Ligand-drug conjugate and medical application thereof

Abstract

The present disclosure relates to ligand-drug conjugates and medical uses thereof. Specifically, the present disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof comprising a ligand and a drug attached to the ligand wherein the drug is an IKZF degrading agent comprising a structure as shown in the general formula (D-H), and the drug is attached to the ligand via a linker.

Description

Technical Field

[0001] This disclosure pertains to the field of biotechnology and relates to ligand-drug conjugates and their pharmaceutical uses. Background Technology

[0002] The statements herein are provided only as background information in connection with this disclosure and do not necessarily constitute prior art.

[0003] Immunomodulators (IMiDs), represented by thalidomide and its derivatives such as lenalidomide and pomalidomide, and cereblon E3 ligase modulators (CELMoDs) are typical molecular glue degraders. By binding to CRBN E3 ubiquitin ligases, they alter their conformation, recruit and degrade new substrates such as IKZF1 and IKZF3 transcription factors, thereby exerting multiple effects such as anti-tumor and immunomodulatory functions.

[0004] Although the clinical efficacy of amine-based molecular gels has been demonstrated in diseases such as multiple myeloma and myelodysplastic syndromes, and is 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 these drugs to specific disease-related tissues and cells, enhance drug efficacy, and increase the treatment safety window. Summary of the Invention

[0005] This disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug attached to the ligand, wherein the drug is an IKZF degrader and the drug is attached to the ligand via a connector.

[0006] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt, as previously described, is used, wherein the drug is an IKZF1 / 3 degrader.

[0007] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein the drug comprises a structure as shown in general formula (DH):

[0008]

[0009] in:

[0010] X is -CR a R b -or -C(O)-;

[0011] Y 1 Y 2 Y 3 and Y 4One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ;

[0012] Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -;

[0013] V represents a chemical bond or -(CR) c R d ) n1 -;

[0014] U is -(CR) e R f ) n1 -;

[0015] R 5 Selected from -(CR) g R h ) n -、-C(O)-、S(O) p -、-NR i -、-NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p -、-S(O) p -NR i -、-NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -;

[0016] R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR 12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -C(O)-O-、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12-S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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.

[0017] R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -;

[0018] 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;

[0019] R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NRr -C(O)NR s R t 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -NR r -CR u6 R u7 -COOR u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) p R 14 One or more identical or different substituents are substituted in the substance;

[0020] R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups;

[0021] R a R b R c Rd R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -CR u4 R u5 -、-C(O)-NR u3 -CR u4 R u5 -COOR 15a -COOR 15a Alkylene-COOR 15a , cycloalkyl, heterocyclic, aryl and heteroaryl, each of which 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;

[0022] 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 d 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 k 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 w2Together 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.

[0023] R 13 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;

[0024] R 9 R 11 R 12 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;

[0025] R u4 R u5 R u6 and R u7 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkylene-SR 15a Alkylene-COOR 15a Alkylene-NR 16a R 16b alkylene-NH-C(=NH)-NR 16a R 16b alkylene-C(O)-NR 16a R 16bAlkylene-O-alkyl, alkylene-S-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic, alkylene-aryl, and alkylene-heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and 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;

[0026] 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;

[0027] 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 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;

[0028] 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.

[0029] p is 0, 1, or 2;

[0030] r can be 0, 1, 2, 3, 4, 5, or 6;

[0031] s can be 0, 1, 2, 3, 4, 5, or 6;

[0032] t can be 0, 1, 2, 3, 4, 5, or 6;

[0033] m can be 0, 1, 2, 3, 4, 5, or 6;

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

[0035] n1 is 0, 1, 2, 3, 4, 5, or 6; and

[0036] u can be 0, 1, 2, 3, 4, 5 or 6.

[0037] In some embodiments, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is used, wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

[0038] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by general formula (I):

[0039] Ab-(LD) y (I)

[0040] Wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody;

[0041] L is a connector that links Ab and D;

[0042] D is shown in the general formula (DH):

[0043]

[0044] in:

[0045] X is -CR a R b -or -C(O)-;

[0046] Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ;

[0047] Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -;

[0048] V represents a chemical bond or -(CR) c R d ) n1 -;

[0049] U is -(CR)e R f ) n1 -;

[0050] R 5 Selected from -(CR) g R h ) n -、-C(O)-、S(O) p -、-NR i -、-NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p -、-S(O) p -NR i -、-NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -;

[0051] R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR 12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12 -S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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.

[0052] R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR)m R n ) n -;

[0053] 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;

[0054] R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NR r -C(O)NR s R t 、-(CR p R q ) m -C(O)R u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -S(O) p NR s Rt 、-(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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) p R 14 One or more identical or different substituents are substituted in the substance;

[0055] R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups;

[0056] R a R b R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -COOR 15a Alkylene-COOR 15a, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0057] 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 d 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 k 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, 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.

[0058] R 13 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;

[0059] R 9 R 11 R 12 R i R r R s R t R u1 R u2 R v1 and R v2They 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;

[0060] 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;

[0061] 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 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;

[0062] R L The group is selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0063] p is 0, 1, or 2;

[0064] r can be 0, 1, 2, 3, 4, 5, or 6;

[0065] s can be 0, 1, 2, 3, 4, 5, or 6;

[0066] t can be 0, 1, 2, 3, 4, 5, or 6;

[0067] m can be 0, 1, 2, 3, 4, 5, or 6;

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

[0069] n1 is 0, 1, 2, 3, 4, 5 or 6;

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

[0071] y ranges from 1 to 10.

[0072] 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-.

[0073] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein V is -(CR c R d ) n1 -, where R c R d and n1 are as defined in general formula (I); preferably, V is -CR c R d -, where R c and R d As defined in general formula (I).

[0074] 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 R e and R f As defined in general formula (I).

[0075] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are all carbon atoms (CR). 10 Or Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and of the remaining three, one is a nitrogen atom, and the other two are CR atoms. 10 , where R 10 As defined in general formula (I).

[0076] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein ring B is a 3- to 6-membered heterocyclic group; preferably, ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen and oxygen atoms; more preferably, ring B is piperidinyl or piperazineyl; most preferably, ring B is piperazineyl.

[0077] In some embodiments, the ligand-drug conjugate as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from... Preferably, ring B is

[0078] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is represented by the general formula (DIH):

[0079]

[0080] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0081] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s and t are as defined in general formula (I).

[0082] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is represented by the general formula (DISH):

[0083]

[0084] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0085] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s and t are as defined in general formula (I).

[0086] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein D is represented by the general formula (DIRH):

[0087]

[0088] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0089] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s and t are as defined in general formula (I).

[0090] In some embodiments, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein X is -CR a R b -, where R a and R b As defined in general formula (I).

[0091] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R a and R b 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, and amino; preferably, R a and R b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R a and R b All are hydrogen atoms.

[0092] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 It is a hydrogen atom.

[0093] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, ring A is phenyl.

[0094] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein ring A is selected from... Preferably, ring A is More preferably, ring A is

[0095] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, the ring C is a phenyl.

[0096] In some embodiments, the ligand-drug conjugate as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the cyclic C is selected from... Preferably, ring C is More preferably, ring C is

[0097] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 3 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CR p R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m are as defined in general formula (I); preferably, R 3 It is a hydrogen atom.

[0098] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein s is 0, 1 or 2; preferably, s is 0.

[0099] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is represented by the general formula (D-II-H):

[0100]

[0101] Where R 2 R 4 To R 9 r and t are as defined in general formula (I).

[0102] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is represented by the general formula (D-II-SH):

[0103]

[0104] Where R 2 R 4 To R 9 r and t are as defined in general formula (I).

[0105] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is represented by the general formula (D-II-RH):

[0106]

[0107] Where R 2 R 4 To R 9 r and t are as defined in general formula (I).

[0108] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -,and

[0109] L 1 Selected from -(succinimide-3-yl-N)-W 1 -C(O)-、-(succinimide-3-yl-N)-W 1 -W 2 -C(O)-、-(succinimide-3-yl-N)-W 1 -、-(succinimide-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -W 1 -、-(succinimide-3-yl-N)-W 1 -(CR 20a R 20b -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 -CR20c R 20d -O) q -C(O)-, -(succinimido-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 1 to 20;

[0110] 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<00006​​​​​​​​​​​​​​​​​21c R 21d ) v -OW 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 -OW 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 -OW 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 chemical bonds, where v is an integer from 1 to 20 and p1 is an integer from 1 to 20;

[0111] L 3 Selected from peptide residues consisting of 1 to 7 amino acid residues,

[0112] The amino acid residues mentioned therein are selected from amino acid residues formed from amino acids of phenylalanine (F), alanine (A), glycine (G), cysteine ​​(C), valine (V), lysine (K), citrulline, serine (S), glutamyl (Q), glutamic acid (E), aspartic acid (D), and asparagine (N), and optionally selected from halogens, hydroxyl groups, cyano groups, amino groups, alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, and -(CR) groups. 22a R 22b ) p2 -NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 One or more substituents in it are replaced, where p2 is an integer from 1 to 20, and *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0113] L 4 Selected from -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 -OC(O)- and chemical bonds;

[0114] W 2 The group is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy.

[0115] W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 - where p3 is an integer from 1 to 20;

[0116] W 4 For -NR 28 C(O)- or -C(O)NR 28 -;

[0117] R 27 and R 28 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl;

[0118] R 17 R 18 R 19 and R 25 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl;

[0119] R 23 and R 24 The same or different, and each independently selected from the same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0120] Or R 23 and R 24 Together with the carbon atoms attached to them, they form a heterocyclic group, which is optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0121] 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 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more of the same or different substituents selected from oxo, halogens, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0122] Or R 20a and R 20b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 20c and R 20d Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21a and R 21b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21c and R 21d Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21e and R 21f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 22a and R 22b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 26a and R 26b 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.

[0123] The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

[0124] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by the general formula (IN):

[0125]

[0126] Among them, Ab and L 3 W 1 R 2 R 4 To R 9 r, t and y are as defined in general formula (I).

[0127] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by the general formula (IN-S):

[0128]

[0129] Among them, Ab and L 3 W 1 R 2 R 4 To R9 r, t and y are as defined in general formula (I).

[0130] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by the general formula (IN-R):

[0131]

[0132] Among them, Ab and L 3 W 1 R 2 R 4 To R 9 r, t and y are as defined in general formula (I).

[0133] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 2 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CR p R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m are as defined in general formula (I); preferably, R 2 It is a hydrogen atom.

[0134] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CRp R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m are as defined in general formula (I); preferably, R 4 Selected from hydrogen atoms, halogens, and cyano groups; more preferably, R 4 It is a hydrogen atom or a halogen; most preferably, R 4 It consists of hydrogen or fluorine atoms.

[0135] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 Selected from -NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p - and -S(O) p -NR i -, where R i and p as defined in general formula (I) or general formula (IN); preferably, R 5 For -NR i -C(O)- or -C(O)-NR i -, where R i As defined in general formula (I) or general formula (IN).

[0136] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 For -NR i -C(O)- or -NR i -S(O) p -, where R i and p as defined in general formula (I) or general formula (IN); preferably, R 5 For -NR i -C(O)-, where R i As defined in general formula (I) or general formula (IN).

[0137] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 Selected from chemical bonds, -C(O)-NR12 -、-NR 12 -C(O)- and -NR 12 -C(O)-NR 12 -, where R 12 As defined in general formula (I); preferably, R 7 It is a chemical bond.

[0138] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 For chemical bonds or -NR 12 -C(O)-NR 12 -, where R 12 As defined in general formula (I); preferably, R 7 It is a chemical bond.

[0139] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -, where R m R n And n is as defined in general formula (I).

[0140] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 9 It is a hydrogen atom.

[0141] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 10 Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 10 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 10 It is a hydrogen atom.

[0142] 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, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 1-6Hydroxyalkyl; preferably, R 11 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 11 It is a hydrogen atom.

[0143] 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.

[0144] 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).

[0145] 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.

[0146] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 3The peptide residues are selected from 1 to 7 amino acid residues, wherein the amino acid residues are selected from amino acids formed from phenylalanine (F), alanine (A), glycine (G), cysteine ​​(C), valine (V), lysine (K), citrulline, serine (S), glutamyl (Q), glutamic acid (E), aspartic acid (D), and asparagine (N), and optionally selected from halogens, hydroxyl groups, cyano groups, amino groups, C groups, etc. 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 One or more substituents in R are replaced, where R 22a R 22b R 23 R 24 R 25 p2 is as defined in general formula (I); preferably, L 3 The amino acid residues are selected from monopeptide residues, dipeptide residues, and tetrapeptide residues, wherein the amino acid residues are selected from amino acids formed from phenylalanine (F), alanine (A), glycine (G), cysteine ​​(C), valine (V), lysine (K), citrulline, serine (S), glutamyl (Q), glutamic acid (E), aspartic acid (D), and asparagine (N); more preferably, L 3 Selected from dipeptide residues represented by VA, VC, valine-citrulline, and tetrapeptide residues represented by GGFG (SEQ ID NO:16); most preferably, L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:16).

[0147] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 3 for Where *1 and L 2 Connect the ends, *2 and L 4 Terminal connection, W 3 As defined in general formula (I).

[0148] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 3 for Where *1 and L2 Connect the ends, *2 and L 4 Terminal connection, W 3 W 4 W 5 and R 27 As defined in general formula (I).

[0149] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 4 For -NR 19 -W 2 -W 1 -OC(O)- or chemical bond, where R 19 W 1 and W 2 As defined in general formula (I); preferably, L 4 It is a chemical bond.

[0150] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6.

[0151] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 -, R 26a and R 26b All are hydrogen atoms, and p3 can be 1, 2, 3, 4, 5 or 6.

[0152] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -,and

[0153] L 1 -(succinimide-3-yl-N)-W1 -C(O)-, where W 1 -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6;

[0154] L 2 It is a chemical bond;

[0155] L 3 The amino acid residues are selected from monopeptide residues, dipeptide residues, and tetrapeptide residues, wherein the amino acid residues are selected from amino acids formed from phenylalanine (F), alanine (A), glycine (G), cysteine ​​(C), valine (V), lysine (K), citrulline, serine (S), glutamyl (Q), glutamic acid (E), aspartic acid (D), and aspartic acid (N); preferably, L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:16);

[0156] L 4 It is a chemical bond;

[0157] The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

[0158] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein -L- is -L 1 -L 3 -,and

[0159] L 1 -(succinimide-3-yl-N)-W 1 -C(O)-, where W 1 -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6;

[0160] L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:16);

[0161] The L of -L- 1 The terminal is connected to Ab, L 3 The terminal is connected to D.

[0162] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 2 The group is selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups, wherein the 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are optionally selected from 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 The alkoxy group is substituted with one or more identical or different substituents in the haloalkoxy group; preferably, W 2 Selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; more preferably, W 2 Selected from cyclohexyl, phenyl, and pyridyl.

[0163] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 2 It is a 3- to 6-membered cycloalkyl or a 5- to 10-membered heteroaryl; more preferably, W 2 It is cyclohexyl or pyridyl.

[0164] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 17 R 18 R 19 and R 25 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 17 R 18 R 19 and R 25 All are hydrogen atoms.

[0165] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 20a R 20b R 20c R 20d R 21a R 21b R 21c R 21d R 21eR 21f R 22a and R 22b 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 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 20a R 20b R 20c R 20d R 21a R 21b R 21c R 21d R 21e R 21f R 22a and R 22b All are hydrogen atoms.

[0166] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 23 and R 24 Same or different, and each independently selected from the same or different, and each independently selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 23 and R 24 They are the same or different, and each is independently selected from the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 23 and R 24 All are hydrogen atoms.

[0167] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 26a and R 26b All are hydrogen atoms.

[0168] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 27 and R 28 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6Hydroxyalkyl; preferably, R 27 and R 28 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 27 and R 28 All are hydrogen atoms.

[0169] In some implementations, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 4 For -NR 28 C(O)- or -C(O)NR 28 -; where R 28 It is a hydrogen atom.

[0170] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein -L- is -L 1 -L 2 -L 3 -L 4 -,and

[0171] L 1 -(succinimide-3-yl-N)-W 1 -C(O)-;

[0172] L 2 It is a chemical bond;

[0173] L 3 for Where *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0174] W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6;

[0175] W 4 For -NR 28 C(O)- or -C(O)NR 28 -;

[0176] R 27 and R 28 They may be the same or different, and each is independently a hydrogen atom or a carbon atom.1-6 alkyl;

[0177] L 4 It is a chemical bond;

[0178] The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

[0179] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein -L- is -L 1 -L 3 -,and

[0180] L 1 -(succinimide-3-yl-N)-W 1 -C(O)-;

[0181] L 3 for Where *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0182] W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6;

[0183] W 4 For -NR 28 C(O)- or -C(O)NR 28 -;

[0184] R 27 and R 28 All are hydrogen atoms;

[0185] The L of -L- 1 The terminal is connected to Ab, L 3 The terminal is connected to D.

[0186] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, 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.

[0187] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any 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.

[0188] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any 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.

[0189] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any 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.

[0190] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any 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.

[0191] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 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 C 1-6 Alkylene-NR u1 R u2 -COOR 15a and C 1-6 Alkylene-COOR 15a , where R u1 R u2 and R 15a As defined in general formula (I); preferably, R c R d R e R f Rg R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 All are hydrogen atoms.

[0192] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 15a R 15b R 16a and R 16b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0193] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R i R s and R t All are hydrogen atoms.

[0194] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 13 R o R u R x R y R z and R 14 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 13 R o R u Rx R y R z and R 14 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0195] In some implementations, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one is used, wherein p is 2.

[0196] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein r is 0 or 4.

[0197] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein r is 0, 1, 2, 3 or 4.

[0198] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein t is 0, 1, 2, 3 or 4; preferably, t is 0, 1 or 2.

[0199] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein n is 0, 1, 2, 3, 4, 5 or 6; preferably, n is 0, 1, 2, 3 or 4.

[0200] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is used, wherein the Ab is selected from IgG1, IgG2, IgG3 and IgG4 antibodies; preferably, the Ab is an IgG1 antibody.

[0201] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein the 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 rules selected from Kabat, IMGT, Chothia, AbM, and Contact. In some embodiments, it is defined according to the Kabat numbering rules. In some embodiments, it is defined according to the IMGT numbering rules. In some embodiments, it is defined according to the Chothia numbering rules. In some embodiments, it is defined according to the AbM numbering rules. In some embodiments, it is defined according to the Contact numbering rules.

[0202] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments is used, wherein the Ab is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody; preferably, the Ab is a humanized antibody.

[0203] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein Ab is an antibody fragment; preferably, the antibody fragment is Fab, Fab′, F(ab′)2, Fd, Fv, scFv, dsFv or dAb.

[0204] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein the Ab is selected from anti-CD38 antibody, anti-CD79b antibody, anti-GPRC5D antibody, and anti-BCMA antibody.

[0205] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, wherein the anti-CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region HCDR1 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 the light chain variable region LCDR1 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.

[0206] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, 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.

[0207] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, 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 IgG1, IgG2, IgG3 or IgG4 heavy chain constant region, and the light chain constant region is a human κ or λ 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.

[0208] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, 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.

[0209] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, wherein the anti-CD38 antibody comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is as shown in SEQ ID NO: 11, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 12.

[0210] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein y refers to the average amount of drug carried by each ligand-drug conjugate molecule in the ligand-drug conjugate population, or may be expressed as the ratio of drug to ligand; preferably, the ligand-drug conjugate is an antibody-drug conjugate.

[0211] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding claims, 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 of any two values; preferably, y is 1-10; more preferably, y is the average of 1-9, or 1-8, or 2-8, or 2-7, or 2-6, or 2-5, or 2-4, or 3-9, or 3-8, or 3-7, or 3-6, or 4-9, or 4-8, or 4-7, or 4-6, or 4-5.

[0212] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is wherein y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 4 to 8.

[0213] In some embodiments, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, is an antibody-drug conjugate or a pharmaceutically acceptable salt thereof represented by formula (I), formula (IN), formula (IN-S), or formula (IN-R).

[0214] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described in any of the preceding embodiments, has the structure shown in Tables 1-3.

[0215] On the other hand, this disclosure relates to a compound of general formula (D) or a pharmaceutically acceptable salt thereof:

[0216]

[0217] in:

[0218] X is -CR a R b -or -C(O)-;

[0219] Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ;

[0220] Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -;

[0221] V represents a chemical bond or -(CR) c R d ) n1 -;

[0222] U is -(CR) e R f ) n1 -;

[0223] R 5 Selected from -(CR) g R h ) n -、-C(O)-、S(O) p -、-NR i -、-NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p -、-S(O) p -NR i -、-NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -;

[0224] R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -C(O)-O-、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12 -S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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.

[0225] R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -;

[0226] 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;

[0227] R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NR r -C(O)NR s R t 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -NR r -CR u6 R u7 -COOR u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) pR 14 One or more identical or different substituents are substituted in the substance;

[0228] R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups;

[0229] R a R b R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -CR u4 R u5 -、-C(O)-NR u3 -CR u4 R u5 -COOR 15a -COOR 15a Alkylene-COOR 15a , cycloalkyl, heterocyclic, aryl and heteroaryl, each of which 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;

[0230] 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 d 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 k Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or Rm 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, 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.

[0231] R 13 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;

[0232] R 9 R 11 R 12 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;

[0233] R u4 R u5 R u6 and R u7 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkylene-SR 15a Alkylene-COOR 15a Alkylene-NR 16a R 16b alkylene-NH-C(=NH)-NR 16a R16b alkylene-C(O)-NR 16a R 16b Alkylene-O-alkyl, alkylene-S-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic, alkylene-aryl, and alkylene-heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and 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;

[0234] 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;

[0235] 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 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;

[0236] 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.

[0237] p is 0, 1, or 2;

[0238] r can be 0, 1, 2, 3, 4, 5, or 6;

[0239] s can be 0, 1, 2, 3, 4, 5, or 6;

[0240] t can be 0, 1, 2, 3, 4, 5, or 6;

[0241] m can be 0, 1, 2, 3, 4, 5, or 6;

[0242] n is 0, 1, 2, 3, 4, 5, or 6;

[0243] n1 is 0, 1, 2, 3, 4, 5, or 6; and

[0244] u can be 0, 1, 2, 3, 4, 5 or 6.

[0245] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein Z is -O- or -NR. 11 -, where R 11 As defined in general formula (D); preferably, Z is -O-.

[0246] In some embodiments, a compound of general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein V is -(CR c R d ) n1 -, where R c R d and n1 are as defined in general formula (D); preferably, V is -CR c R d -, where R c and R d As defined in general formula (D).

[0247] In some embodiments, a compound of general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein U is -CR e R f -, where R e and R f As defined in general formula (D).

[0248] In some embodiments, the compound represented by general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are all carbon atoms (CR). 10 Or Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and of the remaining three, one is a nitrogen atom, and the other two are CR atoms. 10 , where R 10 As defined in general formula (D).

[0249] In some embodiments, the compound represented by general formula (D) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 6-membered heterocyclic group; preferably, ring B is a 3- to 6-membered heterocyclic group containing one or two 3- to 6-membered heterocyclic groups selected from nitrogen and oxygen atoms; more preferably, ring B is piperidinyl or piperazineyl; most preferably, ring B is piperazineyl.

[0250] In some embodiments, the compound represented by general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from... Preferably, ring B is

[0251] In some embodiments, the compound represented by general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is represented by general formula (DI):

[0252]

[0253] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0254] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s, and t are as defined in general formula (D).

[0255] In some embodiments, the compound represented by general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is represented by general formula (DIS):

[0256]

[0257] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0258] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s, and t are as defined in general formula (D).

[0259] In some embodiments, the compound represented by general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is represented by general formula (DIR):

[0260]

[0261] Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms;

[0262] X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s, and t are as defined in general formula (D).

[0263] In some embodiments, a compound or a pharmaceutically acceptable salt thereof of formula (D), (DI), (DIS), or (DIR) as described in any of the preceding embodiments, wherein X is -CR a R b -, where R a and R b As defined in general formula (D).

[0264] In some embodiments, a compound or a pharmaceutically acceptable salt thereof of formula (D), (DI), (DIS), or (DIR) as described in any of the preceding embodiments, wherein R a and R b 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, and amino; preferably, R a and R b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R a and R b All are hydrogen atoms.

[0265] In some embodiments, a compound or a pharmaceutically acceptable salt thereof of formula (D), (DI), (DIS), or (DIR) as described in any of the preceding embodiments, wherein R 1 It is a hydrogen atom.

[0266] In some embodiments, the compound represented by formula (D), formula (DI), formula (DIS) or formula (DIR) as described in 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.

[0267] In some embodiments, the compound represented by formula (D), formula (DI), formula (DIS) or formula (DIR) as described in 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

[0268] In some embodiments, the compound represented by formula (D), formula (DI), formula (DIS) or formula (DIR) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, the ring C is phenyl.

[0269] In some embodiments, the compound represented by formula (D), formula (DI), formula (DIS) or formula (DIR) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the ring C is selected from... Preferably, ring C is More preferably, ring C is

[0270] In some embodiments, a compound or a pharmaceutically acceptable salt thereof of formula (D), (DI), (DIS), or (DIR) as described in any of the preceding embodiments, wherein R 3 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CR p R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m as defined in general formula (D); preferably, R 3 It is a hydrogen atom.

[0271] In some embodiments, the antibody-drug conjugate or its pharmaceutically acceptable salt represented by formula (D), formula (DI), formula (DIS) or formula (DIR) as described in any of the preceding embodiments is used, wherein s is 0, 1 or 2; preferably, s is 0.

[0272] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, represented by general formula (D) or general formula (DI) as described in any of the preceding claims, is represented by general formula (D-II):

[0273]

[0274] Where R 2 R 4 To R 9 r and t are defined as in general formula (D).

[0275] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, represented by general formula (D), general formula (DI), or general formula (DIS) as described in any of the preceding claims, is represented by general formula (D-II-S):

[0276]

[0277] Where R 2 R 4 To R 9 r and t are defined as in general formula (D).

[0278] In some embodiments, a compound or a pharmaceutically acceptable salt thereof of general formula (D), general formula (DI), or general formula (DIR) as described in any of the preceding claims, as indicated by general formula (D-II-R):

[0279]

[0280] Where R 2 R 4 To R 9 r and t are defined as in general formula (D).

[0281] 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 2 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CR p R q ) m -NR s Rt and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m as defined in general formula (D); preferably, R 2 It is a hydrogen atom.

[0282] 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 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR o -SR o 、-(CR p R q ) m -NR s R t and -(CR p R q ) m -C(O)OR u , where R o R p R q R s R t R u and m as defined in general formula (D); preferably, R 4 Selected from hydrogen atoms, halogens, and cyano groups; more preferably, R 4 It is a hydrogen atom or a halogen; most preferably, R 4 It consists of hydrogen or fluorine atoms.

[0283] 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 Selected from -NR i -C(O)-、-C(O)-NR i-、-NR i -S(O) p - and -S(O) p -NR i -, where R i And p as defined in general formula (D); preferably, R 5 For -NR i -C(O)- or -C(O)-NR i -, where R i As defined in general formula (D).

[0284] 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 For -NR i -C(O)- or -NR i -S(O) p -, where R i And p as defined in general formula (D); preferably, R 5 For -NR i -C(O)-, where R i As defined in general formula (D).

[0285] 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 7 Selected from chemical bonds, -C(O)-NR 12 -、-NR 12 -C(O)- and -NR 12 -C(O)-NR 12 -, where R 12 As defined in general formula (D); preferably, R 7 It is a chemical bond.

[0286] 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 7 For chemical bonds or -NR 12 -C(O)-NR 12 -, where R 12 As defined in general formula (D); preferably, R 7It is a chemical bond.

[0287] In some embodiments, a compound of general formula (D) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -, where R m R n And n is as defined in general formula (D).

[0288] 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 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 9 It is a hydrogen atom.

[0289] 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 10 Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 10 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 10 It is a hydrogen atom.

[0290] 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 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 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.

[0291] 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 12 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 12 It is a hydrogen atom.

[0292] 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 c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 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 C 1-6 Alkylene-NR u1 R u2 -COOR 15a and C 1-6 Alkylene-COOR 15a , where R u1 R u2 and R 15a As defined in general formula (D); preferably, R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom.1-6 Alkyl; more preferably, R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 All are hydrogen atoms.

[0293] 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 15a R 15b R 16a and R 16b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0294] 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 i R s and R t All are hydrogen atoms.

[0295] 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 13 R o R u R x R y R z and R 14 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably, R 13 R o Ru R x R y R z and R 14 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0296] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by 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 p is 2.

[0297] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by 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 is 0 or 4.

[0298] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by 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 is 0, 1, 2, 3 or 4.

[0299] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by 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 t is 0, 1, 2, 3 or 4; preferably, t is 0, 1 or 2.

[0300] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by 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 n is 0, 1, 2, 3, 4, 5 or 6; preferably, n is 0, 1, 2, 3 or 4.

[0301] In some embodiments, the compound represented by 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, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a methanesulfonate or a hydrochloride.

[0302] In some embodiments, the compounds of general formula (D), general formula (DI), general formula (DIS), general formula (DIR), general formula (D-II), general formula (D-II-S) or general formula (D-II-R) as described in any of the preceding embodiments, or pharmaceutically acceptable salts thereof, have structures shown in Table 1-1.

[0303] In some embodiments, the use of compounds of formula (D), formula (DI), formula (DIS), formula (DIR), formula (D-II), formula (D-II-S) or formula (D-II-R) or pharmaceutically acceptable salts thereof, as described in any of the preceding embodiments, in the preparation of protein hydrolysis-targeting chimeras, antibody-drug conjugates (e.g., antibody-protein hydrolysis-targeting chimera conjugates, antibody-degrader conjugates), peptide-drug conjugates or small molecule-drug conjugates.

[0304] On the other hand, this disclosure relates to a compound of general formula (LN-D-II) or a salt thereof:

[0305]

[0306] Where L 3 W 1 R 2 R 4 To R 9 r and t are defined as in the general formula (IN).

[0307] On the other hand, this disclosure relates to a compound of the general formula (LN-D-II-S) or a salt thereof:

[0308]

[0309] Where L 3 W 1 R 2 R 4 To R 9 r and t are defined as in the general formula (IN).

[0310] On the other hand, this disclosure relates to a compound of the general formula (LN-D-II-R) or a salt thereof:

[0311]

[0312] Where L 3 W 1 R 2 R 4 To R 9 r and t are defined as in the general formula (IN).

[0313] In some embodiments, the compound of general formula (LN-D-II) or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, has the structure shown in Tables 1-2.

[0314] On the other hand, this disclosure relates to a method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, comprising the step of linking a compound selected from those represented by general formula (D) as described in any of the preceding claims or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride) to a ligand; wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

[0315] In some embodiments, a method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims, comprises linking a compound selected from those represented by general formula (D) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride), to a ligand via a linker; wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

[0316] On the other hand, this disclosure relates to a method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as shown in general formula (IN), comprising the following steps:

[0317]

[0318] After reduction with Ab (e.g., using the reducing agent tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl)), it undergoes a coupling reaction with a compound of general formula (LN-D-II) or a salt thereof to obtain a ligand-drug conjugate of general formula (IN) or a pharmaceutically acceptable salt thereof.

[0319] Among them, Ab and L 3 W 1 R 2 R 4 To R 9 r, t, and y are defined as in the general formula (IN).

[0320] In some embodiments, compounds of general formula (IN-S) or general formula (IN-R) as described in any of the preceding embodiments, or pharmaceutically acceptable salts thereof, may be synthesized by means of the above methods, using appropriate chiral starting materials or chiral resolution.

[0321] On the other hand, this disclosure relates to a method for preparing a compound of the general formula (LN-D-II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0322]

[0323] Compound (M) is coupled with a compound of general formula (D-II) or a pharmaceutically acceptable salt thereof (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 give a compound of general formula (LN-D-II) or a pharmaceutically acceptable salt thereof;

[0324] in:

[0325] L 3a For L 3 Remove the terminal carbonyl group;

[0326] Where L 3 W 1 R 2 R 4 To R 9 r and t are defined as in general formula (LN-D-II).

[0327] In some embodiments, compounds of the general formula (LN-D-II-S) or general formula (LN-D-II-R) as described above, or pharmaceutically acceptable salts thereof, may be synthesized by means of the above method, using appropriate chiral starting materials or chiral resolution.

[0328] Table 1-1 Typical compounds disclosed herein include, but are not limited to:

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] Table 1-2 lists typical compounds disclosed herein, including but not limited to:

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] Table 1-3 lists typical compounds disclosed herein, including but not limited to:

[0349]

[0350]

[0351]

[0352]

[0353]

[0354] On the other hand, this disclosure relates to a pharmaceutical composition comprising a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, 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, or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride), 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 claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0355] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a ligand-drug conjugate as described in any of the preceding embodiments or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0356] In some embodiments, this disclosure relates to a pharmaceutical composition comprising 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, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride salt), and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0357] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a compound of the formula (LN-D-II), (LN-D-II-S), or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0358] In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S) or (D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride), or a compound of formula (LN-D-II), (LN-D-II-S) or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S), or (D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride), or a compound of formula (LN-D-II), (LN-D-II-S), or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S) or (D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride), or a compound of formula (LN-D-II), (LN-D-II-S) or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S) or (D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride), or a compound of formula (LN-D-II), (LN-D-II-S) or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable diluents or excipients based on the total weight of the pharmaceutical composition.

[0363] In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable diluent or excipient.

[0364] In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients.

[0365] In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable diluents or excipients.

[0366] In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable diluents or excipients.

[0367] On the other hand, this disclosure relates to isolated nucleic acids that encode anti-CD38 antibodies as described in the previous one.

[0368] On the other hand, this disclosure relates to isolated nucleic acids that encode anti-CD79b antibodies as described in the previous disclosure.

[0369] On the other hand, this disclosure relates to isolated nucleic acids that encode anti-BCMA antibodies as described in the previous one.

[0370] On the other hand, this disclosure relates to isolated nucleic acids that encode anti-GPRC5D antibodies as described in the previous one.

[0371] On the other hand, this disclosure relates to a host cell containing the isolated nucleic acids as described above.

[0372] On the other hand, this disclosure relates to a method for preventing or treating a disease, the method comprising administering to a subject a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, 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, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride), 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 claims, or a pharmaceutical composition as described above.

[0373] In some embodiments, this disclosure relates to use in the preparation of a medicament for the prevention or treatment of a disease, including administering to a subject a ligand-drug conjugate as described in any of the preceding claims or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above.

[0374] In some embodiments, this disclosure relates to use in the preparation of a medicament for the prevention or treatment of a disease, including administering to a subject 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, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride salt) or a pharmaceutical composition as described above.

[0375] In some embodiments, this disclosure relates to use in the preparation of a medicament for the prevention or treatment of a disease, including administering to a subject 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 claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0376] On the other hand, this disclosure relates to a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding claims, a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S), or (D-II-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride salt), a compound of formula (LN-D-II), (LN-D-II-S), or (LN-D-II-R) as described in any of the preceding claims, or a pharmaceutical composition as described above. In some embodiments, the medicament is used for the prevention or treatment of a disease.

[0377] In some embodiments, this disclosure relates to a ligand-drug conjugate as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, used as a medicament. In some embodiments, the medicament is used for the prevention or treatment of tumors.

[0378] In some embodiments, this disclosure relates to a compound of formula (D), (DI), (DIS), (DIR), (D-II), (D-II-S), or (D-II-R) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof (preferably a mesylate or hydrochloride salt), or a pharmaceutical composition as described above. In some embodiments, the medicament is used for the prevention or treatment of a disease.

[0379] In some embodiments, this disclosure relates to a 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 embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. In some embodiments, the medicament is used for the prevention or treatment of a disease.

[0380] In this disclosure, the disease as described in any of the preceding items is selected from tumors, autoimmune diseases, and inflammation; preferably, the disease is selected from 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 multiple myeloma and diffuse large B-cell lymphoma. Detailed Implementation

[0381] the term

[0382] To facilitate understanding of this disclosure, certain technical and scientific terms are described below. Unless otherwise expressly defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0383] The singular forms “a,” “an,” and “the” used in the specification and claims include plural references unless the context clearly indicates otherwise.

[0384] Unless the context clearly requires otherwise, the words “comprising,” “having,” “including,” etc., in the patent specification and claims should be understood as “including but not limited to,” rather than as exclusive or exhaustive.

[0385] The term "cytokine" is a general term for proteins released by a population of cells that act as intercellular mediators in other cells. Examples of such cytokines include lymphokines, monokines, chemokines, and traditional polypeptide hormones. Exemplary cytokines include mIL-2, IFNγ, TNFα, CCL-2, and IL-6.

[0386] The term "and / or" implies both "and" and "or". For example, the phrase "A, B and / or C" is intended to cover each of the following: 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).

[0387] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem., 243, p3558 (1968).

[0388] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are subsequently modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. These analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are chemical compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids.

[0389] The term "amino acid mutation" includes amino acid substitution (also known as amino acid replacement), deletion, insertion, and modification. Any combination of substitution, deletion, insertion, and modification can be performed to achieve the final construct, provided that the final construct possesses the desired properties, such as reduced or absent binding to Fc receptors. Amino acid sequence deletions and insertions include deletions and insertions at the amino and / or carboxyl ends of the polypeptide chain. A specific amino acid mutation can be an amino acid substitution. In one embodiment, an amino acid mutation is a non-conservative amino acid substitution, i.e., replacing one amino acid with another amino acid that has a different structure and / or chemical properties. Amino acid substitution includes substitution by non-naturally occurring amino acids or by derivatives of 20 naturally occurring 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, etc. Methods other than genetic engineering that alter amino acid side chain groups, such as chemical modification, are also expected to be available. Various names may be used herein to refer to the same amino acid mutation. In this paper, the amino acid residue at a specific site can be represented by the format of position + amino acid residue. For example, 82aR indicates that the amino acid residue at the 82a site is R. S82aR indicates that the amino acid residue at the 82a (also known as 82A) site has changed from S to R.

[0390] The term "ligand" refers to a macromolecular compound that can recognize and bind to antigens or receptors associated with a target cell.

[0391] The term "antigen-binding molecule" is used in the broadest sense to encompass molecules that specifically bind antigens, including but not limited to antibodies, other peptides with antigen-binding activity, and antibody fusion proteins formed by the fusion of the two, as well as any molecule containing the aforementioned antibodies, peptides, or antibody fusion proteins, provided they exhibit the desired antigen-binding activity. The antigen-binding molecules described herein comprise a variable region (VH) and a variable region (VL), which together constitute the antigen-binding domain. Exemplarily, the antigen-binding molecules described herein are bispecific antigen-binding molecules (e.g., bispecific antibodies).

[0392] The term "antibody" is used in the broadest sense and encompasses a wide variety of 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), as long as they exhibit the desired antigen-binding activity. For example, a natural IgG antibody is a heterotetraglycoprotein of approximately 150,000 Daltons, consisting of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable region, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N to the 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 (light chain constant region, CL).

[0393] The term "bispecific antibody" refers to an antibody (including the antibody or its antigen-binding fragment, such as a single-chain antibody) that can specifically bind to two different antigens or at least two different antigenic epitopes of the same antigen. Bispecific antibodies with various structures have been disclosed in the prior art. Based on the integrity of the IgG molecule, they can be classified into IgG-like bispecific antibodies and antibody fragment-type bispecific antibodies; based on the number of antigen-binding regions, they can be classified into bivalent, trivalent, tetravalent, or more bispecific antibodies; and based on whether the structure is symmetrical, they can be classified into symmetrical and asymmetrical bispecific antibodies. Among them, bispecific antibodies based on antibody fragments, such as Fab fragments lacking the Fc fragment, form bispecific antibodies by combining two or more Fab fragments into one molecule. They have low immunogenicity, small molecular weight, and high tumor tissue penetration. Typical antibody structures of this type include F(ab)2, scFv-Fab, and (scFv)2-Fab. IgG-like bispecific antibodies (e.g., those with an Fc fragment) have a relatively large molecular weight. The Fc fragment helps in antibody purification and improves its solubility and stability. The Fc part may also bind to the receptor FcRn, increasing the antibody serum half-life.

[0394] "Natural antibody" refers to naturally occurring immunoglobulin molecules. For example, natural IgG antibodies are heterotetrameric proteins of approximately 150,000 Daltons, composed of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N to the C-terminus, each heavy chain has a variable region (VH), also known as a variable heavy domain or heavy chain variable region, followed by a heavy chain constant region. The natural IgG heavy chain constant region typically contains three constant domains (CH1, CH2, and CH3). Similarly, from the N to the C-terminus, each light chain has a variable region (VL), also known as a variable light domain or light chain variable domain, followed by a constant light domain (light chain constant region, CL). The terms "full-length antibody," "complete antibody," and "all antibody" are used interchangeably herein to refer to antibodies with a structure substantially similar to that of natural antibodies or heavy chains with an Fc region as defined herein. The light chain of a natural intact antibody includes a variable region (VL) and a constant region (CL). VL is located at the amino terminus of the light chain, and the constant region includes the κ chain and the λ chain. The heavy chain includes a variable region (VH) and constant regions (CH1, CH2, and CH3). VH is located at the amino terminus of the heavy chain, and the constant region is located at the carboxyl terminus. CH3 is closest to the carboxyl terminus of the polypeptide. The heavy chain can belong to any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE.

[0395] The term "variable region" or "variable domain" in an antibody refers to the domain in the antibody heavy or light chain involved in antibody binding to the antigen. In this paper, the antibody heavy chain variable region (VH) and light chain variable region (VL) each contain four conserved frame regions (FRs) and three complementarity-determining regions (CDRs). The term "complementarity-determining region" or "CDR" refers to the region within the variable domain that primarily facilitates antigen binding; "frame" or "FR" refers to the variable domain residues other than the CDR residues. The VH contains three CDR regions: HCDR1, HCDR2, and HCDR3; the VL contains three CDR regions: LCDR1, LCDR2, and LCDR3. Each VH and VL consists of three CDRs and four FRs arranged in the following order from the amino terminus (also called the N-terminus) to the carboxyl terminus (also called the C-terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0396] The amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat" numbering system (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering system, the "ABM" numbering system, the "contact" numbering system (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains[J]. 2001), and the ImMunoGenTics (IMGT) numbering system (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77(2003); Front Immunol. 2018 Oct 16; 9:2278), etc.; the correspondence between various numbering systems is well known to those skilled in the art.

[0397] Unless otherwise stated, the variable areas and CDRs in this disclosure embodiment are subject to the "Kabat" numbering rule.

[0398] The term "antibody fragment" refers to a molecule that is distinct from the intact antibody but contains a portion of the intact antibody that binds to the antigen to which the intact antibody is bound. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab′, Fab′-SH, F(ab′)2, single-domain antibodies, single-chain Fab (scFab), biantibodies, linear antibodies, single-chain antibodies (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0399] The term "Fc region" or "fragment crystallizable region" is used to define the C-terminal region of an antibody heavy chain, including both native and modified Fc regions. In some embodiments, the Fc region comprises two identical or different subunits. In some embodiments, the Fc region of a human IgG heavy chain is defined as an amino acid residue extending from the Cys226 position or from Pro230 to its carboxyl terminus. Suitable Fc regions for the antibodies described herein include the Fc regions of human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. In some embodiments, the boundaries of the Fc region may also vary, for example, by omitting the C-terminal lysine (residue 447 according to the EU numbering system) or omitting both the C-terminal glycine and lysine (residues 446 and 447 according to the EU numbering system). Unless otherwise stated, the Fc region is numbered according to the EU numbering system, also known as the EU index.

[0400] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a specific source or species, while the remaining portion of the heavy and / or light chain is derived from another different source or species.

[0401] The term "humanized" antibody refers to an antibody that retains the reactivity of a non-human antibody while exhibiting lower immunogenicity in humans. For example, this can be achieved by retaining the non-human CDR region and replacing the rest of the antibody with its human counterpart (i.e., the frame region portion of the constant region and the variable region).

[0402] The terms "human antibody," "human-derived antibody," "fully human antibody," and "completely human antibody" are used interchangeably, referring to antibodies whose variable and constant regions are human sequences. This term encompasses antibodies derived from human genes but with sequence alterations, such as reduced potential immunogenicity, increased affinity, or the elimination of cysteine ​​residues or glycosylation sites that might cause undesirable folding. This term also encompasses antibodies recombined in non-human cells (which may confer glycosylations not characteristic of human cells). The term also includes antibodies that have been fed to transgenic mice containing some or all human immunoglobulin heavy and light chain loci. The meaning of "human antibody" explicitly excludes humanized antibodies containing non-human antigen-binding residues.

[0403] The term "affinity" refers to the overall strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding ligand (e.g., an antigen). Unless otherwise specified, as used herein, binding "affinity" refers to internal binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its ligand Y can typically be represented by the dissociation constant (KD). Affinity can be measured using conventional methods known in the art, including those described herein.

[0404] As used herein, the term "kassoc" or "ka" refers to the association rate of a specific antibody-antigen interaction, and the term "kdis" or "kd" refers to the dissociation rate of a specific antibody-antigen interaction. The term "KD" refers to the dissociation constant, which is derived from the ratio of kd to ka (i.e., kd / ka) and expressed as a molar concentration (M). The KD value of an antibody can be determined using methods known in the art. For example, it can be measured using a biosensing system such as a system for measuring surface plasmon resonance (e.g., Biacore), or by measuring affinity in solution using solution equilibrium titration (SET).

[0405] The term “surface plasmon resonance” refers to the optical phenomenon of analyzing real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using the BIAcore™ system (Biacore LifeSciences division of GE Healthcare, Piscataway, NJ).

[0406] The term "effector function" refers to biological activities attributable to the antibody's Fc region (either the native Fc region or the Fc region with amino acid sequence mutations) and that vary across antibody isotypes. Examples of antibody effector functions include, but are not limited to: C1q binding and complement-dependent cytotoxicity, Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0407] The term "monoclonal antibody" refers to a group of substantially homogeneous antibodies, meaning that the antibody molecules contained in this group have the same amino acid sequence, except for the possible small number of naturally occurring mutations. In contrast, polyclonal antibody formulations typically contain multiple different antibodies with different amino acid sequences in their variable structural domains, and they generally specifically target different epitopes. "Monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. In some embodiments, the antibodies provided in this disclosure are monoclonal antibodies.

[0408] The term "antigen" refers to a molecule or molecular moiety that can be bound by a selective binder, such as an antigen-binding protein (including, for example, an antibody), and is further capable of being used in animals to produce antibodies that can bind to that antigen. An antigen may have one or more epitopes that can interact with different antigen-binding proteins (e.g., antibodies).

[0409] The term "epitope" refers to a region on an antigen that is capable of specifically binding to an antibody or its antigen-binding fragment. Epitopes can be formed from a continuous string of amino acids (linear epitopes) or contain discontinuous amino acids (conformal epitopes), for example, due to the folding of the antigen (i.e., the tertiary folding of an antigen as a protein). The difference between conformational and linear epitopes is that in the presence of a denaturing solvent, the antibody loses binding to the conformational epitope. An epitope contains 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 specific epitope (i.e., those that bind the same epitope) can be performed using methods routine in the art, such as, but not limited to, alanine scanning, peptide blotting, peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen (see Prot. Sci. 9 (2000) 487-496), and cross-blocking.

[0410] The terms "specific binding," "specific binding," or "binding" refer to the ability of an antibody to bind to a specific antigen or epitope with a higher affinity than other antigens or epitopes. Typically, antibodies bind at an affinity of approximately 1 × 10⁻⁶. -7 M or smaller (e.g., about 1×10⁻⁶) -8 M, 1×10 -9 M, 1×10 -10 M, 1×10 -11 The equilibrium dissociation constant (KD) of an antibody (M or less) binds to an antigen or an epitope within the antigen. In some embodiments, the KD of antibody binding to an antigen is 10% or less (e.g., 1%) of the KD of antibody binding to a nonspecific antigen (e.g., BSA, casein). KD can be measured using known methods, such as by... Surface plasmon resonance assays are used to measure this. However, antibodies that specifically bind to antigens or epitopes within antigens may be cross-reactive to other related antigens, for example, to corresponding antigens from other species (homologous) (such as humans or monkeys, such as the cynomolgus (cyno), chimpanzee (chimp), or common marmoset (marmoset)).

[0411] The terms “antibody-dependent cell cytotoxicity,” “antibody-dependent cell-mediated cytotoxicity,” or “ADCC” refer to mechanisms that induce cell death that rely on the interaction between antibody-coated target cells and lytic effector cells (such as natural killer (NK) cells, monocytes, macrophages, and neutrophils) via Fcγ receptors (FcγR) expressed on the effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of the antibodies described herein can be assessed in vitro using cells expressing the antigen as target cells and NK cells as effector cells. Cell lysis is detected based on the release of markers (e.g., radioactive substrates, fluorescent dyes, or native intracellular proteins) from lysed cells.

[0412] The term "antibody-dependent phagocytosis (ADCP)" refers to the mechanism by which antibody-coated target cells are eliminated through internalization by phagocytes (such as macrophages or dendritic cells).

[0413] The term "complement-dependent cytotoxicity" or "CDC" refers to a mechanism that induces cell death in which the Fc effector domain of a target-binding antibody binds to and activates the complement component C1q. C1q then 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.

[0414] The terms “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acid residues. The term applies to amino acid polymers, where one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers. Unless otherwise stated, a particular peptide sequence also implicitly encompasses variants with conserved modifications.

[0415] The term "sequence identity" refers to the degree (percentage) to which the amino acids / nucleic acids of two sequences are identical at equivalent positions when two sequences are optimally aligned, with gaps introduced where necessary to obtain the maximum percentage of sequence identity, without considering any conserved substitutions as part of sequence identity. To determine the percentage of sequence identity, alignment can be performed using techniques known in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine the parameters suitable for measuring alignment, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.

[0416] The term "vector" refers to a polynucleotide molecule capable of transporting another polynucleotide linked to it. One type of vector is a "plasmid," which is a circular double-stranded DNA loop in which an additional DNA segment can be attached. Another type of vector is a viral vector, such as an adeno-associated virus vector (AAV or AAV2), in which an additional DNA segment can be attached to the viral genome. Some vectors are capable of autonomous replication in the host cells to which they are introduced (e.g., bacterial vectors with bacterial origins of replication and attachable mammalian vectors). Other vectors (e.g., non-attached mammalian vectors) can integrate into the host cell's genome after introduction into the host cell, thereby replicating along with the host genome. The term "expression vector" or "expression construct" refers to a vector capable of transforming host cells and containing a nucleic acid sequence that directs and / or controls (alongside the host cell) the expression of one or more heterologous coding regions operatively linked to it. Expression constructs can include, but are not limited to, sequences that affect or control transcription, translation, and, in the presence of introns, influence RNA splicing of coding regions operatively linked to them.

[0417] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, including the progeny of such cells. Host cells include “transformers” and “transformed cells,” which include primary transformed cells and their derived progeny, regardless of passage number. Progeny may not be identical to parental cells in their nucleic acid contents and may contain mutations. This includes mutant progeny with the same function or biological activity as those screened or selected in the initially transformed cells. 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, dog, monkey, pig, goat, cattle, horse, and hamster cells, including but not limited to Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, young 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*, *Pichiamembranaefaciens*, *Pichia minuta* (Ogataea minuta, *Pichia lindneri*), *Pichia xiaopuntiae*, *Pichia thermotolerans*, *Pichia salictaria*, *Pichia guercuum*, *Pichia pijperi*, *Pichia stiptis*, *Pichia methanolica*, *Pichia* genus, *Saccharomyces cerevisiae*, *Saccharomyces* genus, and *Hansenula*. The fungi include *Candida polymorpha*, *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, any Saccharomyces, Hansenula polymorpha, any Kluyveromyces, Candida albicans, any Aspergillus, Trichoderma reesei, Chrysosporium lucknowense, any Fusarium, Yarrowia lipolytica, and Neurospora crassa.

[0418] The terms “cell,” “cell line,” and “cell culture” are used interchangeably, and all such names include progeny. Therefore, the terms “transformation” and “transformed cell” include primary subject cells and cultures derived from them, regardless of the number of passages. It should also be understood that due to intentional or unintentional mutations, not all progeny will have exactly the same DNA contents. This includes mutant progeny that have the same function or biological activity as the original transformed cells.

[0419] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 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., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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 their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0420] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 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., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6 Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0421] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. Substituents are preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0422] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6(Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0423] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0424] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic 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 is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0425] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0426] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0427] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 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 is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), preferably monospirocyclic alkyl or bispirocyclic alkyl, 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 monospirocyclic alkyl. Non-limiting examples include:

[0428] Its connection point can be anywhere;

[0429] wait.

[0430] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds 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 groups). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl groups), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl groups). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably ternary / quadrivalent, ternary / pentary, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentary, quadrivalent / hexavalent, pentary / pentary ... or pentary / pentary bicyclic fused cyclic alkyl groups. Non-limiting examples include: Its connection point can be anywhere; wait.

[0431] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds 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 is preferably a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0432] Its connection point can be anywhere.

[0433] The cycloalkyl 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, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0434] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) 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-), and 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 heterocyclic groups). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group), for example, a 4 to 12-membered heterocyclic group containing at least one nitrogen atom; more preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group).

[0435] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0436] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0437] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which 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 spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), more preferably a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), preferably monospirocyclic or bispirocyclic, 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 monospirocyclic. Non-limiting examples include:

[0438] wait.

[0439] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group 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 heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic groups, 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 heterocyclic groups. Non-limiting examples include:

[0440]

[0441] wait.

[0442] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system 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., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group with 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0443] wait.

[0444] The heterocyclic 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, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0445] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, 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 is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl further includes fusion of the phenyl with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point 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, non-limiting examples including:

[0446] wait.

[0447] The aryl 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, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0448] 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.

[0449] 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.

[0450] 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:

[0451]

[0452] wait.

[0453] 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.

[0454] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl residues include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0455] In the chemical structure of the compound disclosed herein, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0456] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds disclosed herein include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 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 Grade I, with deuterium as the preferred grade.

[0457] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0458] "Optional" or "optionally" means that the event or circumstances described below may, but do not have to, occur, including the circumstances in which the event or circumstances may or may not occur.

[0459] The term "pharmaceutical composition" means a mixture containing one or more antibody-peptide conjugates or pharmaceutically acceptable salts thereof as described herein, along with other chemical components, such as physiological / pharmaceutical carriers and excipients.

[0460] The term "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical formulation that is distinct from the active ingredient and non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0461] The terms “subject” or “individual” include both humans and non-human animals. Non-human animals include all vertebrates (e.g., mammals and non-mammals) such as non-human primates, sheep, dogs, cattle, chickens, amphibians, and reptiles. Unless otherwise specified, the terms “patient” or “subject” are used interchangeably herein. In some embodiments, the individual or subject is a human being.

[0462] "Administration" or "giving," when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refers to the contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid.

[0463] 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 the subject's body. Exemplary samples include biological fluids such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleura, pericardium, peritoneum, fluids in the abdominal cavity and other body cavities, fluids collected by bronchoalveolar lavage fluid, synovial fluid, liquid solutions in contact with the subject or biological sources, such as cell and organ culture media (including cell or organ conditioned media), lavage fluids, tissue biopsy samples, fine-needle aspiration, surgically removed tissue, organ cultures, or cell cultures.

[0464] "Treatment" and "treatment" (and their grammatical variations) refer to clinical interventions that attempt to alter the natural processes of the individual being treated, and can be implemented for prevention or during a clinicopathological process. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing / decreasing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and resolving or improving prognosis. In some implementations, antibodies disclosed herein are used to delay disease onset or slow disease progression.

[0465] An "effective dose" is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate such symptoms and / or underlying causes, prevent the occurrence of symptoms and / or underlying causes, and / or improve or mitigate damage caused by or associated with a disease state (e.g., lung disease). In some embodiments, an effective dose is a therapeutically effective dose or a preventatively effective dose. A "therapeuticly effective dose" is an amount sufficient to treat a disease state or symptom, particularly a state or symptom associated with that disease state, or otherwise prevent, inhibit, delay, or reverse the progression of the disease state or any other undesirable symptom associated with that disease. A "preventatively effective dose" is an amount that, when administered to a subject, will have a predetermined preventative effect, such as preventing or delaying the onset (or recurrence) of the disease state, or reducing the likelihood of the onset (or recurrence) of the disease state or related symptoms. A complete therapeutic or preventative effect may not occur after the administration of a single dose, but may occur after the administration of a series of doses. Therefore, a therapeutically or preventatively effective dose may be administered in a single or multiple-dose manner. "Therapeutic effective dose" and "preventive effective dose" can vary depending on a number of factors, such as an individual's disease state, age, sex, and weight, as well as the ability of the treatment or combination of treatments to elicit the desired response in the individual. Exemplary indicators of an effective treatment or combination of treatments include, for example, improved health status in the patient.

[0466] Exemplary ligand-drug conjugates or their pharmaceutically acceptable salts:

[0467] This disclosure relates to an antibody-drug conjugate or a pharmaceutically acceptable salt thereof of a general formula (IN), general formula (IN-S) or general formula (IN-R):

[0468]

[0469]

[0470] The Ab is an anti-CD38 antibody, which 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;

[0471] W1 -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6;

[0472] L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:16);

[0473] R 2 It is a hydrogen atom;

[0474] R 4 It can be a hydrogen atom or a halogen;

[0475] R 5 For -NR i -C(O)- or -NR i -S(O) p -;

[0476] R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -,

[0477] R 7 For chemical bonds or -NR 12 -C(O)-NR 12 -;

[0478] R 9 It is a hydrogen atom;

[0479] R 12 It is a hydrogen atom;

[0480] R i It is a hydrogen atom;

[0481] R m and R n All are hydrogen atoms;

[0482] n can be 0, 1, 2, 3, or 4;

[0483] p is 2;

[0484] r is 0 or 4;

[0485] t is 0, 1, or 2;

[0486] y ranges from 1 to 8.

[0487] Exemplary compounds or their pharmaceutically acceptable salts:

[0488] This disclosure relates to a compound of general formula (D-II), general formula (D-II-S) or general formula (D-II-R) or a pharmaceutically acceptable salt thereof (preferably a methanesulfonate or hydrochloride):

[0489]

[0490] Where R 2 It is a hydrogen atom;

[0491] R 4 It can be a hydrogen atom or a halogen;

[0492] R 5 For -NR i -C(O)- or -NR i -S(O) p -;

[0493] R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -,

[0494] R 7 For chemical bonds or -NR 12 -C(O)-NR 12 -;

[0495] R 9 It is a hydrogen atom;

[0496] R 12 It is a hydrogen atom;

[0497] R i It is a hydrogen atom;

[0498] R m and R n All are hydrogen atoms;

[0499] n can be 0, 1, 2, 3, or 4;

[0500] p is 2;

[0501] r is 0 or 4; and t is 0, 1 or 2. Detailed Implementation

[0503] 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.

[0504] Examples and Test Cases

[0505] I. Antibody Examples

[0506] Example 1, Antibody

[0507] The antibody Ab1 used in this disclosure has a sequence derived from WHO, CAS No.: 945721-28-8; the negative control antibody is Ab2, whose VH / VL sequence is derived from patent US6114143A.

[0508] Table 2. CDR sequence of Ab1

[0509] HCDR1 SFAMS SEQ ID NO:1 HCDR2 AISGSGGGTYYADSVKG SEQ ID NO:2 HCDR3 DKILWFGEPVFDY SEQ ID NO:3 LCDR1 RASQSVSSYLA SEQ ID NO:4 LCDR2 DASNRAT SEQ ID NO:5 LCDR3 QQRSNWPPT SEQ ID NO:6

[0510] Note: The amino acids in CDRs are determined by the Kabat numbering system and marked with double underscores, the same applies below.

[0511] The heavy chain variable region of Ab1:

[0512]

[0513] SEQ ID NO: 7

[0514] >Ab1 light chain variable region:

[0515]

[0516] SEQ ID NO: 8

[0517] >Heavy chain constant region of Ab1:

[0518] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0519] SEQ ID NO:9

[0520] >Constant region of the light chain of Ab1:

[0521] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0522] SEQ ID NO:10

[0523] >Heavy chain of Ab1:

[0524]

[0525] SEQ ID NO:11

[0526] >Light chain of Ab1:

[0527]

[0528] SEQ ID NO:12

[0529] >Heavy chain of Ab2:

[0530]

[0531] SEQ ID NO:13

[0532] >Light chain of Ab2:

[0533]

[0534] SEQ ID NO: 14

[0535] The heavy chain constant region of Ab2:

[0536] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

[0537] KSLSLSPGK

[0538] SEQ ID NO: 15

[0539] Note: The underlined part is the variable area, and the italic part is the constant area.

[0540] II. Compound Examples

[0541] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0542] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0543] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector).

[0544] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive).

[0545] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLCe2695-2489 high-performance liquid chromatograph.

[0546] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0547] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0548] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0549] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0550] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0551] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0552] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0553] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0554] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0555] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0556] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0557] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0558] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0559] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0560] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0561] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0562] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate 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.

[0563] Example 2-1

[0564] (4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzoyl)-L-lysine-2,2,2-trifluoroacetate)

[0565]

[0566]

[0567] first step

[0568] (S)-5-amino-4-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 1c

[0569] (S)-5-amino-4-(4-hydroxy-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester 1a (2.0 g, 5.98 mmol, prepared by a known method, "Journal of Medicinal Chemistry, 2020, 63(13), 6648-6676") was dissolved in acetonitrile (30 mL), and 1,4-bis(bromomethyl)benzene 1b (4.8 g, 18.18 mmol, adamas) and anhydrous potassium carbonate (840 mg, 6.1 mmol) were added sequentially. The reaction system was purged with nitrogen three 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 residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (2.6 g, yield: 84.3%).

[0570] MS m / z(ESI): 519.2 [M+1].

[0571] Step 2

[0572] 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid benzyl ester 1f

[0573] Methyl 3,4-difluorobenzoate 1d (2.04 g, 11.85 mmol, BID) and benzyl piperazine-1-carboxylate 1e (2.61 g, 11.85 mmol, SAO) were dissolved in dimethyl sulfoxide (30 mL), and anhydrous potassium carbonate (4.91 g, 35.58 mmol) was added. The reaction system was purged with nitrogen three times, heated to 120 °C, and stirred for 4 hours. The reaction system was cooled to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title product 1f (2.10 g, yield: 47.6%).

[0574] MS m / z(ESI): 373.2 [M+1].

[0575] Step 3

[0576] 1g of 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-3-fluorobenzoic acid

[0577] 1 ppm (710 mg, 1.91 mmol) was dissolved in tetrahydrofuran (6 mL), followed by the addition of methanol (2 mL), water (2 mL), and lithium hydroxide monohydrate (161 mg, 3.84 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. Water (5 mL) was added to the residue, and the mixture was cooled in an ice-water bath. The pH was adjusted to 2 with 2N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1 g (665 mg, yield: 97.3%) of the crude product, which was directly used in the next reaction.

[0578] MS m / z(ESI): 359.4 [M+1].

[0579] Step 4

[0580] (S)-4-(4-((1-(tert-butoxy)-6-((tert-butoxycarbonyl)amino)-1-oxohex-2-yl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 1i

[0581] 1g (350mg, 0.98mmol) and N 6 -(tert-butoxycarbonyl)-L-lysine tert-butyl ester 1h (398 mg, 1.17 mmol, Biotin) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of triethylamine (400 mg, 3.95 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (743 mg, 1.95 mmol, Shaoyuan). The mixture was stirred at room temperature for 3 hours after the addition was complete. Water (70 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 1i (525 mg, yield: 83.6%).

[0582] MS m / z(ESI): 643.7 [M+1].

[0583] Step 5

[0584] N 6 -(tert-butoxycarbonyl)-N 2 -(3-fluoro-4-(piperazin-1-yl)benzoyl)-L-lysine tert-butyl ester

[0585] 1i (525 mg, 0.82 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and palladium on carbon (200 mg, 10% purity, dry type) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain crude product 1j (327 mg, yield: 78.7%), which was directly used in the next step of the reaction.

[0586] MS m / z (ESI): 509.7 [M+1].

[0587] Step 6

[0588] N 2 -(4-(4-(4-(((2-((S)-1-amino-5-(tert-butoxy)-1,5-dioxohex-2-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzoyl)-N 6 -(tert-butoxycarbonyl)-L-lysine tert-butyl ester 1k

[0589] Dissolve 1j (155 mg, 0.30 mmol) and 1c (167 mg, 0.32 mmol) in acetonitrile (5 mL) and N,N-dimethylformamide (0.5 mL), then add N,N-diisopropylethylamine (120 mg, 0.93 mmol, adamas). After the addition is complete, heat to 40 °C and stir for 2 hours. Cool the reaction system to room temperature, add water (50 mL) to the reaction solution, and extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent system A to give the title product 1k (270 mg, yield: 93.7%).

[0590] MS m / z(ESI): 946.1 [M+1].

[0591] Step 7

[0592] (4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzoyl)-L-lysine-2,2,2-trifluoroacetate)

[0593] 1 kJ (278 mg, 0.29 mmol) was dissolved in acetonitrile (5 mL), and benzenesulfonic acid (280 mg, 1.77 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (3 mL) and purified by high performance liquid chromatography (Wasters, 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 give title product 1 (130 mg, yield: 61.8%).

[0594] MS m / z (ESI): 715.4 [M+1].

[0595] 1 H NMR(500MHz,DMSO)δ12.60(br,1H),10.98(s,1H),9.91(s,1H),8.51(d,1H),7.75-7.69(m,2H),7.66-7.54(m,6H), 7.49(t,1H),7.34(t,2H),7.21-7.12(m,1H),5.31(s,2H),5.15-5.09(m,1H),4.51-4.38(m,3H),4.37-4.32(m,1H) ,4.31-4.24(m,1H),3.69-3.61(m,2H),3.26-3.21(m,2H),3.12-3.06(m,2H),2.95-2.89(m,1H),2.81-2.72(m,2H) ,2.63-2.56(m,1H),2.42-2.35(m,1H),2.03-1.95(m,2H),1.89-1.71(m,2H),1.60-1.51(m,2H),1.47-1.36(m,2H).

[0596] Example 2-2

[0597] (S)-N-(2-(3-(2-aminoethyl)ureo)ethyl))-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide2

[0598]

[0599] first step

[0600] 4-(4-((2-aminoethyl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 2a

[0601] 3a (0.4 g, 0.8 mmol, synthesis method see Examples 2-3) was dissolved in anhydrous dichloromethane (5 mL), and 4N hydrochloric acid 1,4-dioxane solution (2 mL) was added. The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (2 mL). The mixture was purified by high performance liquid chromatography (GILSON, column: Sharpsil-T Prep 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 title product 2a (210 mg, yield: 65.6%).

[0602] MS m / z (ESI): 401.2 [M+1].

[0603] Step 2

[0604] 4-(4-((11,11-dimethyl-4,9-dioxo-10-oxa-3,5,8-triazadodecyl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 2b

[0605] N-tert-Butoxycarbonyl-1,2-ethylenediamine (672 mg, 4.2 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (1.69 g, 16.7 mmol) was added. N,N-carbonyldiimidazole (680 mg, 4.2 mmol) was added under ice bath conditions, and the mixture was stirred at this temperature for 30 min. Then, 2a (280 mg, 0.699 mmol) was added, and the mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (3 mL). The solution was purified by high-performance liquid chromatography (GILSON, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 45%-95%, flow rate: 30 mL / min) to obtain the title product 2b (210 mg, yield: 51.2%).

[0606] MS m / z(ESI): 587.4 [M+1].

[0607] Step 3

[0608] (2-(3-(2-(3-fluoro-4-(piperazin-1-yl)benzamido)ethyl)ureo)ethyl)tert-butyl carbamate 2c

[0609] Dissolve 2b (50 mg, 0.085 mmol) in anhydrous tetrahydrofuran (5 mL), add palladium on carbon (50 mg, 10% purity, wet type), purge with hydrogen three times, stir at room temperature for 6 hours, filter the reaction solution through diatomaceous earth, concentrate the filtrate under reduced pressure, and dry under vacuum to obtain crude product 2c, which can be directly used in the next step of the reaction.

[0610] MS m / z(ESI): 453.4 [M+1].

[0611] Step 4

[0612] (S)-5-amino-4-(4-((4-((4-((11,11-dimethyl-4,9-dioxo-10-oxa-3,5,8-triazadodecyl)aminocarbonyl)-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxopentanoic acid tert-butyl ester 2d

[0613] Dissolve 2c (60 mg, 0.133 mmol) and 1c (72.7 mg, 0.14 mmol) in acetonitrile (2 mL) and N,N-dimethylformamide (0.2 mL), then add N,N-diisopropylethylamine (51.4 mg, 0.397 mmol, adamas). After the addition is complete, heat to 40 °C and stir for 1 hour. Cool the reaction system to room temperature, add water (50 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to give the title product 2d (56 mg, yield: 47.5%).

[0614] MS m / z(ESI):890.0[M+1].

[0615] Step 5

[0616] (S)-N-(2-(3-(2-aminoethyl)ureo)ethyl)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide2

[0617] Product 2 (56 mg, 0.063 mmol) was dissolved in acetonitrile (2 mL), and benzenesulfonic acid (59.6 mg, 0.376 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 16 hours. The reaction system was cooled to room temperature, stirring was stopped, and the mixture was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2 mL) and purified by high performance liquid chromatography (GILSON, column: Welch Xtimate Prep C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (containing 10 mmol / L ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 15%-80%, flow rate: 30 mL / min) to give title product 2 (9 mg, yield: 20%).

[0618] MS m / z (ESI): 715.3 [M+1].

[0619] 1H NMR(500MHz,DMSO-d6)δ8.50(t,1H),7.67-7.58(m,2H),7.52-7.46(m,3H ),7.39-7.33(m,4H),7.05(t,1H),6.45-6.33(m,2H),5.24(s,2H),5.15-5 .09(m,1H),4.41(d,1H),4.27(d,1H),3.26-3.23(m,2H),3.17-3.07(m,8 H),2.95-2.81(m,2H),2.66(t,2H),2.52-2.41(m,9H),2.01-1.97(m,1H).

[0620] Example 2-3

[0621] (S)-N-(2-aminoethyl)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide3

[0622]

[0623] first step

[0624] 4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 3a

[0625] 1 g (660 mg, 1.84 mmol) was dissolved in N,N-dimethylformamide (7 mL), and N-tert-butoxycarbonyl-1,2-ethylenediamine (355 mg, 2.22 mmol) was added, followed by triethylamine (560 mg, 5.53 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.40 g, 3.68 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours. Water (70 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 3a (820 mg, yield: 88.9%).

[0626] MS m / z(ESI): 501.4 [M+1].

[0627] Step 2

[0628] (2-(3-fluoro-4-(piperazin-1-yl)benzamido)ethyl)tert-butyl carbamate 3b

[0629] Dissolve 3a (820 mg, 1.64 mmol) in anhydrous tetrahydrofuran (10 mL), add palladium on carbon (320 mg, 10% purity, dry type, Shaoyuan), replace with hydrogen three times, stir at room temperature for 6 hours, filter the reaction solution through diatomaceous earth, wash with methanol (50 mL), concentrate the filtrate under reduced pressure, and dry under vacuum to obtain crude product 3b (610 mg), which is directly used in the next step of the reaction.

[0630] MS m / z (ESI): 367.3 [M+1].

[0631] Step 3

[0632] (S)-5-amino-4-(4-((4-((4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)aminocarbonyl)-2-fluorophenyl)

[0633] Piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester 3c

[0634] Dissolve 3b (150 mg, 0.41 mmol) and 1c (233 mg, 0.45 mmol) in acetonitrile (3 mL) and N,N-dimethylformamide (1 mL), then add N,N-diisopropylethylamine (160 mg, 1.24 mmol, adamas). After the addition is complete, heat to 40 °C and stir for 2 hours. Cool the reaction system to room temperature, add water (50 mL) to the reaction solution, and extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent system A to give the title product 3c (313 mg, yield: 95.2%).

[0635] MS m / z(ESI): 803.7 [M+1].

[0636] Step 4

[0637] (S)-N-(2-aminoethyl)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide3

[0638] 3c (150 mg, 0.19 mmol) was dissolved in acetonitrile (3 mL), and benzenesulfonic acid (90 mg, 0.57 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 16 hours. The reaction system was cooled to room temperature, stirring was stopped, and the mixture was allowed to stand for 1 hour. The supernatant was removed, and the residue was dissolved in dimethyl sulfoxide (3 mL). The mixture was purified by high performance liquid chromatography (Wasters, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 10 mmol / L ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to obtain title product 3 (77 mg, yield: 65.6%).

[0639] MS m / z (ESI): 629.5 [M+1].

[0640] 1H NMR(500MHz,DMSO)δ8.33(t,1H),7.65-7.56(m,2H),7.51-7.43(m,3H),7.38-7.31 (m,4H),7.04(t,1H),5.24(s,2H),5.13-5.09(m,1H),4.42(d,1H),4.26(d,1H),3.5 4(s,2H),3.26-3.22(m,3H),3.12-3.07(m,4H),2.95-2.86(m,1H),2.68(t,2H),2.6 -2.57(m,1H),2.56-2.52m,3H),2.46-2.41(m,1H),2.03-1.94(m,2H),1.89(s,2H).

[0641] Examples 2-4

[0642] (S)-N-(2-aminoethyl)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzenesulfonamide 4

[0643]

[0644] first step

[0645] 2,2,2-Trichloroethyl 3,4-difluorobenzenesulfonate 4c

[0646] 3,4-Difluorobenzenesulfonyl chloride 4a (5.00 g, 23.52 mmol) was dissolved in dichloromethane (50 mL), followed by 2,2,2-trichloroethane-1-ol 4b (3.51 g, 23.52 mmol), and then N,N-diisopropylethylamine (6.08 g, 47.04 mmol). After the addition was complete, the mixture was stirred at room temperature for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title product 4c (6.21 g, yield: 81.1%).

[0647] Step 2

[0648] 4-(2-fluoro-4-((2,2,2-trichloroethoxy)sulfonyl)phenyl)piperazine-1-carboxylic acid benzyl ester 4d

[0649] 4c (3.80 g, 11.67 mmol) and piperazine-1-carboxylic acid benzyl ester 1e (3.34 g, 15.17 mmol) were dissolved in N,N-dimethylformamide (30 mL), and anhydrous potassium carbonate (4.91 g, 35.58 mmol) was added. The reaction system was purged with nitrogen three times and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The solution was concentrated again under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 4d (5.00 g, yield: 81.5%).

[0650] MS m / z(ESI): 525.0 [M+1].

[0651] Step 3

[0652] 4-(4-(N-(2-((tert-butoxycarbonyl)amino)ethyl)aminosulfonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 4e

[0653] Add tert-butyl N-(2-aminoethyl)carbamate (1.22 g, 7.61 mmol) to 4d (400.00 mg, 0.76 mmol). Heat to 40 °C and stir for 12 hours. Adjust the pH to 7.0 with 2N hydrochloric acid aqueous solution and purify by high performance liquid chromatography (Waters Autopurification, column: Sharpsil-T Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (0.1% trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 60%-80%, flow rate: 30 mL / min) to give the title product 4e (408.22 mg, yield: 88.7%).

[0654] MS m / z(ESI):437.5[M-100].

[0655] Step 4

[0656] (2-((3-fluoro-4-(piperazin-1-yl)phenyl)sulfonamido)ethyl)tert-butyl carbamate 4f

[0657] 4e (500.00 mg, 1.14 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and palladium on carbon (121.44 mg, 10% purity, dry type) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 6 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure and dried under vacuum to obtain crude product 4f (261.00 mg), which was directly used in the next step of the reaction.

[0658] MS m / z (ESI): 403.5 [M+1].

[0659] Step 5

[0660] (S)-5-amino-4-(4-((4-((4-(N-(2-((tert-butoxycarbonyl)amino)ethyl)aminosulfonyl)-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester 4g

[0661] 4f (226.00 mg, 0.56 mmol) and 1c (290.53 mg, 0.56 mmol) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (217.72 mg, 1.68 mmol, adamas) was added. After the addition was complete, the mixture was heated to 40 °C and stirred for 2 hours. The reaction system was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give 4 g (454 mg, yield: 96.4%) of the title product.

[0662] MS m / z(ESI): 839.7 [M+1].

[0663] Step 6

[0664] (S)-N-(2-aminoethyl)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzenesulfonamide 4

[0665] 4 g (470.00 mg, 0.56 mmol) was dissolved in acetonitrile (10 mL), and benzenesulfonic acid (265.83 mg, 1.68 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction system was cooled to room temperature, stirring was stopped, and the mixture was allowed to stand for 1 hour. The supernatant was removed, and the residue was dissolved in dimethyl sulfoxide (2 mL). The mixture was purified by high performance liquid chromatography (GILSON-GX-281, column: BOSTONPHLEX PREP C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 20%-55%, flow rate: 30 mL / min) to obtain title product 4 (243.00 mg, yield: 65.3%).

[0666] MS m / z (ESI): 665.2 [M+1].

[0667] 1H NMR(500MHz,DMSO-d6)δ7.46(m,5H),7.36 -7.28(m,4H),7.14(t,1H),5.22(s,2H),5.09(m,1H),4.44-4.36(m,1H),4.27-4.21( m,1H),3.53(s,2H),3.13(t,4H),2.70(t,2H),2.56-2.49(m,8H),2.03-1.76(m,2H).

[0668] Examples 2-5

[0669] (S)-3-amino-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)propionic acid 5

[0670]

[0671] first step

[0672] (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)tert-butyl propionate 5b

[0673] (S)-3-amino-2-(((benzyloxy)carbonyl)amino)propionate tert-butyl ester 5a (500 mg, 1.70 mmol, BIDE) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (878 mg, 6.79 mmol, adamas) and ditert-butyl dicarbonate (741 mg, 3.39 mmol, adamas) were added sequentially. After reacting at room temperature for half an hour, the reaction system was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system A to give the title product 5b (150 mg, yield: 22.3%).

[0674] MS m / z(ESI):417.2[M+23].

[0675] Step 2

[0676] (S)-2-amino-3-((tert-butoxycarbonyl)amino)tert-butyl propionate 5c

[0677] 5b (150 mg, 0.38 mmol) and 10% wet palladium on carbon (40.5 mg, 38 μmol, Shaoyuan) were dissolved in methanol (3 mL), and hydrogen gas was purged three times. The reaction was carried out at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue obtained was the crude product 5c (90 mg), which was directly used in the next step of the reaction.

[0678] MS m / z(ESI):261.3[M+1].

[0679] Step 3

[0680] (S)-4-(4-((1-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-1-oxopropyl-2-yl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 5d

[0681] 5c (90 mg, 307 μmol) and 1 g (146 mg, 368 μmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (125 mg, 1.22 mmol, Sinopharm) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (234 mg, 614 μmol, Shaoyuan). The mixture was stirred at room temperature for 3 hours after the addition was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 5d (115 mg, yield: 62.3%).

[0682] MS m / z(ESI): 601.6 [M+1].

[0683] Step 4

[0684] (S)-3-((tert-butoxycarbonyl)amino)-2-(3-fluoro-4-(piperazin-1-yl)benzamido)tert-butyl propionate 5e

[0685] 5d (115 mg, 191 μmol) and 10% wet palladium on carbon (20.4 mg, 19 μmol, Shaoyuan) were dissolved in methanol (3 mL), and hydrogen gas was purged three times. The reaction was carried out at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue obtained was the crude title product 5e (84 mg), which was directly used in the next step of the reaction.

[0686] MS m / z(ESI): 467.5 [M+1].

[0687] Step 5

[0688] (S)-5-amino-4-(4-((4-((4-(4-(((S))-1-(tert-butoxy)-3-((tert-butoxycarbonyl)amino))-1-oxopropyl-2-yl)aminocarbonyl)-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2-yl)-5-oxopentanoic acid tert-butyl ester 5f

[0689] 5e (84 mg, 180 μmol) and 1c (102 mg, 198 μmol) were dissolved in acetonitrile (5 mL) and N,N-dimethylformamide (0.5 mL). N,N-diisopropylethylamine (69.8 mg, 0.54 mmol, adamas) was added. After the addition was complete, the mixture was heated to 40 °C and stirred for 2 hours. The reaction system was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 5f (160 mg, yield: 98.4%).

[0690] MS m / z (ESI): 903.7 [M+1].

[0691] Step 6

[0692] (S)-3-amino-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)propionic acid 5

[0693] 5f (160 mg, 177 μmol) was dissolved in acetonitrile (5 mL), and benzenesulfonic acid (280 mg, 1.77 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 16 hours. The reaction system was cooled to room temperature, stirring was stopped, and the acetonitrile was evaporated to dryness. The residue was dissolved in dimethyl sulfoxide (2 mL) and purified by high performance liquid chromatography (Waters-2545, column Welch Xtimate C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 20-34%, flow rate: 30 mL / min) to obtain title product 5 (55 mg, yield: 46.1%).

[0694] MS m / z (ESI): 673.5 [M+1].

[0695] 1H NMR(500MHz,DMSO)δ11.30-10.70(m,1H),8.05-8.04(m,1H),7.65-7.55(m,2H),7.52-7.43(m,3H),7.39-7.31(m,4H),7.06(t,1H),5.24(s,2H) ,5.11(dd,1H),4.45-4.23(m,2H),4.13-4.05(m,1H),3.55(s,2H),3.12 -3.05(m,5H),2.96-2.82(m,2H),2.56-2.44(m,5H),2.05-1.94(m,2H).

[0696] Examples 2-6

[0697] (S)-5-amino-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)valerate 6

[0698]

[0699] first step

[0700] (S)-2-(((benzyloxy)carbonyl)amino)-5-((tert-butoxycarbonyl)amino)tert-butyl valerate 6b

[0701] (S)-2-(((benzyloxy)carbonyl)amino)-5-(((tert-butoxycarbonyl)amino)valerate 6a (0.5 g, 1.36 mmol, adamas) was dissolved in dichloromethane (5 mL). The reaction system was purged with nitrogen three times. Boron trifluoride diethyl ether (12.36 mg, 0.041 mmol, adamas) was added dropwise to the system under ice bath conditions. Then, tert-butyltrichloroacetylimine ester (596 mg, 2.73 mmol, adamas) dissolved in n-hexane (5 mL) was added dropwise to the system. The mixture was stirred overnight at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 6b (576 mg, yield: 99.9%).

[0702] MS m / z(ESI):423.3[M+1].

[0703] Step 2

[0704] (S)-2-amino-5-((tert-butoxycarbonyl)amino)tert-butyl valerate 6c

[0705] 6b (260 mg, 0.615 mmol) was dissolved in methanol (2 mL), and palladium on carbon (130.9 mg, 10% purity, wet type) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain the crude product 6c, which was directly used in the next step of the reaction.

[0706] MS m / z(ESI):289.5[M+1].

[0707] Step 3: (S)-4-(4-((1-(tert-butoxy)-5-((tert-butoxycarbonyl)amino)-1-oxopent-2-yl)aminocarbonyl)-2-fluorophenyl)piperazine-1-carboxylic acid benzyl ester 6d

[0708] 1 g (180 mg, 0.502 mmol) and 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid benzyl ester 6c (173.8 mg, 0.602 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (203 mg, 2 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (382 mg, 1.0 mmol). The mixture was stirred at room temperature for 3 hours after the addition was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (20 mL × 3) and saturated sodium chloride solution (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 6d (180 mg, yield: 57%).

[0709] MS m / z(ESI): 629.5 [M+1].

[0710] Step 4

[0711] (S)-5-((tert-butoxycarbonyl)amino)-2-(3-fluoro-4-(piperazin-1-yl)benzamido)tert-butyl valerate 6e

[0712] 6d (97 mg, 0.154 mmol) was dissolved in tetrahydrofuran (2 mL), and palladium on carbon (32.8 mg, 10% purity, wet type) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain the crude product 6e, which was directly used in the next step of the reaction.

[0713] MS m / z(ESI):495.4[M+1].

[0714] Step 5: (S)-5-amino-4-(4-((4-((4-(4(((S)-1-(tert-butoxy)-5-((tert-butoxycarbonyl)amino)-1-oxopentan-2-yl)aminocarbonyl)-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxyisoindoline-2-yl)-5-oxopentanoic acid tert-butyl ester 6f

[0715] Dissolve 6e (56 mg, 0.063 mmol) and 1c (80.2 mg, 0.155 mmol) in acetonitrile (2 mL) and N,N-dimethylformamide (0.2 mL), then add N,N-diisopropylethylamine (57.2 mg, 0.443 mmol, adamas). After the addition is complete, heat to 40 °C and stir for 1 hour. Cool the reaction system to room temperature, add water (50 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL), dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to give the title product 6f (0.1 g, yield: 72.3%).

[0716] MS m / z(ESI): 931.9 [M+1].

[0717] Step 6

[0718] (S)-5-amino-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)valerate 6

[0719] 6f (50 mg, 0.054 mmol) was dissolved in acetonitrile (2 mL), and benzenesulfonic acid (51 mg, 0.322 mmol, Acros) was added. The mixture was heated to 80 °C and stirred for 16 hours. The reaction system was cooled to room temperature, stirring was stopped, and the mixture was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2 mL) and purified by high performance liquid chromatography (GILSON, column: Welch Xtimate Prep C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (containing 10 mmol / L ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 10%-40%, flow rate: 30 mL / min) to give title product 6 (9 mg, yield: 20%).

[0720] MS m / z (ESI): 701.4 [M+1].

[0721] 1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.59-7.44(m,5H),7.39-29(m,4H),7.03(t,1 H),5.24(s,2H),5.15-5.1(m,1H),4.42(d,1H),4.26(d,1H),3.55(s,2H),3.09(t, 3H),2.95-2.87(m,2H),2.81-2.74(m,2H),2.60-2.54(m,5H),2.46-2.36(m,2H),2 .05-1.97(m,2H),1.82-1.76(m,2H),1.66-1.51(m,2H),1.46(t,1H),0.86(t,1H).

[0722] Examples 2-7

[0723] (S)-3-((S)-2-aminopropionamido)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)propionic acid 7

[0724]

[0725]

[0726] Step 1 (S)-3-((S)-2-((tert-butoxycarbonyl)amino)propamido)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)propionic acid 7a

[0727] (tert-butoxycarbonyl)-L-alanine (42.2 mg, 223 μmol, Shaoyuan) was dissolved in N,N-dimethylformamide (3 mL), and N-hydroxysuccinimide (30.8 mg, 267 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55.6 mg, 290 μmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[0728] 5 (50 mg, 74 μmol) and N,N-diisopropylethylamine (96 mg, 743 μmol) 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 30 minutes. The solvent was evaporated to obtain the title product 7a (62.7 mg, yield: 99%), which was used directly in the next step without purification.

[0729] MS m / z(ESI): 844.8 [M+1].

[0730] Step 2

[0731] (S)-3-((S)-2-aminopropionamido)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)propionic acid 7

[0732] 7a (62.7 mg, 74 μmol) was dissolved in N,N-dimethylformamide (2 mL), and hydrochloric acid (4 M, stored in 1,4-dioxane, 6 mL) was added. After reacting at room temperature for half an hour, stirring was stopped, most of the solvent was removed by vortexing, and the residue was dissolved in N,N-dimethylformamide (1 mL). The product was purified by high performance liquid chromatography (GILSON 306, column Phlex ODX C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium acetate) and acetonitrile, gradient ratio: acetonitrile 20-40%, flow rate: 30 mL / min) to obtain title product 7 (23 mg, yield: 42%).

[0733] MS m / z (ESI): 744.6 [M+1].

[0734] 1 H NMR (500MHz, DMSO) δ11.27-10.75(m,1H),8.51-8.33(m,2H),7.60-7.42(m,5H),7.38-7.28(m,4H),6.97(t,1H),5.23(s,2H),5.11(dd,1 H),4.45-4.25(m,3H),3.70-3.53(m,3H),3.12-3.05(m,5H),2.95-2.85(m,2H),2.64-2.52(m,5H),2.01-1.94(m,2H),1.25-1.20(m,3H).

[0735] Examples 2-8

[0736] (S)-3-amino-2-(5-cyano-2-(4-(4-(((2-((S)-2,6-dioxopiridine-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzamido)propionate salt 8

[0737]

[0738] Using the synthetic route of Example 2-1, title product 8 was obtained.

[0739] MS m / z(ESI): 680.4 [M+1].

[0740] 1 H NMR(500MHz,DMSO-d6)δ11.20-11.06(m,1H),10.97(s,1H),9.08(d,1H),8.13(s,3H),8.07(s,1H),7.8 3(d,1H),7.70-7.63(m,2H),7.59(d,2H),7.50(t,1H),7.36-7.31(m,2H),7.18(d,1H),5.35-5.29(m,2H ),5.16-5.09(m,1H),4.68-4.61(m,1H),4.48-4.37(m,3H),4.29(d,1H),3.75-3.60(m,2H),3.21-3.06 (m,4H),2.95-2.88(m,1H),2.65-2.56(m,2H),2.46-2.40(m,1H),2.03-1.96(m,2H),1.32-1.25(m,1H).

[0741] Examples 2-9

[0742] (5-Cyano-2-(4-(4-((((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzoyl)-L-lysine hydrochloride 9

[0743]

[0744] Using the synthetic route of Example 2-1, title product 9 was obtained.

[0745] MS m / z(ESI):722.4[M+1].

[0746] 1H NMR(500MHz,DMSO-d6)δ11.38-11.26(m,1H),10.97(s,1H),8.88(d,1H),7.89-7.78(m,4H),7.71(d,1H),7.68(d, 2H),7.59(d,2H),7.49(t,1H),7.36-7.32(m,2H),7.17(d,1H),5.33-5.28(m,2H),5.16-5.08(m,1H),4.48-4.35(m ,3H),4.32-4.20(m,2H),3.74(d,2H),3.16-3.05(m,2H),2.96-2.88(m,1H),2.84-2.74(m,2H),2.64-2.55(m,2H), 2.45-2.38(m,1H),2.04-1.95(m,2H),1.85-1.67(m,2H),1.65-1.53(m,2H),1.52-1.37(m,2H),1.32-1.25(m,1H).

[0747] Example 2-10

[0748] (2-cyano-5-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzoyl)-L-lysine-formate 10

[0749]

[0750] Using the synthetic route of Example 2-1, title product 10 was obtained.

[0751] MS m / z(ESI):722.4[M+1].

[0752] 1H NMR(500MHz,DMSO-d6)δ8.62-8.55(m,1H),8.27(s,1H),7.54-7.44(m,4H),7.41-7.30(m ,5H),6.97(d,1H),5.25(s,2H),5.15-5.09(m,1H),4.43(d,1H),4.27(d,1H),4.22-4.13( m,1H),3.56-3.50(m,3H),2.96-2.87(m,1H),2.81-2.74(m,2H),2.66-2.56(m,2H),2.47- 2.40(m,5H),2.04-1.95(m,2H),1.84-1.70(m,2H),1.66-1.34(m,5H),1.32-1.27(m,1H).

[0753] Example 3-1

[0754] N 6 -(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexanoyl)glycylglycyl-L-phenylalanylglycyl-N 2 -(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzoyl)-L-lysineLD-1

[0755]

[0756] (6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexanoyl)glycylglycyl-L-phenylalanylglycine LD-1a (64 mg, 0.12 mmol, prepared by the method disclosed in Scheme 8 of patent application "WO202337268A1, compound 8-12") was dissolved in N,N-dimethylformamide (4 mL), and N-hydroxysuccinimide (14 mg, 0.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[0757] 1 (50 mg, 60.3 μmol) and N,N-diisopropylethylamine (39 mg, 0.30 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 title product LD-1 (25 mg, yield: 33.8%).

[0758] MS m / z (ESI): 1226.7 [M+1].

[0759] 1 H NMR(500MHz,DMSO-d6)δ10.92(s,1H),8.33-8.26(m,1H),8.21-8.02(m,4H),7.64-7.56(m,2H),7.47-7.39(m,2H),7.33-7 .27(m,3H),7.22-7.09(m,5H),7.01(t,1H),6.93(s,1H),6.61(s,1H),5.28(t,1H),5.19(s,1H),5.06(dd,1H),4.43-4.35 (m,2H),4.26-4.18(m,2H),3.71-3.48(m,7H),3.09-2.96(m,4H),2.90-2.72(m,3H),2.60-2.47(m,4H),2.41-2.35(m,1H) ,2.05(t,2H),1.98-1.89(m,3H),1.77-1.64(m,2H),1.46-1.33(m,6H),1.26-1.16(m,8H),1.16-1.09(m,2H),0.80(t,2H).

[0760] Example 3-2

[0761] N-((S)-13-benzyl-26-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-4,9,12,15,18,21-hexaoxo-3,5,8,11,14,17,20-heptaazahexacosyl)-4-(4-(4-(((2-(((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide LD-2

[0762]

[0763] LD-2 (8 mg, 11.2 μmol) was dissolved in N,N-dimethylformamide (2 mL), followed by LD-1a (8.2 mg, 15.5 μmol), N,N-diisopropylethylamine (7.23 mg, 56 μmol, adamas), 1-hydroxybenzotriazole (5.1 mg, 33.5 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.82 mg, 33.5 μmol). The mixture was stirred at room temperature for 2 hours after the addition was complete. The reaction solution was purified by high performance liquid chromatography (GILSON, column: Welch Xtimate Prep C18, 30*250 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 10%-95%, flow rate: 30 mL / min) to obtain the title product LD-2 (3 mg, yield: 21.8%).

[0764] MS m / z (ESI): 1226.7 [M+1].

[0765] 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),8.42(s,1H),8.25(t,1H),8.17-8.12 (m,1H),8.08(t,1H),8.02(d,1H),7.72(d,1H),7.60(t,2H),7.52-7.46(m,2 H),7.40-7.31(m,3H),7.29-7.12(m,5H),7.05(t,1H),6.99(s,1H),6.66(s ,1H),6.10(s,1H),6.04(d,1H),5.33(t,1H),5.25(s,1H),5.12(dd,2H),4.5 2-4.39(m,3H),4.27(d,1H),3.78-3.58(m,6H),3.55(s,1H),3.38-3.35(m, 2H),3.26-3.24(m,4H),3.16(t,1H),3.12-3.00(m,6H),2.98-2.87(m,2H),2 .83-2.18(m,2H),2.67-2.64(m,1H),2.41-2.33(m,2H),2.13-2.09(m,2H), 2.05-1.93(m,4H),1.51-1.43(m,4H),1.20-1.16(m,2H),0.87-0.85(m,1H).

[0766] Example 3-3

[0767] N-((S)-8-benzyl-21-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentazabioctyl)-4-(4-(4-(((2-(((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamide LD-3

[0768]

[0769] LD-3 (12 mg, 19.1 μmol) was dissolved in N,N-dimethylformamide (1 mL), followed by LD-1a (14 mg, 26.4 μmol), N,N-diisopropylethylamine (8 mg, 61.9 μmol, adamas), 1-hydroxybenzotriazole (8 mg, 58.8 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10 mg, 57.6 μmol). The mixture was stirred at room temperature for 2 hours after the addition was complete. The reaction solution was purified by high performance liquid chromatography (Wasters, column: Sharpsil-TPrep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 25%-45%, flow rate: 30 mL / min) to obtain the title product LD-3 (6 mg, yield: 27.6%).

[0770] MS m / z (ESI): 1140.7 [M+1].

[0771] 1H NMR(500MHz,DMSO)δ10.97(s,1H),8.46-8.34(m,2H),8.30-8.26(m,1H),8.15(d,1H),8.07(t,1H),8.02(t,1H),7.86-7.80(m,1H), 7.63-7.56(m,2H),7.50(d,1H),7.46(d,2H),7.38-7.31(m,4H),7.29-7.12(m,6H),7.02(t,1H),6.99(s,2H),5.24(s,2H),5.15-5.0 7(m,1H),4.51-4.38(m,2H),4.26(d,1H),3.77-3.56(m,7H),3.54(s,2H),3.24-3.18(m,4H),3.12-3.02(m,6H),2.94-2.87(m,1H),2 .83-2.76(m,1H),2.61-2.56(m,2H),2.13-2.06(m,2H),2.02-1.96(m,2H),1.51-1.42(m,4H),1.20-1.15(m,2H),0.88-0.82(m,1H).

[0772] Examples 3-4

[0773] N-((S)-7-benzyl-14-((4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorophenyl)sulfonamide)-2,5,8,11-tetraoxo-3,6,9,12-tetraazatetradecyl)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)hexanoamide LD-4

[0774]

[0775] Dissolve 4 (10.00 mg, 15.0 μmol) in N,N-dimethylformamide (1 mL), add LD-1a (11.21 mg, 21.6 μmol), N,N-diisopropylethylamine (6.22 mg, 48.13 μmol, adamas), 1-hydroxybenzotriazole (6.87 mg, 45.15 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.83 mg, 45.11 μmol). After the addition is complete, stir at room temperature for 2 hours. The reaction solution was purified by high performance liquid chromatography (GILSON-GX-18, column: BOSTONPHLEX PREP C18, 30*150mm, 5μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-37%, flow rate: 30mL / min) to obtain the title product LD-4 (6.5mg, yield: 36.7%).

[0776] MS m / z (ESI): 1176.6 [M+1].

[0777] 1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),8.28(s,1H),8.20(d,1H),8.12-8.05(m,2H),7.99(d,1H),7.74(d,1H),7.60(s ,1H),7.48(m,5H),7.34(m,4H),7.22(s,2H),7.16(s,1H),6.98(s,2H),5.24(s,2H),5.11(m,1H),4.48(m,1H),4.42( d,1H),4.26(d,1H),3.72(m,1H),3.66(d,3H),3.60(t,2H),3.54(s,3H),3.12(m,6H),3.03(m,2H),2.95-2.86(m,2H) ,2.82-2.71(m,2H),2.61(d,2H),2.36(s,1H),2.09(m,2H),2.00(m,3H),1.49-1.44(m,4H),1.17(d,2H),0.85(t,1H).

[0778] Examples 3-5

[0779] (2S,9S)-9-benzyl-22-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)-5,8,11,14,17-pentoxo-4,7,10,13,16-pentazacosanoic acid LD-5

[0780]

[0781]

[0782] LD-1a was dissolved in N,N-dimethylformamide (2.5 mL), and N-hydroxysuccinimide (4.1 mg, 35 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.4 mg, 38 μmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[0783] LD-5 (10 mg, 14.8 μmol) and N,N-diisopropylethylamine (19.2 mg, 148 μmol) 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 30 minutes. The reaction solution was purified by high performance liquid chromatography (Waters-2545, Welch Xtimate C18 column, 30*150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15-40%, flow rate: 30 mL / min) to obtain the title product LD-5 (7.1 mg, yield: 40.3%).

[0784] MS m / z (ESI): 1184.6 [M+1].

[0785] 1H NMR(500MHz,DMSO)δ12.94-12.48(m,1H),10.97(s,1H),8.54-8.43(m,1H),8.28(t,1H),8.17-7.92(m,4H),7.65-7 .57(m,2H),7.51-7.44(m,3H),7.40-7.29(m,4H),7.27-7.13(m,5H),7.03(t,1H),6.98(s,2H),5.24(s,2H),5.11(d d,1H),4.51-4.46(m,1H),4.45-4.24(m,3H),3.76-3.53(m,8H),3.46-3.38(m,4H),3.13-3.01(m,5H),2.95-2.86( m,1H),2.81-2.71(m,1H),2.61-2.39(m,5H),2.10(t,2H),2.03-1.94(m,2H),1.50-1.40(m,4H),1.21-1.13(m,2H).

[0786] Examples 3-6

[0787] (2S,11S)-11-benzyl-24-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)-7,10,13,16,19-pentoxo-6,9,12,15,18-pentazatetracosanoic acid LD-6

[0788]

[0789] LD-1a (12.8 mg, 24.2 μmol) was dissolved in N,N-dimethylformamide (1 mL), and N-hydroxysuccinimide (2.79 mg, 24.2 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.81 mg, 30.3 μmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[0790] LD-6 (8.5 mg, 12.12 μmol) and N,N-diisopropylethylamine (7.8 mg, 60.3 μmol) 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 (GILSON, column: Welch Xtimate Prep C18, 30*250 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 title product LD-6 (3 mg, yield: 21.8%).

[0791] MS m / z (ESI): 1212.8 [M+1].

[0792] 1H NMR (500MHz, DMSO-d6) δ12.57(s,1H),10.98(s,1H),8.22(t,1H),8.14-8.04(m,2H),8.01(t,1H),7.79-7.44(m,7H),7.40-7. 27(m,3H),7.28-7.02(m,6H),6.99(s,1H),6.66(s,1H),5.33(t,2H),5.25(s,1H),5.12(d,1H),4.49-4.40(m,2H),4.34-4.26 (m,2H),3.80-3.49(m,8H),3.44-3.38(m,4H),3.12-3.00(m,4H),2.95-2.88(m,1H),2.82-2.77(m,2H),2.60-2.51(m,2H),2. 40-2.33(m,1H),2.11(t,2H),2.03-1.91(m,2H),1.83-1.70(m,2H),1.51-1.40(m,5H),1.20-1.16(m,2H),0.88-0.83(m,1H).

[0793] Examples 3-7

[0794] (2S,6S,12S)-12-benzyl-25-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)-2-(4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzamido)-6-methyl-5,8,11,14,17,20-hexaoxo-4,7,10,13,16,19-hexaazatetracosanoic acid LD-7

[0795]

[0796] LD-1a (21 mg, 40.3 μmol) was dissolved in N,N-dimethylformamide (2 mL), and N-hydroxysuccinimide (5.11 mg, 44 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.1 mg, 52 μmol) were added. The reaction system was purged with nitrogen three times and stirred at 25 °C for 16 hours.

[0797] LD-7 (10 mg, 13.5 μmol) and N,N-diisopropylethylamine (17.4 mg, 134 μmol) 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 30 minutes. The reaction solution was purified by high performance liquid chromatography (GILSON 306, chromatographic column Phlex ODX C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 20-40%, flow rate: 30 mL / min) to obtain the title product LD-7 (2 mg, yield: 11.8%).

[0798] MS m / z (ESI): 1255.5 [M+1].

[0799] 1 H NMR(500MHz,DMSO)δ10.96(s,1H),8.78-7.85(m,8H),7.62-7.57(m,2H),7.52-7.43(m,2H),7.40 -7.30(m,3H),7.27-7.14(m,6H),7.05(t,1H),6.98(s,2H),6.70-6.61(m,1H),5.24(s,2H),5.11 (dd,1H),4.49-4.13(m,5H),3.79-3.52(m,8H),3.46-3.38(m,4H),3.13-3.00(m,5H),2.94-2.77 (m,2H),2.65-2.33(m,5H),2.10(t,2H),2.04-1.94(m,2H),1.51-1.41(m,4H),1.23-1.13(m,5H).

[0800] Examples 3-8

[0801] (2S,9S)-9-benzyl-2-(5-cyano-2-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindololin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzamido)-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-8

[0802]

[0803] Using the synthetic route of Example 3-1, the first step compound 1 was replaced with compound 8 to obtain the title product LD-8.

[0804] MS m / z(ESI): 1191.3 [M+1].

[0805] 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H),8.95(d,1H),8.24(t,1H),8.08(d,2H),8.03-7.95(m,2H),7.85(d,1H),7.75(d,1H ),7.51-7.42(m,3H),7.38-7.30(m,4H),7.26-7.11(m,7H),7.01-6.94(s,2H),5.32(t,1H),5.23(s,2H),5.14-5.07(m,1 H),4.53-4.45(m,1H),4.44-4.36(m,2H),4.26(d,1H),3.75-3.50(m,10H),3.18-3.09(m,4H),3.04-2.99(m,1H),2.94-2 .87(m,1H),2.79-2.73(m,1H),2.46-2.38(m,2H),2.10(t,2H),2.05-1.94(m,4H),1.52-1.40(m,6H),1.20-1.12(m,2H).

[0806] Examples 3-9

[0807] N 2 -(5-cyano-2-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzoyl)-N 6 -(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexanoyl)glycylglycyl-L-phenylalanylglycyl-L-lysine LD-9

[0808]

[0809] Using the synthetic route of Example 3-1, the first step compound 1 was replaced with compound 9 to obtain the title product LD-9.

[0810] MS m / z(ESI):1233.3[M+1].

[0811] 1 H NMR(500MHz,DMSO-d6)δ10.97(s,1H),8.92(d,1H),8.21(t,1H),8.14-8.05(m,2H),8.04-7.98(m,1H),7.76(d,1H),7.71(s ,1H),7.65(t,1H),7.51-7.42(m,3H),7.33(t,4H),7.26-7.12(m,8H),6.98(s,2H),6.92-6.60(m,1H),5.32(t,1H),5.23(s, 2H),5.14-5.08(m,1H),4.49-4.38(m,2H),4.29-4.22(m,2H),3.75-3.56(m,7H),3.19-3.11(m,4H),3.07-3.01(m,3H),2.94 -2.87(m,1H),2.83-2.76(m,1H),2.10(t,2H),2.03-1.95(m,6H),1.84-1.75(m,1H),1.74-1.65(m,1H),1.50-1.36(m,11H).

[0812] Examples 3-10

[0813] N 2 -(2-cyano-5-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzoyl)-N 6 -(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexanoyl)glycylglycyl-L-phenylalanylglycyl-L-lysine LD-10

[0814]

[0815] Using the synthetic route of Example 3-1, the first step compound 1 was replaced with compound 10 to obtain the title product LD-10.

[0816] MS m / z(ESI):1233.8[M+1].

[0817] 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),8.82-8.70(m,1H),8.22(t,1H),8.1 7-7.95(m,3H),7.67-7.61(m,2H),7.52-7.44(m,3H),7.40-7.32(m,4H),7. 29-7.14(m,7H),7.09(d,1H),6.99(s,2H),6.69-6.62(m,1H),5.33(t,1H), 5.25(s,2H),5.14-5.09(m,1H),4.52-4.40(m,2H),4.36-4.22(m,2H),3.78 -3.52(m,8H),3.43-3.38(m,4H),3.09-3.02(m,3H),2.97-2.86(m,1H),2.85-2.78(m,1H),2.11(t,2 H),2.05-1.94(m,5H),1.88-1.78(m,1H),1.77-1.67(m,1H),1.55-1.35(m,10H),1.20-1.15(m,2H).

[0818] Example 4-1 DAC-1

[0819]

[0820] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.5 μL, 85 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0821] Compound LD-1 (0.41 mg, 334 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffered aqueous solution at pH 7.4) to obtain the title product DAC-1 in PBS buffer, which was stored at 4 °C.

[0822] MS calculated average: y = 4.05.

[0823] Example 4-2 DAC-2

[0824]

[0825] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 18.6 μL, 186 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 7.4; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0826] Compound LD-1 (0.62 mg, 506 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and reacted at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffered aqueous solution at pH 7.4) to obtain the PBS buffered solution of the title product DAC-2, which was stored at 4 °C.

[0827] MS calculated the average value: y = 7.66.

[0828] Example 4-3 DAC-3

[0829]

[0830] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.5 μL, 85 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 7.4; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0831] Compound LD-2 (0.41 mg, 0.333 μmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffered aqueous solution at pH 7.4) to obtain the PBS buffered product DAC-3, which was stored at 4 °C.

[0832] MS calculated average: DAR = 3.67.

[0833] Example 4-4 DAC-4

[0834]

[0835]

[0836] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.5 μL, 85 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 7.4; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0837] Compound LD-3 (0.5 mg, 438 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffered aqueous solution at pH 7.4) to obtain the title product DAC-4 in PBS buffer, which was stored at 4 °C.

[0838] MS calculated the average value: y = 3.49.

[0839] Example 4-5 DAC-5

[0840]

[0841]

[0842] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.5 μL, 85 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 7.4; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0843] Compound LD-4 (0.5 mg, 438 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column (elution phase: 0.05 M PBS buffer solution at pH 7.4) to obtain the PBS buffer of the title product DAC-5, which was stored at 4 °C.

[0844] MS calculated average: DAR = 4.39.

[0845] Example 4-6 DAC-6

[0846]

[0847]

[0848] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.5 μL, 85 nmol) was added to the buffer solution of antibody Ab1 (0.05 M buffer solution with pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0849] Compound LD-6 (0.42 mg, 346 μmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column to obtain a buffer solution of the title product DAC-6, which was stored at 4 °C.

[0850] MS calculated the average value: y = 4.22.

[0851] Example 4-7 DAC-7

[0852]

[0853]

[0854] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 18.6 μL, 186 nmol) was added to a buffer solution of antibody Ab1 (0.05 M buffer solution with pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C and replaced with a buffer solution with pH = 5.0.

[0855] Compound LD-6 (0.615 mg, 507 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column to obtain a buffer solution of the title product DAC-7, which was stored at 4 °C.

[0856] MS calculates the average value: y = 7.6.

[0857] Example 4-8 DAC-8

[0858]

[0859]

[0860] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 18.3 μL, 183 nmol) was added to the PBS buffer solution of antibody Ab1 (0.05 M PBS buffer solution with pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, the reaction solution was cooled to 25°C, concentrated, and the solution was replaced with His-HOAc buffer solution (0.03 M His-HOAc buffer solution with pH = 5.0, 0.5 mL), which was used directly in the next step.

[0861] Compound LD-5 (0.62 mg, 523 nmol) was dissolved in 30 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column to obtain a buffer solution of the title product DAC-8, which was stored at 4 °C.

[0862] MS calculated the average value: y = 7.31.

[0863] Example 4-9 DAC-9

[0864]

[0865]

[0866] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 8.3 μL, 83 nmol) was added to the PBS buffered aqueous solution of antibody Ab1 (0.05 M PBS buffered aqueous solution of pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0867] Compound LD-5 (0.41 mg, 346 nmol) was dissolved in 30 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column to obtain a buffer solution of the title product DAC-9, which was stored at 4 °C.

[0868] MS calculated the average value: y = 4.28.

[0869] Example 4-10 DAC-10

[0870]

[0871]

[0872] At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP.HCl) (10 mM, 18.3 μL, 183 nmol) was added to the PBS buffered aqueous solution of antibody Ab2 (0.05 M PBS buffered aqueous solution of pH = 6.3; 10.0 mg / mL, 0.5 mL, 33.3 nmol). The solution was placed in a water bath shaker and shaken at 37°C for 3 hours. The reaction was then stopped, and the reaction solution was cooled to 25°C.

[0873] Compound LD-1 (0.62 mg, 506 nmol) was dissolved in 25 μL of dimethyl sulfoxide and added to the above reaction solution. The mixture was placed in a constant temperature shaker and shaken at 25 °C for 3 hours. The reaction solution was then desalted and purified using a Sephadex G25 gel column to obtain a buffer solution of the title product DAC-10, which was stored at 4 °C.

[0874] MS calculated the average value: y = 8.21.

[0875] Biological evaluation

[0876] Test Example 1. Inhibition of proliferation of KMS-12-PE, NCI-H929 and MM.1S cells by the disclosed compounds.

[0877] The in vitro cell experiments described below can determine the inhibitory activity of the test molecule on the proliferation of human multiple myeloma cell lines. This activity can be measured using IC50 assays. 50 Values ​​are used to represent this.

[0878] On the first day of the experiment, KMS-12-PE, NCI-H929, and MM.1S cells were seeded in 96-well cell culture plates (Corning, 3903) at densities of 1000 cells / well, 4000 cells / well, and 8000 cells / well using RPMI-1640 medium containing 20% ​​FBS (Corning, 35-081-CV), 10% FBS (Gibco, 10091-148) and 0.05 mM 2-mercaptoethanol, respectively, with 90 μL of cell suspension per well. 20 mM of the test compound dissolved in DMSO was diluted with DMSO to an initial concentration of 10 mM or 100 μM, followed by 5-fold serial dilutions for a total of 9 concentration points. The compound was then further diluted 100-fold with culture medium. The antibody-drug conjugate (ADC) was diluted with culture medium to an initial concentration of 5 μM, followed by 5-fold serial dilutions, resulting in 9 concentration points. 10 μL of the test molecule diluted with culture medium was added to each well of the cell culture plate. The final concentrations of the compound were determined by 5-fold serial dilutions starting at 10 μM or 100 nM, resulting in 9 concentration points. The final concentrations of the ADC were determined by 5-fold serial dilutions starting at 500 nM, resulting in 9 concentration points. Wells containing only culture medium and no cells were designated as blank control wells, and cell wells containing only culture medium were designated as solvent control wells. The DMSO concentration in the blank control and solvent control wells corresponding to the test compound was 0.1%. The plate was incubated at 37°C and 5% CO2 for five days. On the sixth day, the 96-well cell culture plate was removed, and 50 μL of luminescent cell viability assay reagent was added to each well. The Luminescent Cell Viability Assay (Promega, G7573) was prepared by shaking in the dark for 5 minutes and then incubating at room temperature for 10 minutes. The luminescence signal value (RLU) was read using a microplate reader (PerkinElmer, EnVision2105). The inhibition rate at each concentration of the test molecule was calculated using the following formula. A curve was fitted using GraphPad Prism based on the logarithmic concentration and inhibition rate of the test molecule, and the IC50 was calculated. 50 value.

[0879] Inhibition rate (%) = (RLU) 溶媒对照 -RLU 化合物 ) / (RLU 溶媒对照 -RLU 空白对照 )×100%.

[0880] Table 3. Inhibitory activity of the disclosed compounds on the proliferation of KMS-12-PE, NCI-H929, and MM.1S cells.

[0881]

[0882] Note: "-" indicates that no detection was performed.

[0883] Table 4. Inhibitory activity of the disclosed compounds on the proliferation of KMS-12-PE, NCI-H929, and MM.1S cells.

[0884]

[0885] Conclusion: The compounds disclosed herein exhibit proliferative inhibitory activity against KMS-12-PE, NCI-H929, and MM.1S cells.

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 is an IKZF degrader comprising a structure as shown in general formula (DH), and the drug is linked to the ligand via a linker: in: X is -CR a R b -or -C(O)-; Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ; Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -; V represents a chemical bond or -(CR) c R d ) n1 -; U is -(CR e R f ) n1 -; R 5 Selected from -(CR g R h ) n -, -C(O)-, S(O) p -, -NR i -, -NR i -C(O)-, -C(O)-NR i -, -NR i -S(O) p -, -S(O) p -NR i -, -NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -; R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR 12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -C(O)-O-、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12 -S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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. R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -; Ring A, ring B, and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NR r -C(O)NR s R t 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -NR r -CR u6 R u7 -COOR u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) p R 14 One or more identical or different substituents are substituted in the substance; R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups; R a R b R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -CR u4 R u5 -、-C(O)-NR u3 -CR u4 R u5 -COOR 15a -COOR 15a Alkylene-COOR 15a , cycloalkyl, heterocyclic, aryl and heteroaryl, each of which 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; 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 d 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 k 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, 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. R 13 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; R 9 R 11 R 12 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; R u4 R u5 R u6 and R u7 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkylene-SR 15a Alkylene-COOR 15a Alkylene-NR 16a R 16b alkylene-NH-C(=NH)-NR 16a R 16b alkylene-C(O)-NR 16a R 16b Alkylene-O-alkyl, alkylene-S-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic, alkylene-aryl, and alkylene-heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and 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; 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; 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 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; 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. p is 0, 1, or 2; r can be 0, 1, 2, 3, 4, 5, or 6; s can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6; m can be 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; and u can be 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, wherein it is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by general formula (I): Ab-(L-D) y (I) Wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody; L is a connector that links Ab and D; D is shown in the general formula (DH): in: X is -CR a R b -or -C(O)-; Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ; Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -; V represents a chemical bond or -(CR) c R d ) n1 -; U is -(CR e R f ) n1 -; R 5 selected from -(CR g R h ) n -, -C(O)-, S(O) p -, -NR i -, -NR i -C(O)-, -C(O)-NR i -, -NR i -S(O) p -, -S(O) p -NR i -, -NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -; R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR 12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -C(O)-O-、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12 -S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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. R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -; Ring A, ring B, and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NR r -C(O)NR s R t 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -NR r -CR u6 R u7 -COOR u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) p R 14 One or more identical or different substituents are substituted in the substance; R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups; R a R b R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -CR u4 R u5 -、-C(O)-NR u3 -CR u4 R u5 -COOR 15a -COOR 15a Alkylene-COOR 15a , cycloalkyl, heterocyclic, aryl and heteroaryl, each of which 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; 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 d 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 k 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, 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. R 13 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; R 9 R 11 R 12 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; R u4 R u5 R u6 and R u7 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkylene-SR 15a Alkylene-COOR 15a Alkylene-NR 16a R 16b alkylene-NH-C(=NH)-NR 16a R 16b alkylene-C(O)-NR 16a R 16b Alkylene-O-alkyl, alkylene-S-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic, alkylene-aryl, and alkylene-heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and 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; 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; 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 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; 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. p is 0, 1, or 2; r can be 0, 1, 2, 3, 4, 5, or 6; s can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6; m can be 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; u is 0, 1, 2, 3, 4, 5, or 6; and y ranges from 1 to 10.

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 or 3; 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 c R d ) n1 -, where R c R d and n1 as defined in claim 1 or 3; preferably, V is -CR c R d -, where R c and R d As defined in claim 1 or 3.

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 -, where R e and R f As defined in claim 1 or 3.

7. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are all carbon atoms (CR). 10 Or Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and of the remaining three, one is a nitrogen atom, and the other two are CR atoms. 10 , where R 10 As defined in claim 1 or 3.

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 6-membered heterocyclic group; preferably, ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen and oxygen atoms; more preferably, ring B is piperidinyl or piperazineyl; most preferably, ring B is piperazineyl.

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 the general formula (DIH): Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms; X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s, and t are as defined in claim 1 or 3.

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 -, where R a and R b As defined in claim 1 or 3.

11. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 It 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 phenyl.

13. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, the ring C is phenyl.

14. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 3 It is a hydrogen atom.

15. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein D is as shown in the general formula (D-II-H): Where R 2 R 4 To R 9 r and t are as defined in claim 1 or 3.

16. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein -L- is -L 1 -L 2 -L 3 -L 4 -,and L 1 Selected from -(succinimide-3-yl-N)-W 1 -C(O)-、-(succinimide-3-yl-N)-W 1 -W 2 -C(O)-、-(succinimide-3-yl-N)-W 1 -、-(succinimide-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -W 1 -、-(succinimide-3-yl-N)-W 1 -(CR 20a R 20b -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 1 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 -OW 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 -OW 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 chemical bonds, where v is an integer from 1 to 20 and p1 is an integer from 1 to 20; L 3 Selected from peptide residues consisting of 1 to 7 amino acid residues, The amino acid residues mentioned therein are selected from amino acid residues formed from amino acids of phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamyl, glutamic acid, aspartic acid, and asparagine, and are optionally selected from halogens, hydroxyl groups, cyano groups, amino groups, alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, and -(CR) groups. 22a R 22b ) p2 -NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 One or more substituents in it are replaced, where p2 is an integer from 1 to 20, and *1 and L 2 Connect the ends, *2 and L 4 End connected; L 4 Selected from -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 -OC(O)- and chemical bonds; W 2 The group is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy. W 1 W 3 and W 5 Same or different, and each independently is -(CR) 26a R 26b ) p3 - where p3 is an integer from 1 to 20; W 4 For -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl; R 17 R 18 R 19 and R 25 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl; R 23 and R 24 The same or different, and each independently selected from the same or different, and each independently selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; Or R 23 and R 24 Together with the carbon atoms attached to them, they form a heterocyclic group, which is optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, 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 The same or different, and each independently selected from hydrogen atoms, halogens, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more of the same or different substituents selected from oxo, halogens, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; Or R 20a and R 20b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 20c and R 20d Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21a and R 21b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21c and R 21d Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 21e and R 21f Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 22a and R 22b Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R 26a and R 26b 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. Preferably, -L- is -L 1 -L 2 -L 3 -L 4 -,and L 1 -(succinimide-3-yl-N)-W 1 -C(O)-, where W 1 -(CR) 26a R 26b ) p3 -, R 26a and R 26b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl, p3 is 1, 2, 3, 4, 5 or 6; L 2 It is a chemical bond; L 3 The amino acid residues are selected from monopeptide residues, dipeptide residues, and tetrapeptide residues, wherein the amino acid residues are selected from amino acid residues formed from amino acids selected from phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid, and asparagine; preferably, L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:16); L 4 It is a chemical bond; The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

17. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein it is a ligand-drug conjugate or a pharmaceutically acceptable salt thereof represented by the general formula (IN): Among them, Ab and R 2 R 4 To R 9 r and t as defined in claim 1 or 3; L 3 and W 1 As defined in claim 16; y as defined in claim 3.

18. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 2 It is a hydrogen atom.

19. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 4 Selected from hydrogen atoms, halogens, and cyano groups; preferably, R 4 It can be a hydrogen atom or a halogen.

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 5 Selected from -NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p - and -S(O) p -NR i -, where R i and p as defined in claim 1 or 3; preferably, R 5 For -NR i -C(O)- or -C(O)-NR i -, where R i As defined in claim 1 or 3.

21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 7 Selected from chemical bonds, -C(O)-NR 12 -、-NR 12 -C(O)- and -NR 12 -C(O)-NR 12 -, where R 12 As defined in claim 1 or 3; preferably, R 7 It is a chemical bond.

22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -, where R m R n and n as defined in claim 1 or 3.

23. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 9 It is a hydrogen atom.

24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 23, wherein the Ab is selected from anti-CD38 antibody, anti-CD79b antibody, anti-GPRC5D antibody and anti-BCMA antibody; Preferably, the Ab is an anti-CD38 antibody, which comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region HCDR1 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 the light chain variable region LCDR1 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; More preferably, the Ab is an anti-CD38 antibody, which includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence of SEQ ID NO: 7, and the light chain variable region includes the amino acid sequence of SEQ ID NO: 8; More preferably, the Ab is an anti-CD38 antibody, which 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.

25. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the conjugate is selected from the following structures: Wherein Ab1 is an anti-CD38 antibody, as defined in claim 24; y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 4 to 8.

26. A compound of general formula (D) or a pharmaceutically acceptable salt thereof: in: X is -CR a R b -or -C(O)-; Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are the same or different, and each is independently a nitrogen atom or a carbon atom. 10 ; Z is selected from -O- and -S(O). p -、-C(O)-、-NR 11 - and -(CR c R d ) n1 -; V represents a chemical bond or -(CR) c R d ) n1 -; U is -(CR e R f ) n1 -; R 5 selected from - (CR g R h ) n -, -C(O)-, S(O) p -, -NR i -, -NR i -C(O)-, -C(O)-NR i -, -NR i -S(O) p -, -S(O) p -NR i -, -NR i -(CR j R k ) n - and -(CR j R k ) n -NR i -; R 7 It is a chemical bond or selected from cycloalkyl, heterocyclic, aryl, heteroaryl, -O-, -C(O)-, -C(O)-O-, -OC(O)-, -C(O)-NR 12 -、-NR 12 -C(O)-、-(C=NR 13 )-NR 12 -、-OC(O)-NR 12 -、-NR 12 -C(O)-O-、-NR 12 -、-NR 12 -C(O)-NR 12 -、-NR 12 -S(O) p -S(O) p -、-NR 12 -S(O) p -、-NR 12 -S(O) p -(C=NR 13 )-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. R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -; Ring A, ring B, and ring C may be the same or different, and each is independently selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 2 R 3 R 4 and R 10 The same or different, and each independently selected from hydrogen atom, halogen, cyano, nitro, oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, -OR o -SR 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)OR u -NR r -C(O)NR s R t 、-(CR p R q ) m -C(O)R u 、-(CR p R q ) m -NR r -CR u6 R u7 -COOR u -C(O)OR u -OC(O)R u -C(O)NR s R t -C(=NR) 13 )NR s R t -S(O) p R u -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 -C(O)R 14 -C(O)OR 14 -C(O)NR v1 R v2 and -S(O) p R 14 One or more identical or different substituents are substituted in the substance; R 1 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyl groups, and hydroxyalkyl groups; R a R b R c R d R e R f R g R h R j R k R m R n R p R q R w1 and R w2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, cyano, -NR u1 R u2 Alkylene-NR u1 R u2 -CR u4 R u5 -、-C(O)-NR u3 -CR u4 R u5 -COOR 15a -COOR 15a Alkylene-COOR 15a , cycloalkyl, heterocyclic, aryl and heteroaryl, each of which 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; 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 d 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 k 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, 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. R 13 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; R 9 R 11 R 12 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; R u4 R u5 R u6 and R u7 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkylene-SR 15a Alkylene-COOR 15a Alkylene-NR 16a R 16b alkylene-NH-C(=NH)-NR 16a R 16b alkylene-C(O)-NR 16a R 16b Alkylene-O-alkyl, alkylene-S-alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylene-cycloalkyl, alkylene-heterocyclic, alkylene-aryl, and alkylene-heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and 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; 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; 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 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; 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. p is 0, 1, or 2; r can be 0, 1, 2, 3, 4, 5, or 6; s can be 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6; m can be 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; and u can be 0, 1, 2, 3, 4, 5 or 6.

27. The compound of formula (D) according to claim 26, or a pharmaceutically acceptable salt thereof, wherein Z is -O- or -NR. 11 -, where R 11 As defined in claim 26; preferably, Z is -O-.

28. The compound of formula (D) according to claim 26 or 27, or a pharmaceutically acceptable salt thereof, wherein V is -(CR c R d ) n1 -, where R c R d and n1 as defined in claim 26; preferably, V is -CR c R d -, where R c and R d As defined in claim 26.

29. The compound of general formula (D) according to any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, wherein U is -CR e R f -, where R e and R f As defined in claim 26.

30. The compound of general formula (D) according to any one of claims 26 to 29, or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and the other three are all carbon atoms (CR). 10 Or Y 1 Y 2 Y 3 and Y 4 One of them is a carbon atom, and of the remaining three, one is a nitrogen atom, and the other two are CR atoms. 10 , where R 10 As defined in claim 26.

31. The compound of general formula (D) according to any one of claims 26 to 30, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 6-membered heterocyclic group; preferably, ring B is a 3- to 6-membered heterocyclic group containing one or two 3- to 6-membered heterocyclic groups selected from nitrogen and oxygen atoms; more preferably, ring B is piperidinyl or piperazineyl; most preferably, ring B is piperazineyl.

32. The compound of formula (D) according to any one of claims 26 to 31, or a pharmaceutically acceptable salt thereof, as shown in formula (DI): Where ring B is a 3- to 6-membered heterocyclic group containing one or two nitrogen atoms; X, ring A, ring C, R 1 To R 9 R c R d R e R f r, s, and t are as defined in claim 26.

33. The compound of formula (D) according to any one of claims 26 to 32, or a pharmaceutically acceptable salt thereof, wherein X is -CR a R b -, where R a and R b As defined in claim 26.

34. The compound of formula (D) according to any one of claims 26 to 33, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a hydrogen atom.

35. The compound of general formula (D) according to any one of claims 26 to 34, 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.

36. The compound of general formula (D) according to any one of claims 26 to 35, or a pharmaceutically acceptable salt thereof, wherein the ring C is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; preferably, the ring C is phenyl.

37. The compound of formula (D) according to any one of claims 26 to 36, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydrogen atom.

38. The compound of formula (D) according to any one of claims 26 to 37, or a pharmaceutically acceptable salt thereof, wherein D is as shown in formula (D-II): Where R 2 R 4 To R 9 r and t are as defined in claim 26.

39. The compound of formula (D) according to any one of claims 26 to 38, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

40. The compound of formula (D) according to any one of claims 26 to 39, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, halogens, and cyano groups; preferably, R 4 It can be a hydrogen atom or a halogen.

41. The compound of general formula (D) according to any one of claims 26 to 40, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -NR i -C(O)-、-C(O)-NR i -、-NR i -S(O) p - and -S(O) p -NR i -, where R i and p as defined in claim 26; preferably, R 5 For -NR i -C(O)- or -C(O)-NR i -, where R i As defined in claim 26.

42. The compound of formula (D) according to any one of claims 26 to 41, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from chemical bonds, -C(O)-NR 12 -、-NR 12 -C(O)- and -NR 12 -C(O)-NR 12 -, where R 12 As defined in claim 26; preferably, R 7 It is a chemical bond.

43. The compound of general formula (D) according to any one of claims 26 to 42, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 They may be the same or different, and each is an independent chemical bond or -(CR) m R n ) n -, where R m R n and n as defined in claim 26.

44. The compound of formula (D) according to any one of claims 26 to 43, or a pharmaceutically acceptable salt thereof, wherein R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 9 It is a hydrogen atom.

45. The compound of general formula (D) according to any one of claims 26 to 44, or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride), selected from the following structures:

46. ​​A compound of the general formula (LN-D-II) or a salt thereof: Where L 3 and W 1 As defined in claim 16; R 2 R 4 To R 9 r and t are as defined in claim 17.

47. The compound of general formula (LN-D-II) according to claim 46, or a salt thereof, wherein the compound is selected from the following structures:

48. A method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, comprising the step of linking a compound selected from the general formula (D) of any one of claims 26 to 45 or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride) to a ligand; preferably, comprising linking a compound selected from the general formula (D) of any one of claims 26 to 45 or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride) to a ligand via a linker; wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

49. A method for preparing a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as shown in general formula (IN), comprising the following steps: After reduction, Ab undergoes a coupling reaction with a compound of general formula (LN-D-II) or its salt to give a ligand-drug conjugate of general formula (IN) or its pharmaceutically acceptable salt. Where L 3 and W 1 As defined in claim 16; Ab, R 2 R 4 To R 9 r, t, and y are as defined in claim 17.

50. A pharmaceutical composition comprising a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25, a compound of formula (D) as claimed in any one of claims 26 to 45 or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride), a compound of formula (LN-D-II) as claimed in claims 46 or 47 or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

51. A method for preventing or treating a disease, the method comprising administering to a subject a ligand-drug conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 25, a compound of general formula (D) as claimed in any one of claims 26 to 45 or a pharmaceutically acceptable salt thereof (preferably formate or hydrochloride), a compound of general formula (LN-D-II) as claimed in claims 46 or 47 or a salt thereof, or a pharmaceutical composition according to claim 50; preferably, the disease is selected from tumors, autoimmune diseases, and inflammation; more preferably, the disease is selected from myeloma, myelodysplastic syndrome, lymphoma, leukemia, systemic lupus erythematosus, and lupus nephritis; most preferably, the tumor is selected from multiple myeloma and diffuse large B-cell lymphoma.

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