit may be included, the L 1 The one or more methylene units are each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted, or in L 1 Each of -C(R 3a )(R 3b )-Middle R 3a , R 3b Different can be hydrogen;

[0514] When R 1 It can be -HN-, X can be -L 1 -L 0 -, L 0 When it can be -CH2-, L 1 The one or more methylene units are each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a , R 3b Different can be hydrogen;

[0515] When R 1 Can be -O-, X can be -L 3 -C(O)-,L 3 One methylene unit can be replaced by -NR 8 When replacing, R 8 It cannot be -CH2-CH2-NH2;

[0516] When R 1 It can be -NH-, and X can be -L 3 -C(O)-, L 3 More than one methylene unit may be replaced by -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-、-P(=O)(R 8 )-、-N(R 8 )SO2-、-SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-.

[0517] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0518]

[0519] where R 1 Can be selected from the following group: -O-, -(R 2 )N-, and -S-;

[0520] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0521] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0;

[0522] Among them L 1 The 0 or more methylene units of each independently may be replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0523] R 2It can be halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0524] Each R 1a , R 1b , R 3a , R 3b , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0525] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0526] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0527]

[0528] R 1Can be -S- or -(R 2 )N-;

[0529] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0530] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0;

[0531] Among them L 1 The 0 or more methylene units of each independently may be replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0532] R 2 It can be halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0533] Each R 1a , R 1b , R 3a , R 3b , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0534] Each of R, Ra , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0535] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0536]

[0537] where R 1 Can be -O- or -HN-,

[0538] X can be -L 1 -CH2-C(O)-;

[0539] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 1;

[0540] Among them L 1 The one or more methylene units are each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0541] Each R 3a , R 3b , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0542] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0543] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0544]

[0545] where R 1 Can be -O- or -HN-,

[0546] X can be -L 1 -CH2-C(O)-;

[0547] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0;

[0548] In each -C(R 3a )(R 3b )-Middle R 3a , R 3b Different can be hydrogen, or L 1 The one or more methylene units are each independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0549] Each R 3a , R 3b , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(Rb ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0550] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0551] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0552]

[0553] where R 1 Can be -O-, -S- or -(R 2 )N-,

[0554] X can be -L 1 -L 0 -;

[0555] L 0 Can be -C(R 2a )(R 2b )-, or L 0 It can be -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0556] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0;

[0557] Among them L 1 The 0 or more methylene units of each independently may be replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0558] R 2 It can be halogen, -NO2, -CN, -OR, -SR, -N(R a )(Rb ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0559] Each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0560] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0561] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0562]

[0563] where R 1 Can be -HN-,

[0564] X can be -L 1 -L 0 -;

[0565] L 0 Can be -C(R 2a )(R 2b )-, or L 0 It can be -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0566] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers greater than 0, each R 3a , R 3b Different can be hydrogen;

[0567] Among them L 1 The 0 or more methylene units of each independently may be replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substituted;

[0568] Each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0569] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6Aliphatic group.

[0570] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0571]

[0572] Where X can be -L 3 -L 2 -,

[0573] L 2 Can be -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit can be replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-,

[0574] R 1 Can be -S- or -(R 2 )N-, or R 1 Can be -O- and L 2 Cannot be -C(O)-, or R 1 It can be -NH- and L 2 It cannot be -C(O)-;

[0575] L 3 It can be -(C(R 7a )(R 7b )) n -, n can be selected from integers greater than 1;

[0576] Among them L 3 The one or more methylene units are each independently replaced by -N(R 8 )C(O)-、-C(O)N(R 8 )-、-OC(O)-、-C(O)O-、-NR 8-, -O-, -S-, -SO-, -SO2-, -P(R 8 )-、-P(=O)(R 8 )-、-N(R 8 )SO2-、-SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 The 0 or more methylene units can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- substituted;

[0577] R 2 It can be halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0578] Each R 5a , R 5b , R 6 , R 7a , R 7b , R 8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0579] Each of R, R a , R bEach independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0580] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0581]

[0582] where R 1 Can be -O-,

[0583] X can be -L 3 -L 2 -,;

[0584] Among them L 2 It can be -C(O)-;

[0585] L 3 It can be -(C(R 7a )(R 7b )) n -, n can be selected from integers greater than 0;

[0586] Among them L 3 The one or more methylene units are each independently replaced by -N(R 8 )C(O)-、-C(O)N(R 8 )-、-OC(O)-、-C(O)O-、-NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-、-P(=O)(R 8 )-、-N(R 8 )SO2-、-SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 The 0 or more methylene units can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- substituted;

[0587] Each R 7a , R 7b , R8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0588] Among them, R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups,

[0589] When L 3 One methylene unit can be replaced by -NR 8 When substituted, the R 8 Cannot be a C that can be replaced by -NH2 1-6 Aliphatic group.

[0590] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0591]

[0592] Medium R 1 Can be -HN-,

[0593] X can be -L 3 -L 2 -;

[0594] Among them L 2 It can be -C(O)-,

[0595] L 3 It can be -(C(R 7a )(R 7b )) n-, n can be selected from integers greater than 1;

[0596] The L 3 More than one methylene unit may be replaced by -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-、-P(=O)(R 8 )-、-N(R 8 )SO2-、-SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and wherein L 3 0 or more methylene units can also be independently replaced by -C(O)N(R 8 )-、-NR 8 - or -O- instead, while L 3 The 0 or more methylene units can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- substituted;

[0597] Each R 7a , R 7b , R 8 Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C which may be optionally substituted by R 1-6 aliphatic groups;

[0598] Each of R, R a , R b Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0599] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0600]

[0601] R 1 Can be -O-, -S- or -(R 2 )N-;

[0602] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0603] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be 0, 1 or 2;

[0604] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0605] Each R 1a , R 1b , R 2 , R 3a , R 3b Each independently may be hydrogen or C optionally substituted by R 1-6 aliphatic groups;

[0606] wherein each R may be hydrogen.

[0607] For example, the compound may comprise a structure represented by formula (III-A):

[0608] R 1 Can be -O-;

[0609] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0610] L 1 Can be -(CH2) m -, m can be 1 or 2;

[0611] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0612] Each R 1a, R 1b Each independently may be hydrogen or C optionally substituted by R 1-6 aliphatic groups;

[0613] wherein each R may be hydrogen.

[0614] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0615]

[0616] R 1 Can be -S- or -(R 2 )N-;

[0617] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0618] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be 0, 1 or 2,

[0619] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0620] R 2 Can be C 1-6 aliphatic groups;

[0621] Each R 1a , R 1b , R 3a , R 3b Each independently can be hydrogen or C 1-6 Aliphatic group.

[0622] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0623]

[0624] R 1 Can be -S- or -(R 2 )N-;

[0625] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0626] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be 1 or 2;

[0627] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0628] R 2 Can be C 1-6 aliphatic groups;

[0629] Each R 1a , R 1b , R 3a , R 3b Each independently can be hydrogen or C 1-6 Aliphatic group.

[0630] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0631]

[0632] When R 1 Can be -S- or -(R 2 )N-;

[0633] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0634] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be 0, 1 or 2,

[0635] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0636] R 2 Can be C 1-6 aliphatic groups;

[0637] Each R 1a , R1b , R 3a , R 3b Each independently can be hydrogen or C 1-6 aliphatic groups;

[0638] Or when R 1 Can be -O-;

[0639] X can be -L 1 -CH2-C(O)-;

[0640] L 1 It can be -(C(R 3a )(R 3b ))2-hour;

[0641] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0642] Each R 3a , R 3b Each independently can be hydrogen, or C 1-6 aliphatic groups;

[0643] Every R 3a , R 3b Different can be hydrogen, or L 1 One methylene unit of can be replaced by -C(O)-;

[0644] Each R 3a , R 3b Each independently can be hydrogen, or C 1-6 Aliphatic group.

[0645] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0646]

[0647] R 1 Can be -O-;

[0648] X can be -L 1 -CH2-C(O)-;

[0649] L 1 It can be -(C(R 3a )(R 3b ))2-;

[0650] Among them L 10 or 1 methylene unit may be replaced by -C(O)-;

[0651] Each R 3a , R 3b Each independently can be hydrogen, or C 1-6 aliphatic groups;

[0652] Every R 3a , R 3b Different can be hydrogen, or L 1 One methylene unit of can be replaced by -C(O)-;

[0653] Each R 3a , R 3b Each independently can be hydrogen, or C 1-6 Aliphatic group.

[0654] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0655]

[0656] When R 1 Can be -S- or -(R 2 )N-;

[0657] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0658] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be 0, 1 or 2,

[0659] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0660] R 2 Can be C 1-6 aliphatic groups;

[0661] Each R 1a , R 1b , R 3a , R 3b Each independently can be hydrogen or C 1-6 aliphatic groups;

[0662] Or when R1 Can be -O-,

[0663] X can be -L 1 -CH2-C(O)-,

[0664] L 1 Can be -C(R 3a )(R 3b )-, in each -C(R 3a )(R 3b )-Middle R 3a , R 3b Different can be hydrogen;

[0665] Each R 3a , R 3b Each independently can be hydrogen or C 1-6 Aliphatic group.

[0666] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0667]

[0668] R 1 Can be -O-;

[0669] X can be -L 1 -CH2-C(O)-;

[0670] L 1 It can be -(C(R 3a )(R 3b ))2-;

[0671] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0672] Each R 3a , R 3b Each independently can be hydrogen, or C 1-6 aliphatic groups;

[0673] In each -C(R 3a )(R 3b )-Middle R 3a , R 3b Different can be hydrogen, or L 1 One methylene unit of can be replaced by -C(O)-;

[0674] Each R 3a , R3b Each independently can be hydrogen, or C 1-6 Aliphatic group.

[0675] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0676]

[0677] R 1 Can be -O-;

[0678] X can be -L 1 -CH2-C(O)-;

[0679] L 1 It can be -(CH2)2-;

[0680] Among them L 1 One methylene unit of may be replaced by -C(O)-.

[0681] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0682]

[0683] where R 1 Can be -O-,

[0684] X can be -L 1 -CH2-C(O)-;

[0685] L 1 It can be -(C(R 3a )(R 3b )) m -, m can be selected from integers from 1 to 5, in each -C(R 3a )(R 3b )-Middle R 3a , R 3b Different can be hydrogen;

[0686] Each R 3a , R 3b Each independently may be hydrogen, halogen or C optionally substituted by R 1-6 aliphatic groups;

[0687] wherein each R may be hydrogen or halogen.

[0688] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0689]

[0690] where R 1 Can be -O-,

[0691] X can be -L 1 -CH2-C(O)-;

[0692] L 1 Can be -C(R 3a )(R 3b )-,R 3a , R 3b Different can be hydrogen;

[0693] Each R 3a , R 3b Each independently can be hydrogen or C 1-6 Aliphatic group.

[0694] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0695]

[0696] where R 1 Can be -O- or -(R 2 )N-,

[0697] X can be -L 1 -L 0 -;

[0698] L 0 Can be -CH2-, or L 0 Can be -C(=S)-;

[0699] L 1 Can be -(CH2) m -, m can be selected from integers from 0 to 2;

[0700] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-;

[0701] R 2 Can be C 1-6 Aliphatic group.

[0702] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0703]

[0704] where R 1 It can be -NH-,

[0705] X can be -L 1 -L 0 -;

[0706] L 0 Can be -CH2-, or L 0 Can be -C(=S)-;

[0707] L 1 Can be -(CH2) m -, m can be selected from integers from 0 to 2;

[0708] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-, or -C(=S)-.

[0709] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0710]

[0711] R 1 Can be -S-, or -(R 2 )N-;

[0712] X can be -L 3 -L 2 -,;

[0713] Among them L 2 It can be -C(O)-;

[0714] L 3 Can be -(CH2) n -, n can be 4 or 5;

[0715] Among them L 3 One methylene unit can be replaced by -NR8 -, -O-, -S-, or -SO- substitution;

[0716] R 2 Can be C 1-6 Aliphatic group.

[0717] For example, the compound may comprise a structure represented by formula (III-A):

[0718] R 1 Can be -S- or -(R 2 )N-;

[0719] X can be -L 3 -L 2 -,;

[0720] Among them L 2 It can be -C(O)-;

[0721] L 3 Can be -(CH2) n -, n can be 4 or 5;

[0722] Among them L 3 One methylene unit of can be replaced by -O-;

[0723] R 2 Can be C 1-6 Aliphatic group.

[0724] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0725]

[0726] where R 1 Can be -O-,

[0727] X can be -L 3 -L 2 -,;

[0728] Among them L 2 It can be -C(O)-;

[0729] L 3 It can be -(C(R 7a )(R 7b )) n -, n can be 4 or 5;

[0730] Among them L 3 One methylene unit can be replaced by -NR8 -, or -O-, while L 3 0 or 1 methylene unit of each independently may be replaced by -C(O)-, or -C(=S)-;

[0731] Each R 7a , R 7b , R 8 Each independently can be hydrogen, or C 1-6 Aliphatic group.

[0732] For example, the compound may comprise a structure represented by formula (III-A):

[0733] R 1 Can be -O-,

[0734] X can be -L 3 -L 2 -,;

[0735] Among them L 2 It can be -C(O)-;

[0736] L 3 It can be -(C(R 7a )(R 7b ))4-;

[0737] Among them L 3 One methylene unit can be replaced by -NR 8 -or-O-substitution;

[0738] Each R 7a , R 7b , R 8 Each independently can be hydrogen or C 1-6 Aliphatic group.

[0739] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0740]

[0741] where R 1 Can be -O-,

[0742] X can be -L 3 -L 2 -,;

[0743] Among them L 2 It can be -C(O)-;

[0744] L 3 It can be -(C(R 7a )(R 7b ))4-;

[0745] Among them L 3 One methylene unit can be replaced by -NR 8 Replacement;

[0746] Each R 7a , R 7b , R 8 Each independently can be hydrogen or C 1-6 Aliphatic group.

[0747] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):

[0748]

[0749] where R 1 It can be -NH-,

[0750] X can be -L 3 -L 2 -,;

[0751] Among them L 2 It can be -C(O)-;

[0752] L 3 Can be -(CH2) n -, n can be 4 or 5;

[0753] Among them L 3 One methylene unit of can be replaced by -S-.

[0754] In one embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise the structure of the following group:

[0755]

[0756]

[0757] where R 2 It can be C which may be optionally substituted by R 1-6Aliphatic groups, R can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 an aliphatic group; or wherein R 2 It can be halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0758] For example, R 2 It may be replaced by one or more hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 An aliphatic group is optionally substituted with a methyl group. For example, R 2 It can be replaced by hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 An aliphatic group is optionally substituted with an ethyl group. For example, R 2 It can be replaced by hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 The aliphatic group is optionally substituted propyl.

[0759] In a second aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by formula (IB):

[0760]

[0761] Among them, X a The nitrogen generated by removing two hydrogen atoms from the amino group of a cytotoxic drug;

[0762] The L may be -L a -L b -L c -;

[0763] The-L a - may be selected from the following group:

[0764]

[0765] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn ;

[0766] Where wn can be selected from integers greater than 0,

[0767] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0768] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0769] Wherein zn can be selected from integers greater than 0,

[0770] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NRzx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0771] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0772] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0773] Each R r , R ra , R rbEach independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0774] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0775] The-L c - may be selected from the following group:

[0776]

[0777] where R L1 、R L2 Each independently may be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0778] R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[0779] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by Formula (II-Bx) or Formula (II-By):

[0780]

[0781] Among them, X a The nitrogen generated by removing two hydrogen atoms from the amino group of a cytotoxic drug;

[0782] The L may be -L a -L b -L c -;

[0783] The-L a - may be selected from the following group:

[0784]

[0785] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn ;

[0786] Where wn can be selected from integers greater than 0,

[0787] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0788] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0789] Wherein zn can be selected from integers greater than 0,

[0790] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0791] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0792] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0793] Each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0794] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0795] The-L c - may be selected from the following group:

[0796]

[0797] where R L1 、R L2 Each independently may be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups;

[0798] L 2 , p, ring A, X 1 、L 1 As defined in any one of formula (II-Ax) in the embodiments of the first aspect;

[0799] or X 2 ,q,ring A,X 1 、L 1 As defined in any one of Formula (II-Ay) in the embodiments of the first aspect.

[0800] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise the structure shown in formula (III-B):

[0801]

[0802] Among them, X a The nitrogen generated by removing two hydrogen atoms from the amino group of a cytotoxic drug;

[0803] The L may be -L a -L b -L c -;

[0804] The-L a - may be selected from the following group:

[0805]

[0806] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp , Z can be -(C(R za )(R zb )) zn ,;

[0807] Where wn can be selected from integers greater than 0,

[0808] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0809] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0810] Wherein zn can be selected from integers greater than 0,

[0811] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0812] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0813] Each R wa , R wb , R za , R zb , R wx , Rzx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0814] Each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0815] The-L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0816] The-L c - may be selected from the following group:

[0817]

[0818] where R L1 、R L2 Each independently may be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6aliphatic groups;

[0819] where R 1 , X is as defined in any one of formula (III-A) in the embodiments of the first aspect.

[0820] In another embodiment, wherein wn can be selected from an integer from 2 to 6, 0 or 1 methylene units of W can be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-、-C(O)-、-NR wx -, or -O- instead.

[0821] For example, wherein wn can be 1, 2, 3 or 6, each methylene unit of W can be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, or -C(O)-.

[0822] In another embodiment, wherein yn can be selected from an integer from 0 to 12, yp can be 0 or 1.

[0823] For example, yn can be 0, 4, or 8, and yp can be 0 or 1.

[0824] In another embodiment, wherein zn can be selected from an integer from 0 to 10, 0 or 1 methylene units of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, or -C(O)-.

[0825] For example, wherein zn can be 1, 2 or 3, one methylene unit of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, or -C(O)-.

[0826] In another embodiment, -Cyr- can be selected from the group consisting of 6 to 10 membered arylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted by 1 to 3 substituents R cx replace.

[0827] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclylene group, wherein the -Cyr- is unsubstituted or can be substituted independently by 1 to 3 substituents R cx replace.

[0828] In another embodiment, wherein each R wa, R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 an aliphatic group; wherein each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0829] For example, where each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, halogen, -OR r Or can be R r Optionally substituted C 1-6 an aliphatic group; wherein each R r Each independently may be hydrogen, halogen or C 1-6 Aliphatic group.

[0830] In another embodiment, the -L b- represents a peptide residue consisting of 2 to 7 amino acids, wherein -L b The peptide residue of - may be a peptide residue that can be formed of an amino acid selected from the group consisting of phenylalanine, glycine, alanine, valine, citrulline, lysine, serine, glutamic acid, and aspartic acid.

[0831] For example, the -L b - represents a peptide residue consisting of 2 to 4 amino acids, wherein -L b The peptide residue of - may be a peptide residue that can be formed of an amino acid selected from the group consisting of phenylalanine, glycine, alanine, valine, citrulline and lysine.

[0832] For example, the -L b - may be selected from the following group:

[0833]

[0834] For example, the -L b - can be

[0835]

[0836] In another embodiment, the -L c - may be selected from the following group:

[0837]

[0838]

[0839] For example, the -L c - may be selected from the following group:

[0840]

[0841] The-L c - can be

[0842]

[0843] In another embodiment, wherein R L1 、R L2 Each independently may be selected from the following group: hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 Aliphatic group.

[0844] For example, where RL1 、R L2 Each independently can be selected from the following group: hydrogen, halogen, -OH and C 1-6 Aliphatic group.

[0845] In another embodiment, wherein -L a - can be

[0846] In another embodiment, -L b - may be selected from the following group:

[0847] For example, -L b - may be selected from the following group:

[0848] In one embodiment, -L c - can be

[0849] In one embodiment, wherein -L a -L b -L c - may be selected from the following group:

[0850]

[0851] Wherein, the cytotoxic drug is shown in formula (EXA):

[0852]

[0853] In a third aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by formula (IC):

[0854]

[0855] Wherein, L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (IB) in the embodiments of the second aspect;

[0856] R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[0857] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by Formula (II-Cx) or Formula (II-Cy):

[0858]

[0859] Wherein, L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (II-Bx) in the embodiments of the second aspect;

[0860] L 2 , p, ring A, X 1 、L 1 As defined in any one of formula (II-Ax) in the embodiments of the first aspect;

[0861] or X 2 ,q,ring A,X 1 、L 1 As defined in any one of Formula (II-Ay) in the embodiments of the first aspect.

[0862] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by formula (III-C):

[0863]

[0864] Wherein, L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (III-B) in the embodiments of the second aspect;

[0865] where R 1 , X is as defined in any one of formula (III-A) in the embodiments of the first aspect.

[0866] In a fourth aspect, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by formula (ID):

[0867]

[0868] Among them, Ab can be a ligand, and the average number of connections N a It can be an integer or decimal from 1 to 10;

[0869] L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (IB) in the embodiments of the second aspect;

[0870] R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[0871] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure shown in formula (II-Dx) or formula (II-Dy):

[0872]

[0873]

[0874] Among them, Ab can be a ligand, and the average number of connections N a It can be an integer or decimal from 1 to 10;

[0875] L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (II-Bx) in the embodiments of the second aspect;

[0876] L 2 , Ring A, X 1 、L 1 As defined in any one of formula (II-Ax) in the embodiments of the first aspect;

[0877] or X 2 , Ring A, X 1 、L 1 As defined in any one of Formula (II-Ay) in the embodiments of the first aspect.

[0878] In another embodiment, the present application provides a compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure shown in formula (III-D)

[0879]

[0880] Among them, Ab can be a ligand, and the average number of connections N a It can be an integer or decimal from 1 to 10;

[0881] L can be -L a -L b -L c -, L a 、L b 、L c As defined in any one of formula (III-B) in the embodiments of the second aspect;

[0882] where R 1 , X is as defined in any one of formula (III-A) in the embodiments of the first aspect.

[0883] In another embodiment, the ligand Ab can be an antibody or an antigen-binding fragment thereof.

[0884] For example, the ligand Ab can be selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody.

[0885] For example, the ligand Ab targets the following group: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, and EGFR.

[0886] For example, the ligand Ab targets the following group: For example, the antibody can be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD19,CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, C D71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, D LL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GE DA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KIS S1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-Cadherin , RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, claudin 18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein and tissue factor.

[0887] In another embodiment, the average number of connections N a It can be an integer or decimal from 2 to 8. For example, the average number of connections N a It can be an integer or decimal from 3 to 8. For example, the average number of connections N a It can be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0888] In a fifth aspect, the present application provides a compound represented by general formula (IE) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0889]

[0890] Among them, R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[0891] In another embodiment, the present application provides a general formula (II-E x ) or general formula (II-E y ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0892]

[0893] Among them, L 2 , p, ring A, X 1 、L 1 As defined in any one of formula (II-Ax) in the embodiments of the first aspect;

[0894] or X 2 ,q,ring A,X 1 、L 1 As defined in any one of Formula (II-Ay) in the embodiments of the first aspect.

[0895] In another embodiment, the present application provides a compound represented by general formula (III-E) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0896]

[0897] where R 1, X is as defined in any one of formula (III-A) in the embodiments of the first aspect.

[0898] In a sixth aspect, the present application provides a compound represented by the general formula (IF) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0899]

[0900] Among them, the L x Can be -L ax -L b -L c -;

[0901] The L ax - may be selected from the following group:

[0902]

[0903] where R hal It can be iodine or bromine;

[0904] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn ;

[0905] Where wn can be selected from integers greater than 0,

[0906] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0907] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0908] Wherein zn can be selected from integers greater than 0,

[0909] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0910] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0911] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0912] Each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0913] L b 、L c As defined in any one of formula (IB) in the embodiments of the second aspect;

[0914] R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[0915] In another embodiment, the present application provides a general formula (II-F x ) or general formula (II-F y ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0916]

[0917] Among them, the L x Can be -L ax -L b -L c -;

[0918] The L ax - may be selected from the following group:

[0919]

[0920] where R hal It can be iodine or bromine;

[0921] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn ;

[0922] Where wn can be selected from integers greater than 0,

[0923] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0924] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0925] Wherein zn can be selected from integers greater than 0,

[0926] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0927] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0928] Each R wa , R wb , R za , R zb , R wx , Rzx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0929] Each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0930] L b 、L c As defined in any one of formula (II-Bx) in the embodiments of the second aspect;

[0931] Among them, L 2 , p, ring A, X 1 、L 1 As defined in any one of formula (II-Ax) in the embodiments of the first aspect;

[0932] or X 2 ,q,ring A,X 1 、L 1 As defined in any one of Formula (II-Ay) in the embodiments of the first aspect.

[0933] In another embodiment, the present application provides a compound represented by general formula (III-F) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0934]

[0935] Among them, the L x Can be -L ax -L b -L c -;

[0936] The L ax - may be selected from the following group:

[0937]

[0938] where R hal It can be iodine or bromine;

[0939] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn ;

[0940] Where wn can be selected from integers greater than 0,

[0941] Zero or more methylene units of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-、-P(=O)(R wx )-、-N(R wx )SO2-、-SO2N(R wx )-、-C(=S)-、-C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0942] Wherein yn can be selected from an integer greater than 0, and yp can be 0 or 1;

[0943] Wherein zn can be selected from integers greater than 0,

[0944] The zero or more methylene units of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-、-P(=O)(R zx )-、-N(R zx )SO2-、-SO2N(R zx )-、-C(=S)-、-C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[0945] -Cyr- can be selected from the following group: 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or can be substituted by one or more substituents R cx replace;

[0946] Each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(R rb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 aliphatic groups;

[0947] Each R r, R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[0948] L b 、L c As defined in any one of formula (III-B) in the embodiments of the second aspect;

[0949] where R 1 , X is as defined in any one of formula (III-A) in the embodiments of the first aspect.

[0950] In another embodiment, the L ax - may be selected from the following group:

[0951]

[0952] where R hal It can be iodine or bromine;

[0953] Wherein, W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, Z can be -(C(R za )(R zb )) zn .

[0954] In another embodiment, wherein wn can be selected from an integer from 2 to 6, 0 or 1 methylene units of W can be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-、-C(O)-、-NR wx -, or -O- instead.

[0955] For example, wherein wn can be 1, 2, 3 or 6, each methylene unit of W can be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-, or -C(O)-.

[0956] In another embodiment, wherein yn can be selected from an integer from 0 to 12, yp can be 0 or 1.

[0957] For example, yn can be 0, 4, or 8, and yp can be 0 or 1.

[0958] In another embodiment, wherein zn can be selected from an integer from 0 to 10, 0 or 1 methylene units of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, or -C(O)-.

[0959] For example, wherein zn can be 1, 2 or 3, one methylene unit of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )-, or -C(O)-.

[0960] In another embodiment, -Cyr- can be selected from the group consisting of 6 to 10 membered arylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein said -Cyr- is unsubstituted or independently substituted by 1 to 3 substituents R cx replace.

[0961] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclylene group, wherein the -Cyr- is unsubstituted or can be substituted independently by 1 to 3 substituents R cx replace.

[0962] In another embodiment, wherein each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r 、-SR r 、-N(R ra )(R rb ),-C(O)R r 、-CO2R r 、-C(O)C(O)R r 、-C(O)CH2C(O)R r 、-S(O)R r 、-S(O)2R r 、-C(O)N(R ra )(R rb )、-SO2N(R ra )(Rrb ),-OC(O)R r 、-N(R)SO2R r , or can be R r Optionally substituted C 1-6 an aliphatic group; wherein each R r , R ra , R rb Each independently may be hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic group.

[0963] For example, where each R wa , R wb , R za , R zb , R wx , R zx ,R cx Each independently can be hydrogen, halogen, -OR r Or can be R r Optionally substituted C 1-6 an aliphatic group; wherein each R r Each independently may be hydrogen, halogen or C 1-6 Aliphatic group.

[0964] In another embodiment, L ax - can be

[0965] In another embodiment, wherein L ax -L b -L c - may be selected from the following group:

[0966]

[0967] Compounds disclosed in this application

[0968] In one embodiment, the compounds disclosed herein include, but are not limited to:

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003] The average number of connections n in the above list may be an integer or decimal from 1 to 10. The average number of connections n in the above list may be an integer or decimal from 2 to 8. For example, the average number of connections n may be an integer or decimal from 3 to 8. For example, the average number of connections n may be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[1004] In one embodiment, the compounds disclosed herein include, but are not limited to:

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035] The average number of connections n in the above list may be an integer or decimal from 1 to 10. The average number of connections n in the above list may be an integer or decimal from 2 to 8. For example, the average number of connections n may be an integer or decimal from 3 to 8. For example, the average number of connections n may be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[1036] In one embodiment, the compounds disclosed herein include, but are not limited to:

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064] The average number of connections n in the above list may be an integer or decimal from 1 to 10. The average number of connections n in the above list may be an integer or decimal from 2 to 8. For example, the average number of connections n may be an integer or decimal from 3 to 8. For example, the average number of connections n may be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[1065] ligand

[1066] The ligands described herein can be protein hormones, lectins, growth factors, antibodies, or other molecules that can bind to cells, receptors, and / or antigens. For example, the ligands described herein can be antibodies or antigen-binding fragments thereof.

[1067] In the present application, the ligand may comprise at least one CDR in the variable region VL of the antibody light chain. The CDR may be defined according to Kabat.

[1068] In the present application, the antigen binding protein may comprise LCDR1, and the LCDR1 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 1 to 4. The CDRs may be defined according to Kabat.

[1069] In the present application, the antigen binding protein may comprise LCDR2, and the LCDR2 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 5 to 8. The CDRs may be defined according to Kabat.

[1070] In the present application, the antigen binding protein may comprise LCDR3, and the LCDR3 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 9 to 12. The CDRs may be defined according to Kabat.

[1071] In the present application, the isolated antigen-binding protein may comprise LCDR1-3. The LCDR1 may comprise the amino acid sequence of any one of SEQ ID NOs: 1-4; the LCDR2 may comprise the amino acid sequence of any one of SEQ ID NOs: 5-8; and the LCDR3 may comprise the amino acid sequence of any one of SEQ ID NOs: 9-12. The CDRs may be defined according to Kabat.

[1072] For example, the antigen-binding protein described herein may comprise LCDR1-3 identical to trastuzumab, wherein LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 1; LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 5; and LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 9. For example, the antigen-binding protein described herein may comprise LCDR1-3 identical to pertuzumab, wherein LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 2; LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 6; and LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 10. The CDRs may be defined according to Kabat.

[1073] For example, the antigen-binding protein described herein may comprise LCDRs 1-3 identical to those of sacituzumab, wherein LCDR 1 may comprise the amino acid sequence set forth in SEQ ID NO: 3; LCDR 2 may comprise the amino acid sequence set forth in SEQ ID NO: 7; and LCDR 3 may comprise the amino acid sequence set forth in SEQ ID NO: 11. The CDRs may be defined according to Kabat.

[1074] For example, the antigen-binding protein described herein may comprise LCDR1-3 identical to Zolbetuximab, wherein LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 4; LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 8; and LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 12. The CDRs may be defined according to Kabat.

[1075] The antigen-binding protein described in the present application may comprise at least one CDR in the variable region VH of the heavy chain of an antibody. The CDR may be defined according to Kabat.

[1076] In the present application, the antigen binding protein may comprise HCDR1, and the HCDR1 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 13 to 16. The CDRs may be defined according to Kabat.

[1077] In the present application, the antigen binding protein may comprise HCDR2, and the HCDR2 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 17 to 20. The CDRs may be defined according to Kabat.

[1078] In the present application, the antigen binding protein may comprise HCDR3, and the HCDR3 may comprise the amino acid sequence shown in any one of SEQ ID NOs: 21 to 24. The CDRs may be defined according to Kabat.

[1079] In the present application, the isolated antigen-binding protein may comprise HCDR1-3. The HCDR1 may comprise the amino acid sequence of any one of SEQ ID NOs: 13-16; the HCDR2 may comprise the amino acid sequence of any one of SEQ ID NOs: 17-20; and the HCDR3 may comprise the amino acid sequence of any one of SEQ ID NOs: 21-24. The CDRs may be defined according to Kabat.

[1080] For example, the antigen-binding protein described herein may comprise HCDR1-3 identical to trastuzumab, wherein the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 13; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 17; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 21. The CDRs may be defined according to Kabat.

[1081] For example, the antigen-binding protein described herein may comprise HCDR1-3 identical to pertuzumab, wherein the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 14; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 18; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 22. The CDRs may be defined according to Kabat.

[1082] For example, the antigen-binding protein described herein may comprise HCDR1-3 identical to sacituzumab, wherein the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 15; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 19; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 23. The CDRs may be defined according to Kabat.

[1083] For example, the antigen-binding protein described herein may comprise HCDR1-3 identical to Zolbetuximab, wherein the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 16; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 20; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 24. The CDRs may be defined according to Kabat.

[1084] In the present application, the isolated antigen-binding protein may comprise LCDR1-3 and HCDR1-3. The LCDR1 may comprise the amino acid sequence of any one of SEQ ID NOs: 1-4; the LCDR2 may comprise the amino acid sequence of any one of SEQ ID NOs: 5-8; the LCDR3 may comprise the amino acid sequence of any one of SEQ ID NOs: 9-12; the HCDR1 may comprise the amino acid sequence of any one of SEQ ID NOs: 13-16; the HCDR2 may comprise the amino acid sequence of any one of SEQ ID NOs: 17-20; and the HCDR3 may comprise the amino acid sequence of any one of SEQ ID NOs: 21-24. The CDRs may be defined according to Kabat.

[1085] For example, the antigen-binding protein described herein may comprise LCDR1-3 and HCDR1-3 identical to those of trastuzumab. The LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 1; the LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 5; the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 9; the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 13; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 17; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 21. The CDRs may be defined according to Kabat.

[1086] For example, the antigen-binding proteins described herein may comprise LCDR1-3 and HCDR1-3 identical to those of Pertuzumab. The LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:2; the LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:6; the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:10; the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:14; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:18; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:22. The CDRs may be defined according to Kabat.

[1087] For example, the antigen-binding protein described herein may comprise LCDR1-3 and HCDR1-3 identical to sacituzumab. The LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:3; the LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:7; the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:11; the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:15; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:19; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:23. The CDRs may be defined according to Kabat.

[1088] For example, the antigen-binding proteins described herein may comprise LCDR1-3 and HCDR1-3 identical to those of Zolbetuximab. The LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:4; the LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:8; the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:12; the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO:16; the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO:20; and the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO:24. The CDRs may be defined according to Kabat.

[1089] In the present application, the antigen-binding protein may comprise a light chain variable region VL, and the VL may comprise the amino acid sequence shown in any one of SEQ ID NOs: 25-28.

[1090] In the present application, the antigen-binding protein may comprise a heavy chain variable region VH, and the VH may comprise the amino acid sequence shown in any one of SEQ ID NOs: 29-32.

[1091] In the present application, the antigen-binding protein may comprise a light chain variable region VL and a heavy chain variable region VH, wherein the VL may comprise the amino acid sequence shown in any one of SEQ ID NOs: 25-28, and the VH may comprise the amino acid sequence shown in any one of SEQ ID NOs: 29-32.

[1092] For example, the antigen-binding protein described herein may comprise the same light chain variable region VL and heavy chain variable region VH as trastuzumab, wherein the VL may comprise the amino acid sequence shown in SEQ ID NO: 25, and the VH may comprise the amino acid sequence shown in SEQ ID NO: 29.

[1093] For example, the antigen-binding protein described herein may comprise the same light chain variable region VL and heavy chain variable region VH as Pertuzumab, wherein the VL may comprise the amino acid sequence set forth in SEQ ID NO: 26, and the VH may comprise the amino acid sequence set forth in SEQ ID NO: 30.

[1094] For example, the antigen-binding protein described herein may comprise the same light chain variable region VL and heavy chain variable region VH as sacituzumab, wherein the VL may comprise the amino acid sequence set forth in SEQ ID NO: 27, and the VH may comprise the amino acid sequence set forth in SEQ ID NO: 31.

[1095] For example, the antigen-binding protein described herein may comprise the same light chain variable region VL and heavy chain variable region VH as Zolbetuximab, wherein the VL may comprise the amino acid sequence set forth in SEQ ID NO: 28, and the VH may comprise the amino acid sequence set forth in SEQ ID NO: 32.

[1096] In the present application, the antigen-binding protein may comprise a light chain, and the light chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 33-36.

[1097] In the present application, the antigen binding protein may comprise a heavy chain, and the heavy chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 37-40.

[1098] In the present application, the antigen-binding protein may comprise an antibody light chain and an antibody heavy chain, wherein the light chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 33-36, and the heavy chain may comprise the amino acid sequence shown in any one of SEQ ID NOs: 37-40.

[1099] For example, the antigen-binding protein described in the present application may comprise the same antibody light chain and antibody heavy chain as Trastuzumab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 33, and the heavy chain may comprise the amino acid sequence shown in SEQ ID NO: 37.

[1100] For example, the antigen-binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Pertuzumab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 34, and the heavy chain may comprise the amino acid sequence shown in SEQ ID NO: 38.

[1101] For example, the antigen-binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Sacituzumab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 35, and the heavy chain may comprise the amino acid sequence shown in SEQ ID NO: 39.

[1102] For example, the antigen-binding protein described herein may comprise the same antibody light chain and antibody heavy chain as Zolbetuximab, wherein the light chain may comprise the amino acid sequence shown in SEQ ID NO: 36, and the heavy chain may comprise the amino acid sequence shown in SEQ ID NO: 40.

[1103] Prevent and / or prevent tumors

[1104] In another aspect, the present application provides the use of the compound described herein or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing a tumor. The tumor may be selected from tumors associated with the expression of HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, or EGFR. The tumor may be selected from the group consisting of lung cancer, renal cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

[1105] On the other hand, the present application provides a method for treating and / or preventing tumors, comprising administering to a subject in need thereof a compound described herein or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition comprising the same. The tumor may be selected from tumors associated with the expression of HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, or EGFR. The tumor may be selected from the group consisting of lung cancer, renal cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

[1106] On the other hand, the present application provides a compound described herein or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition comprising the same, for use in treating and / or preventing tumors. The tumor may be selected from tumors associated with the expression of HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70, or EGFR. The tumor may be selected from the group consisting of lung cancer, renal cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

[1107] For example, the tumor can be selected from tumors associated with the following group of expression: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD11c, CD123, CD138, CD142, CD147, CD166, CD19, CD19,CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, C D71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, D LL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GE DA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KIS S1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-Cadherin , RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, claudin 18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein and tissue factor.

[1108] The compounds described in this application may have inhibitory activity on the in vitro proliferation of tumor cells. The inhibitory activity may be that when the compounds of this application are added to the culture medium of tumor cells, the proliferation ability of the tumor cells decreases by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% compared to the addition of negative control or control drug. For example, the inhibitory activity may be for the IC 50 The value (nM) may be 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less, 98 or less, 97 or less, 95 or less, 90 or less, 80 or less, 75 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 or less, 8.5 or less, 7 or less, 6.7 or less, 6 or less, 5.9 or less, 5.5 or less, 5.0 or less, 4.8 or less, 4.5 or less, 4.4 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1.0 or less, 0.5 or less, 0.3 or less, 0.29 or less, 0.25 or less, 0.21 or less, 0.20 or less, 0.18 or less, 0.17 or less, 0.15 or less, 0.12 or less, 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less. For example, the tumor cells may include but are not limited to solid tumor cells, for example, the tumor cells may include but are not limited to gastric cancer cells, or breast cancer cells, for example, the tumor cells may include but are not limited to NCI-N87 cells, JIMT-1 cells or MBA-MB-231 cells.

[1109] The compounds described in the present application may have targeted inhibition. The targeted inhibition may be that the compound of the present application is added to the culture medium of tumor cells with high expression of a specific target, and compared with the addition of a negative control or a control drug, the cell proliferation ability of the tumor cells with high expression of the specific target decreases by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95%. For example, the targeted inhibition may be an IC for tumor cells with high expression of a specific target. 50 The value (nM) may be 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 185 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less, 98 or less, 97 or less, 95 or less, 91 or less, 80 or less, 74 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 Below, 8.5 below, 7 below, 6.7 below, 6 below, 5.9 below, 5.5 below, 5.0 below, 4.8 below, 4.5 below, 4.4 below, 4 below, 3.5 below, 3 below, 2.5 below, 2 below, 1.5 below, 1.0 below, 0.5 below, 0.3 below, 0.29 below, 0.25 below, 0.21 below, 0.20 below, 0.18 below, 0.17 below, 0.15 below, 0.12 below, 0.10 below, 0.09 below, 0.08 below, 0.07 below, 0.06 below, 0.05 below, 0.04 below, 0.03 below, 0.02 below, or 0.01 below. For example, tumor cells that highly express the specific target may include, but are not limited to, solid tumor cells. For example, tumor cells that highly express the specific target may include, but are not limited to, gastric cancer cells or breast cancer cells. For example, tumor cells that highly express the specific target may include, but are not limited to, NCI-N87 cells or JIMT-1 cells. The specific target may include, but is not limited to, HER2 or TROP2.

[1110] The compounds described herein may have plasma stability. The plasma stability may be that when a compound of the present application is added to plasma, the compound releases a cytotoxic drug at a rate of no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 7%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than 1.6%, no more than 1.5%, no more than 1.4%, no more than 1.3%, no more than 1.2%, no more than 1.1%, no more than 1.0%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% over 1 day, 3 days, 5 days, 7 days, 14 days, 20 days, or 30 days.

[1111] The compounds described herein may have an in vivo tumor-suppressing effect. The tumor-suppressing effect may be that when the compounds of the present application are administered to an animal, the volume of the animal's tumor is reduced by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 55%, more than 60%, more than 70%, more than 73%, more than 75% on day 1, 3, 5, 7, 14, 20, 21, or 30 compared to the addition of a negative control or control drug. The invention relates to a method for treating a tumor of an animal that is administered a negative control or a control drug, wherein the tumor volume of the animal is reduced by more than 1.1 times, more than 1.3 times, more than 1.5 times, more than two times, more than three times, more than five times, more than ten times, more than twenty times, more than twenty-two times, more than thirty times, more than fifty times, more than one hundred times, more than five hundred times, more than one thousand times, or more than one thousand five hundred times, compared to administration of a negative control or a control drug on day 1, 3, 5, 7, 14, 20, 21, or 30. The animal may include, but is not limited to, a mammal, for example, the animal may include, but is not limited to, a cat, a dog, a horse, a pig, a cow, a sheep, a rabbit, a mouse, a rat, a monkey, or a human. The administration may include, but is not limited to, oral administration, intravenous injection, intravenous drip, intraperitoneal injection, or local administration.

[1112] The compounds described in the present application may have a bystander killing effect. The bystander killing effect may be that the compounds of the present application have no obvious inhibitory effect on the cell proliferation of tumor cells with low expression of a specific target, while in the co-culture of tumor cells with low expression of a specific target and tumor cells with high expression of a specific target, the compounds of the present application can simultaneously inhibit the cell proliferation of tumor cells with low expression of a specific target and tumor cells with high expression of a specific target. For example, in the co-culture of tumor cells with low expression of a specific target and tumor cells with high expression of a specific target, the inhibitory activity may be an IC for tumor cells with low expression of a specific target. 50The value (nM) may be 10000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, 400 or less, 300 or less, 200 or less, 185 or less, 150 or less, 120 or less, 110 or less, 100 or less, 99 or less, 98 or less, 97 or less, 95 or less, 91 or less, 80 or less, 74 or less, 70 or less, 65 or less, 62 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 23 or less, 22 or less, 20 or less, 19 or less, 18 or less, 18.5 or less, 17 or less, 15 or less, 12 or less, 10 or less, 9 Below, 8.5 below, 7 below, 6.7 below, 6 below, 5.9 below, 5.5 below, 5.0 below, 4.8 below, 4.5 below, 4.4 below, 4 below, 3.5 below, 3 below, 2.5 below, 2 below, 1.5 below, 1.0 below, 0.5 below, 0.3 below, 0.29 below, 0.25 below, 0.21 below, 0.20 below, 0.18 below, 0.17 below, 0.15 below, 0.12 below, 0.10 below, 0.09 below, 0.08 below, 0.07 below, 0.06 below, 0.05 below, 0.04 below, 0.03 below, 0.02 below, or 0.01 below. Compared with tumor cells with high expression of the specific target, the expression of the specific target in tumor cells with low expression of the specific target can be reduced by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95%. For example, tumor cells with high expression of the specific target may include but are not limited to solid tumor cells, for example, tumor cells with high expression of the specific target include but are not limited to gastric cancer cells, or breast cancer cells, for example, tumor cells with high expression of the specific target may include but are not limited to NCI-N87 cells or JIMT-1 cells. For example, tumor cells with low expression of the specific target may include but are not limited to solid tumor cells, for example, tumor cells with low expression of the specific target include but are not limited to breast cancer cells, for example, tumor cells with low expression of the specific target may include but are not limited to HCC1187 cells.

[1113] The compounds described herein may have anti-transporter transport ability. The anti-transport ability may be that the efflux ratio of the compounds described herein is reduced by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95% compared to a standard substance of a transport substrate. For example, the test of the efflux ratio may be a commonly used method for those skilled in the art, or may be recorded in the embodiments of the present application.

[1114] The compounds described in the present application may have in vivo tumor targeting capabilities. The in vivo targeting capability may refer to administering the compound labeled with a signal substance to an animal, and the distribution of the labeled compound in the tumor tissue of the animal may be increased by more than 1%, more than 2%, more than 4%, more than 5%, more than 8%, more than 10%, more than 15%, more than 18%, more than 20%, more than 25%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 95%, or the distribution may be increased by more than 1.1 times, more than 1.3 times, more than 1.5 times, more than two times, more than three times, more than five times, more than ten times, more than twenty times, more than twenty-two times, more than thirty times, more than fifty times, more than one hundred times, more than five hundred times, more than one thousand times, or more than one thousand five hundred times. The signal substance may be a radioactive substance, for example, the signal substance includes but is not limited to 125 The animal may include, but is not limited to, a mammal, for example, a cat, dog, horse, pig, cow, sheep, rabbit, mouse, rat, monkey, or human. The administration may include, but is not limited to, oral administration, intravenous injection, intravenous drip, intraperitoneal injection, or topical administration. The tissue or organ may include, but is not limited to, the heart, liver, spleen, lung, kidney, brain, or bone marrow.

[1115] The compounds described herein can have good in vivo safety. The in vivo safety can be that after the compounds of the present application are administered to animals, the free toxin release rate in the body of the animals is no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 7%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than 1.6%, no more than 1.5%, no more than 1.4%, no more than 1.3%, no more than 1.2%, no more than 1.1%, no more than 1.0%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2% or no more than 0.1%. For example, the in vivo safety can be that the administration concentration of the compound described in the present application can be 0.5 mg / kg or more, 1 mg / kg or more, 2 mg / kg or more, 3 mg / kg or more, 4 mg / kg or more, 5 mg / kg or more, 10 mg / kg or more, 20 mg / kg or more, 30 mg / kg or more, 50 mg / kg or more, 70 mg / kg or more, 100 mg / kg or more, 200 mg / kg or more, 500 mg / kg or more, or 1000 mg / kg or more when the animal does not produce toxicity. For example, the animal can include but is not limited to cats, dogs, horses, pigs, cows, sheep, rabbits, mice, rats, monkeys or humans. The administration can include but is not limited to oral administration, intravenous injection, intravenous drip, intraperitoneal injection, or topical administration.

[1116] Pharmaceutical composition

[1117] The pharmaceutical compositions described herein may contain, in addition to the active compound, one or more excipients, which may be selected from the following groups: fillers (diluents), binders, wetting agents, disintegrants, and excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[1118] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and may contain a binder, a filler, a lubricant, a disintegrant, or a pharmaceutically acceptable wetting agent. The composition may also contain one or more ingredients selected from the group consisting of a sweetener, a flavoring agent, a colorant, and a preservative.

[1119] Aqueous suspensions may contain the active ingredient and excipients suitable for preparing aqueous suspensions for mixing. Aqueous suspensions may also contain one or more preservatives, such as one or more colorants, one or more flavorings, and one or more sweeteners. Oil suspensions may be prepared by suspending the active ingredient in a vegetable oil. Oil suspensions may contain a thickening agent. The sweeteners and flavorings mentioned above may also be added.

[1120] The pharmaceutical composition may also be provided as a dispersible powder or granule for preparing an aqueous suspension, wherein the active ingredient is mixed with water to form one or more of a dispersant, a wetting agent, a suspending agent, or a preservative. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. The pharmaceutical composition of the present application may also be in the form of an oil-in-water emulsion.

[1121] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that may be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution may then be added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. For example, the device may be a Deltec CADD-PLUS™ 5400 intravenous pump.

[1122] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such suspensions may be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents as described herein. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a parenterally acceptable nontoxic diluent or solvent. Alternatively, a sterile fixed oil may conveniently be used as a solvent or suspending medium.

[1123] The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum, thereby dissolving and releasing the drug in the rectum. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[1124] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode, such as the mode of treatment, the daily dosage of the compound described in the present application or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and / or the compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the type of pharmaceutically acceptable salt thereof can be verified according to traditional treatment regimens.

[1125] Synthesis technology solutions

[1126] In order to achieve the synthesis purpose of the present disclosure, the present application adopts the following synthesis technology scheme:

[1127] Option 1A:

[1128] The present invention discloses a method for preparing a compound represented by general formula (IE) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1129]

[1130] Step 1: The compound of formula (Y1) and the compound of formula (KI3) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of formula (IEM)

[1131] Step 2: removing the protecting group of the compound of formula (IEM) to obtain the compound of formula (IE).

[1132] in:

[1133] Rp is a hydroxyl protecting group;

[1134] R 1 , L 1 , L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[1135] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1136] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1137] Plan 1B

[1138] The present invention discloses a method for preparing a compound represented by general formula (IE) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1139]

[1140] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[1141] L 2 -(C(R 3a )(R 3b )) m -R,

[1142] Among them L 2 0 or more methylene units are each independently replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1143] L 1 -(C(R 5a )(R 5b )) n -,

[1144] Among them L 1 0 or more methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1145] -Cy- is selected from the group consisting of 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or independently substituted with one or more substituents R 7 Substitution; for example, wherein R 3a With R 5a Together with the atoms between them, they form a ring B selected from the group consisting of a 5- to 8-membered heteroarylene group, and a 3- to 10-membered saturated or partially unsaturated heterocyclylene group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 Replace, each R 3b , R 4 , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 replace;

[1146] For example, where R 4 With R 5a Together with the atoms between them, they form a ring B selected from the group consisting of a 5- to 8-membered heteroarylene group, and a 3- to 10-membered saturated or partially unsaturated heterocyclylene group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 Replace, each R 3a , R 3b , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 replace;

[1147] For example, where R 3a With R 6Together with the atoms between them, they form a ring B selected from the group consisting of a 5- to 8-membered heteroarylene group, and a 3- to 10-membered saturated or partially unsaturated heterocyclylene group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 Replace, each R 3b , R 4 , R 5a , R 5b are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 replace;

[1148] For example, where R 4 With R 6 Each independently optionally together with the atoms between them form a ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 Replace, each R 3a , R 3b , R 5a , R 5b are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b)、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein the ring B is unsubstituted or substituted with one or more substituents R 8 replace;

[1149] Each R 2 , R 7 , R 8 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[1150] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[1151] m and n are each independently selected from integers of 1 or greater.

[1152] Step 1: The compound of formula (Y1-2) and the compound of formula (KI4) react in the presence or absence of a reducing agent under acidic or alkaline conditions to obtain a compound of formula (IEM)

[1153] Step 2: removing the protecting group of the compound of formula (IEM) to obtain the compound of formula (IE).

[1154] in:

[1155] Rp is a hydroxyl protecting group;

[1156] R 1 、L 1 、L 2 As defined in any one of Formula (IA) in the embodiments of the first aspect.

[1157] Reducing agents include, but are not limited to, sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[1158] Reagents providing acidic conditions include protonic acids and Lewis acids, the protonic acids including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids including but not limited to boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, tin chloride, ferric chloride.

[1159] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, methyl acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1160] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1161] Option 2:

[1162] The present disclosure provides a method for preparing a compound represented by formula (II-E), including a compound represented by formula (II-Ex) or formula (II-Ey), or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1163]

[1164] Step 1: The compound of formula (Y2x) or the compound of formula (Y2y) and the compound of formula (KI4) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of formula (II-Ex-M) or (II-Ey-M)

[1165] Step 2: removing the protecting group from the compound of formula (II-Ex-M) or (II-Ey-M) to obtain the compound of formula (II-Ex) or (II-Ey).

[1166] in:

[1167] Rp is a hydroxyl protecting group;

[1168] Among them, L 2 , p, ring A, X 1 、L 1 As defined in any one of (II-Ax) in the embodiments of the first aspect;

[1169] or X 2 ,q,ring A,X 1 、L 1 As defined in any one of (II-Ay) of the embodiments of the first aspect.

[1170] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1171] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1172] Option 3:

[1173] The present invention discloses a method for preparing a compound represented by general formula (III-E) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1174]

[1175] The compound of general formula (Y3) and the compound of general formula (KI4) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of general formula (III-E)

[1176] in:

[1177] R 1 , X is as defined in any one of (III-A) in the embodiments of the first aspect.

[1178] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1179] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1180] Option 4A

[1181] The present invention discloses a method for preparing a compound represented by general formula (IF) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1182]

[1183] Step 1: The compound of the general formula (IF-M1A) and the compound of the general formula (KI3) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain the compound of the general formula (IF-M2A).

[1184] Step 2: Remove the protective group of the compound of general formula (IF-M2A) to obtain the compound of general formula (IF-M3A)

[1185] Step 3: The compound of formula (KI1) and the compound of formula (IF-M3A) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of formula (IF)

[1186] in:

[1187] Re is an amino protecting group, preferably Fomc W, Y, Z, R L1 , R L2 , R 1 , L 1 , L 2, as defined in any one of the formulas (IF) in the embodiments of the sixth aspect. Reagents providing alkaline conditions include organic bases and inorganic bases, the organic bases including but not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases including but not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1188] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1189] Option 4B

[1190] The present invention discloses a method for preparing a compound represented by general formula (IF) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1191]

[1192] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[1193] L 2 -(C(R 3a )(R 3b )) m -R, where L 2 0 or more methylene units are each independently replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4-, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1194] L 1 -(C(R 5a )(R 5b )) n -,

[1195] Among them L 1 0 or more methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1196] -Cy- is selected from the group consisting of 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or independently substituted with one or more substituents R 7 Replace; wherein each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B, said ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein said ring B is unsubstituted or independently substituted with one or more substituents R 8 replace;

[1197] Each R 2 , R 7 , R 8 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[1198] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[1199] m and n are each independently selected from integers of 1 or greater.

[1200] Step 1: The compound of general formula (IF-M1B) and the compound of general formula (KI3) react in the presence or absence of a reducing agent, optionally under acidic or alkaline conditions to obtain the compound of general formula (IF-M2B).

[1201] Step 2: Remove the protective group of the compound of formula (IF-M2B) to obtain the compound of formula (IF-M3B)

[1202] Step 3: The compound of formula (KI1) and the compound of formula (IF-M3B) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of formula (IF)

[1203] in:

[1204] Re is an amino protecting group, preferably Fomc W, Y, Z, R L1 , R L2 , R 1 , L 1 , L 2 , as defined in any one of formula (IF) in the embodiment of the sixth aspect. Reducing agents include but are not limited to sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[1205] Reagents providing acidic conditions include protonic acids and Lewis acids, the protonic acids including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids including but not limited to boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, tin chloride, ferric chloride.

[1206] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, methyl acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1207] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1208] Option 4C

[1209] The present invention discloses a method for preparing a compound represented by general formula (IF) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1210]

[1211] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-, and -S-;

[1212] L 2 -(C(R 3a )(R 3b )) m -R, where L 2 0 or more methylene units are each independently replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1213] L1 -(C(R 5a )(R 5b )) n -, where L 1 0 or more methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1214] -Cy- is selected from the group consisting of 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or independently substituted with one or more substituents R 7 Replace; wherein each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6Each independently optionally together with the atoms between them form a ring B, said ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein said ring B is unsubstituted or independently substituted with one or more substituents R 8 replace;

[1215] Each R 2 , R 7 , R 8 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[1216] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[1217] m and n are each independently selected from integers of 1 or greater.

[1218] Step 1: The compound of formula (IE) and the compound of formula (KI2) react under optional acidic conditions to obtain the compound of formula (IF-M1C).

[1219] Step 2: Remove the protective group of the compound of formula (IF-M1C) to obtain the compound of formula (IF-M2C)

[1220] Step 3: The compound of formula (KI1) and the compound of formula (IF-M2C) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of formula (IF)

[1221] Re is an amino protecting group, preferably Fomc

[1222] W, Y, Z, R L1 , R L2, R 1 , L 1 , L 2 , as defined in any one of the general formulas (IF) in the embodiments of the sixth aspect. Reducing agents include but are not limited to sodium hydride, calcium hydride, lithium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium triethylborohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

[1223] Reagents providing acidic conditions include protonic acids and Lewis acids, the protonic acids including but not limited to hydrochloric acid, sulfuric acid, nitric acid, nitrous acid, sulfurous acid, phosphoric acid, phosphorous acid, formic acid, acetic acid, propionic acid, butyric acid, citric acid, benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; the Lewis acids including but not limited to boron trifluoride, zinc chloride, magnesium chloride, aluminum chloride, tin chloride, ferric chloride.

[1224] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, methyl acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1225] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1226] Plan 5

[1227] The present invention discloses a method for preparing a compound represented by general formula (II-F), including general formula (II-Fx) or general formula (II-Fy), or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1228]

[1229] Step 1: A compound of the general formula (II-F-M1x) or the general formula (II-F-M1y) and a compound of the general formula (KI4) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain a compound of the general formula (II-F-M2x) or the general formula (II-F-M2y).

[1230] Step 2: Remove the protecting group of the compound of formula (II-F-M2x) or the compound of formula (II-F-M2y) to obtain the compound of formula (II-F-M3x) or the compound of formula (II-F-M3y)

[1231] Step 3: The compound of formula (KI1) and the compound of formula (II-F-M3x) or the compound of formula (II-F-M3y) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain the compound of formula (II-Fx) or (II-Fy).

[1232] in:

[1233] Re is an amino protecting group, preferably Fomc

[1234] W, Y, Z, R L1 , R L2 ,A,X 1 , L 1 , L 2 , p is as defined in any one of the formulas (II-Fx) in the embodiments of the sixth aspect, or W, Y, Z, R L1 , R L2 ,A,X 1 , L 1 , X 2 , q is as defined in any one of Formula (II-Fy) in the embodiments of the sixth aspect.

[1235] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, etc.; the inorganic bases include but are not limited to sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, etc.

[1236] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1237] Plan 6

[1238] The present invention discloses a method for preparing a compound represented by general formula (III-F) or a pharmaceutically acceptable salt or solvate thereof, the method comprising:

[1239]

[1240] Step 1: The compound of general formula (III-F-M1) and the compound of general formula (KI4) react in the presence of a condensing agent, optionally under alkaline conditions, to obtain the compound of general formula (III-F-M2).

[1241] Step 2: Remove the protecting group from the compound of formula (III-F-M2) to obtain the compound of formula (III-F-M3)

[1242] Step 3: The compound of formula (KI1) and the compound of formula (III-F-M3) react with each other in the presence of a condensing agent, optionally under alkaline conditions, to obtain the compound of formula (III-F)

[1243] in:

[1244] Re is an amino protecting group, preferably Fomc

[1245] W, Y, Z, R L1 , R L2 , R 1, X is as defined in any of the general formulas (III-F) in the embodiments of the sixth aspect. Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, diethylamine, N-methylmorpholine, pyridine, hexahydropyridine, NN-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and the like; the inorganic bases include, but are not limited to, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and the like.

[1246] The condensing agent can be selected from 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 0-benzotriazole-N,N , N', N'-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[1247] Plan 7

[1248] The present invention discloses a method for preparing a compound represented by general formula (ID), comprising the following steps:

[1249]

[1250] in:

[1251] Ab is the ligand. After reducing Ab, it reacts with the general formula (IF) to obtain the general formula (ID);

[1252] Reducing agents include, but are not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, it is preferred to reduce the disulfide bonds on the antibody;

[1253] W, Y, Z, R L1 , R L2 , R 1 , L 1 , L 2 As defined in any one of Formula (ID) in the embodiments of the fourth aspect.

[1254] Plan 8

[1255]

[1256] in:

[1257] Ab is a ligand, and after reducing Ab, it reacts with general formula (II-F) including general formula (II-Fx) or general formula (II-Fy) to obtain general formula (II-Dx) or general formula (II-Dy);

[1258] Reducing agents include, but are not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, it is preferred to reduce the disulfide bonds on the antibody;

[1259] W, Y, Z, R L1 , R L2 ,A,X 1 , L 1 , L 2 , p is as defined in any one of formula (II-Dx) in the embodiment of the fourth aspect, or W, Y, Z, R L1 , R L2 ,A,X 1 , L 1 , X 2 , q is as defined in any one of Formula (II-Dy) in the embodiments of the fourth aspect.

[1260] Plan 9

[1261]

[1262] in:

[1263] Ab is a ligand, and after reducing Ab, it reacts with general formula (III-F) to obtain general formula (III-D);

[1264] Reducing agents include, but are not limited to, tris(2-carboxyethyl)phosphine, mercaptoethanol, dithiothreitol, cysteine, reduced glutathione, and the like; in particular, it is preferred to reduce the disulfide bonds on the antibody;

[1265] W, Y, Z, R L1 , R L2 , R 1 , X is as defined in any one of the general formulas (III-D) in the embodiments of the fourth aspect.

[1266] Technical Solution

[1267] 1. A compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the structure represented by formula (IA):

[1268]

[1269] where R 1 Selected from the following group: -O-, -(R 2 )N-,-P(=O)(R 2 )-,-P(R 2 )-, and -S-;

[1270] L 2 -(C(R 3a )(R 3b )) m -R,

[1271] Among them L 2 0 or more methylene units are each independently replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1272] L 1 -(C(R 5a )(R 5b )) n -,

[1273] Among them L 1 0 or more methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1274] -Cy- is selected from the group consisting of 6 to 10-membered arylene, 5 to 8-membered heteroarylene, 3 to 10-membered heterocyclylene, and 3 to 10-membered saturated or partially unsaturated carbocyclylene, wherein said -Cy- is unsubstituted or independently substituted with one or more substituents R 7 replace;

[1275] Each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group, or R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B, said ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein said ring B is unsubstituted or independently substituted with one or more substituents R 8 replace;

[1276] Each R 2 , R 7 , R 8 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6aliphatic groups;

[1277] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[1278] m and n are each independently selected from integers of 1 or greater.

[1279] 2. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 Aliphatic group.

[1280] 3. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a With R 5a 、R 4 With R 5a 、R 3a With R 6 , or R 4 With R 6 Each independently optionally together with the atoms between them form a ring B, said ring B selected from the following group: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, wherein said ring B is unsubstituted or independently substituted with one or more substituents R 8 replace.

[1281] 4. The compound according to any one of technical solutions 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[1282] 5. The compound according to any one of technical solutions 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1, L 2 -C(R 3a )(R 3b )-R.

[1283] 6. The compound according to any one of technical solutions 1 to 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R 3b )-R,L 2 The 0 methylene units are replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1284] 7. The compound according to any one of technical solutions 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 2, L 2 -(C(R 3a )(R 3b ))2-R.

[1285] 8. The compound according to any one of technical solutions 1-4 and 7, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L2 The 0 methylene units are replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1286] 9. The compound according to any one of technical solutions 1-4 and 7, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 2 One methylene unit is replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1287] 10. The compound according to any one of technical solutions 1-4, 7, and 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 2 One methylene unit is replaced by -C(O)- or -Cy-.

[1288] 11. The compound according to any one of technical solutions 1-4, 7, 9-10, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 2 One methylene unit is replaced by -C(O)-.

[1289] 12. The compound according to any one of technical solutions 1-4, 7, 9-11, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(O)-C(R 3a )(R 3b )-R.

[1290] 13. The compound according to any one of technical solutions 1-4, 7, 9-10, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 2 One methylene unit of the molecule is replaced by -Cy-.

[1291] 14. The compound according to any one of technical solutions 1-4, 7, 9-10, 13, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b )-Cy-R.

[1292] 15. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 The 0 methylene units are replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4)-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1293] 16. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 One methylene unit is replaced by -Cy-, -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1294] 17. The compound according to any one of technical solutions 1 and 16, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 One methylene unit is replaced by -C(O)- or -Cy-.

[1295] 18. The compound according to any one of technical solutions 1, 16-17, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 One methylene unit is replaced by -C(O)-.

[1296] 19. The compound according to any one of technical solutions 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2, 3 or 5.

[1297] 20. The compound according to any one of technical solutions 1 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2, L 1 -(C(R 5a )(R 5b ))2-.

[1298] 21. The compound according to any one of technical solutions 1 to 20, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-,L 1 The 0 methylene units are replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1299] 22. The compound according to any one of technical solutions 1 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1300] 23. The compound according to any one of technical solutions 1-19 and 22, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b))2-,L 1 One methylene unit of the is replaced by -C(O)- or -C(=S)-.

[1301] 24. The compound according to any one of technical solutions 1-19, 22-23, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -C(O)-.

[1302] 25. The compound according to any one of technical solutions 1-19, 22-24, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -C(R 5a )(R 5b )-C(O)-.

[1303] 26. The compound according to any one of technical solutions 1-19, 22-23, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit of is replaced by -C(=S)-.

[1304] 27. The compound according to any one of technical solutions 1-19, 22-23, and 26, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -C(R 5a )(R 5b )-C(=S)-.

[1305] 28. The compound according to any one of technical solutions 1 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 3, L 1 -(C(R 5a )(R 5b ))3-.

[1306] 29. The compound according to any one of technical solutions 1-19 and 28, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))3-,L 1 The 0 methylene units are replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1307] 30. The compound according to any one of technical solutions 1-19 and 28, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))3-,L 1 One methylene unit is replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1308] 31. The compound according to any one of technical solutions 1-19, 28, and 30, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R5b ))3-,L 1 One methylene unit is replaced by -C(O)-.

[1309] 32. The compound according to any one of technical solutions 1-19, 28, 30-31, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-C(O)-.

[1310] 33. The compound according to any one of technical solutions 1 to 19, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 5, L 1 -(C(R 5a )(R 5b ))5-.

[1311] 34. The compound according to any one of technical solutions 1-19 and 33, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 One methylene unit is replaced by -NR 6 -or-O- instead.

[1312] 35. The compound according to any one of technical solutions 1-19, 33-34, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 One methylene unit is replaced by -NR 6 -Alternative.

[1313] 36. The compound according to any one of technical solutions 1-19, 33-35, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-NR 6 -(C(R 5a )(R 5b )) 2- .

[1314] 37. The compound according to any one of technical solutions 1-19, 33-34, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 One methylene unit is replaced by -O-.

[1315] 38. The compound according to any one of technical solutions 1-19, 33-34, 37, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-O-(C(R 5a )(R 5b )) 2- .

[1316] 39. The compound according to any one of technical solutions 1-19 and 33, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 The two methylene units are each independently replaced by -C(O)-, -NR 6 -or-O- instead.

[1317] 40. The compound according to any one of technical solutions 1-19, 33, and 39, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 The two methylene units are each independently replaced by -C(O)- or -NR 6 -.

[1318] 41. The compound according to any one of technical solutions 1-19, 33, 39-40, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -C(R 5a )(R 5b )-C(O)-NR 6-(C(R 5a )(R 5b ))2-.

[1319] 42. The compound according to any one of technical solutions 1-19, 33, 39-41, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-NR 6 -C(O)-C(R 5a )(R 5b )-.

[1320] 43. The compound according to any one of technical solutions 1-19, 33, and 39, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 The two methylene units are each independently replaced by -C(O)- or -O-.

[1321] 44. The compound according to any one of technical solutions 1-19, 33, 39, 43, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))2-OC(R 5a )(R 5b )-C(O)-.

[1322] 45. The compound according to any one of technical solutions 1-19 and 33, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a )(R 5b ))5-,L 1 The three methylene units are each independently replaced by -C(O)- or -NR 6 -Alternative.

[1323] 46. ​​The compound according to any one of technical solutions 1-19, 33, and 45, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 -(C(R 5a)(R 5b ))2-NR 6 -C(O)-C(O)-.

[1324] 47. The compound according to any one of technical solutions 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The 0 methylene units are replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1325] 48. The compound according to any one of technical solutions 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit is replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1326] 49. The compound according to any one of technical solutions 1-18 and 48, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -NR 6 -or-O- instead.

[1327] 50. The compound according to any one of technical solutions 1-18, 48-49 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit of the is replaced by -C(O)- or -C(=S)-.

[1328] 51. The compound according to any one of technical solutions 1-18, 48-50, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit is replaced by -C(O)-.

[1329] 52. The compound according to any one of technical solutions 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The two methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1330] 53. The compound according to any one of technical solutions 1-18 and 52, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The two methylene units are each independently replaced by -C(O)-, -NR 6 -or-O- instead.

[1331] 54. The compound according to any one of technical solutions 1-18, 52-53, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The two methylene units are each independently replaced by -C(O)- or -NR 6 -Alternative.

[1332] 55. The compound according to any one of technical solutions 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The three methylene units are each independently replaced by -Cy-, -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1333] 56. The compound according to any one of technical solutions 1-18 and 55, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 The three methylene units are each independently replaced by -C(O)- or -NR 6 -Alternative.

[1334] 57. The compound according to any one of technical solutions 1 and 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1335] 58. The compound according to any one of technical solutions 1, 3, and 57, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclylene group.

[1336] 59. The compound according to any one of technical solutions 1, 3, 57-58, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 3- to 6-membered saturated or partially unsaturated heterocyclylene group.

[1337] 60. The compound according to any one of technical solutions 1, 3, 57-59, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 5-membered saturated or partially unsaturated heterocyclylene group.

[1338] 61. The compound according to any one of technical solutions 1, 3, 57-60, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 5-membered saturated heterocyclylene group.

[1339] 62. The compound according to any one of technical solutions 1 and 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1340] 63. The compound according to any one of technical solutions 1, 3, and 62, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclylene group.

[1341] 64. The compound according to any one of technical solutions 1, 3, 62-63, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 6-membered saturated or partially unsaturated heterocyclylene group.

[1342] 65. The compound according to any one of technical solutions 1, 3, 62-64, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 6-membered saturated heterocyclylene group.

[1343] 66. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R 3b )-R, or -(C(R 3a )(R 3b ))2-R,L 1 -(C(R 5a )(R 5b ))2-、-(C(R 5a )(R5b ))3-、or-(C(R 5a )(R 5b ))5-.

[1344] 67. The compound according to any one of technical solutions 1 and 66, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 1 -(C(R 5a )(R 5b ))2-.

[1345] 68. The compound according to any one of technical solutions 1, 66-67, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -NR 6 -or-O- instead.

[1346] 69. The compound according to any one of technical solutions 1, 66-68, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -C(O)-.

[1347] 70. The compound according to any one of technical solutions 1, 66-69, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -(C(R 3a )(R 3b ))2-R,L 1 -C(R 5a )(R 5b )-C(O)-.

[1348] 71. The compound according to any one of technical solutions 1, 66-70, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1349] 72. The compound according to any one of technical solutions 1, 66-71, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclylene group.

[1350] 73. The compound according to any one of technical solutions 1, 66-72, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 5-membered saturated heterocyclylene group.

[1351] 74. The compound according to any one of technical solutions 1 and 66, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R 3b )-R,L 1 -(C(R 5a )(R 5b ))2-.

[1352] 75. The compound according to any one of technical solutions 1, 66, and 74, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R 3b )-R,L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -NR 6 -or-O- instead.

[1353] 76. The compound according to any one of technical solutions 1, 66, 74-75, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R3b )-R,L 1 -(C(R 5a )(R 5b ))2-,L 1 One methylene unit is replaced by -C(O)-.

[1354] 77. The compound according to any one of technical solutions 1, 66, 74-76, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 2 -C(R 3a )(R 3b )-R,L 1 -C(R 5a )(R 5b )-C(O)-.

[1355] 78. The compound according to any one of technical solutions 1 to 77, or its tautomer, meso-racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1 Selected from the following group: -O-, -(R 2 )N-, and -S-.

[1356] 79. The compound according to any one of technical solutions 1-78 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1 It is -O-.

[1357] 80. The compound according to any one of technical solutions 1-78 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1 For -(R 2 )N-.

[1358] 81. The compound according to any one of technical solutions 1-78 and 80, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 is hydrogen or C 1-6 Aliphatic group.

[1359] 82. The compound according to any one of technical solutions 1-78, 80-81 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1 It is -HN-.

[1360] 83. The compound according to any one of technical solutions 1 to 82, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the -Cy- is a 6- to 10-membered arylene group.

[1361] 84. The compound according to any one of technical solutions 1 to 83, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein -Cy- is phenylene.

[1362] 85. The compound according to any one of technical solutions 1 to 84, or its tautomer, meso-racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 7 For hydrogen.

[1363] 86. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 3a , R 3b are each independently hydrogen, or R 3a With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1364] 87. The compound according to any one of technical solutions 1 and 86, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclic group.

[1365] 88. The compound according to any one of Technical Solutions 1 and 86-87, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring B is a 5-membered saturated heterocyclylene group.

[1366] 89. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4 is hydrogen, or R 4 With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1367] 90. The compound according to technical solution 1 or its tautomer, meso-racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4 is hydrogen, or R 4 With R 5a Each independently optionally forms Ring B together with the atoms between them.

[1368] 91. The compound according to any one of technical solutions 1, 86-90, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 8 For hydrogen.

[1369] 92. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R, R a , R b are each independently hydrogen.

[1370] 93. The compound according to technical solution 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ligand drug conjugate comprises a structure of the following group:

[1371]

[1372] 94. A compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the structure represented by formula (II-A):

[1373]

[1374] where X 1 Selected from the following group: N, P, and saturated or unsaturated C, when X 1 When the C is saturated, the X 1 R n replace;

[1375] When X 1 When C is saturated, ring A is selected from the following group: 3 to 10 membered saturated or partially unsaturated heterocyclic group, and 3 to 10 membered saturated or partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or more substituents R 1a replace;

[1376] Or, when X 1When C is unsaturated, ring A is selected from the following group: 6 to 10 membered aryl, 5 to 8 membered heteroaryl, 3 to 10 membered partially unsaturated heterocyclic group, and 3 to 10 membered partially unsaturated carbocyclic group, wherein the ring A is substituted by 0 or more substituents R 1b replace;

[1377] Or, when X 1 When N or P, ring A is selected from the following group: 5 to 8 membered heteroaryl, and 3 to 10 membered saturated or partially unsaturated heterocyclic group, wherein the ring A is substituted by 0 or more substituents R 1c replace;

[1378] When ring A is selected from the group consisting of 6 to 10-membered aryl, 5 to 8-membered heteroaryl, and 3 to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 Substitute, the L 2 Not for R n ;

[1379] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 substituted, or the ring A contains q ring heteroatoms X 2 And the X 2 For direct or indirect attachment of ligands;

[1380] X 2 Selected from the following groups: N, and P;

[1381] L 2 -R 2 -L 3 -, the R 2 For direct or indirect attachment of ligands;

[1382] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, the L 3 0 or more methylene units are each independently replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1383] R 2 Selected from the following group: -O-, -(R 2a )N-, -S-, and -P(=O)(R 2a )-;

[1384] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, the L 1 0 or more methylene units are each independently replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1385] Each R 1a , R 1b , R 1c , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b )、-SO2N(R a )(R b ), -OC(O)R, -N(R)SO2R, or C optionally substituted by R 1-6 aliphatic groups;

[1386] Each of R, R a , R b Each is independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 aliphatic groups;

[1387] m and n are each independently selected from integers of 0 or greater, and p and q are each independently selected from integers of 1 or greater.

[1388] 95. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 It is saturated C.

[1389] 96. The compound according to any one of technical solutions 94-95 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following group: a 3- to 10-membered saturated heterocyclic group, and a 3- to 10-membered saturated carbocyclic group.

[1390] 97. The compound according to any one of technical solutions 94-96 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 10-membered saturated carbocyclic group.

[1391] 98. The compound according to any one of technical solutions 94-97 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered saturated carbocyclic group.

[1392] 99. The compound according to any one of technical solutions 94-98 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-membered saturated carbocyclic group.

[1393] 100. The compound according to any one of technical solutions 94-98 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered saturated carbocyclic group.

[1394] 101. The compound according to any one of technical solutions 94-96 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 10-membered saturated heterocyclic group.

[1395] 102. The compound according to any one of technical solutions 94-96 and 101, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered saturated heterocyclic group.

[1396] 103. The compound according to any one of technical solutions 94-96, 101-102, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3-membered saturated heterocyclic group.

[1397] 104. The compound according to any one of technical solutions 94-96, 101-103, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A contains 1 heteroatom.

[1398] 105. The compound according to any one of technical solutions 94-96, 101-104, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A contains 1 nitrogen atom.

[1399] 106. The compound according to any one of technical solutions 94-96, 101-102, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered saturated heterocyclic group.

[1400] 107. The compound according to any one of technical solutions 94-96, 101-102, 106, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A contains 1 heteroatom.

[1401] 108. The compound according to any one of technical solutions 94-96, 101-102, 106-107, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A contains 1 nitrogen atom.

[1402] 109. The compound according to any one of technical solutions 94-108, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is substituted by 0 substituents R 1a replace.

[1403] 110. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 It is unsaturated C.

[1404] 111. The compound according to any one of technical solutions 94 and 110, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: 6- to 10-membered aryl groups, and 5- to 8-membered heteroaryl groups.

[1405] 112. The compound according to any one of technical solutions 94, 110-111, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aromatic group.

[1406] 113. The compound according to any one of technical solutions 94, 110-112, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

[1407] 114. The compound according to any one of technical solutions 110-113 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is substituted by 0 substituents R 1b replace.

[1408] 115. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 N or P.

[1409] 116. The compound according to technical solution 94 or 115, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

[1410] 117. The compound according to any one of technical solutions 94, 115-116 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated heterocyclic group.

[1411] 118. The compound according to any one of technical solutions 94, 115-117, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 10-membered saturated heterocyclic group.

[1412] 119. The compound according to any one of technical solutions 94, 115-118, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered saturated heterocyclic group.

[1413] 120. The compound according to any one of technical solutions 94, 115-119 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered saturated heterocyclic group.

[1414] 121. The compound according to any one of technical solutions 94, 115-120, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A independently contains 2 heteroatoms.

[1415] 122. The compound according to any one of technical solutions 94, 115-121, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A independently contains 2 nitrogen atoms.

[1416] 123. The compound according to any one of technical solutions 115-121 or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is substituted by 0 substituents R 1c replace.

[1417] 124. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the formula (II-A) is a structure represented by formula (II-Ax):

[1418]

[1419] When ring A is selected from the group consisting of 6 to 10-membered aryl, 5 to 8-membered heteroaryl, and 3 to 10-membered saturated or partially unsaturated carbocyclic group, said ring A is surrounded by p L 2 replace;

[1420] Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the ring A is surrounded by p L 2 replace.

[1421] 125. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the formula (II-A) is a structure represented by formula (II-Ay):

[1422]

[1423] wherein Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, said Ring A containing q ring heteroatoms X 2 And the X 2 Used to directly or indirectly attach ligands.

[1424] 126. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the following group: a 6- to 10-membered aryl group, a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated carbocyclic group.

[1425] 127. A compound according to any one of technical solutions 94 and 126, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the following groups: phenyl, and a 3- to 6-membered saturated carbocyclic group.

[1426] 128. A compound according to any one of technical solutions 94, 126-127, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered saturated carbocyclic group.

[1427] 129. A compound according to any one of technical solutions 94, 126-128, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-membered saturated carbocyclic group or a 6-membered saturated carbocyclic group.

[1428] 130. The compound according to any one of technical solutions 94, 126-127, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is phenyl.

[1429] 131. The compound according to any one of technical solutions 94, 126-130, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is replaced by one or more L 2 replace.

[1430] 132. The compound according to any one of technical solutions 94, 126-131, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is replaced by 1 L 2 replace.

[1431] 133. A compound according to any one of technical solutions 94 and 126, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 10-membered saturated heterocyclic group.

[1432] 134. The compound according to any one of technical solutions 94, 126, and 133, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3- to 6-membered saturated heterocyclic group.

[1433] 135. The compound according to any one of technical solutions 94, 126, 133-134, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 3-membered saturated heterocyclic group.

[1434] 136. The compound according to any one of technical solutions 94, 126, 133-134, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered saturated heterocyclic group.

[1435] 137. A compound according to any one of technical solutions 94, 126, 133-134, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered saturated heterocyclic group.

[1436] 138. The compound according to any one of technical solutions 133-137, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is replaced by one or more L 2 replace.

[1437] 139. The compound according to any one of technical solutions 133-138, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is replaced by 1 L 2 replace.

[1438] 140. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

[1439] 141. A compound according to any one of technical solutions 94 and 140, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0, L 3 It is a covalent bond.

[1440] 142. The compound according to any one of technical solutions 94 and 140, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1, L 3 -C(R 5a )(R 5b )-.

[1441] 143. The compound according to any one of technical solutions 94, 140, and 142, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 3 The 0 methylene units are replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1442] 144. The compound according to any one of technical solutions 94 and 140, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 2, L 3 -(C(R 3a )(R 3b ))2-.

[1443] 145. The compound according to any one of technical solutions 94, 140, and 144, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 3 The 0 methylene units are replaced by -N(R 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 )SO2-、-SO2N(R 4 )-、-C(=S)-、-C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1444] 146. The compound according to any one of technical solutions 94 and 125, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A contains one or more ring heteroatoms X 2 And the X 2 Used to directly or indirectly attach ligands.

[1445] 147. The compound according to any one of technical solutions 94, 125, and 146, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A contains one of the ring heteroatoms X 2 .

[1446] 148. The compound according to any one of technical solutions 94, 125, 146-147, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said X 2 is N.

[1447] 149. The compound according to any one of technical solutions 94-148 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

[1448] 150. The compound according to any one of technical solutions 94-149, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, L 1 It is a covalent bond.

[1449] 151. The compound according to any one of technical solutions 94-149 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, L 1 -C(R 5a )(R 5b )-.

[1450] 152. The compound according to any one of technical solutions 94-149 and 151, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit is replaced by -N(R 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-.

[1451] 153. The compound according to any one of technical solutions 94-149, 151-152 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L 1 One methylene unit is replaced by -C(O)-.

[1452] 154. The compound according to any one of technical solutions 94-153 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2Selected from the following group: -O-, -(R 2a )N-, and -S-.

[1453] 155. The compound according to any one of technical solutions 94-154 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 It is -O-.

[1454] 156. The compound according to any one of technical solutions 94-153 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 For -(R 2a )N-.

[1455] 157. A compound according to any one of technical solutions 94-153 and 156, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2a For hydrogen.

[1456] 158. A compound according to any one of technical solutions 94-153, 156-157, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 2 It is -HN-.

[1457] 159. The compound according to any one of technical solutions 94-109 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1a For hydrogen.

[1458] 160. The compound according to any one of technical solutions 94, 110-114, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1b For hydrogen.

[1459] 161. A compound according to any one of technical solutions 94, 115-123, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 1c For hydrogen.

[1460] 162. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 3a , R 3b are each independently hydrogen.

[1461] 163. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 4 For hydrogen.

[1462] 164. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 5a , R 5b are each independently hydrogen.

[1463] 165. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R 6 For hydrogen.

[1464] 166. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R, R a , R b are each independently hydrogen.

[1465] 167. The compound according to technical solution 94 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the structure of the following group:

[1466]

[1467]

[1468] 168. A compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutica...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following structural formula: in, Ab is the ligand, N a An integer or decimal from 1 to 10.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the average number of connections N a An integer or decimal number from 2 to 8.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the average number of connections N a An integer or decimal number from 3 to 8. 4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ligand Ab is an antibody or an antigen-binding fragment thereof. 5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ligand Ab is selected from the group consisting of a chimeric antibody, a humanized antibody, and a fully human antibody.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the ligand Ab targets the following group: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 and EGFR.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following structural formula: in, n is an integer or decimal from 1 to 10.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein n is an integer or decimal from 3 to 8.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and / or a pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing a tumor selected from the group consisting of gastric cancer, breast cancer, colon cancer and ovarian cancer.

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