Ligand-drug conjugate and medical use thereof

Abstract

A ligand-drug conjugate and medical use thereof. In particular, the present invention relates to an antibody-drug conjugate and use thereof in the treatment of tumors.

Description

Ligand-drug conjugates and medical uses thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of biotechnology, and relates to ligand-drug conjugates and medical uses thereof. BACKGROUND

[0002] The statements herein are merely provided for background information related to the present disclosure and do not necessarily constitute the prior art.

[0003] Immunomodulators (IMiD) and Cereblon E3 ligase modulators (CELMoD) represented by thalidomide and its derivatives such as lenalidomide and pomalidomide are a typical class of molecular glues, which bind to the Cereblon E3 ubiquitin ligase, change its conformation, recruit IKZF1 and IKZF3 transcription factors and other neosubstrates, and degrade them, thereby exerting multiple effects such as anti-tumor and immunomodulation.

[0004] Although the clinical effects of thalidomide molecules have been proven in diseases such as multiple myeloma and myelodysplastic syndrome, and are being expanded to indications such as diffuse large B-cell lymphoma and systemic lupus erythematosus, there is still a need to improve the targeting of such drugs to specific disease-related tissues and cells, enhance the efficacy of the drugs, and improve the safety window of the treatment. SUMMARY

[0005] Ligand-drug conjugate or pharmaceutically acceptable salt thereof

[0006] The present disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug linked to the ligand, wherein the drug is an IKZF degrader, and the drug is linked to the ligand through a linker.

[0007] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as previously described, wherein the drug is an IKZF1 / 3 degrader.

[0008] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as previously described, wherein the drug is an IKZF1 / 3 degrader with a hydrophilic group.

[0009] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as previously described, wherein the drug is an IKZF1 / 3 degrader with poor membrane permeability.

[0010] In another aspect, the present disclosure relates to a ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug linked to the ligand, wherein the drug comprises a structure according to Formula (D-M-H):

[0011] wherein:

[0012] X is -CR a R b - or -C(O)-;

[0013] Y 1 , Y 2 , Y 3 , and Y 4 are each independently a nitrogen atom or CR 29 ;

[0014] Z is selected from -O-, -S(O) p -, -C(O)-, -NR 11 -, and -(CR c R cc ) n1 -;

[0015] V is a bond or -(CR d R dd ) n1 -;

[0016] U is -(CR e R f ) n1 -;

[0017] R 5 is selected from a bond, -(CR g R h ) n -, -C(O)-, -S(O) p -, and -NR i -;

[0018] L M is one or more substituted or unsubstituted amino acids or variants thereof;

[0019] Ring A, Ring B, and Ring C are the same or different, and each is independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0020] R 2 , R 3 , R 4 , and R 29 are the same or different, and each is independently selected from a hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o, -(CR p R q ) m - cycloalkyl, -(CR p R q ) m - heterocyclyl, -(CR p R q ) m - aryl, -(CR p R q ) m - heteroaryl, -(CR p R q ) m - NR s R t , -(CR p R q ) m - C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m - (NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m -C(O)OR u , -(CR p R q ) m - OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m-C(=NR 13 )NR s R t 、-(CR p R q ) m -S(O) p R u 、-(CR p R q ) m -S(O) p NR s R t 、-(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups therein are each independently and optionally selected from halogen, cyano, nitro, -OR z , oxoyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 、-(CR w1 R w2 ) u -C(O)R 14 、-(CR w1 R w2 ) u -C(O)OR 14 、-(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O) p R 14 One or more identical or different substituents are substituted in the substance;

[0021] Or two adjacent R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or two adjacent R groups. 3 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or two adjacent R groups. 4together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0022] R 1 is selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxy and hydroxyalkyl;

[0023] R u4 , R u5 , R u6 and R u7 are identical or different and each independently selected from a group consisting of a hydrogen atom, halogen, hydroxy, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30a R 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , -(CR 30aR 30b ) p4 -S(O) p -R 33 、-(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0024] R 13 R 33 R o R u R x R y R z and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] R 9 R 11 R 31 R 32 R 34 R i R r R s R t R u1 R u2 R u3 R v1 and R v2 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 15b Alkylene-COOR 15b -NR 16a R 16b Alkylene-NR 16a R 16b cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0026] R a R b, R c , R cc , R d , R dd , R e , R f , R g , R h , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR w3 R w4 ) u - cycloalkyl group, -(CR w3 R w4 ) u - heterocyclyl group, -(CR w3 R w4 ) u - aryl group, and -(CR w3 R w4 ) u - heteroaryl group, each of said cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, a halogen, a cyano group, an amino group, a hydroxy group, a carboxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group;

[0027] R w3 , Rw4 R 15a R 15b R 16a and R 16b They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0028] Or R a and R b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R c and R cc Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R d and R dd Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R e and R f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R g and R h Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R p and R q Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w1 and R w2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 30a and R 30b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w3 and R w4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0029] Or R s and R t Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R u1 and R u2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R v1 and R v2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 31 and R 32 Together with the nitrogen atoms attached to them, they form a heterocyclic group; wherein the heterocyclic group is optionally selected from halogen, cyano, nitro, -OR Lone or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

[0030] R L selected from the group consisting of hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

[0031] p is 0, 1, or 2;

[0032] r is 0, 1, 2, 3, 4, 5, or 6;

[0033] s is 0, 1, 2, 3, 4, 5, or 6;

[0034] t is 0, 1, 2, 3, 4, 5, or 6;

[0035] m is 0, 1, 2, 3, 4, 5, or 6;

[0036] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0037] p4 is 0, 1, 2, 3, 4, 5, or 6;

[0038] p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0039] p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0040] u is 0, 1, 2, 3, 4, 5, or 6.

[0041] In another aspect, the present disclosure relates to a ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug linked to the ligand, wherein the drug comprises a structure as shown in formula (D-H):

[0042] wherein:

[0043] X is -CR a R b - or -C(O)-;

[0044] Y 1 , Y 2 , Y 3 , and Y 4 one of X, Y, Y, Y, and Y is a carbon atom, the other three are identical or different, and each independently is a nitrogen atom or CR29 ;

[0045] Z is selected from -0-, -S(O) p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -;

[0046] V is a bond or -(CR d R dd ) n1 -;

[0047] U is -(CR e R f ) n1 -;

[0048] R 5 is selected from a bond, -(CR g R h ) n -, -C(O)-, -S(O) p - and -NR i -;

[0049] R 6 is selected from a bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii -, -C(O)-, -C(O)-NR ii -, -NR ii -, -S(O) p -, -S(O) p -, -NR ii -, -NR ii -, -(CR j R jj ) n -, -(CR j R jj ) n -, -NR ii -,

[0050] R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n -, -0-, -C(O)-, -NR 12 -, -S(O) p -, -(CRk R kk ) n -O-, -O-(CR k R kk ) n -, -(CR k R kk ) n -C(O)-, -C(O)-(CR k R kk ) n -, -(CR k R kk ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0051] R 8 is a bond or -(CR m R n ) n -;

[0052] R 10 is selected from the group consisting of a bond,

[0053] ring A, ring B and ring C are identical or different, and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0054] R 2 , R 3 , R 4 and R 29 are identical or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 Ru7 -COOR u ) p5 -C(O)-(NR) r -CR u6 R u7 -COOR u ) p5 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -C(O)OR u 、-(CR p R q ) m -OC(O)R u 、-(CR p R q ) m -C(O)NR s R t 、-(CR p R q ) m -C(=NR 13 )NR s R t 、-(CR p R q ) m -S(O) p R u 、-(CR p R q ) m -S(O) p NR s R t 、-(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups therein are each independently and optionally selected from halogen, cyano, nitro, -OR z , oxoyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 、-(CR w1 Rw2 u -C(O)R 14 w1 R w2 u -C(O)OR 14 w1 R w2 u -C(O)-NR v1 R v2 w1 R w2 u -S(O) p R 14 one or more of the same or different substituents;

[0055] or two adjacent R 2 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, or two adjacent R 3 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, or two adjacent R 4 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, optionally substituted with one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0056] R 1 is selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxy and hydroxyalkyl;

[0057] R 35 , R u4 , R u5 , R u6 and R u7 are the same or different, and each is independently selected from a hydrogen atom, halogen, hydroxy, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30a R 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R​​​​​​​32 -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 -(CR 30a R 30b ) p4 -O-R 33 -(CR 30a R 30b ) p4 -C(O)-O-R 33 -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 -(CR 30a R 30b ) p4 -S(O) p -R 33 -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0058] R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are identical or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

[0059] R 9 , R 11 , R 12 , R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 and R v2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a -COOR 15b group, an alkylene-COOR 15b group, a -NR 16a R 16b group, an alkylene-NR 16a R 16b group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

[0060] R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R j , R jj , R k , R kk , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a -NR u1 R u2 group, a -(CR w3 R w4 )2-CR u R u1 group, a -(CR u2 R w3 )2-CR w4 R u group, a -(NR u3 -CR u4R u5 -COOR 15a ) p6 -C(O)-(NR) u3 -CR u4 R u5 -COOR 15a ) p6 -COOR 15a 、-(CR w3 R w4 ) u -COOR 15a cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR) w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclic group, -(CR) w3 R w4 ) u -Aryl and-(CR w3 R w4 ) u - Heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0061] R w3 R w4 R 15a R 15b R 16a and R 16b They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0062] Or R a and R b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R c and R cc Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R d and R dd Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R e and R f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R g and R h Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R j and R jjTogether with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R k and R kk Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R n Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R p and R q Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w1 and R w2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 30a and R 30b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w3 and R w4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0063] Or R s and R t Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R u1 and R u2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R v1 and R v2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 31 and R 32 Together with the nitrogen atoms attached to them, they form a heterocyclic group; wherein the heterocyclic group is optionally selected from halogen, cyano, nitro, -OR L It is substituted by one or more of the same or different substituents from hydroxyalkyl, oxoalkyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0064] R L The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0065] p is 0, 1, or 2;

[0066] r is 0, 1, 2, 3, 4, 5, or 6;

[0067] s is 0, 1, 2, 3, 4, 5, or 6;

[0068] t is 0, 1, 2, 3, 4, 5, or 6;

[0069] m is 0, 1, 2, 3, 4, 5, or 6;

[0070] n is 0, 1, 2, 3, 4, 5, or 6;

[0071] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0072] p4 is 0, 1, 2, 3, 4, 5, or 6;

[0073] p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0074] p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0075] w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0076] u is 0, 1, 2, 3, 4, 5, or 6.

[0077] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the ligand is an antigen binding molecule; preferably, the ligand is an antibody.

[0078] In another aspect, the disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, which is a ligand-drug conjugate of Formula (I) or a pharmaceutically acceptable salt thereof:

[0079] Ab-(L-D) y (I)

[0080] wherein Ab is an antigen binding molecule; preferably, Ab is an antibody;

[0081] L is a linker connecting Ab and D;

[0082] D is a structure of Formula (D-H):

[0083] wherein:

[0084] X is -CR a R b - or -C(O)-;

[0085] Y 1 , Y 2 , Y3 and Y 4 is carbon atom, the remaining three are the same or different, and each independently is a nitrogen atom or CR 29 ;

[0086] Z is selected from -0-, -S(O) p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -;

[0087] V is a bond or -(CR d R dd ) n1 -;

[0088] U is -(CR e R f ) n1 -;

[0089] R 5 is selected from a bond, -(CR g R h ) n -, -C(O)-, -S(O) p - and -NR i -;

[0090] R 6 is selected from a bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii - C(O)-, -C(O)-NR ii -, -NR ii - S(O) p -, -S(O) p - NR ii -, -NR ii - (CR j R jj ) n -, -(CR j R jj ) n - NR ii -,

[0091] R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n-, -O-, -C(O)-, -NR 12 -, -S(O) p -, -(CR k R kk ) n -, -O-(CR k R kk ) n -, -(CR k R kk ) n -, -C(O)-(CR k R kk ) n -, -(CR k R kk ) n -, -NR 12 -, -NR 12 -(CR k R kk ) n -, -(CR k R kk ) n -, -S(O) p -, -S(O) p -(CR k R kk ) n -, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(=NR 13 )-NR 12 -, -NR 12 -C(=NR 13 )-, -O-C(O)-NR 12 -, -NR 12 -C(O)-O-, -NR 12 -C(O)-NR 12 -, -NR 12 -S(O) p -, -S(O) p -NR 12 -, -NR 12 -S(O) p -C(=NR 13 )-, -C(=NR 13 )-S(O) p -NR 12 - and each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0092] R 8 is a bond or -(CR m R n ) n -;

[0093] R 10 is selected from the group consisting of a bond,

[0094] ring A, ring B and ring C are identical or different, and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0095] R 2 , R 3 , R 4 and R 29 are identical or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 Ru7 -COOR u ) p5 -C(O)-(NR) r -CR u6 R u7 -COOR u ) p5 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -C(O)OR u 、-(CR p R q ) m -OC(O)R u 、-(CR p R q ) m -C(O)NR s R t 、-(CR p R q ) m -C(=NR 13 )NR s R t 、-(CR p R q ) m -S(O) p R u 、-(CR p R q ) m -S(O) p NR s R t 、-(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups therein are each independently and optionally selected from halogen, cyano, nitro, -OR z , oxoyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 、-(CR w1 Rw2 ) u -C(O)R 14 、-(CR w1 R w2 ) u -C(O)OR 14 、-(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O) p R 14 One or more identical or different substituents are substituted in the substance;

[0096] Or two adjacent R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or two adjacent R groups. 3 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or two adjacent R groups. 4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0097] R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups;

[0098] R 35 R u4 R u5 R u6 and R u7 The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclic group, -(CR) 30a R 30b ) p4 -Aryl, -(CR 30a R 30b ) p4 -Heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R32 -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 -(CR 30a R 30b ) p4 -O-R 33 -(CR 30a R 30b ) p4 -C(O)-O-R 33 -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 -(CR 30a R 30b ) p4 -S(O) p -R 33 -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 each independently optionally substituted with one or more of the same or different substituents selected from oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0099] R 13 , R 33 , R o , R u , R x , R y , R z , and R 14 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0100] R 9 R 11 R 12 R 31 R 32 R 34 R 36 R i R ii R r R s R t R u1 R u2 R u3 R v1 and R v2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a -COOR 15b alkylene-COOR 15b group, a -NR 16a R 16b alkylene-NR 16a R 16b group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0101] R a R b R c R cc R d R dd R e R f R g R h R j R jj R k R kk R m R n R p R q R w1 R w2 R 30a and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a -NR u1 R u2 -(CR w3 R w4 ) u -NR u1 R u2 -(CR w3 R w4 ) u -(NR u3 -CR u4R u5 -COOR 15a ) p6 -C(O)-(NR) u3 -CR u4 R u5 -COOR 15a ) p6 -COOR 15a 、-(CR w3 R w4 ) u -COOR 15a cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR) w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclic group, -(CR) w3 R w4 ) u -Aryl and-(CR w3 R w4 ) u - Heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0102] R w3 R w4 R 15a R 15b R 16a and R 16b They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0103] Or R a and R b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R c and R cc Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R d and R dd Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R e and R f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R g and R h Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R j and R jjTogether with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R k and R kk Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R n Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R p and R q Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w1 and R w2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 30a and R 30b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w3 and R w4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0104] Or R s and R t Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R u1 and R u2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R v1 and R v2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 31 and R 32 Together with the nitrogen atoms attached to them, they form a heterocyclic group; wherein the heterocyclic group is optionally selected from halogen, cyano, nitro, -OR L It is substituted by one or more of the same or different substituents from hydroxyalkyl, oxoalkyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0105] R L The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0106] p is 0, 1, or 2;

[0107] r can be 0, 1, 2, 3, 4, 5, or 6;

[0108] s can be 0, 1, 2, 3, 4, 5, or 6;

[0109] t can be 0, 1, 2, 3, 4, 5, or 6;

[0110] m can be 0, 1, 2, 3, 4, 5, or 6;

[0111] n is 0, 1, 2, 3, 4, 5, or 6;

[0112] n1 is 0, 1, 2, 3, 4, 5 or 6;

[0113] p4 is 0, 1, 2, 3, 4, 5, or 6;

[0114] p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0115] p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0116] w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0117] u is 0, 1, 2, 3, 4, 5, or 6; and

[0118] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0119] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein Z is -O- or -NR. 11 -, where R 11 As defined in general formula (I); preferably, Z is -O-.

[0120] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein V is -(CR d R dd ) n1 -, where R d R dd and n1 are as defined in general formula (I); preferably, V is -CR d R dd -, where R d and R dd As defined in general formula (I).

[0121] In some embodiments, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein U is a -CR e R f -, where Re and R f as defined in general formula (I).

[0122] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 29 ; or one of Y 1 , Y 2 , Y 3 and Y 4 is a carbon atom, one of the remaining three is a nitrogen atom, and the remaining two are the same or different and each independently CR 29 , wherein R 29 is as defined in general formula (I).

[0123] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein ring B is a 3- to 12-membered heterocyclyl; preferably, ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; more preferably, ring B is a 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms; most preferably, ring B is a piperazinyl.

[0124] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein ring B is selected from In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein ring B is

[0125] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein ring B is selected from In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein ring B is

[0126] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein D is represented by formula (D-I-H):

[0127] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0128] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s and t are as defined in general formula (I).

[0129] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein D is represented by formula (D-I-S-H):

[0130] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0131] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s, and t are as defined in general formula (I).

[0132] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein D is represented by formula (D-I-R-H):

[0133] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0134] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s, and t are as defined in general formula (I).

[0135] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein X is -CR a R b - wherein R a and R b are as defined in general formula (I).

[0136] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a cyano group, and an amino group; preferably, R a and R b are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; more preferably, R a and R b are both hydrogen atoms.

[0137] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.

[0138] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is phenyl.

[0139] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from preferably, ring A is more preferably, ring A is

[0140] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring C is phenyl.

[0141] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from preferably, ring C is more preferably, ring C is

[0142] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R d , R dd , R e , and R f are each a hydrogen atom.

[0143] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 10 is a chemical bond or wherein R 35 , R 36 , and w are as defined in general formula (I); preferably, R 10 is a chemical bond.

[0144] In some embodiments, the ligand-drug conjugate of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein D is represented by formula (D-II M-H):

[0145] wherein L M is one or more substituted or unsubstituted amino acids or variants thereof;

[0146] R 2 to R5 r, s, and t are as defined in general formula (I).

[0147] In some embodiments, the ligand-drug conjugate, or the pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein D is represented by formula (D-II-H):

[0148] wherein R 2 to R 9 r, s, and t are as defined in general formula (I).

[0149] In some embodiments, the ligand-drug conjugate, or the pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein D is represented by formula (D-II-S-H):

[0150] wherein R 2 to R 9 r, s, and t are as defined in general formula (I).

[0151] In some embodiments, the ligand-drug conjugate, or the pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein D is represented by formula (D-II-R-H):

[0152] wherein R 2 to R 9 r, s, and t are as defined in general formula (I).

[0153] In some embodiments, the ligand-drug conjugate, or the pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -, and

[0154] L 1 is selected from -(succinimid-3-yl-N)-W 1 -C(O)-, -(succinimid-3-yl-N)-W 1 -W 2 -C(O)-, -(succinimid-3-yl-N)-W 1 -, -(succinimid-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -W 1 -, -(succinimid-3-yl-N)-W 1 -(CR 20a R20b -CR 20c R 20d -O) q -W 1 -、-(succinimide-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-、-(succinimide-3-yl-N)-W 1 -(CR 20a R 20b -CR 20c R 20d -O) q -C(O)-、-(succinimide-3-yl-N)-W 1 -NR 17 -C(O)-、-C(O)-NR 17 -W 1 -C(O)-、-W 1 -C(O)-NR 17 -W 1 -C(O)-、-C(O)-W 1 -C(O)-、 Where q is an integer from 0 to 20;

[0155] L 2 Selected from -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d-O) v -W 1 -C(O)-NR 18 -、-W 1 -C(O)-、-NR 18 -W 1 -C(O)-NR 18 -、-S-(CR 21e R 21f ) p1 -C(O)-、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -O-W 1 -C(O)-NR 18 -、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-、-NR 18 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -O-W 1 -NR 18 -C(O)-、-NR 18 -W 1 -W 2 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-W 1 -O-W 1 -C(O)-、-NR 18 -W 1 -W 2 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -W 2 -W1 - C(O)- and a bond, wherein v is an integer from 0 to 20, and pi is an integer from 0 to 20;

[0156] L 3 selected from the group consisting of a bond, a peptide residue consisting of 1 to 12 amino acid residues,

[0157] wherein the amino acid residues are selected from the group consisting of phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid and asparagine, and are optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 22a R 22b ) p2 - cycloalkyl, -(CR 22a R 22b ) p2 - heterocyclyl, -(CR 22a R 22b ) p2 - aryl, -(CR 22a R 22b ) p2 - heteroaryl, -(CR 22a R 22b ) p2 - SR 25 , -(CR 22a R 22b ) p2 - COOR 25 , -(CR 22a R 22b ) p2 - NR 23 R 24 , -(CR 22a R 22b ) p2 - C(O)-NR 23 R 24 , -(CR 22a R 22b ) p2 - NR 25 - C(=NR 25 )-NR 23 R 24 and -(CR 22a R 22b ) p2 - NR 25 - C(O)-NR 23 R 24substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; wherein p2 is an integer from 0 to 20, *1 and L 2 are connected at the terminal, *2 and L 4 are connected at the terminal;

[0158] L 4 is selected from the group consisting of -NR 19 -W 1 -, -C(O)NR 19 -, -NR 19 C(O)-, -NR 19 -W 1 -C(O)-, -C(O)-NR 19 -W 1 -, -NR 19 -W 2 -W 1 -, -NR 19 -W 2 -W 1 -O-C(O)- and a chemical bond;

[0159] W 2 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, which cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, sugar, uronic acid (e.g. ), nitro, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

[0160] W 1 , W 3 , and W 5 are identical or different, and each independently is -(CR 26a R 26b ) p3 -, wherein p3 is an integer from 1 to 20;

[0161] W 4 is -NR 28 C(O)- or -C(O)NR 28 -;

[0162] R 27 and R 28 are identical or different, and each independently is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, and hydroxyalkyl;

[0163] R 17 , R 18 , R19 and R 25 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

[0164] R 23 and R 24 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being optionally substituted with one or more same or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group;

[0165] or R 23 and R 24 together with the carbon atom to which they are attached form a heterocyclyl group, said heterocyclyl group being optionally substituted with one or more same or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group;

[0166] R 20a , R 20b , R 20c , R 20d , R 21a , R 21b , R 21c , R 21d , R 21e , R 21f , R 22a , R 22b , R 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being optionally substituted with one or more same or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group;

[0167] or R 20a and R 20b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R 20c and R 20d together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R 21a and R 21b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R 21c and R 21dtogether with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21e and R 21f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 22a and R 22b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 26a and R 26b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy 1 is attached at the end to Ab, L 4 is attached at the end to D.

[0168] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein L 3 is selected from a peptide residue consisting of 1 to 12 amino acid residues, wherein the amino acid residues are selected from the group consisting of phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid, and asparagine, and are optionally substituted with one or more identical or different substituents selected from the group consisting of halo, hydroxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 22a R 22b ) p2 cycloalkyl, -(CR 22a R 22b ) p2 heterocyclyl, -(CR 22a R 22b ) p2 aryl, -(CR 22a R 22b ) p2 heteroaryl, -(CR 22a R 22b ) p2 SR 25 , -(CR 22a R 22b ) p2 COOR 25 , -(CR 22a R 22b ) p2 NR 23 R 24 , -(CR 22a R 22b ) p2-C(O)-NR 23 R 24 , -(CR 22a R 22b ) p2 -NR 25 -C(=NR 25 )-NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 , each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; wherein p2 is an integer from 0 to 20, *1 is attached to the terminal L 2 *2 is attached to the terminal L 4 ; wherein W 3 , W 4 , W 5 , R 22a , R 22b , R 23 , R 24 , R 25 and p2 are as defined in general formula (I).

[0169] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 2 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0170] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, is a ligand-drug conjugate of general formula (IN) or a pharmaceutically acceptable salt thereof:

[0171] wherein Ab, L 3 , W 1 , R 2 to R 9 , r, s, t and y are as defined in general formula (I).

[0172] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is a ligand-drug conjugate of Formula (IN-S) or a pharmaceutically acceptable salt thereof:

[0173] wherein Ab, L 3 , W 1 , R 2 to R 9 , r, s, t, and y are as defined in Formula (I).

[0174] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is a ligand-drug conjugate of Formula (IN-R) or a pharmaceutically acceptable salt thereof:

[0175] wherein Ab, L 3 , W 1 , R 2 to R 9 , r, s, t, and y are as defined in Formula (I).

[0176] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein R 2 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, -OR o , -(CR p R q ) m -3 to 6-membered cycloalkyl, -(CR p R q ) m -3 to 6-membered heterocyclyl, -(CR p R q ) m -6 to 10-membered aryl, -(CR p R q ) m -5 to 10-membered heteroaryl, -(CR p R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , wherein R o , R pR q R s R t R u and m are as defined in general formula (I); preferably, R 2 is selected from the group consisting of hydrogen atom, halogen, cyano, C 2-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; more preferably, R 2 is hydrogen atom.

[0177] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding items, wherein r is 0, 1 or 2; preferably, r is 0.

[0178] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding items, wherein R 3 is selected from the group consisting of hydrogen atom, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -(CR p R q ) m -6 to 10 membered aryl and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and 6 to 10 membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, C 2-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl or 3 to 6 membered heterocyclyl, wherein R p , R q , R s , R t , R zand m are as defined in general formula (I);

[0179] R is preferably hydrogen atom or -(CR 3 selected from the group consisting of hydrogen atom, oxo, C 1-6 alkyl, -(CR p R q ) m -6 to 10 membered aryl and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl and 6 to 10 membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group, wherein R p , R q , R s , R t and m are as defined in general formula (I);

[0180] More preferably, R 3 is hydrogen atom or -(CR p R q ) m -NR s R t , wherein R p , R q , R s , R t and m are as defined in general formula (I).

[0181] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein R 3 is selected from the group consisting of hydrogen atom, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and -(CR p R q ) m -6 to 10 membered aryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and 6 to 10 membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR z, oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 form, together with the carbon atom to which they are attached, a 3- to 6- membered cycloalkyl or a 3- to 6-membered heterocyclyl, wherein R p , R q , R z and m are as defined in general formula (I);

[0182] Preferably, R 3 is selected from the group consisting of a hydrogen atom, oxo, C 1-6 alkyl and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl and 6- to 10-membered aryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 form, together with the carbon atom to which they are attached, a 3- to 6- membered cycloalkyl, wherein R p , R q and m are as defined in general formula (I).

[0183] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein R 3 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl, C 1-6 haloalkyl and 6- to 10-membered aryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 form, together with the carbon atom to which they are attached, a 3- to 6- membered cycloalkyl or a 3- to 6-membered heterocyclyl, wherein Rp R q R z and m are as defined in general formula (I);

[0184] R 3 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group and -(CR p R q ) m -6 to 10 membered aryl; wherein said C 1-6 alkyl and 6 to 10 membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group, wherein R p , R q and m are as defined in general formula (I).

[0185] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R 3 is a hydrogen atom.

[0186] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein s is 0, 1 or 2; preferably s is 0.

[0187] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , R t and m are as defined in general formula (I); preferably R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , Rt and m is as defined in general formula (I).

[0188] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen and cyano.

[0189] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any of the preceding items, wherein t is 0, 1 or 2; preferably, t is 2.

[0190] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 5 is -(CR g R h ) n - or -C(O)-, wherein R g , R h and n are as defined in general formula (I); preferably, R 5 is -C(O)-.

[0191] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 6 is -NR ii - or wherein R ii , R 35 , R 36 and w are as defined in general formula (I); preferably, R 6 is -NR ii - wherein R ii is as defined in general formula (I).

[0192] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 7 is selected from the group consisting of -(CR k R kk ) n -, -(CR k R kk ) n -NR 12 - and -NR 12 -(CR k R kk ) n -, wherein R k , R kk , R12 and n are as defined in general formula (I); preferably, R 7 is -(CR k R kk ) n -; wherein R k , R kk and n are as defined in general formula (I).

[0193] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 8 is -(CR m R n ) n -; wherein R m , R n and n are as defined in general formula (I).

[0194] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 9 is a hydrogen atom or C 1-6 alkyl; preferably, R 9 is a hydrogen atom.

[0195] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 5 is -C(O)-; R 6 is -NR ii -; R 7 is -(CR k R kk ) n -; R 8 is -(CR m R n ) n -; R 10 is a chemical bond; wherein R ii , R k , R kk , R m , R n and n are as defined in general formula (I).

[0196] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 5 is -C(O)-; R 6 is -NR ii -; R 7 is -(CR k R kk ) n -; R 8 is -(CR m Rn ) n -;R 10 It is a chemical bond; and R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R ii R k R kk R m R n And n is as defined in general formula (I).

[0197] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 It is a chemical bond; where R 12 R 35 R 36 R k R kk R m R n , n and w are as defined in general formula (I).

[0198] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 It is a chemical bond; and R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R 12 R 35R 36 R k R kk R m R n , n and w are as defined in general formula (I).

[0199] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 for Where R 35 R 36 R ii R k R kk R m R n , n and w are as defined in general formula (I).

[0200] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 for And R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R 35 R 36 R ii R k R kk R m R n , n and w are as defined in general formula (I).

[0201] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 for Where R 12 R 35 R 36 R k R kk R m R n , n and w are as defined in general formula (I).

[0202] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 for And R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R 12 R 35 R 36 R k R kk R m R n , n and w are as defined in general formula (I).

[0203] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 11 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 11 It is a hydrogen atom.

[0204] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 12 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 12 It is a hydrogen atom.

[0205] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 1 -(succinimide-3-yl-N)-W 1 -C(O)-, where W 1 As defined in general formula (I).

[0206] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 2 Selected from -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-NR 18 -、-NR 18 -W 1 -C(O)-NR 18 - and chemical bonds, where W 1 R 18 R 21a R 21b R 21c R 21d and v as defined in general formula (I); preferably, L 2 It is a chemical bond.

[0207] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 3peptide residues consisting of 1 to 12 amino acid residues, wherein the amino acid residues are selected from the group consisting of amino acids selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline, serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D) and asparagine (N), and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -(CR 22a R 22b ) p2 -NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 , wherein R 22a , R 22b , R 23 , R 24 , R 25 and p2 are as defined in general formula (I);

[0208] Preferably, L 3 is a peptide residue consisting of 1 to 4 amino acid residues (i.e. a mono-, di-, tri- and tetrapeptide residue), wherein the amino acid residues are selected from the group consisting of amino acids selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline (Cit), serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D) and asparagine (N);

[0209] More preferably, L 3 is selected from the group consisting of G, F, GG, GF, FG, VA, valine-citrulline (Val-Cit), GGF, GFG and GGFG (SEQ ID NO: 37);

[0210] Further more preferably, L 3 is GGF, GFG or GGFG (SEQ ID NO: 37);

[0211] Most preferably, L 3 is GGFG (SEQ ID NO: 37).

[0212] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof as described in any one of the preceding embodiments, wherein L 3a peptide residue selected from the group consisting of one, two or four amino acid residues (i.e. a mono-, di- and tetrapeptide residue), wherein the amino acid residues are selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline (Cit), serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D) and asparagine (N); preferably, L 3 is selected from the group consisting of VA, valine-citrulline (Val-Cit) and GGFG (SEQ ID NO: 37); more preferably, L 3 is GGFG (SEQ ID NO: 37).

[0213] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein L 3 is wherein *1is attached to the L 2 terminus and *2is attached to the L 4 terminus, W 3 is as defined in general formula (I).

[0214] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein L 3 is wherein *1is attached to the L 2 terminus and *2is attached to the L 4 terminus, W 3 , W 4 , W 5 and R 27 are as defined in general formula (I).

[0215] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein L 4 is -NR 19 -W 2 -W 1 -O-C(O)- or a chemical bond, wherein R 19 , W 1 and W 2 are as defined in general formula (I); preferably, L 4 is a chemical bond.

[0216] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein W 1 , W 3 and W 5 are the same or different and each independently is -(CR 26a R 26b ) p3- R 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6.

[0217] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 - and

[0218] L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-;

[0219] L 2 is a chemical bond;

[0220] L 3 is selected from the group consisting of a peptide residue consisting of 1 to 4 amino acid residues (i.e. a mono-, di-, tri- and tetrapeptide residue), wherein the amino acid residues are selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline (Cit), serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D) and asparagine (N); preferably, L 3 is selected from the group consisting of G, F, GG, GF, FG, VA, valine-citrulline (Val-Cit), GGF, GFG and GGFG (SEQ ID NO: 16); more preferably, L 3 is GGF, GFG and GGFG (SEQ ID NO: 37); still more preferably, L 3 is GGFG (SEQ ID NO: 37);

[0221] or L 3 is wherein *1 is attached to the L 2 end and *2 is attached to the L 4 end;

[0222] W 4 is -NR 28 C(O)- or -C(O)NR 28 -;

[0223] R 27 and R 28 are the same or different and each is independently a hydrogen atom or a C 1-6 alkyl group;

[0224] L 4 is -NR 19 -W 2 -W 1 -O-C(O)- or a chemical bond;

[0225] W 1 , W 3 and W 5 are the same or different and each independently -(CR 26a R 26b ) p3 -, R 26a and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6

[0226] W 2 is a phenyl group, a phenyl group substituted with or a phenyl group substituted with ;

[0227] R 19 is a hydrogen atom;

[0228] wherein the L 1 end of said -L- is attached to Ab and the L 4 end is attached to D.

[0229] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -, and

[0230] L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-, wherein W 1 is -(CR 26a R 26b ) p3 -, R 26a and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6;

[0231] L 2 is a chemical bond;

[0232] L 3a peptide residue selected from the group consisting of a one amino acid residue, a two amino acid residue, and a four amino acid residue, wherein the amino acid residues are selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline, serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D), and asparagine (N); preferably, L 3 G, F, GG, GF, FG, GGF, GFG, and GGFG (SEQ ID NO: 37); more preferably, L 3 is GGFG (SEQ ID NO: 37);

[0233] L 4 is a chemical bond;

[0234] wherein L 1 of said -L- is attached to Ab, and L 4 of said -L- is attached to D.

[0235] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding items, wherein -L- is -L 1 -L 3 - and

[0236] L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-, wherein W 1 is -(CR 26a R 26b ) p3 -, R 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group, and p3 is 1, 2, 3, 4, 5, or 6;

[0237] L 3 is GGF, GFG, or GGFG (SEQ ID NO: 37);

[0238] wherein L 1 of said -L- is attached to Ab, and L 3 of said -L- is attached to D.

[0239] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding items, wherein -L- is -L 1 -L 3 - and

[0240] L 1is -(succinimid-3-yl-N)-W 1 -C(O)-, wherein W 1 is -(CR 26a R 26b ) p3 -, 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6;

[0241] L 3 is GGFG (SEQ ID NO: 37);

[0242] wherein the L 1 terminal of said -L- is attached to Ab, and the L 3 terminal is attached to D.

[0243] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein W 2 is selected from the group consisting of a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group, which 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclyl group, 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group is optionally substituted with one or more same or different substituents selected from the group consisting of oxo, a halogen, a sugar, a uronic acid (e.g. ), a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group;

[0244] Preferably, W 2 is selected from the group consisting of a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group, which 3- to 6-membered cycloalkyl group, 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group is optionally substituted with one or more same or different substituents selected from the group consisting of a uronic acid (e.g. ), a hydroxyl group, a carboxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group;

[0245] More preferably, W 2 is selected from the group consisting of a cyclohexyl group, a phenyl group and a pyridyl group, which cyclohexyl group, phenyl group and pyridyl group is optionally substituted with one or more same or different substituents selected from the group consisting of a uronic acid (e.g. ), a hydroxyl group, a carboxyl group, a C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; preferably, W

[0246] Most preferably, W 2 is phenyl, phenyl substituted by phenyl or phenyl substituted by one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxyl, C

[0247] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein W 2 is selected from the group consisting of 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl, which 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; preferably, W 2 is 3- to 6-membered cycloalkyl or 5- to 10-membered heteroaryl; more preferably, W 2 is cyclohexyl or pyridinyl.

[0248] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 17 , R 18 , R 19 and R 25 are identical or different and each independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R 17 , R 18 , R 19 and R 25 are all hydrogen atoms.

[0249] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding items, wherein R 20a , R 20b , R 20c , R 20d , R 21a , R 21b , R 21c , R 21d , R21e R 21f R 22a R 22b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, and a C 1-6 hydroxyalkyl group; preferably, R 20a R 20b R 20c R 20d R 21a R 21b R 21c R 21d R 21e R 21f R 22a R 22b are each a hydrogen atom.

[0250] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein R 23 R 24 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 hydroxyalkyl group; preferably, R 23 R 24 are the same or different and each is independently a hydrogen atom or a C 1-6 alkyl group; more preferably, R 23 R 24 are each a hydrogen atom.

[0251] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein R 26a R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; preferably, R 26a R 26b are each a hydrogen atom.

[0252] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein R 27 R 28 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C1-6 hydroxyalkyl; preferably, R 27 and R 28 are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group; more preferably, R 27 and R 28 are each a hydrogen atom.

[0253] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein W 4 is -NR 28 C(O)- or -C(O)NR 28 -; wherein R 28 is a hydrogen atom.

[0254] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -; and

[0255] L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-;

[0256] L 2 is a chemical bond;

[0257] L 3 is wherein *1 is attached to the L 2 end and *2 is attached to the L 4 end;

[0258] W 1 , W 3 , and W 5 are the same or different and each independently -(CR 26a R 26b ) p3 -, R 26a , and R 26b are the same or different and each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5, or 6;

[0259] W 4 is -NR 28 C(O)- or -C(O)NR 28 -;

[0260] R 27 and R 28the same or different, and each independently is a hydrogen atom or C 1-6 alkyl;

[0261] L 4 is a chemical bond;

[0262] wherein L 1 of said -L- is attached to Ab, and L 4 of said -L- is attached to D.

[0263] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein -L- is -L 1 -L 3 -,

[0264] L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-;

[0265] L 3 is wherein *1 is attached to L 2 and *2 is attached to L 4 ;

[0266] W 1 , W 3 , and W 5 are the same or different, and each independently is -(CR 26a R 26b ) p3 -, 26a and R 26b are the same or different, and each independently is selected from a hydrogen atom, a halogen, C 1-6 alkyl, and C 1-6 haloalkyl, p3 is 1, 2, 3, 4, 5, or 6;

[0267] W 4 is -NR 28 C(O)- or -C(O)NR 28 -;

[0268] R 27 and R 28 are both hydrogen atoms;

[0269] wherein L 1 of said -L- is attached to Ab, and L 3 of said -L- is attached to D.

[0270] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any of the preceding items, wherein q is an integer from 1 to 20; preferably, q is an integer from 1 to 12; more preferably, q is an integer from 1 to 6.

[0271] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein p1 is an integer from 1 to 20; preferably, p1 is an integer from 1 to 12; more preferably, p1 is an integer from 1 to 6.

[0272] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein p2 is an integer from 1 to 20; preferably, p2 is an integer from 1 to 12; more preferably, p2 is an integer from 1 to 6.

[0273] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein p3 is an integer from 1 to 20; preferably, p3 is an integer from 1 to 12; more preferably, p3 is an integer from 1 to 6.

[0274] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein v is an integer from 1 to 20; preferably, v is an integer from 1 to 12; more preferably, v is an integer from 1 to 6.

[0275] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein R 35 is selected from a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10-membered aryl, -(CR 30a R 30b ) p4 -5 to 10-membered heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4-NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 one or more substituents selected from the group consisting of halogen, cyano, amino, hydroxy, carboxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; wherein R 13 , R 30a , R 30b , R 31 , R 32 , R 33 , R 34 , p and p4 are as defined in general formula (I).

[0276] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein R 35 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 membered aryl, -(CR 30a R 30b ) p4 -5 to 10 membered heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32and -(CR 30a R 30b ) p4 -S(O) p -R 33 ; each of said aryl and heteroaryl is independently optionally substituted with hydroxy; wherein R 30a , R 30b , R 31 , R 32 , R 33 , R 34 , p and p4 are as defined in general formula (I).

[0277] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 35 is a hydrogen atom or -(CR 30a R 30b ) p4 -6 to 10 membered aryl, wherein R 30a , R 30b and p4 are as defined in general formula (I).

[0278] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 35 is a hydrogen atom.

[0279] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R u4 and R u5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 membered aryl, -(CR 30a R 30b ) p4 -5 to 10 membered heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30aR 30b ) p4 -C(O)-OR 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 One or more substituents are substituted in the group; the 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 The alkoxy group is substituted by one or more identical or different substituents; wherein R 13 R 30a R 30b R 31 R 32 R 33 R 34 p and p4 are as defined in general formula (I).

[0280] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R u6 and R u7 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 aryl groups, -(CR 30a R 30b ) p4 -5 to 10-membered heteroaryl groups, -(CR 30a R 30b ) p4 -NR 31 R 32 、-(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 、-(CR 30a R30b ) p4 -OR 33 、-(CR 30a R 30b ) p4 -C(O)-OR 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 One or more substituents are substituted in the group; the 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 The alkoxy group is substituted by one or more identical or different substituents; wherein R 13 R 30a R 30b R 31 R 32 R 33 R 34 p and p4 are as defined in general formula (I).

[0281] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R k and R kk They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, -NR u1 R u2 、-(CR w3 R w4 ) u -NR u1 R u2 、-(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6-CR u3 -CR u4 R u5 -COOR 15a ) p6 -COOR 15a and -(CR w3 R w4 ) u -COOR 15a wherein R u1 , R u2 , R u3 , R u4 , R u5 , R w3 , R w4 , R 15a , u and p6 are as defined in general formula (I); preferably, R k and R kk are identical or different and each independently selected from the group consisting of a hydrogen atom, -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 -COOR u3 -CR u4 R u5 -COOR 15a ) p6 -COOR 15a and -(CR w3 R w4 ) u -COOR 15a wherein R u3 , R u4 , R u5 , R w3 , R w4 , R 15a , u and p6 are as defined in general formula (I); more preferably, R k and R kk are identical or different and each independently a hydrogen atom or -COOR 15a wherein R 15a is as defined in general formula (I); most preferably, R k is a hydrogen atom and R kk is -COOR 15a wherein R 15a is as defined in general formula (I).

[0282] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein R 13 , R 33 , R o , R u , R x , R y , R z , and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 haloalkyl group, and a C 1-6 hydroxyalkyl group; preferably, R 13 , R 33 , R o , R u , R x , R y , R z , and R 14 are the same or different and each is independently a hydrogen atom or a C 1-6 alkyl group.

[0283] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 , and R v2 are each a hydrogen atom.

[0284] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein R c , R cc , R g , R h , R j , R jj , R m , R n , R p , R q , R w1 , R w2 , R 30a , and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 hydroxyalkyl, cyano, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -COOR 15a and -(CR w3 R w4 ) u -COOR 15a wherein R u1 , R u2 , R w3 , R w4 , R 15a and u are as defined in general formula (I); preferably, R c , R g , R h , R j , R jj , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are each a hydrogen atom.

[0285] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R w3 and R w4 are the same or different and each independently a hydrogen atom or C 1-6 alkyl.

[0286] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 15a and R 15b are the same or different and each independently a hydrogen atom or C 1-6 alkyl.

[0287] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R 16a and R 16b are the same or different and each independently a hydrogen atom or C 1-6 alkyl.

[0288] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein R Lis a hydrogen atom or C 1-6 alkyl.

[0289] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein p is 0 or 2; preferably, p is 0.

[0290] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein m is 0, 1, 2, 3, 4, 5, or 6; preferably, m is 0, 1, 2, 3, or 4.

[0291] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein m is 0.

[0292] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein n is 0, 1, 2, 3, 4, 5, or 6; preferably, n is 0, 1, 2, 3, or 4.

[0293] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein n1 is 0, 1, 2, 3, 4, 5, or 6; preferably, n1 is 0, 1, 2, 3, or 4.

[0294] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein p4 is 0, 1, 2, 3, 4, 5, or 6; preferably, p4 is 0, 1, 2, 3, or 4.

[0295] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein p5 is 0, 1, 2, 3, 4, 5, or 6; preferably, p5 is 0, 1, or 2.

[0296] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein p6 is 0, 1, 2, 3, 4, 5, or 6; preferably, p6 is 0, 1, or 2.

[0297] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein w is 0, 1, 2, 3, 4, 5, or 6; preferably, w is 0, 1, or 2; more preferably, w is 0 or 1; most preferably, w is 1.

[0298] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof of any of the preceding claims, wherein u is 0, 1, 2, 3, 4, 5, or 6; preferably, u is 0, 1, 2, 3, or 4.

[0299] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is selected from the following structures:

[0300] wherein Ab is an antibody; preferably, Ab is an anti-CD38 antibody, an anti-CD79b antibody, or an anti-BCMA antibody, and is as defined in any of the preceding embodiments;

[0301] and y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0302] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is selected from the following structures:

[0303] wherein Ab is an antibody; preferably, Ab is an anti-CD38 antibody, an anti-CD79b antibody, or an anti-BCMA antibody, and is as defined in any of the preceding embodiments;

[0304] and y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0305] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein Ab is selected from an IgGl, an IgG2, an IgG3, and an IgG4 antibody; preferably, Ab is an IgGl antibody.

[0306] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein Ab comprises a heavy chain variable region and a light chain variable region, wherein the HCDR1, HCDR2, and HCDR3 of the heavy chain variable region and the LCDR1, LCDR2, and LCDR3 of the light chain variable region are defined according to the same numbering scheme selected from Kabat, IMGT, Chothia, AbM, and Contact. In some embodiments, it is defined according to the Kabat numbering scheme. In some embodiments, it is defined according to the IMGT numbering scheme. In some embodiments, it is defined according to the Chothia numbering scheme. In some embodiments, it is defined according to the AbM numbering scheme. In some embodiments, it is defined according to the Contact numbering scheme.

[0307] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein Ab is a murine, a chimeric, a humanized, or a fully human antibody; preferably, Ab is a humanized antibody.

[0308] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein Ab is an antibody fragment; preferably, the antibody fragment is a Fab, Fab', F(ab')2, Fd, Fv, scFv, dsFv, or dAb.

[0309] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein Ab is selected from the group consisting of an anti-CD38 antibody, an anti-CD79b antibody, an anti-GPRC5D antibody, and an anti-BCMA antibody.

[0310] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein HCDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1, HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, and LCDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO: 4, LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 6.

[0311] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0312] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD38 antibody comprises a heavy chain constant region and a light chain constant region; preferably, the heavy chain constant region is a human IgGl, IgG2, IgG3, or IgG4 heavy chain constant region, and the light chain constant region is a human kappa or lambda light chain constant region; more preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 9, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10.

[0313] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD38 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, and the light chain comprises the amino acid sequence of SEQ ID NO: 12.

[0314] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO: 11 and the amino acid sequence of the light chain is set forth in SEQ ID NO: 12.

[0315] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain variable region and a light chain variable region, wherein the HCDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 13, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, and the LCDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO: 16, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 17, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0316] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 19 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 20.

[0317] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain constant region and a light chain constant region; preferably, the heavy chain constant region is a human IgGl, IgG2, IgG3, or IgG4 heavy chain constant region, and the light chain constant region is a human kappa or lambda light chain constant region; more preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 21 and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10; or the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 24 and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10.

[0318] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 22 and the light chain comprises the amino acid sequence of SEQ ID NO: 23.

[0319] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO: 22 and the amino acid sequence of the light chain is set forth in SEQ ID NO: 23.

[0320] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 25 and the light chain comprises the amino acid sequence of SEQ ID NO: 23.

[0321] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO: 25 and the amino acid sequence of the light chain is set forth in SEQ ID NO: 23.

[0322] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the anti-BCMA antibody comprises a heavy chain variable region and a light chain variable region, wherein the HCDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 26, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 27, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 28, and the LCDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO: 29, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 30, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 31.

[0323] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof of any of the preceding embodiments, wherein the anti-BCMA antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 32 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 33.

[0324] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-BCMA antibody comprises a heavy chain constant region and a light chain constant region; preferably, the heavy chain constant region is a human IgGl, IgG2, IgG3 or IgG4 heavy chain constant region, and the light chain constant region is a human kappa or lambda light chain constant region; more preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 34, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10.

[0325] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-BCMA antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35, and the light chain comprises the amino acid sequence of SEQ ID NO: 36.

[0326] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein the anti-BCMA antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35, and the light chain comprises the amino acid sequence of SEQ ID NO: 36.

[0327] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein y represents the average number of drugs carried by each ligand-drug conjugate molecule in a population of ligand-drug conjugate molecules, and can also be expressed as the ratio of drugs to ligands; preferably, the ligand-drug conjugate is an antibody-drug conjugate.

[0328] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or the average value of any two numerical values; preferably, y is 1-10; more preferably, y is 1-8, or 2-8, or 2-7, or 2-6, or 2-5, or 2-4, or 3-8, or 3-7, or 3-6, or 4-8, or 4-7, or 4-6, or 4-5.

[0329] In some embodiments, the ligand-drug conjugate or the pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0330] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding embodiments is an antibody-drug conjugate of Formula (I), Formula (IN), Formula (IN-S), or Formula (IN-R), or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the ligand-drug conjugate or pharmaceutically acceptable salt thereof according to any of the preceding embodiments has a structure as shown in Tables 1-3.

[0332] a compound of Formula (D-M), or a pharmaceutically acceptable salt thereof

[0333] In another aspect, the disclosure relates to a compound of Formula (D-M), or a pharmaceutically acceptable salt thereof:

[0334] wherein:

[0335] X is -CR a R b - or -C(O)-;

[0336] Y 1 , Y 2 , Y 3 , and Y 4 are each independently a nitrogen atom or CR 29 ;

[0337] Z is selected from the group consisting of -O-, -S(O) p -, -C(O)-, -NR 11 -, and -(CR c R cc ) n1 -;

[0338] V is a bond or -(CR d R dd ) n1 -;

[0339] U is -(CR e R f ) n1 -;

[0340] R 5 is selected from the group consisting of a bond, -(CR g R h ) n -, -C(O)-, -S(O) p -, and -NR i -;

[0341] L M is one or more substituted or unsubstituted amino acids or variants thereof;

[0342] Ring A, Ring B and Ring C are the same or different, and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0343] R 2 , R 3 , R 4 and R 29 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m-C(O)OR u , -(CR p R q ) m -OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m -C(=NR 13 )NR s R t , -(CR p R q ) m -S(O) p R u , -(CR p R q ) m -S(O) p NR s R t , -(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 , -(CR w1 R w2 ) u -C(O)R 14 , -(CR w1 R w2 ) u -C(O)OR 14 , -(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O)p R 14 one or more identical or different substituents selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an amino group, a hydroxy group, an alky l group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -(CR

[0344] or two adjacent R 2 , together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocyclyl group, or two adjacent R 3 , together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocyclyl group, or two adjacent R 4 , together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocyclyl group, said cycloalkyl group or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxy group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group;

[0345] R 1 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxy group and a hydroxyalkyl group;

[0346] R u4 , R u5 , R u6 and R u7 are identical or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxy group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -(CR 30a R 30b ) p4 a cycloalkyl group, a -(CR 30a R 30b ) p4 a heterocyclyl group, a -(CR 30a R 30b ) p4 an aryl group, a -(CR 30a R 30b ) p4 a heteroaryl group, a -(CR 30a R 30b ) p4 an NR 31 R 32 , a -(CR 30a R 30b ) p4 a C(O)-NR 31 R 32 , a -(CR 30a R 30b ) p4 an O-R 33 , a -(CR 30a R 30b ) p4 a C(O)-O-R 33 , a -(CR 30a R 30b )p4 -NR 34 -C(O)-R 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 、-(CR 30a R 30b ) p4 -S(O) p -R 33 、-(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0347] R 13 R 33 R o R u R x R y R z and R 14 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0348] R 9 R 11 R 31 R 32 R 34 R i R r R s R t R u1 R u2 R u3 R v1 and R v2the same or different and each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 15b , an alkylene-COOR 15b group, 16a R 16b , an alkylene-NR 16a R 16b group,

[0349] R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, a cyano group, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclyl, -(CR w3 Rw4 ) u -aryl and -(CR w3 R w4 ) u -heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0350] R w3 , R w4 , R 15a , R 15b , R 16a and R 16b are identical or different and each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

[0351] or R a and R b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R c and R cc together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R d and R dd together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R p and R q together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R w1 and R w2 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R 30a and R 30b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R w3 and R w4 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, said cycloalkyl group or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0352] or R s and R t together with the nitrogen atom to which they are attached form a heterocyclyl group, or R u1 and R u2together with the nitrogen atom to which they are attached form a heterocyclyl group, or R v1 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R v2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 31 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 32 together with the nitrogen atom to which they are attached form a heterocyclyl group; wherein said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR L , hydroxyalkyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0353] R L is selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

[0354] p is 0, 1, or 2;

[0355] r is 0, 1, 2, 3, 4, 5, or 6;

[0356] s is 0, 1, 2, 3, 4, 5, or 6;

[0357] t is 0, 1, 2, 3, 4, 5, or 6;

[0358] m is 0, 1, 2, 3, 4, 5, or 6;

[0359] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0360] p4 is 0, 1, 2, 3, 4, 5, or 6;

[0361] p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0362] p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0363] u is 0, 1, 2, 3, 4, 5, or 6.

[0364] a compound represented by Formula (D) or a pharmaceutically acceptable salt thereof

[0365] In another aspect, the present disclosure relates to a compound represented by Formula (D) or a pharmaceutically acceptable salt thereof:

[0366] wherein:

[0367] X is -CR a R b - or -C(O)-;

[0368] Y 1 , Y 2 , Y 3 and Y 4 are each independently nitrogen or CR 29 ;

[0369] Z is selected from -O-, -S(O) p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -;

[0370] V is a bond or -(CR d R dd ) n1 -;

[0371] U is -(CR e R f ) n1 -;

[0372] R 5 is selected from a bond, -(CR g R h ) n -, -C(O)-, -S(O) p - and -NR i -;

[0373] R 6 is selected from a bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii -C(O)-, -C(O)-NR ii -, -NR ii -S(O) p -, -S(O) p -NR ii -, -NR ii -(CR j R jj ) n -, -(CR j R jj )n -NR ii -,

[0374] R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n -, -O-, -C(O)-, -NR 12 -, -S(O) p -, -(CR k R kk ) n -O-, -O-(CR k R kk ) n -, -(CR k R kk ) n -C(O)-, -C(O)-(CR k R kk ) n -, -(CR k R kk ) n -NR 12 -, -NR 12 -(CR k R kk ) n -, -(CR k R kk ) n -S(O) p -, -S(O) p -(CR k R kk ) n -, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(=NR 13 )-NR 12 -, -NR 12 -C(=NR 13 )-, -O-C(O)-NR 12 -, -NR 12 -C(O)-O-, -NR 12 -C(O)-NR 12 -, -NR 12 -S(O) p -, -S(O) p-NR 12 -、-NR 12 -S(O) p -C(=NR 13 )-、-C(=NR 13 )-S(O) p -NR 12 -and Each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy groups.

[0375] R 8 For chemical bonds or -(CR) m R n ) n -;

[0376] R 10 Selected from chemical bonds,

[0377] Ring A, ring B, and ring C may be the same or different, and each may be independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0378] R 2 R 3 R 4 and R 29 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o 、-(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclic group, -(CR) p R q ) m -Aryl, -(CR p R q ) m -Heteroaryl, -(CR p R q ) m -NR s R t 、-(CR p R q ) m -C(O)OR u -NR r -C(O)R u -NR r -C(O)ORu , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m -C(O)OR u , -(CR p R q ) m -OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m -C(=NR 13 )NR s R t , -(CR p R q ) m -S(O) p R u , -(CR p R q ) m -S(O) p NR s R t , -(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u ; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, cyano, nitro, -ORz , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 , -(CR w1 R w2 ) u -C(O)R 14 , -(CR w1 R w2 ) u -C(O)OR 14 , -(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O) p R 14 , one or more of which are the same or different substituents;

[0379] or two adjacent R 2 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, or two adjacent R 3 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, or two adjacent R 4 , together with the carbon atom to which they are attached, form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0380] R 1 is selected from a hydrogen atom, halogen, alkyl, haloalkyl, hydroxy and hydroxyalkyl;

[0381] R 35 , R u4 , R u5 , R u6 and R u7 are the same or different, and each is independently selected from a hydrogen atom, halogen, hydroxy, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30aR 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , -(CR 30a R 30b ) p4 -S(O) p -R 33 , -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 , and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 each independently optionally substituted with one or more of the same or different halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituents;

[0382] R 13 , R 33 , Ro , R u , R x , R y , R z , and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0383] R 9 , R 11 , R 12 , R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 , and R v2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 15b , alkylene-COOR 15b , -NR 16a R 16b , alkylene-NR 16a R 16b , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0384] R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R j , R jj , R k , R kk , R m , R n , R p , R q , R w1 , R w2 , R 30a , and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, -NR u1 R u2, -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclyl, -(CR w3 R w4 ) u -aryl and -(CR w3 R w4 ) u -heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0385] R w3 , R w4 , R 15a , R 15b , R 16a and R 16b are identical or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

[0386] or R a and R b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R c and R cc together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclyl group, or R d and R ddTogether with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R e and R f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R g and R h Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R j and R jj Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R k and R kk Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R n Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R p and R q Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w1 and R w2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 30a and R 30b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R w3 and R w4 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0387] Or R s and R t Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R u1 and R u2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R v1 and R v2 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 31 and R 32 Together with the nitrogen atoms attached to them, they form a heterocyclic group; wherein the heterocyclic group is optionally selected from halogen, cyano, nitro, -OR L It is substituted by one or more of the same or different substituents from hydroxyalkyl, oxoalkyl, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0388] R Lselected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group;

[0389] p is 0, 1, or 2;

[0390] r is 0, 1, 2, 3, 4, 5, or 6;

[0391] s is 0, 1, 2, 3, 4, 5, or 6;

[0392] t is 0, 1, 2, 3, 4, 5, or 6;

[0393] m is 0, 1, 2, 3, 4, 5, or 6;

[0394] n is 0, 1, 2, 3, 4, 5, or 6;

[0395] n1 is 0, 1, 2, 3, 4, 5, or 6;

[0396] p4 is 0, 1, 2, 3, 4, 5, or 6;

[0397] p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0398] p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0399] w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0400] u is 0, 1, 2, 3, 4, 5, or 6.

[0401] In some embodiments, the compound of Formula (D-M) or Formula (D) as previously described, or a pharmaceutically acceptable salt thereof, wherein Z is -O- or -NR 11 , wherein R 11 is as defined in Formula (D); preferably, Z is -O-.

[0402] In some embodiments, the compound of Formula (D-M) or Formula (D) as previously described in any one of the foregoing, or a pharmaceutically acceptable salt thereof, wherein V is -(CR d R dd ) n1 , wherein R d , R dd , and n1 are as defined in Formula (I); preferably, V is -CR d Rdd - wherein R d and R dd are as defined in general formula (D).

[0403] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M) or general formula (D), or a pharmaceutically acceptable salt thereof, wherein U is -CR e R f - wherein R e and R f are as defined in general formula (D).

[0404] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M) or general formula (D), or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 29 ; or one of Y 1 , Y 2 , Y 3 and Y 4 is a carbon atom, one of the remaining three is a nitrogen atom, and the remaining two are the same or different and are each independently CR 29 , wherein R 29 are as defined in general formula (D).

[0405] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M) or general formula (D), or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 12-membered heterocyclyl; preferably, ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; more preferably, ring B is a 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms; most preferably, ring B is a piperazinyl.

[0406] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M) or general formula (D), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from In some embodiments, ring B is

[0407] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M) or general formula (D), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from In some embodiments, ring B is

[0408] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-I), or a pharmaceutically acceptable salt thereof:

[0409] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0410] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s, and t are as defined in Formula (D).

[0411] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-I-S), or a pharmaceutically acceptable salt thereof:

[0412] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0413] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s, and t are as defined in Formula (D).

[0414] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-I-R), or a pharmaceutically acceptable salt thereof:

[0415] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms;

[0416] X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s, and t are as defined in Formula (D).

[0417] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein X is -CR a Rb - wherein R a and R b are as defined in general formula (D).

[0418] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), or general formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein R a and R b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a cyano group, and an amino group; preferably, R a and R b are the same or different and each is independently a hydrogen atom or a C 1-6 alkyl group; more preferably, R a and R b are each a hydrogen atom.

[0419] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), or general formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.

[0420] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), or general formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is a phenyl group.

[0421] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), or general formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from preferably, ring A is more preferably, ring A is

[0422] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), or general formula (D-I-R), or a pharmaceutically acceptable salt thereof, wherein ring C is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring C is a phenyl group.

[0423] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II), or a pharmaceutically acceptable salt thereof: Preferably, ring C is More preferably, ring C is

[0424] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II), or a pharmaceutically acceptable salt thereof: d , R dd , R e , and R f are each hydrogen atoms.

[0425] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II), or a pharmaceutically acceptable salt thereof: 10 is a bond or wherein R 35 , R 36 , and w are as defined in Formula (D); preferably, R 10 is a bond.

[0426] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-IIM), or a pharmaceutically acceptable salt thereof:

[0427] wherein L M is one or more substituted or unsubstituted amino acids or variants thereof;

[0428] R 2 through R 5 , r, s, and t are as defined in Formula (D-M).

[0429] In some embodiments, the compound according to any of the preceding embodiments of Formula (D) or Formula (D-I), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II), or a pharmaceutically acceptable salt thereof:

[0430] wherein R 2 through R 9 , r, s, and t are as defined in Formula (D).

[0431] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), Formula (D-I), or Formula (D-I-S), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II-S), or a pharmaceutically acceptable salt thereof:

[0432] wherein R 2 to R 9 , r, s, and t are as defined in Formula (D).

[0433] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), Formula (D-I), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, is a compound according to Formula (D-II-R), or a pharmaceutically acceptable salt thereof:

[0434] wherein R 2 to R 9 , r, s, and t are as defined in Formula (D).

[0435] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II-M), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a C 2-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, -OR o , -(CR p R q ) m -3 to 6-membered cycloalkyl, -(CR p R q ) m -3 to 6-membered heterocyclyl, -(CR p R q ) m -6 to 10-membered aryl, -(CR p R q ) m -5 to 10-membered heteroaryl, -(CR p R q ) m -NR s R t and -(CR p R q )m -C(O)OR u , wherein R o , R p , R q , R s , R t , R u and m are as defined in general formula (D); preferably, R 2 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 2-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; more preferably, R 2 is a hydrogen atom.

[0436] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2; preferably, r is 0.

[0437] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of a hydrogen atom, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -(CR p R q ) m -6 to 10 membered aryl, and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and 6 to 10 membered aryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 form, together with the carbon atom to which they are attached, a 3- to 6- membered cycloalkyl or 3- to 6-membered heterocyclyl, wherein R p , R q , R s , R t , R z and m are as defined in general formula (D);

[0438] Preferably, R 3 is selected from the group consisting of a hydrogen atom, oxo, C 1-6 alkyl, -(CR p R q ) m -6- to 10-membered aryl and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl and 6- to 10-membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, or two adjacent R 3 form, together with the carbon atom to which they are attached, a 3- to 6- membered cycloalkyl, wherein R p , R q , R s , R t and m are as defined in general formula (D);

[0439] More preferably, R 3 is a hydrogen atom or -(CR p R q ) m -NR s R t , wherein R p , R q , R s , R t and m are as defined in general formula (D).

[0440] In some embodiments, the compound according to any of the preceding embodiments of formula (D-M), formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-IIM), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of a hydrogen atom, halogen, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and 6- to 10-membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl, wherein R p , R q , R z and m are as defined in formula (D);

[0441] Preferably, R 3 is selected from the group consisting of a hydrogen atom, oxo, C 1-6 alkyl, and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl, and 6- to 10-membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, wherein R p , R q and m are as defined in formula (D).

[0442] In some embodiments, the compound according to any of the preceding embodiments of formula (D-M), formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-IIM), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and -(CR p R q ) m -6 to 10 membered aryl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, and 6 to 10 membered aryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, nitro, -OR z , oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl or 3 to 6 membered heterocyclyl, wherein R p , R q , R z and m are as defined in formula (D);

[0443] Preferably, R 3 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, and -(CR p R q ) m -6 to 10 membered aryl; wherein said C 1-6 alkyl, and 6 to 10 membered aryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl, wherein R p , R q and m are as defined in formula (D).

[0444] In some embodiments, the compound according to any of the preceding embodiments of formula (D-M), formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-IIM), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom.

[0445] In some embodiments, the compound according to any of the preceding embodiments of formula (D-M), formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-IIM), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, or 2; preferably, s is 0.

[0446] In some embodiments, the compound according to any of the preceding embodiments of formula (D-M), formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-IIM), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and -(CR p R q ) m -C(O)NR s R t , R p , R q , R s , R t and m are as defined in formula (D); preferably, R 4 is selected from a hydrogen atom, halogen, cyano, and -(CR p R q ) m -C(O)NR s R t , R p , R q , R s , R t and m are as defined in formula (D).

[0447] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 4 It is selected from hydrogen atoms, halogens, and cyano groups.

[0448] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein t is 0, 1 or 2; preferably, t is 2.

[0449] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R 5 -(CR) g R h ) n -or -C(O)-, where R g R h and n as defined in general formula (D); preferably, R 5 It is -C(O)-.

[0450] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 6 For -NR ii -or Where R ii R 35 R 36 and w as defined in general formula (D); preferably, R 6 For -NR ii -, where R ii As defined in general formula (D).

[0451] In some embodiments, the compound according to any of the preceding embodiments of formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from -(CR k R kk ) n -, -(CR k R kk ) n -NR 12 - and -NR 12 -(CR k R kk ) n - wherein R k , R kk , R 12 and n are as defined in formula (D); preferably R 7 is -(CR k R kk ) n - wherein R k , R kk and n are as defined in formula (D).

[0452] In some embodiments, the compound according to any of the preceding embodiments of formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 8 is -(CR m R n ) n - wherein R m , R n and n are as defined in formula (D).

[0453] In some embodiments, the compound according to any of the preceding embodiments of formula (D), formula (D-I), formula (D-I-S), formula (D-I-R), formula (D-II), formula (D-II-S), or formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 9 is a hydrogen atom or a C 1-6 alkyl group; preferably R 9 is a hydrogen atom.

[0454] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 It is a chemical bond; where R ii R k R kk R m R n And n is as defined in general formula (I).

[0455] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 It is a chemical bond; and R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R ii R k R kk R m R n And n is as defined in general formula (I).

[0456] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 5 is -C(O)-; R 6 is R 7 is -(CR k R kk ) n -NR 12 -; R 8 is -(CR m R n ) n -; R 10 is a bond; wherein R 12 , R 35 , R 36 , R k , R kk , R m , R n , n and w are as defined in Formula (I).

[0457] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 5 is -C(O)-; R 6 is R 7 is -(CR k R kk ) n -NR 12 -; R 8 is -(CR m R n ) n -; R 10 is a bond; and R 5 and the bond attached to ring B or the piperazine ring may be or or both configurations ; wherein R 12 , R 35 , R 36 , R k , R kk , R m , R n , n and w are as defined in Formula (I).

[0458] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 for Where R 35 R 36 R ii R k R kk R m R n , n and w are as defined in general formula (I).

[0459] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 For -NR ii -;R 7 -(CR) k R kk ) n -;R 8 -(CR) m R n ) n -;R 10 for And R 5 The bond attached to ring B or piperazine ring It can be or Or simultaneously include Two configurations; where R 35 R 36 R ii R k R kk R m R n , n and w are as defined in general formula (I).

[0460] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 for Where R 12 R 35 R 36 R k R kk R m R n , n and w are as defined in general formula (I).

[0461] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding embodiments, wherein R 5 -C(O)-; R 6 for R 7 -(CR) k R kk ) n -NR 12 -;R 8 -(CR) m R n ) n -;R 10 for And R 5 The bond attached to ring B or piperazine ring It can be Or simultaneously include Two configurations; where R 12 R 35 R 36 R k R kk R m R n, n and w are as defined in general formula (I).

[0462] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl; preferably, R 11 is a hydrogen atom or C 1-6 alkyl; more preferably, R 11 is a hydrogen atom.

[0463] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 12 is a hydrogen atom or C 1-6 alkyl; preferably, R 12 is a hydrogen atom.

[0464] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 35 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 membered aryl, -(CR 30a R 30b ) p4 -5 to 10 membered heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR30a R 30b ) p4 -C(O)-NR 31 R 32 、-(CR 30a R 30b ) p4 -OR 33 、-(CR 30a R 30b ) p4 -C(O)-OR 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 One or more substituents are substituted in the group; the 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 The alkoxy group is substituted by one or more identical or different substituents; wherein R 13 R 30a R 30b R 31 R 32 R 33 R 34 p and p4 are as defined in general formula (D).

[0465] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R 35 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 aryl groups, -(CR 30a R 30b ) p4 -5 to 10-membered heteroaryl groups, -(CR30a R 30b ) p4 -NR 31 R 32 、-(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 、-(CR 30a R 30b ) p4 -C(O)-OR 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 The aryl and heteroaryl groups are each optionally substituted with a hydroxyl group independently; wherein R 30a R 30b R 31 R 32 R 33 R 34 p and p4 are as defined in general formula (D).

[0466] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R 35 It is a hydrogen atom or -(CR) 30a R 30b ) p4 -6 to 10 aryl groups, of which R 30a R 30b p4 is as defined in general formula (I).

[0467] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R 35 It is a hydrogen atom.

[0468] In some embodiments, a compound or a pharmaceutically acceptable salt thereof represented by formula (DM), formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-IIM), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R u4 and R u5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, -(CR 30a R 30b ) p4 -6 to 10 aryl groups, -(CR 30a R 30b ) p4 -5 to 10-membered heteroaryl groups, -(CR 30a R 30b ) p4 -NR 31 R 32 、-(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 、-(CR 30a R 30b ) p4 -OR 33 、-(CR 30a R 30b ) p4 -C(O)-OR 33 、-(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 and -(CR 30a R 30b ) p4 -S(O) p -R 33 One or more substituents are substituted in the group; the 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 The alkoxy group is substituted by one or more identical or different substituents; wherein R13 , R 30a , R 30b , R 31 , R 32 , R 33 , R 34 , p and p4 are as defined in general formula (D).

[0469] In some embodiments, the compound according to any of the preceding embodiments, general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R u6 and R u7 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 hydroxyalkyl group, -(CR 30a R 30b ) p4 -6 to 10 membered aryl group, -(CR 30a R 30b ) p4 -5 to 10 membered heteroaryl group, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , and -(CR 30a R 30b ) p4 -S(O) p -R 33One or more substituents are substituted in the group; the 6- to 10-membered aryl and 5- to 10-membered heteroaryl groups are each independently and optionally selected from halogen, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 The alkoxy group is substituted by one or more identical or different substituents; wherein R 13 R 30a R 30b R 31 R 32 R 33 R 34 p and p4 are as defined in general formula (D).

[0470] In some embodiments, a compound of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) as described in any of the preceding claims, wherein R k and R kk They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl, C 1-6 Hydroxyalkyl, cyano, -NR u1 R u2 、-(CR w3 R w4 ) u -NR u1 R u2 、-(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 -C(O)-(NR) u3 -CR u4 R u5 -COOR 15a ) p6 -COOR 15a and -(CR w3 R w4 ) u -COOR 15a , where R u1 R u2 R u3 R u4 R u5, R w3 , R w4 , R 15a , u and p6 are as defined in general formula (I); preferably, R k and R kk are the same or different and each is independently selected from the group consisting of a hydrogen atom, -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a and -(CR w3 R w4 ) u -COOR 15a , wherein R u3 , R u4 , R u5 , R w3 , R w4 , R 15a , u and p6 are as defined in general formula (D); more preferably, R k and R kk are the same or different and each is independently a hydrogen atom or -COOR 15a , wherein R 15a is as defined in general formula (I); most preferably, R k is a hydrogen atom and R kk is -COOR 15a , wherein R 15a is as defined in general formula (I).

[0471] In some embodiments, the compound according to any of the preceding embodiments of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, C 1-6 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; preferably, R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are the same or different and each independently a hydrogen atom or C 1-6 alkyl.

[0472] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), wherein R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 and R v2 are each a hydrogen atom.

[0473] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R c , R g , R h , R j , R jj , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, -NR u1R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -COOR 15a and -(CR w3 R w4 ) u -COOR 15a wherein R u1 , R u2 , R w3 , R w4 , R 15a and u are as defined in general formula (D); preferably, R c , R g , R h , R j , R jj , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are hydrogen atoms.

[0474] In some embodiments, the compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is according to general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), wherein R w3 and R w4 are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group.

[0475] In some embodiments, the compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is according to general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R), wherein R 15a and R 15b are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group.

[0476] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R 16a and R 16b are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group.

[0477] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein R L is a hydrogen atom or a C 1-6 alkyl group.

[0478] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein p is 0 or 2; preferably, p is 0.

[0479] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, 5, or 6; preferably, m is 0, 1, 2, 3, or 4.

[0480] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0481] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4, 5, or 6; preferably, n is 0, 1, 2, 3, or 4.

[0482] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein n1 is 0, 1, 2, 3, 4, 5, or 6; preferably, n1 is 0, 1, 2, 3, or 4.

[0483] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein p4 is 0, 1, 2, 3, 4, 5, or 6; preferably, p4 is 0, 1, 2, 3, or 4.

[0484] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein p5 is 0, 1, 2, 3, 4, 5, or 6; preferably, p5 is 0, 1, or 2.

[0485] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein p6 is 0, 1, 2, 3, 4, 5, or 6; preferably, p6 is 0, 1, or 2.

[0486] In some embodiments, the compound according to any of the preceding embodiments of Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein w is 0, 1, 2, 3, 4, 5, or 6; preferably, w is 0, 1, or 2; more preferably, w is 0 or 1; most preferably, w is 1.

[0487] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, wherein u is 0, 1, 2, 3, 4, 5, or 6; preferably, u is 0, 1, 2, 3, or 4.

[0488] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, having a structure according to Table 1-1 and Table 1-5.

[0489] In some embodiments, the compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt thereof, having a structure according to Table 1-4.

[0490] In some embodiments, the use of a compound according to any of the preceding embodiments of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R), or a pharmaceutically acceptable salt thereof, in the manufacture of a proteolysis targeting chimera, an antibody-drug conjugate (e.g., an antibody-proteolysis targeting chimera conjugate, an antibody-degrader conjugate), a polypeptide-drug conjugate, or a small molecule-drug conjugate.

[0491] a compound according to Formula (LN-D-II), or a pharmaceutically acceptable salt thereof

[0492] In another aspect, the disclosure relates to a compound according to Formula (LN-D-II), or a pharmaceutically acceptable salt thereof:

[0493] wherein L 3 , W1 , R 2 to R 9 , r, s, and t are as defined in general formula (IN).

[0494] In another aspect, the disclosure relates to a compound of Formula (LN-D-II-S), or a pharmaceutically acceptable salt thereof:

[0495] wherein L 3 , W 1 , R 2 to R 9 , r, s, and t are as defined in general formula (IN).

[0496] In another aspect, the disclosure relates to a compound of Formula (LN-D-II-R), or a pharmaceutically acceptable salt thereof:

[0497] wherein L 3 , W 1 , R 2 to R 9 , r, s, and t are as defined in general formula (IN).

[0498] In some embodiments, the compound of Formula (LN-D-II), Formula (LN-D-II-R), or Formula (LN-D-II-R) as described in any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, has a structure as shown in Table 1-2.

[0499] Methods of preparation

[0500] In another aspect, the disclosure relates to a method of preparing a Ligand- Drug Conjugate or a pharmaceutically acceptable salt thereof as described in any one of the preceding aspects, comprising the step of linking a compound selected from Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) as described in any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, to a ligand; wherein the ligand is an antigen binding molecule; preferably, the ligand is an antibody.

[0501] In some embodiments, the method of preparing the ligand-drug conjugate or the pharmaceutically acceptable salt thereof as in any of the preceding comprises coupling a compound selected from the group consisting of the compound of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as in any of the preceding, or a pharmaceutically acceptable salt thereof, with a ligand via a linker; wherein the ligand is an antigen binding molecule; preferably, the ligand is an antibody.

[0502] In another aspect, the disclosure relates to a method of preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as shown in general formula (IN), comprising the steps of:

[0503] Ab reduction (e.g., with a reducing agent tris(2-carboxyethyl)phosphine hydrochloride (TCEP.HCl)) followed by a coupling reaction with a compound of general formula (LN-D-II) or a pharmaceutically acceptable salt thereof to obtain a ligand-drug conjugate or a pharmaceutically acceptable salt thereof of general formula (IN);

[0504] wherein Ab, L 3 , W 1 , R 2 to R 9 , r, s, t, and y are as defined in general formula (IN).

[0505] In some embodiments, the compound of general formula (IN-S) or general formula (IN-R) as in any of the preceding or a pharmaceutically acceptable salt thereof can be synthesized by referring to the above-mentioned methods with corresponding chiral starting materials replaced, or chiral resolution.

[0506] In another aspect, the disclosure relates to a method of preparing a compound of general formula (LN-D-II) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0507] a coupling reaction of compound (M) with a compound of general formula (D-II) or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) (e.g., in the presence of a base (e.g., N,N-diisopropylethylamine) and a coupling agent (e.g., 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)) to obtain a compound of general formula (LN-D-II) or a pharmaceutically acceptable salt thereof;

[0508] wherein:

[0509] L 3a is L3 a moiety that removes the terminal carbonyl group;

[0510] wherein L 3 , W 1 , R 2 to R 9 , r, s and t are as defined in general formula (LN-D-II).

[0511] In some embodiments, a compound of general formula (LN-D-II-S) or general formula (LN-D-II-R) as previously described, or a pharmaceutically acceptable salt thereof, can be synthesized according to the above described methods, with the corresponding chiral starting material substituted, or chiral resolution.

[0512] In some embodiments, a compound of general formula (D-M), general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-IIM), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as previously described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is a formate salt or a hydrochloride salt.

[0513] Table 1-1 Typical compounds of the present disclosure include, but are not limited to:

[0514] Table 1-2 Typical compounds of the present disclosure include, but are not limited to:

[0515] Table 1-3 Typical compounds of the present disclosure include, but are not limited to:

[0516] Table 1-4 Typical compounds of the present disclosure include, but are not limited to:

[0517] Table 1-5 Typical compounds of the present disclosure include, but are not limited to:

[0518] In another aspect, the disclosure relates to a pharmaceutical composition comprising the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding, the compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, the compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0519] In some embodiments, the disclosure relates to a pharmaceutical composition comprising the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0520] In some embodiments, the disclosure relates to a pharmaceutical composition comprising the compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0521] In some embodiments, the disclosure relates to a pharmaceutical composition comprising the compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0522] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding, the compound of Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, the compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, based on the total weight of the pharmaceutical composition.

[0523] In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, the compound of general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof, the compound of general formula (LN-D-II), general formula (LN-D-II-S), or general formula (LN-D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, the compound of general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof, the compound of general formula (LN-D-II), general formula (LN-D-II-S), or general formula (LN-D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof.

[0525] In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, the compound of general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof, the compound of general formula (LN-D-II), general formula (LN-D-II-S), or general formula (LN-D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof.

[0526] In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, the compound of general formula (D), general formula (D-I), general formula (D-I-S), general formula (D-I-R), general formula (D-II), general formula (D-II-S), or general formula (D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof, the compound of general formula (LN-D-II), general formula (LN-D-II-S), or general formula (LN-D-II-R) as described in any of the preceding items, or a pharmaceutically acceptable salt thereof.

[0527] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable diluent or excipient, based on the total weight of the pharmaceutical composition.

[0528] In some embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable diluent or excipient.

[0529] In some embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient.

[0530] In some embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable diluent or excipient.

[0531] In some embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable diluent or excipient.

[0532] Anti-CD79b antibodies

[0533] In another aspect, the disclosure relates to an anti-CD79b antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 23.

[0534] In some embodiments, the anti-CD79b antibody as previously described comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO: 25, and the amino acid sequence of the light chain is set forth in SEQ ID NO: 23.

[0535] In another aspect, the disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, comprising the anti-CD79b antibody of any one of the previous embodiments and a drug, wherein the drug is conjugated to the anti-CD79b antibody; preferably, the drug is an IKZF degrader; more preferably, the drug is an IKZF1 / 3 degrader.

[0536] Nucleic acids, host cells, methods, and uses

[0537] In another aspect, the disclosure relates to an isolated nucleic acid encoding the anti-CD38 antibody of any one of the previous embodiments.

[0538] In another aspect, the disclosure relates to an isolated nucleic acid encoding the anti-CD79b antibody of any one of the previous embodiments.

[0539] In another aspect, the disclosure relates to an isolated nucleic acid encoding the anti-BCMA antibody of any one of the previous embodiments.

[0540] In another aspect, the disclosure relates to an isolated nucleic acid encoding the anti-GPRC5D antibody of any one of the previous embodiments.

[0541] In another aspect, the disclosure relates to a host cell comprising the isolated nucleic acid as described above.

[0542] In another aspect, the disclosure relates to a method of preventing or treating a disease, comprising administering to a subject a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding, a compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, a compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, or a pharmaceutical composition as described previously.

[0543] In some embodiments, the disclosure relates to a use in the manufacture of a medicament for preventing or treating a disease, comprising administering to a subject a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding, or a pharmaceutical composition as described previously.

[0544] In some embodiments, the disclosure relates to a use in the manufacture of a medicament for preventing or treating a disease, comprising administering to a subject a compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, or a pharmaceutical composition as described previously.

[0545] In some embodiments, the disclosure relates to a use in the manufacture of a medicament for preventing or treating a disease, comprising administering to a subject a compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, or a pharmaceutical composition as described previously.

[0546] In another aspect, the disclosure relates to a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding, a compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, a compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) or a pharmaceutically acceptable salt thereof as described in any of the preceding, or a pharmaceutical composition as described previously for use as a medicament. In some embodiments, the medicament is for preventing or treating a disease.

[0547] In some embodiments, the disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding for use as a medicament. In some embodiments, the medicament is for preventing or treating a tumor.

[0548] In some embodiments, the disclosure relates to a compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) as described in any of the preceding or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in the preceding for use as a medicament. In some embodiments, the medicament is for preventing or treating a disease.

[0549] In some embodiments, the disclosure relates to a compound of Formula (LN-D-II), Formula (LN-D-II-S), or Formula (LN-D-II-R) as described in any of the preceding or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in the preceding for use as a medicament. In some embodiments, the medicament is for preventing or treating a disease.

[0550] In some embodiments, the compound of Formula (D-M), Formula (D), Formula (D-I), Formula (D-I-S), Formula (D-I-R), Formula (D-IIM), Formula (D-II), Formula (D-II-S), or Formula (D-II-R) as described in any of the preceding or a pharmaceutically acceptable salt thereof is a formate salt or a hydrochloride salt.

[0551] The disease as described in any of the preceding in the disclosure is selected from the group consisting of a tumor, an autoimmune disease, and an inflammation; preferably, the disease is selected from the group consisting of myeloma (e.g., multiple myeloma), myelodysplastic syndrome, lymphoma (e.g., diffuse large B-cell lymphoma), leukemia, systemic lupus erythematosus, and lupus nephritis; more preferably, the tumor is selected from the group consisting of multiple myeloma and diffuse large B-cell lymphoma.

[0552] The term

[0553] For the purposes of the present disclosure, certain technical and scientific terms are described below. Unless specifically defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0554] As used in the specification and claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise.

[0555] The plural form "a plurality" as used in the specification and claims means "two or more" unless expressly specified otherwise by context, and thus naturally includes, for example, 2, 3, 4, etc. up to an infinite number of items.

[0556] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

[0557] The term "cytokine" is a general term for proteins released by a cell population that act as intercellular mediators on other cells. Examples of such cytokines include lymphokines, monokines, chemokines, and traditional polypeptide hormones. Exemplary cytokines include: mIL-2, IFNy, TNFa, CCL-2, and IL-6.

[0558] The term "and / or", refers to both the inclusive and exclusive sense of "and" and "or". For example, the phrase "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0559] The three letter code and one letter code for amino acids used herein are as described in J. Biol. Chem, 243, p 3558 (1968).

[0560] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, such as those listed above, as well as those modified after translation. Amino acid analogs refer to compounds that have the same basic chemical structure (i.e., an alpha carbon bonded to a hydrogen, a carboxyl, an amino, and an R group) as a naturally occurring amino acid, but having modified R groups (e.g., norleucine) or modified peptide backbones. Such analogs are inositive to have the same basic chemical structure of a naturally occurring amino acid, but have modified R groups (e.g., norleucine) or modified peptide backbones. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

[0561] The term "amino acid mutation" includes amino acid substitutions (also referred to as amino acid replacements), deletions, insertions, and modifications. Any combination of substitutions, deletions, insertions and modifications can be made to arrive at the final construct, as long as the final construct possesses the desired properties, such as reduced or no binding to Fc receptors. Amino acid sequence deletions and insertions include deletions and insertions at the amino- and / or carboxyl-terminus of a polypeptide chain. A particular amino acid mutation can be an amino acid substitution. In one embodiment, the amino acid mutation is a non-conservative amino acid substitution, i.e., replacing one amino acid with another amino acid of different structure and / or chemical characteristics. Amino acid substitutions include substitutions by non-naturally occurring amino acids or by derivatives of the 20 natural amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be generated using genetic or chemical methods known in the art. Genetic methods can include site-directed mutagenesis, PCR, gene synthesis, and the like. Methods other than genetic engineering to alter the side chain groups of amino acids, such as chemical modifications, are also expected to be useful. Various names can be used herein to refer to the same amino acid mutation. In this regard, the position + amino acid residue format can be used herein to indicate the amino acid residue at a particular position, e.g., 82aR, indicates that the amino acid residue at position 82a is R. S82aR indicates that the amino acid residue at position 82a (also referred to as 82A) has been mutated from S to R.

[0562] The term "ligand" is a macromolecular compound that recognizes and binds to an antigen or receptor associated with a target cell.

[0563] The term "antigen binding molecule" is used in the broadest sense, covering various species of molecules that specifically bind an antigen including but not limited to antibodies, other polypeptides having antigen binding activity and antibody fusion proteins in which an antibody is fused to another protein, as well as any molecule comprising an antibody, polypeptide, antibody fusion protein described above, as long as they exhibit the desired antigen binding activity. An antigen binding molecule herein comprises a variable region (VH) and a variable region (VL), which collectively make up an antigen binding domain. Exemplarily, an antigen binding molecule herein is a bispecific antigen binding molecule (e.g., a bispecific antibody).

[0564] The term "antibody" is used in the broadest sense, and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), so long as they exhibit the desired antigen-binding activity. For example, a native IgG antibody is a heterotetrameric glycoprotein of about 150,000 Daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain, heavy chain variable region, followed by three constant domains (CHI, CH2 and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain, or light chain variable domain, followed by a constant light domain (CL).

[0565] The term "bispecific antibody" refers to an antibody (including an antibody or antigen-binding fragment thereof, such as a single chain antibody) capable of specifically binding to two different antigens or at least two different epitopes of the same antigen. Various structures of bispecific antibodies have been disclosed in the prior art, which can be divided into IgG-like bispecific antibodies and antibody fragment type bispecific antibodies according to the integrity of the IgG molecule, into bivalent, trivalent, tetravalent or more valent bispecific antibodies according to the number of antigen binding regions, and into symmetric structure bispecific antibodies and asymmetric structure bispecific antibodies according to whether the structure is symmetric. Among them, the bispecific antibody based on antibody fragments, such as Fab fragments lacking Fc fragments, forms a bispecific antibody by combining 2 or more Fab fragments in one molecule, which has lower immunogenicity, smaller molecular weight, higher tumor tissue penetration, and the typical antibody structure of this type is F(ab)2, scFv-Fab, (scFv)2-Fab; IgG-like bispecific antibodies (e.g., with Fc fragments), which have relatively large molecular weight, the Fc fragment helps to purify the antibody, and improves its solubility, stability, and the Fc part can also bind to the receptor FcRn, increasing the serum half-life of the antibody.

[0566] A "native antibody" refers to an immunoglobulin molecule naturally occurring in an organism. For example, a native IgG antibody is a heterotetrameric glycoprotein of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has one variable region (VH), also called a variable heavy domain, a heavy chain variable region, followed by three constant regions (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has one variable region (VL), also called a variable light domain, or light chain variable domain, followed by one constant light region (CL). The terms "full-length antibody," "intact antibody," and "whole antibody" are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain with an Fc region as defined herein. A native intact antibody light chain includes a light chain variable region, VL, at the amino-terminal end of the light chain, and a constant region, CL, including kappa and lambda chains; a heavy chain includes a variable region, VH, at the amino-terminal end of the heavy chain, and a constant region at the carboxy-terminal end, where CH3 is closest to the carboxy-terminal end of the polypeptide, and the heavy chain can be of any isotype, including IgG (including IgGl, IgG2, IgG3, and IgG4 subtypes), IgA (including IgAl and IgA2 subtypes), IgM, and IgE.

[0567] The term "variable region" or "variable domain" of an antibody refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. In this document, the variable domains of a

[0568] The boundaries of the CDRs can be determined by various known schemes, such as the "Kabat" numbering convention (see Kabat et al. (1991) "Sequences of Proteins of Immunological Interest", 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering convention, the "ABM" numbering convention, the "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001), and the ImMunoGenTics (IMGT) numbering convention (Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16;9:2278), among others; the correspondence between the various numbering systems is well known to those skilled in the art.

[0569] Unless otherwise indicated, the variable regions and CDRs in the embodiments of the present disclosure are in accordance with the "Kabat" numbering convention.

[0570] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2, single-domain antibody, single-chain Fab (scFab), diabodies, linear antibodies, single-chain antibodies (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0571] The term "Fc region" or "fragment crystallizable region" is used to define a C-terminal region of an antibody heavy chain, including native and engineered Fc regions. In some embodiments, the Fc region comprises two subunits, which are identical or different. In some embodiments, the Fc region of a human IgG heavy chain is defined as stretching from an amino acid residue at the position of Cys226 or from Pro230 to its carboxyl terminus. Suitable Fc regions for use in the antibodies described herein include Fc regions of human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. In some embodiments, the boundaries of the Fc region can also vary, for example, by deleting the C-terminal lysine (residue 447 according to the EU numbering system) or by deleting the C-terminal glycine and lysine (residue 446 and 447 according to the EU numbering system) of the Fc region. Unless otherwise specified, the numbering of the Fc region is in accordance with the EU numbering system, also known as the EU index.

[0572] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chains is derived from a particular source or species, while the remaining portion of the heavy and / or light chains is derived from a different, distinct source or species.

[0573] The term "humanized" antibody is an antibody that retains the reactivity of a non-human antibody while having less immunogenicity in humans. For example, this can be achieved by retaining the non-human CDR regions and replacing the remainder of the antibody with its human counterpart, i.e., the constant region as well as the framework region portion of the variable region.

[0574] The terms "human antibody," "humanized antibody," "fully human antibody," "fully human antibody" are used interchangeably and mean an antibody in which the variable and constant regions are of human sequence. The term encompasses antibodies derived from human genes but which have had sequences altered, e.g., to reduce possible immunogenicity, increase affinity, eliminate a cysteine or glycosylation site that can cause undesirable folding, etc. The term encompasses these antibodies that are recombinantly produced in non-human cells, which can impart a glycosylation that is not characteristic of human cells. The term also encompasses antibodies that have been raised in transgenic mice that contain some or all of the human immunoglobulin heavy and light chain loci. The definition of human antibody expressly excludes humanized antibodies that contain non-human antigen binding residues.

[0575] The term "affinity" refers to the overall strength of the noncovalent interactions between individual binding sites of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, binding "affinity" refers to intrinsic binding affinity, which reflects the 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its ligand Y can be generally represented by the dissociation constant (KD). Affinity can be measured by routine methods known in the art, including those described herein.

[0576] The term "kassoc" or "ka", as used herein, refers to the association rate of a particular antibody-antigen interaction. The term "kdis" or "kd", as used herein, refers to the dissociation rate of a particular antibody-antigen interaction. The term "KD" refers to the dissociation constant, which is obtained from the ratio of kd to ka (i.e., kd / ka) and is expressed as a molar concentration (M). KDvalues for antibodies can be determined using methods well known in the art. For example, affinity in solution can be measured using a biosensor system such as a Biacore® system, which measures surface plasmon resonance (e.g., Biacore), or by solution equilibrium titration (SET).

[0577] The term "surface plasmon resonance" refers to an optical phenomenon that detects alterations in protein concentrations within a biosensor matrix in real-time, for example, using the BIAcore™ system (Biacore LifeSciences division of GE Healthcare, Piscataway, NJ).

[0578] The term "effector function" refers to those biological activities attributable to an antibody Fc region (native sequence Fc region or an amino acid sequence mutated Fc region) and which depend on the isotype of the antibody. Examples of antibody effector functions include but are not limited to: Clq binding and complement dependent cytotoxicity, Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down regulation of B cell receptor (BCR) expression, and B cell activation.

[0579] The term "monoclonal antibody" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in their amino acid sequences except for possible naturally occurring mutations that can be present in minor amounts. In contrast, polyclonal antibody preparations typically include a multitude of different antibodies that are specific for different epitopes of the antigen, often due to immunization with a whole organism or with a protein complex, as opposed to a single epitope. "Monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method. In some embodiments, the antibodies provided by the present disclosure are monoclonal antibodies.

[0580] The term "antigen" refers to a molecule or portion of a molecule capable of being bound by a selective binding agent such as an antigen binding protein (including, e.g., an antibody) and further capable of being used to produce antibodies in an animal that are capable of binding to the antigen. An antigen can have one or more epitopes capable of interacting with different antigen binding proteins (e.g., antibodies).

[0581] The term "epitope" refers to a region (area or region) on an antigen to which an antibody or antigen-binding fragment thereof specifically binds. An epitope can be formed by contiguous amino acids (linear epitope) or comprise non-contiguous amino acids (conformational epitope), e.g., brought into spatial proximity due to folding of the antigen (i.e., tertiary folding of the antigen by virtue of the protein nature). The difference between a conformational and a linear epitope is that binding of an antibody to a conformational epitope is lost in the presence of a denaturing solvent. An epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation. Screening for antibodies that bind to a particular epitope (i.e., those that bind to the same epitope) can be performed using routine methods in the art, such as, but not limited to, alanine scanning, peptide mapping, peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen (see Prot. Sci. 9 (2000) 487-496), and cross-blocking.

[0582] The terms "capable of specifically binding," "specifically binding," or "bind" mean that an antibody is capable of binding to a certain antigen or epitope within that antigen with higher affinity than to other antigens or epitopes. Typically, an antibody binds to an antigen or an epitope within an antigen with an equilibrium dissociation constant (KD) of about 1 x 10 -7 M or less (e.g., about 1 x 10 -8 M, 1 x 10 -9 M, 1 x 10 -10 M, 1 x 10 -11 M or less). In some embodiments, the KD of an antibody binding to an antigen is 10% or less (e.g., 1%) of the KD of that antibody binding to a non-specific antigen (e.g., BSA, casein). KD can be measured using known methods, e.g., by surface plasmon resonance assays. However, an antibody that specifically binds to an antigen or an epitope within an antigen can have cross-reactivity to other related antigens, e.g., cross-reactivity to the corresponding antigen from other species (homologs), such as human or monkey, e.g., Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp), or Callithrix jacchus (common marmoset, marmoset). The terms "antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity," or "ADCC" is a mechanism of inducing cell death that relies on the interaction of antibody-coated target cells with effector cells having lytic activity, such as natural killer cells (NK), monocytes, macrophages, and neutrophils, via Fcy receptors (FcyRs) expressed on the effector cells. For example, NK cells express FcyRIIIa, while monocytes express FcyRI, FcyRII, and FcyRIIIa. The ADCC activity of the antibodies provided herein can be assessed using an in vitro assay using cells expressing an antigen as target cells and NK cells as effector cells. Cell lysis is detected based on the release of a label (e.g., a radioactive substrate, a fluorescent dye, or a native intracellular protein) from the lysed cells.

[0583] The terms "antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity," or "ADCC" is a mechanism of inducing cell death that relies on the interaction of antibody-coated target cells with effector cells having lytic activity, such as natural killer cells (NK), monocytes, macrophages, and neutrophils, via Fcy receptors (FcyRs) expressed on the effector cells. For example, NK cells express FcyRIIIa, while monocytes express FcyRI, FcyRII, and FcyRIIIa. The ADCC activity of the antibodies provided herein can be assessed using an in vitro assay using cells expressing an antigen as target cells and NK cells as effector cells. Cell lysis is detected based on the release of a label (e.g., a radioactive substrate, a fluorescent dye, or a native intracellular protein) from the lysed cells.

[0584] The term "antibody-dependent cellular phagocytosis (ADCP)" refers to a mechanism of eliminating antibody-coated target cells through internalization by phagocytic cells, such as macrophages or dendritic cells.

[0585] The term "complement-dependent cytotoxicity" or "CDC" refers to a mechanism of inducing cell death in which the Fc effector domain of a target-bound antibody binds and activates complement component Clq, which in turn activates the complement cascade, leading to target cell death. Activation of complement can also result in the deposition of complement components on the surface of target cells, which promote CDC by binding to complement receptors (e.g., CR3) on leukocytes.

[0586] The terms "polypeptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. Unless otherwise specified, a particular polypeptide sequence is also intended to encompass conservatively modified variants thereof.

[0587] The term "sequence identity" means degrees (percentages) of identity, when two sequences are optimally aligned, gaps introduced to achieve maximum percent sequence identity, and no conserved sequence substitutions are permitted to be part of the sequence identity. Alignment can be achieved by techniques known in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters to achieve maximal alignment, including any algorithms necessary to achieve the maximum alignment over the full length of the sequences being compared.

[0588] The term "vector" means a polynucleotide molecule capable of transporting another polynucleotide to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, e.g., adenoviral vector (AAV or AAV2), into which additional DNA segments can be ligated. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. The term "expression vector" or "expression construct" refers to a vector that can be transformed into a host cell, and which contains nucleic acid sequences that direct and / or control the expression of one or more heterologous coding regions operably linked thereto, along with the host cell. Expression constructs can include, but are not limited to, sequences that affect or control transcription, translation, and, where introns are present, RNA splicing of coding regions operably linked thereto.

[0589] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. The progeny can not be completely identical to the parent cell from which it was derived, but may, for example, contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the original transformant cell are included herein. Host cells include prokaryotic and eukaryotic host cells, with eukaryotic host cells including, but not limited to, mammalian cells, insect cell lines, plant cells, and fungal cells. Mammalian host cells include human, mouse, rat, canine, monkey, porcine, goat, bovine, equine, and hamster cells, including but not limited to Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, and HEK-293 cells.Fungal cells include yeast and filamentous fungal cells, including, for example, Pichia pastoris, Pichia finlandica, Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichia minuta (Ogataea minuta, Pichia lindneri), Pichia opuntiae, Pichia thermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi, Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomyces cerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp., Kluyveromyces lactis, Candida albicans, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporium lucknowense, Fusarium sp., Fusarium gramineum, Fusarium venenatum, Physcomitrella patens, and Neurospora crassa. Pichia sp., any Saccharomyces sp., Hansenula polymorpha, any Kluyveromyces sp., Candida albicans, any Aspergillus sp., Trichoderma reesei, Chrysosporium lucknowense, any Fusarium sp., Yarrowia lipolytica, and Neurospora crassa.

[0590] "Cell," "cell line," "cell culture," and "cell population" are used interchangeably and all such designations include the progeny of the original subject cell. Thus, the words "transformant" and "transformed cell" include the primary subject cell and cultures derived from it, regardless of the number of transfers. It is also understood that, as a result of either natural or induced mutations, not all progeny will be identical to the original subject cell, but all possess the same functional or biological activity.

[0591] The term "alkyl" refers to saturated straight-chain or branched-chain aliphatic hydrocarbon groups having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkyl). The alkyl group preferably has from 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably from 1 to 6 carbon atoms (i.e., C 1-6 alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0592] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 alkylene). The alkylene group preferably has from 1 to 12 carbon atoms (i.e., C 1-12 alkylene). The alkylene group more preferably has from 1 to 6 carbon atoms (i.e., C 1-6 alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. The alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0593] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, having from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkenyl). The alkenyl group preferably has from 2 to 6 carbon atoms (i.e., C 2-6 alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of D atoms, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0594] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, having from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 alkynyl). The alkynyl group preferably has from 2 to 6 carbon atoms (i.e., C 2-6The term "alkynyl" refers to a straight or branched hydrocarbon chain that contains one or more triple bonds. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group can be substituted or non-substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0595] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, and the like. The alkoxy group can be substituted or non-substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0596] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a multicyclic ring system (i.e., multicyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl), more preferably 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), and most preferably 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl).

[0597] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0598] The multicyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0599] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds within the rings, or which can contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the rings (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), provided that at least one fully carbon ring is present and the point of attachment is on the fully carbon ring, having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spirocycloalkyl). The spirocycloalkyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl group includes mono- and polyspirocycloalkyl groups (e.g., dispirocycloalkyl groups, etc.), preferably a monospriocycloalkyl group or a dispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospriocycloalkyl group. Non-limiting examples include:

[0600] which can be attached at any position;

[0601] etc.

[0602] The term "fused cycloalkyl" refers to a polycyclic ring system sharing two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyl, or a monocyclic cycloalkyl fused with one or more of heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples include: which can be at any position; and the like.

[0603] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system sharing two non-adjacent carbon atoms between the rings, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5- to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0604] which can be at any position.

[0605] The cycloalkyl group can be substituted or unsubstituted, when substituted, it can be substituted at any available point of attachment, preferably with one or more substituents selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0606] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic ring (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from the group consisting of nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-) in the ring and having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3- to 20-membered heterocyclyl). The heterocyclyl group preferably has from 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), e.g., 4- to 12-membered heterocyclyl having at least one nitrogen atom; further preferably, the heterocyclyl group has from 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); more preferably, the heterocyclyl group has from 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl); most preferably, the heterocyclyl group has 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl).

[0607] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0608] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0609] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system sharing one atom (referred to as the spiro atom) between rings, which can contain one or more double bonds in the ring and which has at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from the group consisting of nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-) in the ring, provided that at least one monocyclic heterocyclyl group is present and the point of attachment is on the monocyclic heterocyclyl group, and which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered spiroheterocyclyl). The spiroheterocyclyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl). The spiroheterocyclyl group includes mono- and polyspiroheterocyclyl groups (e.g., dispiroheterocyclyl groups and the like), preferably a monosprioheterocyclyl group or a dispiroheterocyclyl group, more preferably a 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monosprioheterocyclyl group. Non-limiting examples include:

[0610] etc.

[0611] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system sharing adjacent atoms between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-) within the ring, which is fused to a monocyclic heterocyclyl group or to one or more monocyclic heterocyclyl groups, or to one or more of a cycloalkyl, aryl, or heteroaryl group, with the point of attachment being on the monocyclic heterocyclyl group, and having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused heterocyclyl). The fused heterocyclyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (e.g., tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, etc.), preferably bicyclic fused heterocyclyl groups or tricyclic fused heterocyclyl groups, more preferably 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused heterocyclyl groups. Non-limiting examples include:

[0612] etc.

[0613] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system sharing two non-adjacent atoms between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-) within the ring, which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered bridged heterocyclyl). The bridged heterocyclyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). The bridged heterocyclyl group includes bicyclic and polycyclic bridged heterocyclyl groups (e.g., tricyclic bridged heterocyclyl groups, tetracyclic bridged heterocyclyl groups, etc.), preferably bicyclic bridged heterocyclyl groups or tricyclic bridged heterocyclyl groups. Non-limiting examples include:

[0614] etc.

[0615] Heterocyclyl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0616] The term "aryl" refers to a monocyclic all-carbon aromatic ring having a conjugated pi-electron system (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6- to 14-membered aryl). The aryl group preferably has 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). The monocyclic aryl group is exemplified by phenyl. The polycyclic aryl group is exemplified by, without limitation, naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused with one or more heterocyclyl or cycloalkyl groups, where the point of attachment is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, which is exemplified by, without limitation:

[0617] etc.

[0618] Aryl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0619] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered monocyclic heteroaryl group) or a bicyclic heteroaryl group having 8 to 10 ring atoms (i.e., an 8 to 10-membered bicyclic heteroaryl group), and most preferably a 5 or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur or an 8 to 10-membered bicyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0620] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0621] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0622] wait.

[0623] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0624] The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from removal of one hydrogen atom from a parent ring atom, or residues derived from removal of two hydrogen atoms from the same ring atom or from two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0625] In the chemical structure of the compounds of the present disclosure, the bond represents unspecified configuration, i.e. if chiral isomers exist in the chemical structure, the bond may be or simultaneously include both configurations.

[0626] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term "isotopic variations" means compounds which have at least one atom replaced by an atom having the same atomic number but an atomic mass different from the atomic mass of the atom typically occurring in in nature. Examples of isotopes that can be introduced into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, preferably deuterium.

[0627] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each of the available hydrogen atoms attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0628] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0629] The term "pharmaceutical composition" denotes a mixture of one or more antibody-polypeptide conjugates described herein, or a pharmaceutically acceptable salt thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients.

[0630] The term "pharmaceutically acceptable carrier" refers to a component of a pharmaceutical formulation that differs from the active ingredients and is nontoxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0631] The term "subject" or "individual" includes both human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles. The terms "patient" or "subject" are used interchangeably herein, unless indicated otherwise. In certain embodiments, the individual or subject is a human.

[0632] "Administer" or "administration," when applied to an animal, human, test subject, cell, tissue, organ, or biological fluid, means the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, test subject, cell, tissue, organ, or biological fluid.

[0633] The term "sample" refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Exemplary samples are biological fluids, such as blood, serum and serosal fluids, plasma, lymphatic fluid, urine, saliva, cyst fluid, lacrimal fluid, fecal matter, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleural, pericardial, peritoneal, peritoneal cavity, and other body cavities fluids, fluids collected by bronchial lavage, synovial fluid, liquid solutions in contact with a subject or biological source, such as cell and organ culture media (including cell or organ conditioned media), lavage fluids, and the like, tissue biopsy samples, fine needle aspirations, surgically resected tissues, organ cultures, or cell cultures.

[0634] “Treatment” and “treating” (and grammatical alterations thereof) refer to clinical intervention with the intent to alter the natural course of the individual being treated, and can be administered to prevent or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or reoccurrence of disease, alleviation of symptoms, diminishment / lessening of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the antibodies of the disclosure are used to delay development of a disease or slow the progression of a disease.

[0635] An “effective amount” is generally the amount that is sufficient to reduce the severity and / or frequency of symptoms, eliminate the symptoms and / or their underlying cause, prevent the symptoms and / or their underlying cause from occurring, or ameliorate or improve damage caused or associated with a disease state (e.g., a lung disease). In some embodiments, an effective amount is a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” is an amount that is sufficient to treat a disease state or symptoms, particularly states or symptoms associated with the disease state, or otherwise prevent, hinder, delay, or reverse the progression of the disease state or any other undesirable symptoms associated with the disease in any way. A “prophylactically effective amount” is an amount that will have the intended prophylactic effect, such as preventing or delaying the onset (or reoccurrence) of the disease state, or reducing the likelihood of the onset (or reoccurrence) of the disease state or associated symptoms, when administered to a subject. The full therapeutic or prophylactic effect does not necessarily occur by administration of one dose, and can occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount can be administered in one or more administrations. “Therapeutically effective amount” and “prophylactically effective amount” can vary depending on factors such as the disease state of the individual, the age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health status of the patient.

[0636] An exemplary antibody-drug conjugate or a pharmaceutically acceptable salt thereof:

[0637] The disclosure relates to an antibody-drug conjugate of the general formula (I) or a pharmaceutically acceptable salt thereof:

[0638] Ab-(L-D) y (I)

[0639] wherein Ab is an antibody;

[0640] L is a linker connecting Ab and D;

[0641] D is as shown in formula (D-I-H):

[0642] Ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; preferably, ring B is a 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms;

[0643] X is -CR a R b -; wherein R a and R b are each hydrogen atoms;

[0644] Ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is phenyl;

[0645] Ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring C is phenyl;

[0646] R 1 is a hydrogen atom;

[0647] R d , R dd , R e and R f are each hydrogen atoms;

[0648] R 2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 2-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group;

[0649] R 3 is selected from the group consisting of a hydrogen atom, an oxo group, a C 1-6 alkyl group and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl group and 6- to 10-membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group; or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group, wherein R p and R q are each hydrogen atoms, and m is 0, 1, 2, 3 or 4;

[0650] R 4 is selected from the group consisting of a hydrogen atom, a halogen and a cyano group;

[0651] R 5-C(O)-;

[0652] R 6 -NR ii -;

[0653] R 7 -(CR k R kk ) n -;

[0654] R 8 -(CR m R n ) n -;

[0655] R 9 hydrogen atom;

[0656] R 10 a bond or wherein R 35 hydrogen atom or -(CR 30a R 30b ) p4 -6 to 10 membered aryl, wherein R 30a and R 30b are each hydrogen atom; p4 is 0, 1, 2, 3 or 4; R 36 hydrogen atom; w is 0, 1 or 2;

[0657] R ii hydrogen atom;

[0658] R k and R kk are the same or different, and each independently hydrogen atom or -COOR 15a ; R 15a hydrogen atom;

[0659] R m and R n are each hydrogen atom;

[0660] n is 0, 1, 2, 3 or 4;

[0661] r is 0, 1 or 2;

[0662] s is 0, 1 or 2;

[0663] t is 0, 1 or 2; and

[0664] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0665] The present disclosure relates to an antibody-drug conjugate represented by general formula (IN), general formula (IN-S) or general formula (IN-R), or a pharmaceutically acceptable salt thereof:

[0666] wherein:

[0667] (1) Ab is an anti-CD38 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, and the light chain comprises the amino acid sequence of SEQ ID NO: 12; or

[0668] (2) Ab is an anti-CD79b antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 22, and the light chain comprises the amino acid sequence of SEQ ID NO: 23; or the heavy chain comprises the amino acid sequence of SEQ ID NO: 25, and the light chain comprises the amino acid sequence of SEQ ID NO: 23; or

[0669] (3) Ab is an anti-BCMA antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35, and the light chain comprises the amino acid sequence of SEQ ID NO: 36;

[0670] W 1 is -(CR 26a R 26b ) p3 -, R 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6;

[0671] L 3 is selected from the group consisting of G, F, GG, GF, FG, GGF, GFG and GGFG (SEQ ID NO: 37); preferably, L 3 is GGFG (SEQ ID NO: 37);

[0672] R 4 is selected from the group consisting of a hydrogen atom, a halogen and a cyano group;

[0673] R 5 is -C(O)-;

[0674] R 6 is -NR ii -;

[0675] R 7 is -(CR k R kk ) n -;

[0676] R 8-(CR) m R n ) n -;

[0677] R 9 It is a hydrogen atom;

[0678] R ii It is a hydrogen atom;

[0679] R k and R kk They may be the same or different, and each is independently a hydrogen atom or -COOR. 15a ;

[0680] R 15a It is a hydrogen atom;

[0681] R m and R n All are hydrogen atoms;

[0682] n can be 0, 1, 2, 3, or 4;

[0683] r is 0;

[0684] s is 0;

[0685] t is 0, 1, or 2; and

[0686] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0687] In some embodiments, the antibody-drug conjugate or its pharmaceutically acceptable salt, as shown in the previously described formula (IN), formula (IN-S), or formula (IN-R), wherein R 5 The bond attached to the piperazine ring It can be Or simultaneously include Two configurations.

[0688] This disclosure relates to an antibody-drug conjugate or a pharmaceutically acceptable salt thereof, selected from the following structures:

[0689] in:

[0690] (1) The Ab is an anti-CD38 antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, and the light chain comprises the amino acid sequence of SEQ ID NO: 12; or

[0691] (2) Ab is an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; or a heavy chain comprising the amino acid sequence of SEQ ID NO: 25 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; or

[0692] (3) Ab is an anti-BCMA antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;

[0693] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0694] The disclosure relates to an antibody-drug conjugate or a pharmaceutically acceptable salt thereof selected from the following structures:

[0695] wherein:

[0696] (1) Ab is an anti-CD38 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12; or

[0697] (2) Ab is an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; or a heavy chain comprising the amino acid sequence of SEQ ID NO: 25 and a light chain comprising the amino acid sequence of SEQ ID NO: 23; or

[0698] (3) Ab is an anti-BCMA antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;

[0699] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0700] Exemplary compounds or pharmaceutically acceptable salts thereof:

[0701] The disclosure relates to a compound of Formula (D-I), Formula (D-I-S), or Formula (D-I-R), or a pharmaceutically acceptable salt (preferably formate or hydrochloride salt) thereof:

[0702] wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; preferably, ring B is a 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms;

[0703] X is -CR a R b is a hydrogen atom; a and R b are each a hydrogen atom;

[0704] ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is a phenyl;

[0705] ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring C is a phenyl;

[0706] R 1 is a hydrogen atom;

[0707] R d , R dd , R e and R f are each a hydrogen atom;

[0708] R 2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 2-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group;

[0709] R 3 is selected from the group consisting of a hydrogen atom, an oxo group, a C 1-6 alkyl group and -(CR p R q ) m -6- to 10-membered aryl; wherein said C 1-6 alkyl group and 6- to 10-membered aryl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group, wherein R p and R q are each a hydrogen atom, and m is 0, 1, 2, 3 or 4;

[0710] R 4 is selected from the group consisting of a hydrogen atom, a halogen and a cyano group;

[0711] R 5-C(O)-;

[0712] R 6 -NR ii -;

[0713] R 7 -(CR k R kk ) n -;

[0714] R 8 -(CR m R n ) n -;

[0715] R 9 hydrogen atom;

[0716] R 10 a bond or wherein R 35 hydrogen atom or -(CR 30a R 30b ) p4 -6 to 10-membered aryl group, wherein R 30a and R 30b are each hydrogen atom; p4 is 0, 1, 2, 3 or 4; R 36 hydrogen atom; w is 0, 1 or 2;

[0717] R ii hydrogen atom;

[0718] R k and R kk are the same or different, and each independently hydrogen atom or -COOR 15a ; R 15a hydrogen atom;

[0719] R m and R n are each hydrogen atom;

[0720] n is 0, 1, 2, 3 or 4;

[0721] r is 0, 1 or 2;

[0722] s is 0, 1 or 2; and

[0723] t is 0, 1 or 2.

[0724] The present disclosure relates to a compound represented by General Formula (D-II), General Formula (D-II-S) or General Formula (D-II-R) or a pharmaceutically acceptable salt (preferably formate or hydrochloride) thereof:

[0725] wherein:

[0726] R 2 is selected from a hydrogen atom, a halogen, a cyano group, a C 2-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group;

[0727] R 3 is selected from a hydrogen atom, an oxo group, a C 1-6 alkyl group and -(CR p R q ) m -6 to 10 membered aryl group; wherein said C 1-6 alkyl group and 6 to 10 membered aryl group are each independently optionally substituted with one or more identical or different substituents selected from a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group, wherein R p and R q are each a hydrogen atom, m is 0, 1, 2, 3 or 4;

[0728] R 4 is selected from a hydrogen atom, a halogen and a cyano group;

[0729] R 5 is -C(O)-;

[0730] R 6 is -NR ii -;

[0731] R 7 is -(CR k R kk ) n -;

[0732] R 8 is -(CR m R n ) n -;

[0733] R 9 is a hydrogen atom;

[0734] R ii is a hydrogen atom;

[0735] R k and R kkthe same or different, and each independently is a hydrogen atom or -COOR 15a ;

[0736] R 15a is a hydrogen atom;

[0737] R m and R n are each a hydrogen atom;

[0738] n is 0, 1, 2, 3 or 4;

[0739] r is 0, 1 or 2;

[0740] s is 0, 1 or 2; and

[0741] t is 0, 1 or 2.

[0742] The present disclosure relates to a compound of Formula (D-II), Formula (D-II-S) or Formula (D-II-R) or a pharmaceutically acceptable salt (preferably formate or hydrochloride salt) thereof:

[0743] wherein:

[0744] R 4 is selected from a hydrogen atom, a halogen and a cyano group;

[0745] R 5 is -C(O)-;

[0746] R 6 is -NR ii -;

[0747] R 7 is -(CR k R kk ) n -;

[0748] R 8 is -(CR m R n ) n -;

[0749] R 9 is a hydrogen atom;

[0750] R ii is a hydrogen atom;

[0751] R k and R kk are the same or different, and each independently is a hydrogen atom or -COOR 15a ;

[0752] R 15a is a hydrogen atom;

[0753] R m and R n All are hydrogen atoms;

[0754] n can be 0, 1, 2, 3, or 4;

[0755] r is 0;

[0756] s is 0; and

[0757] t can be 0, 1, or 2.

[0758] In some embodiments, compounds of general formula (D-II), general formula (D-II-S), or general formula (D-II-R) or pharmaceutically acceptable salts thereof, as previously described, wherein R 5 The bond attached to the piperazine ring It can be Or simultaneously include Two configurations. Detailed Implementation

[0759] The present disclosure is further described below with reference to embodiments and test examples, but these embodiments and test examples are not intended to limit the scope of the disclosure. Experimental methods in the embodiments or test examples of this disclosure that do not specify specific conditions are generally performed under conventional conditions, such as those described in Cold Spring Harbor's Antibody Technology Manual or Molecular Cloning Manual; or under conditions recommended by the raw material or product manufacturer; reagents and materials whose specific sources are not specified are commercially available.

[0760] Examples and Test Cases

[0761] I. Antibody Examples

[0762] Example 1, Antibody

[0763] The conjugate antibody Ab1 used in this disclosure has a sequence from WHO, CAS number: 945721-28-8; Ab2 has a sequence from patent WO2020156439A1; Ab3 has only the Fc of antibody Ab2 mutated; Ab4 has a sequence from WHO, CAS number: 2061894-48-0.

[0764] Table 2. CDR sequence of Ab1

[0765] Note: The amino acids in CDRs are determined by the Kabat numbering system and marked with double underscores, the same applies below.

[0766] The heavy chain variable region of Ab1:

[0767] >Ab1 light chain variable region:

[0768] Heavy chain constant region of Ab1:

[0769] Light chain constant region of Ab1:

[0770] Heavy chain of Ab1:

[0771] Light chain of Ab1:

[0772] Table 3. CDR sequences of Ab2 and Ab3

[0773] Note: The amino acids of CDRs are determined by Kabat numbering system and marked with double underlines, the same below. Heavy chain variable region of Ab2 and Ab3:

[0774] Light chain variable region of Ab2 and Ab3:

[0775] Heavy chain constant region of Ab2:

[0776] Light chain constant region of Ab2: SEQ ID NO: 10

[0777] Heavy chain of Ab2:

[0778] Light chain of Ab2:

[0779] Heavy chain constant region of Ab3:

[0780] Light chain constant region of Ab3: SEQ ID NO: 10

[0781] Heavy chain of Ab3:

[0782] Light chain of Ab3: SEQ ID NO: 23.

[0783] Note: The bold part is the variable region sequence; the shaded part is the mutation site, the same below.

[0784] Table 4. CDR sequences of Ab4

[0785] Note: The amino acids of CDRs are determined by Kabat numbering system and marked with double underlines, the same below.

[0786] Heavy chain variable region of Ab4:

[0787] Light chain variable region of Ab4:

[0788] Heavy chain constant region of Ab4:

[0789] Light chain constant region of Ab4: SEQ ID NO: 10

[0790] Heavy chain of Ab4:

[0791] Light chain of Ab4:

[0792] II. Compound Examples

[0793] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is measured by Bruker AVANCE-400 NMR or Bruker AVANCE NEO 500M, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0794] The determination of MS is measured by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0795] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector).

[0796] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0797] High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

[0798] Chiral HPLC analysis was determined using Agilent 1260 DAD high performance liquid chromatograph.

[0799] High performance liquid preparation used Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0800] Chiral preparation used Shimadzu LC-20AP preparative chromatograph.

[0801] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0802] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography was 0.15mm-0.2mm, and the specification of product purified by thin layer chromatography was 0.4mm-0.5mm.

[0803] Silica gel column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0804] Determination of average inhibition rate and IC 50 values of kinases used NovoStar microplate reader (Germany BMG company).

[0805] Known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals and the like.

[0806] Unless otherwise specified in the examples, the reactions can be carried out under argon or nitrogen atmosphere.

[0807] Argon or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0808] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0809] Pressurized hydrogenation reaction used Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0810] Hydrogenation reaction was usually vacuumed, filled with hydrogen, and repeated for 3 times.

[0811] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0812] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0813] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0814] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: dichloromethane / ethanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0815] Example 2-1 1-P1 and 1-P2

[0816] ((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formate 1-P1

[0817] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formate 1-P2

[0818] Step 1 (S)-5-amino-4-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester 1c

[0819] (S)-tert-butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate 1a (2.0 g, 5.98 mmol, prepared by the known method “Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676”) was dissolved in acetonitrile (30 mL), 1,4-bis(bromomethyl)benzene 1b (4.8 g, 18.18 mmol, adamas) and anhydrous potassium carbonate (840 mg, 6.1 mmol) were added successively, the reaction system was replaced with nitrogen for 3 times, heated to 60 °C, and stirred overnight. The reaction system was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1c (2.6 g, yield: 84.3%).

[0820] MS m / z (ESI): 519.2 [M+1].

[0821] Second step

[0822] 1-(tert-butyl) 2-methyl 4-(4-cyano-2-fluorophenyl)piperazine-1,2-dicarboxylate 1f

[0823] 3,4-difluorobenzonitrile 1d (4.27 g, 30.69 mmol, purchased from Titan Scientific) was dissolved in dimethyl sulfoxide (60 mL), 1-(tert-butyl) 2-methyl piperazine-1,2-dicarboxylate 1e (5 g, 20.46 mmol, purchased from Shaoyuan) and anhydrous potassium carbonate (8.34 g, 60.43 mmol) were added successively, the reaction system was replaced with nitrogen for 3 times, heated to 120 °C, and stirred for 16 hours. The reaction system was cooled to room temperature, the reaction solution was filtered, the filtrate was extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed successively with water (50 mL x 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1f (2.8 g, yield: 37.7%).

[0824] MS m / z (ESI): 364.2 [M+1].

[0825] Third step

[0826] 4-(4-cyano-2-fluorophenyl)piperazine-2-carboxylic acid methyl ester 1g

[0827] 1f (800 mg, 2.2 mmol) was placed in a reaction bottle, dichloromethane (3 mL) was added, and a hydrochloric acid dioxane solution (1 mL, purchased from Titan Scientific) was added, and the reaction was stirred at room temperature for 2 hours. The crude title product 1g was obtained after concentration, which was directly used for the next reaction.

[0828] MS m / z (ESI): 264.1 [M+1].

[0829] Fourth step

[0830] 1 -(4-(((2-((S)-1 -amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1 - oxoisoindolin-4-yl)oxy)methyl)benzyl)-4-(4-cyano-2-fluorophenyl)piperazine-2- carboxylic acid methyl ester 1h

[0831] Dissolve 1g (600mg, 2.27mmol) and 1c (1.18g, 2.28mmol) in acetonitrile (20ml), add N,N-diisopropylethylamine (2g, 15.47mmol, purchased from Titan Scientific), heat to 40°C, and stir for 30 hours. Cool the reaction system to room temperature, concentrate the reaction solution, dissolve the obtained residue in ethyl acetate (50ml), wash with saturated citric acid solution (20ml x 2), water (20ml x 2), and saturated sodium chloride solution (20ml) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the obtained residue by silica gel column chromatography using eluent system B to obtain the title product 1h (1.3g, yield: 81.5%).

[0832] MS m / z (ESI): 701.1 [M+1].

[0833] Fifth step

[0834] 1 -(4-(((2-((S)-1 -amino-4-carboxy-1 -oxobutan-2-yl)-1 -oxoisoindolin-4-yl)oxy)methyl)benzyl)-4-(4-cyano-2-fluorophenyl)piperazine-2-carboxylic acid 1i

[0835] Place 1h (1.3g, 1.85mmol) in a reaction flask, add tetrahydrofuran (8ml), methanol (2ml), and water (2ml) in sequence, and then add lithium hydroxide (311.8mg, 7.43mmol). Stir at room temperature for 16 hours after completion of the addition. Concentrate the reaction solution, slurry in a mixture of DCM / MeOH=10 / 1 (10ml), filter, and dry the filter cake by oil pump to obtain 1i (1.02g, yield: 87%), which is directly used in the next step.

[0836] MS m / z (ESI): 630.5 [M+1].

[0837] Sixth step

[0838] 4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxylic acid 1j

[0839] Dissolve 1i (525 mg, 0.83 mmol) in acetonitrile (10 mL), add benzenesulfonic acid (1.06 g, 6.67 mmol, purchased from Acros), heat to 80 °C, stir for 12 hours. Cool the reaction system to room temperature, concentrate under reduced pressure, dissolve the residue in dimethyl sulfoxide (3 mL), purify by high performance liquid chromatography (Waters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: water phase (containing 0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 10%-35%, flow rate: 30 mL / min) to obtain the title product 1j (56 mg, yield: 10.9%).

[0840] MS m / z (ESI): 612.7 [M+1].

[0841] Seventh step

[0842] N 6 -(tert-butoxycarbonyl)-N 2 -(4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine tert-butyl ester 1k

[0843] Dissolve 1j (80 mg, 0.13 mmol) and N 6 -(tert-butoxycarbonyl)-L-lysine tert-butyl ester (47.5 mg, 0.16 mmol, purchased from Bide) in N,N-dimethylformamide (2 mL), add 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (50 mg, 0.26 mmol), 1-hydroxybenzotriazole (39.8 mg, 0.26 mmol, purchased from Titan) and 4-dimethylaminopyridine (48.3 mg, 0.39 mmol, purchased from Shaoyuan) in sequence, stir for 2 hours at room temperature after completion of addition. Add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL x 3), wash the combined organic phase with water (10 mL x 2) and saturated sodium chloride solution (10 mL) in sequence, dry over anhydrous sodium sulfate, concentrate under reduced pressure after filtration, purify the obtained residue by silica gel column chromatography with eluent system A to obtain the title product 1k (56 mg, yield: 47.7%).

[0844] MS m / z (ESI): 896.7 [M+1].

[0845] Eighth step ((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formic acid salt 1-P1

[0846] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formic acid salt 1-P2

[0847] Put 1k (40 mg, 0.45 mmol) in a reaction bottle, add dichloromethane (1 mL), then add a solution of hydrochloric acid in dioxane (3 mL, 4N, purchased from Titan Kogen). Stir the reaction at room temperature for 2 hours. Concentrate under reduced pressure. Dissolve the residue in dimethyl sulfoxide (3 mL) and purify by high performance liquid chromatography (Waters-2545, chromatographic column Boston Phlex ODS C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15-95%, flow rate: 30 mL / min) to obtain the target compound 1-P2 (11 mg, yield: 33.3%) and 1-P1 (13 mg, yield: 39.3%).

[0848] Compound 1-P2 (shorter retention time):

[0849] High performance liquid chromatography: instrument model: Waters 2689-2495; chromatographic column: Waters Sunfire C18 4.6*75 mm, 3.5 um; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile (containing 0.1% formic acid); gradient ratio: acetonitrile 5-95%, flow rate: 1.0 mL / min, retention time 8.915 min.

[0850] MS m / z (ESI): 740.2 [M+1].

[0851] Compound 1-P1 (longer retention time):

[0852] High performance liquid chromatography: instrument model: Waters 2689-2495; chromatographic column: Waters Sunfire C18 4.6*75 mm, 3.5 um; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile (containing 0.1% formic acid); gradient ratio: acetonitrile 5-95%, flow rate: 1.0 mL / min, retention time 9.381 min.

[0853] MS m / z (ESI): 740.2 [M+1].

[0854] Example 2-2 2-P1 and 2-P2

[0855] (S)-3-amino-2-((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 2-P1

[0856] (S)-3-amino-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 2-P2

[0857] First step

[0858] (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanoic acid tert-butyl ester 2b

[0859] (S)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoic acid tert-butyl ester 2a (500 mg, 1.70 mmol, bid) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (878 mg, 6.79 mmol, adamas) and di-tert-butyl dicarbonate (741 mg, 3.39 mmol, adamas) were added successively, the reaction system was concentrated under reduced pressure after reacting at room temperature for half an hour, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2b (150 mg, yield: 22.3%).

[0860] MS m / z (ESI): 417.2 [M+23].

[0861] Second step

[0862] (S)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid tert-butyl ester 2c

[0863] 2b (150 mg, 0.38 mmol) and 10% wet palladium-carbon (40.5 mg, 38 μmol, shao yuan) were dissolved in methanol (3 mL), hydrogen was replaced for three times, and the reaction was carried out at room temperature for 16 hours. The reaction liquid was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The obtained residue was the crude title product 2c (90 mg), which was directly used in the next step reaction.

[0864] MS m / z(ESI):261.3[M+1].

[0865] Step 3

[0866] (2S)-3-((tert-butoxycarbonyl)amino)-2-(4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)tert-butyl propionate 2d

[0867] Dissolve 1j (70 mg, 0.114 mmol) and 2c (35.7 mg, 0.137 mmol) in N,N-dimethylformamide (2 mL), then add triethylamine (34.7 mg, 0.342 mmol, Sinopharm) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (87 mg, 0.229 mmol, Shaoyuan) sequentially. After the addition is complete, stir at room temperature for 3 hours. Add water (10 mL) to the reaction solution, extract with ethyl acetate (15 mL × 2), combine the organic phases, wash successively with water (10 mL × 2) and saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product 2d (97 mg, yield: 100%), which is directly used in the next reaction.

[0868] MS m / z(ESI): 854.7 [M+1].

[0869] Step 4

[0870] (S)-3-amino-2-((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propionic acid formate 2-P1

[0871] (S)-3-amino-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propionic acid formate 2-P2

[0872] 2d (97 mg, 0.113 mmol) was placed in a reaction vial, dichloromethane (1 mL) was added, then hydrochloric acid dioxane solution (3 mL, 4N, purchased from Titan Scientific) was added, the reaction was stirred at room temperature for 2 hours, concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (3 mL), purified by high performance liquid chromatography (Waters-2545, chromatographic column Boston Phlex ODS C18, 30*150mm, 5um; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15-95%, flow rate: 30 mL / min) to obtain the target product 2-P2 (22 mg, yield: 27.7%) and 2-P1 (16 mg, yield: 20.2%).

[0873] Compound 2-P2 (shorter retention time):

[0874] High performance liquid chromatography: instrument model: Waters 2689-2495; chromatographic column: Waters Sunfire C18 4.6*75mm, 3.5um; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile (containing 0.1% formic acid); gradient ratio: acetonitrile 5-95%, flow rate: 1.0 mL / min, retention time 9.656 min.

[0875] MS m / z (ESI): 698.6 [M+1].

[0876] Compound 2-P1 (longer retention time):

[0877] High performance liquid chromatography: instrument model: Waters 2689-2495; chromatographic column: Waters Sunfire C18 4.6*75mm, 3.5um; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile (containing 0.1% formic acid); gradient ratio: acetonitrile 5-95%, flow rate: 1.0 mL / min, retention time 10.299 min.

[0878] MS m / z (ESI): 698.6 [M+1].

[0879] Example 2-3 1-P1 and 1-P2

[0880] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formic acid salt 1-P2

[0881] First step

[0882] (R)-4-(4-cyano-2-fluorophenyl)piperazine-2-carboxylic acid 3b

[0883] (R)-Piperazine-2-carboxylic acid dihydrochloride 3a (5.0 g, 24.62 mmol, commercially available from Bide) was mixed in dimethyl sulfoxide (24 mL) and water (6 mL), 3,4-difluorobenzonitrile 1d (4.1 g, 29.47 mmol, commercially available from Adamas) and N,N-diisopropylethylamine (11.2 g, 86.66 mmol, commercially available from Titan Scientific) were added successively, the reaction system was heated to 120 °C and stirred overnight. The reaction solution was directly filtered while hot, the filter cake was rinsed successively with acetonitrile (2 mL x 4) and n-hexane (3 mL x 3), the filter cake was collected and dried under vacuum to obtain the title product 3b (2.3 g, yield: 37.5%).

[0884] MS m / z (ESI): 250.3 [M+1].

[0885] Second step

[0886] (R)-1-(4-(((2-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)-4-(4-cyano-2-fluorophenyl)piperazine-2-carboxylic acid 3c

[0887] 3b (2.3 g, 9.23 mmol) and 1c (4.3 g, 8.31 mmol) were dissolved in dichloromethane (40 mL) and dimethyl sulfoxide (40 mL), N,N-diisopropylethylamine (2.4 g, 18.57 mmol) was added, the reaction was stirred at room temperature for 90 minutes. The reaction solution was filtered, the filtrate was collected, then water (200 mL), dichloromethane (100 mL) and ethanol (10 mL) were added to the filtrate, the organic phase was collected after separation, the aqueous phase was extracted with 5% ethanol in dichloromethane (80 mL x 3), the organic phases were combined, washed with water (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel column chromatography with eluent system C to obtain the title product 3c (2.57 g, yield: 40.6%).

[0888] MS m / z (ESI): 686.6 [M+1].

[0889] Third step

[0890] (R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxylic acid 3d

[0891] Dissolve 3c (2.2 g, 3.21 mmol) in acetonitrile (20 mL), add benzenesulfonic acid (1.78 g, 11.25 mmol, purchased from Acros), heat to 85 °C, stir for 4 hours. Cool the reaction to room temperature, concentrate under reduced pressure, purify the resulting residue by silica gel column chromatography using eluent system C to obtain the crude product, dissolve the crude product in dimethyl sulfoxide (3 mL), purify by high performance liquid chromatography (Waters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 10%-35%, flow rate: 30 mL / min) to obtain the title product 3d (720 mg, yield: 36.7%).

[0892] MS m / z (ESI): 612.6 [M+1].

[0893] Fourth Step

[0894] N 6 -(tert-butoxycarbonyl)-N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine tert-butyl ester 3e

[0895] Dissolve 3d (100 mg, 0.16 mmol) and N 6 -(tert-butoxycarbonyl)-L-lysine tert-butyl ester (55 mg, 0.16 mmol, purchased from Bide) in dichloromethane (3.5 mL), add 2-(7-azabenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (93 mg, 0.25 mmol, purchased from Bide) and triethylamine (58 mg, 0.57 mmol) in sequence, stir for 20 minutes at room temperature after the addition is complete. Concentrate the reaction under reduced pressure, purify the resulting residue by silica gel column chromatography using eluent system C to obtain the title product 3e (140 mg, yield: 95.6%).

[0896] MS m / z (ESI): 896.7 [M+1].

[0897] Fifth Step

[0898] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formic acid salt 1-P2

[0899] To a reaction vial was placed 3e (140 mg, 0.16 mmol), dichloromethane (1 mL), and a solution of hydrochloric acid in 1,4-dioxane (3 mL, 4 N, purchased from Titan Kogen). The reaction was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (3 mL) and purified by high performance liquid chromatography (Waters Autopurification, Column: Welch Xtimate Prep C18, 30*150 mm, 5 μm; Mobile phase: water phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-55%, flow rate: 30 mL / min) to give the target compound 1-P2 (17 mg, yield: 13.8%).

[0900] MS m / z (ESI): 740.5 [M+1].

[0901] 1 H NMR (500 MHz, DMSO-d6) δ 8.23-8.17 (m, 1H), 7.71-7.66 (m, 1H), 7.57-7.53 (m, 1H), 7.51-7.39 (m, 5H), 7.36-7.31 (m, 2H), 7.13 (t, 1H), 5.23 (s, 2H), 5.14-5.07 (m, 1H), 4.45-4.38 (m, 1H), 4.30-4.22 (m, 1H), 4.04-3.96 (m, 1H), 3.92 (d, 1H), 3.53 (d, 1H), 3.42-3.24 (m, 2H), 3.14-3.07 (m, 2H), 2.99-2.80 (m, 4H), 2.72-2.65 (m, 2H), 2.61-2.54 (m, 1H), 2.45-2.41 (m, 1H), 2.34-2.25 (m, 1H), 2.01-1.94 (m, 1H), 1.75-1.62 (m, 2H), 1.56-1.43 (m, 2H), 1.36-1.27 (m, 2H).

[0902] ((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-formic acid salt 1-P1

[0903] Prepared using the same method as 1-P2, except replacing 3a.

[0904] MS m / z (ESI): 740.2 [M+1].

[0905] 1H NMR (500 MHz, DMSO-d6) δ 8.08 - 8.03 (m, 1H), 7.73 - 7.67 (m, 1H), 7.60 - 7.52 (m, 3H), 7.52 - 7.47 (m, 1H), 7.46 - 7.42 (m, 2H), 7.37 - 7.31 (m, 2H), 7.09 (m, 1H), 5.24 (s, 2H), 5.14 - 5.07 (m, 1H), 4.46 - 4.39 (m, 1H), 4.32 - 4.24 (m, 1H), 3.92 - 3.82 (m, 2H), 3.63 (d, 1H), 3.42 - 3.30 (m, 2H), 3.21 - 3.14 (m, 2H), 3.05 - 2.86 (m, 4H), 2.78 - 2.71 (m, 2H), 2.61 - 2.56 (m, 1H), 2.47 - 2.42 (m, 1H), 2.30 - 2.21 (m, 1H), 2.04 - 1.94 (m, 1H), 1.75 - 1.60 (m, 2H), 1.58 - 1.42 (m, 2H), 1.39 - 1.27 (m, 2H).

[0906] Example 2-4 2-P1 and 2-P2

[0907] (S)-3-amino-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 2-P2

[0908] First Step

[0909] (S)-3-((tert-butoxycarbonyl)amino)-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid tert-butyl ester 4a

[0910] 3d (118 mg, 0.193 mmol) and 2c (63 mg, 0.242 mmol) were mixed well in dichloromethane (5 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (110 mg, 0.289 mmol, purchased from Bide) and triethylamine (69 mg, 0.682 mmol) were added in turn, and the mixture was stirred at room temperature for 30 minutes after the addition was completed. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system C to obtain the title product 4a (185 mg, yield: >100%).

[0911] MS m / z (ESI): 854.7 [M+1].

[0912] Second step

[0913] (S)-3-amino-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-2-carboxamido)propanoic acid-formic acid salt 2-P2

[0914] 4a (300 mg, 0.35 mmol) was placed in a reaction flask, dichloromethane (2 mL) was added, then a 1,4-dioxane solution of hydrochloric acid (6 mL, 4N, purchased from Titan Scientific) was added, the reaction was stirred at room temperature for 3 hours, concentrated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (5 mL), purified by high performance liquid chromatography (Waters Autopurification, column: ODS-BIO C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-45%, flow rate: 30 mL / min) to obtain the target product 2-P2 (130 mg, yield: 49.8%).

[0915] MS m / z (ESI): 698.5 [M+1].

[0916] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32-8.27 (m, 1H), 7.73-7.67 (m, 1H), 7.59-7.54 (m, 1H), 7.52-7.40 (m, 5H), 7.37-7.29 (m, 2H), 7.14 (t, 1H), 5.25 (s, 2H), 5.14-5.08 (m, 1H), 4.46-4.39 (m, 1H), 4.30-4.24 (m, 1H), 4.04-3.99 (m, 1H), 3.96 (d, 1H), 3.59 (d, 1H), 3.42-3.38 (m, 1H), 3.19-3.10 (m, 3H), 3.01-2.82 (m, 4H), 2.73-2.69 (m, 1H), 2.66-2.55 (m, 1H), 2.48-2.41 (m, 1H), 2.38-2.30 (m, 1H), 2.04-1.93 (m, 1H).

[0917] (S)-3-amino-2-((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formate salt 2-P1

[0918] Prepared in the same manner as 2-P2 by replacing 3d.

[0919] MS m / z (ESI): 698.6 [M+1].

[0920] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.19 (s, 1H), 8.15-8.10 (m, 1H), 7.74-7.67 (m, 1H), 7.60-7.54 (m, 3H), 7.53-7.43 (m, 3H), 7.38-7.30 (m, 2H), 7.14 (t, 1H), 5.25 (s, 2H), 5.14-5.07 (m, 1H), 4.48-4.40 (m, 1H), 4.32-4.23 (m, 1H), 3.94-3.82 (m, 2H), 3.65-3.58 (m, 1H), 3.41-3.31 (m, 1H), 3.23-3.17 (m, 1H), 3.15-3.09 (m, 1H), 3.09-3.00 (m, 2H), 2.95-2.86 (m, 2H), 2.78-2.71 (m, 2H), 2.61-2.55 (m, 1H), 2.48-2.41 (m, 1H), 2.30-2.22 (m, 1H), 2.05-1.95 (m, 1H).

[0921] Example 2-5

[0922] N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-N 6 -glycyl-L-lysine-formate salt 5

[0923] First step

[0924] 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl) glycinate ester 5b

[0925] To a solution of (tert-butoxycarbonyl)glycine 5a (Adamas, 361.0 mg, 2.06 mmol) in N,N-dimethylformamide (5 mL) was added N-hydroxysuccinimide (355.75 mg, 3.09 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (987.60 mg, 5.15 mmol). The reaction system was replaced with nitrogen for 3 times and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (50 mL x 3) and saturated sodium chloride solution (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title product 5b (462.0 mg, yield: 82.3%).

[0926] MS m / z (ESI): 295.2 [M+23].

[0927] Second step

[0928] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine 5c

[0929] To a solution of 3e (400.0 mg, 0.45 mmol) in dichloromethane (10 mL) was added hydrochloric acid-1,4-dioxane (3.5 mL) and stirred for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude title product 5c (265.5 mg, yield: 80.4%).

[0930] MS m / z (ESI): 740.4 [M+1].

[0931] Third step

[0932] N 6 -((tert-butoxycarbonyl)glycyl)-N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine 5d

[0933] To a solution of 5c (300.0 mg, 0.41 mmol) and 5b (220.8 mg, 0.81 mmol) in N,N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (157.2 mg, 1.22 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was purified by high performance liquid chromatography (Waters, column: Kromasil C18, 50*250 mm, 10 μm; mobile phase: water phase (containing 0.1% ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 15%-95%, flow rate: 80 mL / min) to give the title product 5d (240.0 mg, yield: 66.0%).

[0934] MS m / z (ESI): 897.4 [M+1].

[0935] Fourth step

[0936] N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-N 6 -glycyl-L-lysine-formate 5

[0937] To a solution of 5d (200.0 mg, 0.22 mmol) in dichloromethane (10.0 mL) was added hydrochloric acid-1,4-dioxane (3.5 mL) and the reaction was stirred for 30 minutes. The reaction was purified by high performance liquid chromatography (Waters, column: Kromasil C18, 50*250 mm, 10 μm; mobile phase: water phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 10%-30%, flow rate: 80 mL / min) to give the title product 5 (90.0 mg, yield: 50.7%).

[0938] MS m / z (ESI): 797.4 [M+1].

[0939] 1H NMR (500 MHz, DMSO) δ 8.35 (s, 1H), 8.28-8.20 (m, 1H), 8.10-8.03 (m, 1H), 7.71-7.64 (m, 1H), 7.57-7.51 (m, 1H), 7.51-7.39 (m, 5H), 7.36-7.29 (m, 2H), 7.11 (t, 1H), 5.23 (s, 2H), 5.15-5.08 (m, 1H), 4.46-4.38 (m, 1H), 4.31-4.23 (m, 1H), 4.07-3.99 (m, 1H), 3.93 (d, 1H), 3.54 (d, 1H), 3.42-3.34 (m, 2H), 3.33-3.26 (m, 1H), 3.15-3.06 (m, 2H), 3.03-2.80 (m, 5H), 2.62-2.55 (m, 2H), 2.48-2.40 (m, 1H), 2.4-2.25 (m, 1H), 2.03-1.95 (m, 1H), 1.79-1.57 (m, 2H), 1.40-1.30 (m, 2H), 1.29-1.20 (m, 2H).

[0940] Example 2-6

[0941] (S)-3-(2-aminopropanoylamino)-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido) propanoic acid - formate salt 6

[0942] First step

[0943] (S)-3-amino-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid tert-butyl ester 6a

[0944] 4a (109.0 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL), hydrochloric acid-1,4-dioxane (1 mL) was added, the reaction was stirred for 10 minutes, and directly concentrated under reduced pressure to obtain the crude title product 6a (67.00 mg, yield: 69.6%), which was directly used in the next step.

[0945] MS m / z (ESI): 754.5 [M+1].

[0946] Second step

[0947] (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-2-((R)-4-(4-cyano-2- fluorophenyl)-1 -(4-(((2-(S)-2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid tert-butyl ester 6b

[0948] To a solution of 5b (39.73 mg, 0.15 mmol) and 6a (55.00 mg, 0.073 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (28.29 mg, 0.22 mmol) and stirred at room temperature for 30 min. The reaction mixture was purified by high performance liquid chromatography (Waters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: water phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 45%-75%, flow rate: 30 mL / min) to give the title product 6b (50.0 mg, yield: 75.2%).

[0949] MS m / z (ESI): 911.6 [M+1].

[0950] Third step

[0951] (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-2-((R)-4-(4-cyano-2- fluorophenyl)-1 -(4-(((2-(S)-2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid- formic acid salt 6

[0952] To a solution of 6b (30.0 mg, 0.033 mmol) in dichloromethane (4.5 mL) was added hydrochloric acid-1,4-dioxane (1.5 mL) and stirred for 4 h. The reaction mixture was purified by high performance liquid chromatography (Waters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: water phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 10%-50%, flow rate: 30 mL / min) to give the title product 6 (10.0 mg, yield: 39.9%).

[0953] MS m / z (ESI): 755.4 [M+1].

[0954] 1H NMR (500 MHz, DMSO-d6) δ 8.37-8.33 (m, 1H), 8.28-8.25 (m, 2H), 7.67 (d, 1H), 7.54 (d, 1H), 7.53-7.41 (m, 5H), 7.33 (d, 2H), 7.14 (t, 1H), 5.23 (s, 2H), 5.12 (dd, 1H), 4.42 (d, 1H), 4.27 (d, 1H), 4.16-4.12 (m, 1H), 3.94 (d, 1H), 3.64-3.55 (m, 2H), 3.36-3.43 (m, 3H), 3.29-3.23 (m, 2H), 3.13-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.80 (d, 1H), 2.58 (d, 1H), 2.50-2.42 (m, 1H), 2.25 (t, 1H), 2.05-1.95 (m, 1H).

[0955] Example 2-7

[0956] (S)-3-(2-((S)-2-amino-3-phenylpropanamido)acetamido)-2-((R)-4-(4-cyano-2- fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 7

[0957] First step

[0958] (Boc)-L-phenylalanyl glycine 7b

[0959] L-phenylalanyl glycine 7a (Shawm, 437.00 mg, 1.97 mmol) was dissolved in dichloromethane (8 mL), di-tert-butyl dicarbonate (858.30 mg, 3.93 mmol) and N,N-diisopropyl ethylamine (1.02 g, 7.89 mmol) were added, the reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title crude product 7b (600.00 mg, yield: 94.7%).

[0960] MS m / z (ESI): 323.3 [M+1].

[0961] Second step

[0962] 2,5-dioxopyrrolidin-1-yl (Boc)-L-phenylalanyl glycine ester 7c

[0963] To a solution of 7b (123.00 mg, 0.38 mmol) in N,N-dimethylformamide (3 mL) was added N-hydroxysuccinimide (87.83 mg, 0.76 mmol) and l-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (219.44 mg, 1.14 mmol). The reaction system was replaced with nitrogen for 3 times and stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (50 mL x 3) and saturated sodium chloride solution (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title product 7c (120.00 mg, yield: 75.0%).

[0964] MS m / z (ESI): 839.4 [2M+1].

[0965] Third step

[0966] (S)-3-(2-((S)-2-amino-3-phenylpropanamido)acetamido)-2-((R)-4-(4-cyano-2- fluorophenyl)-l-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 7

[0967] To a solution of compound 7c (126.00 mg, 0.19 mmol) and compound 6a (117.00 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) was added N,N- diisopropylethylamine (60.18 mg, 0.47 mmol). The reaction was stirred at room temperature for 30 minutes and purified by high performance liquid chromatography (GILSON, column: Phlex ODS C18, 30*150 mm, 5 μm; mobile phase: water phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%-95%, flow rate: 30 mL / min) to obtain the title product 7d (130.00 mg, yield: 79.2%).

[0968] MS m / z (ESI): 1058.9 [M+1].

[0969] Fourth step

[0970] (S)-3-(2-((S)-2-amino-3-phenylpropanamido)acetamido)-2-((R)-4-(4-cyano-2- fluorophenyl)-l-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid-formic acid salt 7

[0971] To a solution of 7d (20.0 mg, 0.019 mmol) in dichloromethane (1.0 mL) was added hydrochloric acid-1,4-dioxane (3.0 mL) and stirred for 4 h. The reaction mixture was purified by HPLC (Waters, Column: ODS-BIO C18, 30*250 mm, 5 μm; mobile phase: water phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 10%-95%, flow rate: 30 mL / min) to give the title product 7 (8.0 mg, yield: 44.7%).

[0972] MS m / z (ESI): 902.5 [M+1].

[0973] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.68 (s, 1H), 8.20-8.12 (m, 2H), 7.71-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.52-7.39 (m, 5H), 7.34-7.27 (m, 4H), 7.25-7.18 (m, 3H), 7.12 (t, 1H), 5.22 (s, 2H), 5.11 (dd, 1H), 4.45-4.37 (m, 1H), 4.29-4.21 (m, 1H), 3.98-3.87 (m, 2H), 3.80 (t, 1H), 3.72-3.63 (m, 1H), 3.59-3.47 (m, 3H), 3.42-3.35 (m, 1H), 3.31-3.25 (m, 1H), 3.11-3.01 (m, 3H), 2.98-2.85 (m, 2H), 2.84-2.77 (m, 2H), 2.64-2.54 (m, 1H), 2.47-2.39 (m, 1H), 2.28 (t, 1H), 2.02-1.94 (m, 1H), 2.30 (t, 1H), 2.00-1.93 (m, 1H).

[0974] Example 2-8

[0975] N 6 -L-phenylalanyl-glycyl-N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-2,2,2- trifluoroacetate salt 8

[0976] First step

[0977] ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine tert-butyl ester 8a

[0978] Compound 3e (186 mg, 0.21 mmol) was dissolved in dichloromethane (4 mL), hydrochloric acid-1,4-dioxane (1 mL) was added, and the reaction was stirred at room temperature for 7 minutes. The reaction was directly concentrated under reduced pressure to obtain the crude title product 8a (174 mg), which was used directly in the next step without purification.

[0979] MS m / z (ESI): 796.5 [M+1].

[0980] Second Step

[0981] N 6 -(tert-butoxycarbonyl)-L-phenylalanylglycyl-N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine tert-butyl ester 8b

[0982] Compound 8a (50 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), N,N- diisopropylethylamine (24 mg, 0.19 mmol) was added, and then compound 7c (51 mg, 0.12 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system C to obtain the title product 8b (28 mg, yield: 42.4%).

[0983] MS m / z (ESI): 1100.7 [M+1].

[0984] Third Step

[0985] N 6 -L-phenylalanylglycyl-N 2 -((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-L-lysine-2,2,2- trifluoroacetate salt 8

[0986] Compound 8b (28 mg, 0.025 mmol) was dissolved in dichloromethane (0.5 mL), hydrochloric acid 1,4-dioxane (2 mL) was added, and the reaction was stirred at room temperature for 3 hours. Purification by high performance liquid chromatography (Waters, column: ODS-BIO C18, 30*250 mm, 5 μm (Xtimate C18); mobile phase: aqueous phase (containing 0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 20%-60%, flow rate: 30 mL / min) gave the title product 8 (22 mg, yield: 81.7%).

[0987] MS m / z (ESI): 944.6 [M+1].

[0988] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.71 (t, 1H), 8.12 (s, 2H), 7.91 (t, 1H), 7.74 (d, 1H), 7.59 (d, 1H), 7.54-7.43 (m, 4H), 7.35-7.29 (m, 4H), 7.29-7.24 (m, 3H), 7.23-7.16 (m, 1H), 5.27 (s, 2H), 5.14-5.08 (m, 1H), 4.45-4.38 (m, 1H), 4.30-4.23 (m, 1H), 4.23-4.19 (m, 1H), 4.10-4.05 (m, 1H), 3.78 (d, 1H), 3.75 (d, 2H), 3.71 (d, 2H), 3.68 (d, 1H), 3.52-3.35 (m, 1H), 3.28-3.17 (m, 1H), 3.13-3.06 (m, 2H), 3.04-2.99 (m, 2H), 2.95-2.87 (m, 2H), 2.61-2.54 (m, 1H), 2.46-2.33 (m, 2H), 2.03-1.94 (m, 2H), 1.78-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.47-1.36 (m, 2H), 1.36-1.27 (m, 2H).

[0989] Example 2-9

[0990] (S)-3-amino-2-((2R,5R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)-5-methylpiperazine-2-carboxamido)propanoic acid hydrochloride 9

[0991] MS m / z (ESI): 712.3 [M+1].

[0992] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28-8.23 (m, 1H), 8.14 (s, 1H), 7.73-7.67 (m, 1H), 7.56-7.41 (m, 6H), 7.37-7.29 (m, 2H), 7.23 (t, 1H), 5.25 (s, 2H), 5.15-5.07 (m, 1H), 4.46-4.39 (m, 1H), 4.30-4.23 (m, 1H), 3.88 (d, 1H), 3.70-3.58 (m, 2H), 3.49-3.40 (m, 1H), 3.23-3.15 (m, 2H), 3.11-3.04 (m, 1H), 2.95-2.84 (m, 2H), 2.66-2.54 (m, 3H), 2.48-2.41 (m, 1H), 2.28-2.20 (m, 1H), 2.02-1.93 (m, 1H), 0.92-0.87 (m, 3H).

[0993] Example 2-10

[0994] (S)-3-amino-2-((R)-4-(4-aminocarbonyl-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid hydrochloride 10

[0995] MS m / z (ESI): 716.2 [M+1].

[0996] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28-8.23 (m, 1H), 8.14 (s, 1H), 7.73-7.67 (m, 1H), 7.56-7.41 (m, 6H), 7.37-7.29 (m, 2H), 7.23 (t, 1H), 5.25 (s, 2H), 5.15-5.07 (m, 1H), 4.46-4.39 (m, 1H), 4.30-4.23 (m, 1H), 3.88 (d, 1H), 3.70-3.58 (m, 2H), 3.49-3.40 (m, 1H), 3.23-3.15 (m, 2H), 3.11-3.04 (m, 1H), 2.95-2.84 (m, 2H), 2.66-2.54 (m, 3H), 2.48-2.41 (m, 1H), 2.28-2.20 (m, 1H), 2.02-1.93 (m, 1H), 0.92-0.87 (m, 3H).

[0997] Example 2-11

[0998] (S)-3-amino-2-((R)-1-(2-amino-4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)-4-(4-cyano-2-fluorophenyl)piperazine-2- carboxamido)propanoic acid dihydrochloride salt 11

[0999] MS m / z (ESI): 713.2 [M+1].

[1000] 1 H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.23-8.09 (m, 2H), 7.76 (d, 1H), 7.64-7.60 (m, 1H), 7.51-7.44 (m, 1H), 7.36-7.19 (m, 4H), 7.17-7.08 (m, 1H), 6.97-6.60 (m, 2H), 5.20-5.09 (m, 3H), 4.65-4.59 (m, 1H), 4.45-4.39 (m, 1H), 4.29-4.22 (m, 1H), 4.08-3.91 (m, 2H), 3.63-3.56 (m, 1H), 3.19-2.87 (m, 6H), 2.64-2.57 (m, 3H), 2.46-2.38 (m, 2H), 2.05-1.95 (m, 2H).

[1001] Example 2-12

[1002] (S)-3-amino-2-((R)-4-(2,4-dicyanophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid hydrochloride salt 12

[1003] MS m / z (ESI): 705.3 [M+1].

[1004] 1H NMR (500 MHz, DMSO-de) δ 10.97 (s, 1H), 8.35-8.29 (m, 1H), 8.25-8.06 (m, 2H), 8.04-7.96 (m, 1H), 7.59-7.47 (m, 5H), 7.37-7.30 (m, 2H), 5.29 (s, 2H), 5.16-5.09 (m, 1H), 4.68-4.60 (m, 1H), 4.47-4.40 (m, 1H), 4.31-4.24 (m, 1H), 3.99-3.80 (m, 1H), 3.39-3.28 (m, 4H), 3.21-3.10 (m, 2H), 2.98-2.87 (m, 1H), 2.66-2.57 (m, 3H), 2.48-2.41 (m, 2H), 2.04-1.96 (m, 2H).

[1005] Example 2-13

[1006] (S)-3-amino-2-((R)-4-(2-aminocarbonyl-4-cyanophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carboxamido)propanoic acid hydrochloride salt 13

[1007] MS m / z (ESI): 723.3 [M+1];

[1008] 1 H NMR (500 MHz, DMSO-de) δ 10.97 (s, 1H), 8.35-8.29 (m, 1H), 8.25-8.06 (m, 2H), 8.04-7.96 (m, 1H), 7.59-7.47 (m, 5H), 7.37-7.30 (m, 2H), 5.29 (s, 2H), 5.16-5.09 (m, 1H), 4.68-4.60 (m, 1H), 4.47-4.40 (m, 1H), 4.31-4.24 (m, 1H), 3.99-3.80 (m, 1H), 3.39-3.28 (m, 4H), 3.21-3.10 (m, 2H), 2.98-2.87 (m, 1H), 2.66-2.57 (m, 3H), 2.48-2.41 (m, 2H), 2.04-1.96 (m, 2H).

[1009] Example 3-1 LD-1 and LD-2

[1010] N 2- ((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-N 6 - (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L- phenylalanylglycyl-L-lysine LD-1

[1011] N 2 - ((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-2-carbonyl)-N 6 - (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L- phenylalanylglycyl-L-lysine LD-2

[1012] (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)glycylglycyl-L- phenylalanylglycine LD-1a (50 mg, 0.094 mmol, prepared by the method disclosed in the specification of patent application “WO2023037268A1, page 149, example 8, compound 8-12”) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (21.8 mg, 0.189 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (36.3 mg, 0.189 mmol) were added, the reaction system was replaced with nitrogen three times, and stirred at 25 °C for 16 hours.

[1013] 1-P2 (18 mg, 0.022 mmol) and N,N-diisopropylethylamine (10.9 mg, 0.084 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) and added to the above reaction solution, and after addition, stirring was continued for 90 minutes. The reaction solution was purified by high performance liquid chromatography (Waters-2545, chromatographic column BostonPhlex ODS C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25-95%, flow rate: 30 mL / min) to obtain the target product LD-2 (9 mg, yield: 31.4%).

[1014] MS m / z (ESI): 1251.5 [M+1].

[1015] LD-1a (27.9 mg, 0.052 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N-hydroxysuccinimide (12.1 mg, 0.105 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.2 mg, 0.105 mmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[1016] 1-P1 (10 mg, 0.012 mmol) and N,N-diisopropylethylamine (6.1 mg, 0.046 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) and added to the above reaction solution. After the addition was complete, the mixture was stirred for 90 minutes. The reaction solution was purified by high performance liquid chromatography (Wasters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-50%, flow rate: 30 mL / min) to obtain the target product LD-1 (5 mg, yield: 31.4%).

[1017] MS m / z (ESI): 1251.5 [M+1].

[1018] Example 3-2 LD-3 and LD-4

[1019] (2S,9S)-9-benzyl-2-((S)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-2-carboxamido)-22-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-5,8,11,14,17-pentaoxo-4,7,10,13,16-pentazacosanoic acid LD-3

[1020] (2S,9S)-9-benzyl-2-((R)-4-(4-cyano-2-fluorophenyl)-1-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-2-carboxamido)-22-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-5,8,11,14,17-pentaoxo-4,7,10,13,16-pentazacosanoic acid LD-4

[1021] LD-1a (32.6 mg, 0.062 mmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (12.7 mg, 0.11 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) were added, the reaction system was replaced with nitrogen for three times, and stirred at 25 °C for 16 hours.

[1022] 2-P2 (10 mg, 0.013 mmol) and N,N-diisopropylethylamine (6.4 mg, 0.049 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and added to the above reaction solution, and after the addition, stirring was continued for 90 minutes. The reaction solution was purified by high performance liquid chromatography (Waters-2545, chromatographic column BostonPhlex ODS C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30-95%, flow rate: 30 mL / min) to obtain the target product LD-4 (7 mg, yield: 43.2%).

[1023] MS m / z (ESI): 1209.4 [M+1].

[1024] LD-1a (32.6 mg, 0.062 mmol) was dissolved in N,N-dimethylformamide (2 mL), N-hydroxysuccinimide (12.7 mg, 0.11 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) were added, the reaction system was replaced with nitrogen for three times, and stirred at 25 °C for 16 hours.

[1025] 2-P1 (10 mg, 0.013 mmol) and N,N-diisopropylethylamine (6.4 mg, 0.049 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and added to the above reaction solution, and after the addition, stirring was continued for 90 minutes. The reaction solution was purified by high performance liquid chromatography (Waters-2545, chromatographic column BostonPhlex ODS C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30-95%, flow rate: 30 mL / min) to obtain the target product LD-3 (6 mg, yield: 37.0%).

[1026] MS m / z (ESI): 1209.4 [M+1].

[1027] Example 3-3 LD-2 and LD-1

[1028] N 2- ((R)-4-(4-cyano-2-fluorophenyl)- 1 -(4-(((2-((S)-2, 6-dioxopiperidin-3-yl)- 1 - oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-2-yl)-N 6 - (6-(2, 5-dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)hexanoyl)glycylglycyl-L-phenylalanyl- glycyl-L-lysine LD-2

[1029] LD-1a (61.4 mg, 0.116 mmol) was dissolved in N,N-dimethylformamide (1 mL), N- hydroxysuccinimide (26.6 mg, 0.231 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (44.4 mg, 0.231 mmol) were added, the reaction system was replaced with nitrogen three times, and stirred at 25 °C for 16 hours.

[1030] Compound 1-P2 (45 mg, 0.058 mmol) and N,N-diisopropylethylamine (22.5 mg, 0.174 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) and added to the above reaction solution, and after addition, stirring was continued for 90 minutes. The reaction solution was purified by high performance liquid chromatography (Waters-2545, chromatographic column Boston Phlex ODS C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25-95%, flow rate: 30 mL / min) to obtain the target product LD-2 (16 mg, yield: 22.2%).

[1031] MS m / z (ESI): 1251.5 [M+1].

[1032] 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.32-8.27 (m, 1H), 8.23-8.17 (m, 1H), 8.13-8.05 (m, 2H), 8.05-7.99 (m, 1H), 7.72-7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.57-7.53 (m, 1H), 7.50-7.43 (m, 3H), 7.43-7.38 (m, 2H), 7.35-7.30 (m, 2H), 7.27-7.20 (m, 4H), 7.19-7.10 (m, 2H), 6.98 (s, 2H), 5.24 (s, 2H), 5.11 (dd, 1H), 4.51-4.39 (m, 2H), 4.29-4.23 (m, 1H), 4.19-4.12 (m, 1H), 3.91 (d, 1H), 3.77-3.56 (m, 7H), 3.53-3.47 (m, 2H), 3.42-3.35 (m, 4H), 3.27-3.21 (m, 1H), 3.20-3.14 (m, 2H), 3.07-2.94 (m, 4H), 2.92-2.75 (m, 3H), 2.65-2.54 (m, 1H), 2.47-2.41 (m, 1H), 2.32-2.24 (m, 1H), 2.14-2.06 (m, 2H), 2.04-1.96 (m, 1H), 1.77-1.62 (m, 2H), 1.52-1.43 (m, 4H), 1.39-1.33 (m, 1H), 1.31-1.26 (m, 1H), 1.22-1.14 (m, 2H).

[1033] LD-1a (13.6 mg, 0.025 mmol) was dissolved in N,N-dimethylformamide (1 mL), N-hydroxysuccinimide (4.5 mg, 0.039 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (7.4 mg, 0.038 mmol) were added, the reaction system was replaced with nitrogen three times, and stirred at 25 °C for 16 hours.

[1034] Compound 1-P1 (10 mg, 0.0...

Claims

1. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug linked to the ligand, wherein the drug comprises a structure as shown in formula (D-H): wherein: X is -CR a R b - or -C(O)-; Y 1 , Y 2 , Y 3 and Y 4 is carbon atom, the other three are the same or different, and each independently is nitrogen atom or CR 29 ; Z is selected from -0-, -S(O) p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -; V is a chemical bond or -(CR d R dd ) n1 -; U is -(CR e R f ) n1 -; R 5 is selected from a chemical bond, -(CR g R h ) n -, p - and -NR i -; R 6 is selected from a chemical bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii -C(O)-, -C(O)-NR ii -, -NR ii -S(O) p -, -S(O) p -NR ii -, -NR ii -(CR j R jj ) n -, -(CR j R jj ) n -NR ii -, R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n -, -O-, -C(O)-, -NR 12 -, -S(O) p -, -(CR k R kk ) n -O-, -O-(CR k R kk ) n -, -(CR k R kk ) n -C(O)-, -C(O)-(CR k R kk ) n -, -(CR k R kk ) n -NR 12 -, -NR 12 -(CR k R kk ) n -, -(CR k R kk ) n -S(O) p -, -S(O) p -(CR k R kk ) n -, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(=NR 13 )-NR 12 -, -NR 12 -C(=NR 13 )-, -O-C(O)-NR 12 -, -NR 12 -C(O)-O-, -NR 12 -C(O)-NR 12 -, -NR 12 -S(O) p -, -S(O) p -NR 12 -, -NR 12 -S(O) p -C(=NR 13 )-, -C(=NR 13 )-S(O) p -NR 12 - and each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 8 is a chemical bond or -(CR m R n ) n -; R 10 a chemical bond, rings A, B and C are identical or different and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 , R 3 , R 4 , and R 29 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m -C(O)OR u , -(CR p R q ) m -OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m -C(=NR 13 )NR s R t , -(CR p R q ) m -S(O) p R u , -(CR p R q ) m -S(O) p NR s R t , -(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, cyano, nitro, -OR z , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 , -(CR w1 R w2 ) u -C(O)R 14 , -(CR w1 R w2 ) u -C(O)OR 14 , -(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O) p R 14 ; or two adjacent R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 1 selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, and a hydroxyalkyl group; R 35 , R u4 , R u5 , R u6 and R u7 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30a R 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , -(CR 30a R 30b ) p4 -S(O) p -R 33 , -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 one or more substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 , R 11 , R 12 , R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 and R v2 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 15b , an alkylene-COOR 15b , -NR 16a R 16b , an alkylene-NR 16a R 16b , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R j , R jj , R k , R kk , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclyl, -(CR w3 R w4 ) u -aryl, and -(CR w3 R w4 ) u - heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R w3 , R w4 , R 15a , R 15b , R 16a , and R 16b are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R cc together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R d and R dd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R j and R jj together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R k and R kk together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R p and R q together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w1 and R w2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 30a and R 30b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w3 and R w4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more, the same or different, substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; or R s and R t together with the nitrogen atom to which they are attached form a heterocyclyl group, or R u1 and R u2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R v1 and R v2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 31 and R 32 together with the nitrogen atom to which they are attached form a heterocyclyl group; wherein said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR L , hydroxyalkyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R L is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being independently optionally substituted with one or more identical or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group; p is 0, 1 or 2; r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6; n1 is 0, 1, 2, 3, 4, 5 or 6; p4 is 0, 1, 2, 3, 4, 5 or 6; p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and u is 0, 1, 2, 3, 4, 5 or 6.

2. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

3. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a ligand-drug conjugate of the general formula (I) or a pharmaceutically acceptable salt thereof: wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody; L is a linker connecting Ab and D; wherein: Ab-(L-D) y (I) each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; rings A, B and C are identical or different and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; D a structure according to formula (D-H): p is 0, 1 or 2; X is -CR a R b - or -C(O)-; Y 1 , Y 2 , Y 3 and Y 4 is carbon atom, the remaining three are the same or different, and each independently is a nitrogen atom or CR 29 ; Z is selected from -0-, -S(O)0-2- p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -; V is a chemical bond or -(CR d R dd ) n1 -; U is -(CR e R f ) n1 -; R 5 is selected from a chemical bond, -(CR g R h ) n -, -C(O)-, -S(O) p - and -NR i -; R 6 is selected from a chemical bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii -C(O)-, -C(O)-NR ii -, -NR ii -S(O) p -, -S(O) p -NR ii -, -NR ii -(CR j R jj ) n -, -(CR j R jj ) n -NR ii -, R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n -, -O-, -C(O)-, -NR 12 -, -S(O) p -, -(CR k R kk ) n -O-, -O-(CR k R kk ) n -, -(CR k R kk ) n -C(O)-, -C(O)-(CR k R kk ) n -, -(CR k R kk ) n -NR 12 -, -NR 12 -(CR k R kk ) n -, -(CR k R kk ) n -S(O) p -, -S(O) p -(CR k R kk ) n -, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(=NR 13 )-NR 12 -, -NR 12 -C(=NR 13 )-, -O-C(O)-NR 12 -, -NR 12 -C(O)-O-, -NR 12 -C(O)-NR 12 -, -NR 12 -S(O) p -, -S(O) p -NR 12 -, -NR 12 -S(O) p -C(=NR 13 )-, -C(=NR 13 )-S(O) p -NR 12 - and r is 0, 1, 2, 3, 4, 5 or 6; R 8 is a chemical bond or -(CR m R n ) n -; R 10 a chemical bond, s is 0, 1, 2, 3, 4, 5 or 6; R 2 , R 3 , R 4 and R 29 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m -C(O)OR u , -(CR p R q ) m -OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m -C(=NR 13 )NR s R t , -(CR p R q ) m -S(O) p R u , -(CR p R q ) m -S(O) p NR s R t , -(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, cyano, nitro, -OR z , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 , -(CR w1 R w2 ) u -C(O)R 14 , -(CR w1 R w2 ) u -C(O)OR 14 , -(CR w1 R w2 ) u -C(O)-NR v1 R v2 and -(CR w1 R w2 ) u -S(O) p R 14 ; or two adjacent R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 1 selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, and a hydroxyalkyl group; R 35 , R u4 , R u5 , R u6 and R u7 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30a R 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , -(CR 30a R 30b ) p4 -S(O) p -R 33 , -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 one or more of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93 R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 , R 11 , R 12 , R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 and R v2 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 15b , an alkylene-COOR 15b , -NR 16a R 16b , an alkylene-NR 16a R 16b , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R j , R jj , R k , R kk , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR w3 R w4 ) u - cycloalkyl group, -(CR w3 R w4 ) u - heterocyclyl group, -(CR w3 R w4 ) u - aryl group, and -(CR w3 R w4 ) u - heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R w3 , R w4 , R 15a , R 15b , R 16a and R 16b are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R cc together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R d and R dd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R j and R jj together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R k and R kk together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R p and R q together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w1 and R w2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 30a and R 30b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w3 and R w4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more, the same or different, substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; or R s and R t together with the nitrogen atom to which they are attached form a heterocyclyl group, or R u1 and R u2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R v1 and R v2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 31 and R 32 together with the nitrogen atom to which they are attached form a heterocyclyl group; wherein said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, cyano, nitro, -OR L , hydroxyalkyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R L is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group; t is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6; n1 is 0, 1, 2, 3, 4, 5 or 6; p4 is 0, 1, 2, 3, 4, 5 or 6; p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; u is 0, 1, 2, 3, 4, 5 or 6; and y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8. ​ ​ ​ 4. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Z is -O- or -NR. 11 -, where R 11 As defined in claim 1; preferably, Z is -O-.

5. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein V is -(CR d R dd ) n1 - wherein R d , R dd and n1 are as defined in claim 1 ; preferably, V is -CR d R dd - wherein R d and R dd are as defined in claim 1.

6. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein U is -CR e R f - wherein R e and R f are as defined in claim 1.

7. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein one of Y 1 , Y 2 , Y 3 , and Y 4 is a carbon atom, the remaining three are the same or different, and each is independently CR 29 ; or one of Y 1 , Y 2 , Y 3 , and Y 4 is a carbon atom, one of the remaining three is a nitrogen atom, the remaining two are the same or different, and each is independently CR 29 , wherein R 29 is as defined in claim 1.

8. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein ring B is a 3- to 12-membered heterocyclyl; preferably, ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; more preferably, ring B is a 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms; most preferably, ring B is a piperazinyl.

9. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein D is represented by formula (D-I-H): wherein ring B is a 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s and t are as defined in claim 1.

10. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein X is -CR a R b - wherein R a and R b are as defined in claim 1.

11. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 is a hydrogen atom.

12. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is a phenyl.

13. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring C is a phenyl.

14. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R d , R dd , R e and R f are each a hydrogen atom.

15. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 10 is a chemical bond or wherein R 35 , R 36 and w are as defined in claim 1 ; preferably, R 10 is a chemical bond.

16. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein D is represented by formula (D-II-H): wherein R 2 to R 9 r, s and t are as defined in claim 1.

17. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein -L- is -L 1 -L 2 -L 3 -L 4 -, and L 1 -(CR 1 -C(O)-, -(succinimid-3-yl-N)-W 1 -W 2 -C(O)-, -(succinimid-3-yl-N)-W 1 -, 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -W 1 -, 1 -(CR 20a R 20b -CR 20c R 20d -O) q -W 1 -, 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, -(succinimid-3-yl-N)-W 1 -(CR 20a R 20b -CR 20c R 20d -O) q -C(O)-, -(succinimid-3-yl-N)-W 1 -NR 17 -C(O)-, -C(O)-NR 17 -W 1 -C(O)-, -W 1 -C(O)-NR 17 -W 1 -C(O)-, -C(O)-W 1 -C(O)-, wherein q is an integer from 0 to 20; L 2 selected from -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-, -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-, -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-, -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-NR 18 -, -W 1 -C(O)-, -NR 18 -W 1 -C(O)-NR 18 -, -S-(CR 21e R 21f ) p1 -C(O)-, -NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -O-W 1 -C(O)-NR 18 -, -NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-, -NR 18 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -O-W 1 -NR 18 -C(O)-, -NR 18 -W 1 -W 2 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-W 1 -O-W 1 -C(O)-, -NR 18 -W 1 -W 2 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -W 2 -W 1 -C(O)- and a chemical bond, wherein v is an integer from 0 to 20, pi is an integer from 0 to 20; L 3 a peptide residue consisting of 1 to 12 amino acid residues, wherein the amino acid residues are selected from the group consisting of amino acid residues formed from phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid, and asparagine, and are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 22a R 22b ) p2 - cycloalkyl, -(CR 22a R 22b ) p2 - heterocyclyl, -(CR 22a R 22b ) p2 - aryl, -(CR 22a R 22b ) p2 - heteroaryl, -(CR 22a R 22b ) p2 - SR 25 , -(CR 22a R 22b ) p2 - COOR 25 , -(CR 22a R 22b ) p2 - NR 23 R 24 , -(CR 22a R 22b ) p2 - C(O)-NR 23 R 24 , -(CR 22a R 22b ) p2 - NR 25 - C(=NR 25 )-NR 23 R 24 , and -(CR 22a R 22b ) p2 - NR 25 - C(O)-NR 23 R 24 , are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; wherein p2 is an integer from 0 to 20, *1 is attached to the left end of L 2 , and *2 is attached to the right end of L 4 ; L 4 -NR 19 -W 1 -, -C(O)NR 19 -, -NR 19 C(O)-, -NR 19 -W 1 -C(O)-, -C(O)-NR 19 -W 1 -, -NR 19 -W 2 -W 1 -, -NR 19 -W 2 -W 1 -O-C(O)- and a chemical bond; W 2 The group is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from oxo groups, halogens, sugars, and uronic acids (e.g., ...). one or more same or different substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; W 1 , W 3 , and W 5 are the same or different and each independently is -(CR 26a R 26b ) p3 - wherein p3 is an integer from 1 to 20; W 4 -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group; R 17 , R 18 , R 19 and R 25 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; R 23 and R 24 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted with one or more same or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R 23 and R 24 together with the carbon atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 20a , R 20b , R 20c , R 20d , R 21a , R 21b , R 21c , R 21d , R 21e , R 21f , R 22a , R 22b , R 26a and R 26b are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R 20a and R 20b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 20c and R 20d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21a and R 21b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21c and R 21d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21e and R 21f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 22a and R 22b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 26a and R 26b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more, the same or different, substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; Preferably, -L- is -L 1 -L 2 -L 3 -L 4 - and L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-; L 2 is a chemical bond; L 3 a peptide residue consisting of 1 to 4 amino acid residues (i.e. a mono-, di-, tri- and tetrapeptide residue), wherein the amino acid residues are selected from the group consisting of phenylalanine (F), alanine (A), glycine (G), cysteine (C), valine (V), lysine (K), citrulline (Cit), serine (S), glutamine (Q), glutamic acid (E), aspartic acid (D) and asparagine (N); preferably, L 3 is selected from the group consisting of G, F, GG, GF, FG, VA, valine-citrulline (Val-Cit), GGF, GFG and GGFG (SEQ ID NO: 16); more preferably, L 3 is GGF, GFG and GGFG (SEQ ID NO: 37); still more preferably, L 3 is GGFG (SEQ ID NO: 37); or L 3 To wherein *1 is attached to L 2 and *2 is attached to L 4 and *2 is attached to L W 4 -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group; L 4 -NR 19 -W 2 -W 1 -O-C(O)- or a direct bond; W 1 , W 3 , and W 5 are the same or different and each independently -(CR 26a R 26b ) p3 , R 26a and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, p3 is 1, 2, 3, 4, 5 or 6 W 2 For phenyl, substituted phenyl or substituted phenyl; R 19 is a hydrogen atom; wherein L of said -L- is 1 attached to Ab, L 4 attached to D; More preferably, -L- is -L 1 -L 2 -L 3 -L 4 - and L 1 is -(succinimid-3-yl-N)-W 1 -C(O)-, wherein W 1 is -(CR 26a R 26b ) p3 -, R 26a and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl, p3 is 1, 2, 3, 4, 5 or 6; L 2 is a chemical bond; L 3 a peptide residue consisting of 1 to 4 amino acid residues (i.e. a mono-, di-, tri- and tetrapeptide residue), wherein the amino acid residues are selected from the group consisting of phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid and asparagine; preferably, L 3 is selected from the group consisting of G, F, GG, GF, FG, GGF, GFG and GGFG (SEQ ID NO: 37); more preferably, L 3 is GGFG (SEQ ID NO: 37); L 4 is a chemical bond; wherein L of said -L- is 1 attached to Ab, L 4 attached to D.

18. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, which is a ligand-drug conjugate represented by the general formula (IN) or a pharmaceutically acceptable salt thereof: wherein Ab, R 2 to R 9 , r, s, t and y are as defined in claim 1 ; L 3 and W 1 as defined in claim 17.

19. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein R 2 is a hydrogen atom.

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 3 Selected from hydrogen atom, halogen, cyano group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -(CR p R q ) m -6 to 10 aryl groups and -(CR) p R q ) m -NR s R t ; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 The haloalkyl group and the 6- to 10-membered aryl group are each independently selected from halogen, cyano, nitro, -OR z , Oxide group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The hydroxyalkyl group is substituted by one or more identical or different substituents, or by two adjacent R groups. 3 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups, wherein R p R q R s R t R z and m as defined in claim 1; preferably, R 3 Selected from hydrogen atom, oxo group, C 1-6 Alkyl, -(CR p R q ) m -6 to 10 aryl groups and -(CR) p R q ) m -NR s R t ; wherein C 1-6 The alkyl group and the 6- to 10-membered aryl group are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 The hydroxyalkyl group is substituted by one or more identical or different substituents, or by two adjacent R groups. 3 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups, where R p R q R s R t and m are as defined in claim 1 ; more preferably, R 3 is a hydrogen atom or -(CR p R q ) m -NR s R t wherein R p , R q , R s , R t and m are as defined in claim 1.

21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , R t and m are as defined in claim 1 ; preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , R t and m are as defined in claim 1.

22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 5 is -(CR g ) h n - or -C(O)-, wherein R g , R h and n are as defined in claim 1; preferably R 5 is -C(O)-.​ 23. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein R 6 is -NR ii - or wherein R ii , R 35 , R 36 and w are as defined in claim 1 ; preferably, R 6 is -NR ii -, wherein R ii is as defined in claim 1.

24. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, wherein R 7 is selected from -(CR k R kk ) n -, -(CR k R kk ) n -NR 12 - and -NR 12 -(CR k R kk ) n -, wherein R k , R kk , R 12 and n are as defined in claim 1 ; preferably, R 7 is -(CR k R kk ) n -, wherein R k , R kk and n are as defined in claim 1.

25. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 24, wherein R 8 is -(CR m ) n ) n - wherein R m , R n and n are as defined in claim 1.

26. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein R 9 is a hydrogen atom or C 1-6 alkyl; preferably, R 9 is a hydrogen atom.

27. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 26, selected from the following structures: wherein Ab is an antibody as defined in claim 3; and y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

28. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 27, wherein Ab is selected from the group consisting of an anti-CD38 antibody, an anti-CD79b antibody, an anti-GPRC5D antibody, and an anti-BCMA antibody.

29. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 28, wherein: (1) Ab is an anti-CD38 antibody comprising a heavy chain variable region and a light chain variable region, wherein the HCDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, and the LCDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO: 4, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 6; preferably, Ab is an anti-CD38 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8; more preferably, Ab is an anti-CD38 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, and the light chain comprises the amino acid sequence of SEQ ID NO: 12; or (2) Ab is an anti-BCMA antibody comprising a heavy chain variable region and a light chain variable region, wherein the HCDR1 of the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 26, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 27, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 28, and the LCDR1 of the light chain variable region comprises the amino acid sequence of SEQ ID NO: 29, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 30, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 31; Preferably, Ab is an anti-BCMA antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 32, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 33; More preferably, Ab is an anti-BCMA antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35, and the light chain comprises the amino acid sequence of SEQ ID NO:

36.

30. A compound of Formula (D) or a pharmaceutically acceptable salt thereof: ###00023### (D) wherein: X is -CR a R b - or -C(O)-; Y 1 , Y 2 , Y 3 and Y 4 one of which is a carbon atom, the other three being the same or different and each independently a nitrogen atom or CR 29 ; Z is selected from -0-, -S(O) p -, -C(O)-, -NR 11 - and -(CR c R cc ) n1 -; V is a chemical bond or -(CR d R dd ) n1 -; U is -(CR e R f ) n1 -; R 5 is selected from a chemical bond, -(CR g R h ) n -, -C(O)-, -S(O) p - and -NR i -; R 6 is selected from a chemical bond, -C(O)-, -NR ii -, -S(O) p -, -(CR j R jj ) n -, -NR ii -C(O)-, -C(O)-NR ii -, -NR ii -S(O) p -, -S(O) p -NR ii -, -NR ii -(CR j R jj ) n -, -(CR j R jj ) n -NR ii -, R 7 is selected from a bond, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR k R kk ) n -, -O-, -C(O)-, -NR 12 -, -S(O) p -, -(CR k R kk ) n -O-, -O-(CR k R kk ) n -, -(CR k R kk ) n -C(O)-, -C(O)-(CR k R kk ) n -, -(CR k R kk ) n -NR 12 -, -NR 12 -(CR k R kk ) n -, -(CR k R kk ) n -S(O) p -, -S(O) p -(CR k R kk ) n -, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-NR 12 -, -NR 12 -C(O)-, -C(=NR 13 )-NR 12 -, -NR 12 -C(=NR 13 )-, -O-C(O)-NR 12 -, -NR 12 -C(O)-O-, -NR 12 -C(O)-NR 12 -, -NR 12 -S(O) p -, -S(O) p -NR 12 -, -NR 12 -S(O) p -C(=NR 13 )-, -C(=NR 13 )-S(O) p -NR 12 - and each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; R 8 is a chemical bond or -(CR m R n ) n -; R 10 a chemical bond, ring A, ring B, and ring C are identical or different, and each is independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 2 , R 3 , R 4 and R 29 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -OR o , -(CR p R q ) m -cycloalkyl, -(CR p R q ) m -heterocyclyl, -(CR p R q ) m -aryl, -(CR p R q ) m -heteroaryl, -(CR p R q ) m -NR s R t , -(CR p R q ) m -C(O)OR u , -NR r -C(O)R u , -NR r -C(O)OR u , -NR r -C(O)-NR s R t , -(CR p R q ) m -(NR r -CR u6 R u7 -COOR u ) p5 , -C(O)-(NR r -CR u6 R u7 -COOR u ) p5 , -(CR p R q ) m -C(O)R u , -(CR p R q ) m -C(O)OR u , -(CR p R q ) m -OC(O)R u , -(CR p R q ) m -C(O)NR s R t , -(CR p R q ) m -C(=NR 13 )NR s R t , -(CR p R q ) m -S(O) p R u , -(CR p R q ) m -S(O) p NR s R t , -(CR p R q ) m -P(O)R x R y and -NR r S(O) p R u ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halo, cyano, nitro, -OR z , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR w1 R w2 ) u -NR v1 R v2 , -(CR w1 R w2 ) u -C(O)R 14 , -(CR w1 R w2 ) u -C(O)OR 14 , -(CR w1 R w2 ) u -C(O)-NR v1 R v2 , and -(CR w1 R w2 ) u -S(O) p R 14 ; or two adjacent R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or two adjacent R 4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 1 selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, and a hydroxyalkyl group; R 35 , R u4 , R u5 , R u6 and R u7 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR 30a R 30b ) p4 -cycloalkyl, -(CR 30a R 30b ) p4 -heterocyclyl, -(CR 30a R 30b ) p4 -aryl, -(CR 30a R 30b ) p4 -heteroaryl, -(CR 30a R 30b ) p4 -NR 31 R 32 , -(CR 30a R 30b ) p4 -C(O)-NR 31 R 32 , -(CR 30a R 30b ) p4 -O-R 33 , -(CR 30a R 30b ) p4 -C(O)-O-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(O)-R 33 , -(CR 30a R 30b ) p4 -NR 34 -C(=NR 13 )-NR 31 R 32 , -(CR 30a R 30b ) p4 -S(O) p -R 33 , -(CR 30a R 30b ) p4 -C(O)-S(O) p -R 33 and -(CR 30a R 30b ) p4 -NR 34 -C(O)-NR 31 R 32 one or more of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93 R 13 , R 33 , R o , R u , R x , R y , R z and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 , R 11 , R 12 , R 31 , R 32 , R 34 , R 36 , R i , R ii , R r , R s , R t , R u1 , R u2 , R u3 , R v1 and R v2 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 15b , an alkylene-COOR 15b , -NR 16a R 16b , an alkylene-NR 16a R 16b , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R a , R b , R c , R cc , R d , R dd , R e , R f , R g , R h , R j , R jj , R k , R kk , R m , R n , R p , R q , R w1 , R w2 , R 30a and R 30b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, -NR u1 R u2 , -(CR w3 R w4 ) u -NR u1 R u2 , -(CR w3 R w4 ) u -(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -C(O)-(NR u3 -CR u4 R u5 -COOR 15a ) p6 , -COOR 15a , -(CR w3 R w4 ) u -COOR 15a , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR w3 R w4 ) u -cycloalkyl, -(CR w3 R w4 ) u -heterocyclyl, -(CR w3 R w4 ) u -aryl, and -(CR w3 R w4 ) u - heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R w3 , R w4 , R 15a , R 15b , R 16a and R 16b are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R cc together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R d and R dd together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R j and R jj together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R k and R kk together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R p and R q together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w1 and R w2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 30a and R 30b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R w3 and R w4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R s and R t together with the nitrogen atom to which they are attached form a heterocyclyl group, or R u1 and R u2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R v1 and R v2 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 31 and R 32 together with the nitrogen atom to which they are attached form a heterocyclyl group; wherein said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of halo, cyano, nitro, -OR L , hydroxyalkyl, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R L is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group being independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group; p is 0, 1, or 2; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, or 6; t is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; n1 is 0, 1, 2, 3, 4, 5, or 6; p4 is 0, 1, 2, 3, 4, 5, or 6; p5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p6 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and u is 0, 1, 2, 3, 4, 5, or 6.

31. The compound of formula (D) or a pharmaceutically acceptable salt thereof according to claim 30, wherein Z is -O- or -NR 11 , wherein R 11 is as defined in claim 30; preferably, Z is -O-.

32. The compound according to claim 30 or 31 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein V is -(CR d R dd ) n1 - wherein R d , R dd and n1 are as defined in claim 30; preferably V is -CR d R dd - wherein R d and R dd are as defined in claim 30.

33. The compound according to any one of claims 30 to 32 of Formula (D) or a pharmaceutically acceptable salt thereof, wherein U is -CR e R f - wherein R e and R f are as defined in claim 30.

34. The compound according to any one of claims 30 to 33 represented by the general formula (D) or a pharmaceutically acceptable salt thereof, wherein one of Y 1 , Y 2 , Y 3 and Y 4 is a carbon atom, the remaining three are the same or different and each independently CR 29 ; or one of Y 1 , Y 2 , Y 3 and Y 4 is a carbon atom, one of the remaining three is a nitrogen atom, the remaining two are the same or different and each independently CR 29 , wherein R 29 is as defined in claim 30.

35. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 34, wherein ring B is 3- to 12-membered heterocyclyl; preferably, ring B is 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; more preferably, ring B is 3- to 6-membered heterocyclyl containing 1 or 2 nitrogen atoms; most preferably, ring B is piperazinyl.

36. The compound of any one of claims 30-35, or a pharmaceutically acceptable salt thereof, according to Formula (D-I): wherein ring B is 3- to 12-membered heterocyclyl containing 1 to 4 nitrogen atoms; X, ring A, ring C, R 1 to R 10 , R d , R dd , R e , R f , r, s and t are as defined in claim 30.

37. The compound according to any one of claims 30 to 36 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein X is -CR a R b - wherein R a and R b are as defined in claim 30.

38. The compound according to any one of claims 30 to 37 represented by the general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.

39. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 38, wherein ring A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; preferably, ring A is phenyl.

40. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 39, wherein ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring C is phenyl.

41. The compound according to any one of claims 30 to 40 represented by General Formula (D) or a pharmaceutically acceptable salt thereof, wherein R d , R dd , R e and R f are each a hydrogen atom.

42. The compound according to any one of claims 30 to 41 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 10 is a chemical bond or wherein R 35 , R 36 and w are as defined in claim 30; preferably R 10 is a chemical bond.

43. The compound of general formula (D) according to any one of claims 30 to 42, or a pharmaceutically acceptable salt thereof, wherein D is as shown in formula (D-II): wherein R 2 to R 9 r, s and t are as defined in claim 30.

44. The compound according to any one of claims 30 to 43 represented by General Formula (D) or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom.

45. The compound according to any one of claims 30 to 44 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an oxo group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, -(CR p R q ) m a 6- to 10-membered aryl group and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group and 6- to 10-membered aryl group are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a nitro group, -OR z , an oxo group, a C 2-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, wherein R p , R q , R s , R t , R z and m are as defined in claim 30; preferably, R 3 is selected from the group consisting of a hydrogen atom, an oxo group, a C 1-6 alkyl group, -(CR p R q ) m a 6- to 10-membered aryl group and -(CR p R q ) m -NR s R t ; wherein said C 1-6 alkyl group and 6- to 10-membered aryl group are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, or two adjacent R 3 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group, wherein R p , R q , R s , R t and m are as defined in claim 30; more preferably, R 3 is a hydrogen atom or -(CR p R q ) m -NR s R t , wherein R p , R q , R s , R t and m are as defined in claim 30.

46. The compound according to any one of claims 30 to 45 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , R t and m are as defined in claim 30; preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano and -(CR p R q ) m -C(O)NR s R t , wherein R p , R q , R s , R t and m are as defined in claim 30.

47. The compound according to any one of claims 30 to 46 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 5 is -(CR g R h ) n - or -C(O)-, wherein R g , R h and n are as defined in claim 30; preferably R 5 is -C(O)-.

48. The compound according to any one of claims 30 to 47 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 6 is -NR ii - or wherein R ii , R 35 , R 36 and w are as defined in claim 30; preferably R 6 is -NR ii -, wherein R ii is as defined in claim 30.

49. The compound according to any one of claims 30 to 48 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from -(CR k R kk ) n -, -(CR k R kk ) n -NR 12 - and -NR 12 -(CR k R kk ) n - wherein R k , R kk , R 12 and n are as defined in claim 30; preferably R 7 is -(CR k R kk ) n - wherein R k , R kk and n are as defined in claim 30.

50. The compound according to any one of claims 30 to 49 of Formula (D) or a pharmaceutically acceptable salt thereof, wherein R 8 is -(CR m ) n ) n , wherein R m , R n and n are as defined in claim 30.

51. The compound according to any one of claims 30 to 50 represented by General Formula (D) or a pharmaceutically acceptable salt thereof, wherein R 9 is a hydrogen atom or a C 1-6 alkyl group; preferably, R 9 is a hydrogen atom.

52. The compound of any one of claims 30-42 or pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) of Formula (D) selected from the following structures:

53. A compound of Formula (LN-D-II) or a pharmaceutically acceptable salt thereof: wherein L 3 and W 1 as defined in claim 17; R 2 to R 9 , r, s and t are as defined in claim 18.

54. The compound of claim 53 of the general formula (LN-D-II) or a pharmaceutically acceptable salt thereof, selected from the following structures:

55. A method of preparing a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, comprising the step of linking a compound of Formula (D) or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) according to any one of claims 30 to 52 to a Ligand; preferably, it comprises the step of linking a compound of Formula (D) or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) according to any one of claims 30 to 52 to a Ligand via a Linker; wherein the Ligand is an antigen-binding molecule; preferably, the Ligand is an antibody.

56. A method of making a ligand-drug conjugate of the formula (IN) or a pharmaceutically acceptable salt thereof, comprising the steps of: after reduction of Ab, a coupling reaction with a compound of Formula (LN-D-II) or a pharmaceutically acceptable salt thereof to obtain a Ligand-Drug Conjugate of Formula (IN) or a pharmaceutically acceptable salt thereof; wherein L 3 and W 1 as defined in claim 17; Ab, R 2 to R 9 , r, s, t and y are as defined in claim 18.

57. A pharmaceutical composition comprising a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, a compound of Formula (D) or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) according to any one of claims 30 to 52, a compound of Formula (LN-D-II) or a pharmaceutically acceptable salt thereof according to claim 53 or 54, and one or more pharmaceutically acceptable carriers, diluents or excipients.

58. A method of preventing or treating a disease, the method comprising administering to a subject a Ligand-Drug Conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, a compound of Formula (D) or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride salt) according to any one of claims 30 to 52, a compound of Formula (LN-D-II) or a pharmaceutically acceptable salt thereof according to claim 53 or 54, or a pharmaceutical composition according to claim 57; preferably, the disease is selected from the group consisting of a tumor, an autoimmune disease and an inflammation; more preferably, the disease is selected from the group consisting of myeloma, myelodysplastic syndrome, lymphoma, leukemia, systemic lupus erythematosus and lupus nephritis; most preferably, the tumor is selected from the group consisting of multiple myeloma and diffuse large B-cell lymphoma.

Images