Ligand-drug conjugate and pharmaceutical use thereof

Abstract

The present disclosure relates to a ligand-drug conjugate and pharmaceutical use thereof. In particular, the present disclosure relates to an antibody-drug conjugate and use thereof in the treatment of tumors.

Description

Ligand-drug conjugates and their pharmaceutical uses 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] In eukaryotic cells, N-myristoylation is an important post-translational modification of proteins, regulating various biological functions, including protein transport and localization in the inner membrane, protein aggregate formation, protein stability, and influencing downstream effector proteins through signaling pathways. More than 100 substrate proteins modified by N-myristoylation have been identified to date.

[0004] N-Myristyltransferase (NMT) is a monomeric enzyme ubiquitous in eukaryotes that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the glycine residue at the N-terminus of a protein. It is associated with various diseases, including tumors, viral infections, and fungal infections. Humans possess two types of NMT: NMT1 (HsNMT1) and NMT2 (HsNMT2), with NMT1 being more closely linked to tumors. Developing NMT inhibitors for use in the preparation of ADCs (anti-cancer drug agents) holds promise for improving toxicity and tolerability while exhibiting high tumor-killing activity. 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 linked to the ligand, wherein the drug comprises a structure as shown in general formula (DH):

[0006] in:

[0007] X represents a chemical bond or -(CR) a R b ) n -;

[0008] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0009] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0010] U is selected from -O- and -CRc R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0011] V represents a chemical bond or -(CR) e R f ) j -;

[0012] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0013] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0014] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0015] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j )q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0016] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0017] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0018] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CRm R n ) s -NR 16c -S(O) p R 15 、-NR 16c -C(O)R 15 、-NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b 、-C(O)-NR 16c -(CR m R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0019] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0020] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0021] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0022] Ra R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0023] 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 i and R j 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, 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.

[0024] R 5 R 8 R 16c and R 32 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] R 9 R 10 R 13 R 14 R 15 and R 29They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0026] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0027] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0028] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0029] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0030] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

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

[0032] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0033] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0034] t can be 0, 1, 2, 3, 4, 5 or 6.

[0035] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described above, comprises a ligand and a drug linked to the ligand, wherein the drug comprises a structure as shown in general formula (DH):

[0036] in:

[0037] X represents a chemical bond or -(CR) a R b ) n -;

[0038] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0039] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0040] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0041] V represents a chemical bond or -(CR) e R f ) j -;

[0042] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0043] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0044] Or R 1 and R 2Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0045] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0046] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0047] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0048] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 alkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)p R 15 、 -C(O)-NR 16a R 16b 、 -NR 16a R 16b 、 -C(O)R 15 、 -C(O)OR 15 、 -(CR m R n ) s -NR 16a R 16b 、 -(CR m R n ) s -NR 16c -C(O)R 15 、 -(CR m R n ) s -NR 16c -S(O) p R 15 、 -NR 16c -C(O)R 15 、 -NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 、 -(CR m R n ) s -C(O)-NR 16a R 16b 、 -C(O)-NR<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0049] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0050] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0051] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0052] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0053] 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 i and R j Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R nTogether 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.

[0054] R 5 R 8 R 16c and R 32 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;

[0055] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0056] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0057] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0058] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0059] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0060] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0061] p is 0, 1, or 2;

[0062] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0063] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0064] t can be 0, 1, 2, 3, 4, 5 or 6.

[0065] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described above, comprises a ligand and a drug linked to the ligand, wherein the drug comprises a structure as shown in general formula (DH):

[0066] Where: X represents a chemical bond or -(CR) a R b ) n -;

[0067] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0068] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0069] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0070] V represents a chemical bond or -(CR) e R f ) j -;

[0071] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0072] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CRg R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0073] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0074] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0075] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0076] Or R aand R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0077] R 4 Selected from hydrogen, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl and -OR 14 The alkyl, alkenyl, and alkynyl groups thereon are each optionally selected independently from halogens, hydroxyl groups, -OR groups, etc. 15 -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c -S(O) p R 15 -NR 16c -C(O)R 15 -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)N((CR) mR n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b One or more identical or different substituents are substituted in the substance;

[0078] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0079] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31-NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0080] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0081] 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 i and R j Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R nTogether 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.

[0082] R 8 R 16c and R 32 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;

[0083] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0084] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0085] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0086] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0087] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0088] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0089] p is 0, 1, or 2;

[0090] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0091] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0092] t can be 0, 1, 2, 3, 4, 5 or 6.

[0093] In some implementations, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein the ligand is an antigen-binding molecule.

[0094] In some implementations, a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein the ligand is an antibody.

[0095] 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):

[0096] Ab-(LD) y (I)

[0097] Wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody;

[0098] L is a connector that links Ab and D;

[0099] D is a structure as shown in the general formula (DH):

[0100] in:

[0101] X represents a chemical bond or -(CR) a R b ) n -;

[0102] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0103] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0104] U is selected from -O- and -CR c R d -、-C(O)-、-NR8 - and -S(O) p -;

[0105] V represents a chemical bond or -(CR) e R f ) j -;

[0106] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0107] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0108] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0109] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0110] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0111] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0112] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s-NR 16c -S(O) p R 15 、-NR 16c -C(O)R 15 、-NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b 、-C(O)-NR 16c -(CR m R n ) s -OR 15 、-C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 、-C(O)-N((CR m R<00(00760>) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n )s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0113] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0114] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0115] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0116] R a R b R cR d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0117] 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 i and R j 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, 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.

[0118] R 5 R 8 R 16c and R 32 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;

[0119] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0120] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0121] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0122] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0123] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0124] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0125] p is 0, 1, or 2;

[0126] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0127] s can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0128] t is 0, 1, 2, 3, 4, 5, or 6; and

[0129] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[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 general formula (I):

[0131] Ab-(LD) y (I)

[0132] Wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody;

[0133] L is a connector that links Ab and D;

[0134] D is a structure as shown in the general formula (DH):

[0135] in:

[0136] X represents a chemical bond or -(CR) a R b ) n -;

[0137] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0138] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0139] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0140] V represents a chemical bond or -(CR) e R f ) j -;

[0141] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0142] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h )k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0143] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0144] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0145] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0146] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0147] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 alkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c -S(O) p R 15 -NR 16c -C(O)R 15 -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)N((CR) m R n ) s -O-(CR m R n ) s )m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0148] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0149] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p-NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0150] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0151] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0152] 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 Rh Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R i and R j 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, 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.

[0153] R 5 R 8 R 16c and R 32 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;

[0154] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0155] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0156] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0157] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0158] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0159] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0160] p is 0, 1, or 2;

[0161] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0162] s can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0163] t is 0, 1, 2, 3, 4, 5, or 6; and

[0164] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0165] 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):

[0166] Ab-(LD) y (I)

[0167] Wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody;

[0168] L is a connector that links Ab and D;

[0169] D is a structure as shown in the general formula (DH):

[0170] in:

[0171] X represents a chemical bond or -(CR) a R b ) n -;

[0172] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0173] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0174] U is selected from -O- and -CRc R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0175] V represents a chemical bond or -(CR) e R f ) j -;

[0176] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0177] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0178] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0179] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j )q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0180] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0181] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0182] R 4 Selected from hydrogen, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl and -OR 14 The alkyl, alkenyl, and alkynyl groups thereon are each optionally selected independently from halogens, hydroxyl groups, -OR groups, etc. 15 -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c-S(O) p R 15 、-NR 16c -C(O)R 15 、-NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b One or more identical or different substituents are substituted in the substance;

[0183] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0184] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0185] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0186] 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 i and R j 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, 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.

[0187] R 8 R 16c and R 32 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;

[0188] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0189] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0190] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0191] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0192] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0193] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0194] p is 0, 1, or 2;

[0195] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0196] s can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0197] t is 0, 1, 2, 3, 4, 5, or 6; and

[0198] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0199] 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, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 alkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, -OR 15 Alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b, -(CR m R n ) s -NR 16c -C(O)R 15 , -(CR m R n ) s -NR 16c -S(O) p R 15 , -NR 16c -C(O)R 15 , -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 , -(CR m R n ) s -C(O)-NR 16a R 16b , -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)-NR 16c -(CR m R<% n ) s -OR 15 , -C(O)-N((CR m R n ) s -O-(CR m R n )s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 The substituent is one or more of the same or different substituents selected from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; wherein R 14 R 15 R 16a R 16b R 16c R m R n p, m and s are as defined in general formula (I).

[0200] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4 Selected from hydrogen, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl and -OR 14 The alkyl, alkenyl, and alkynyl groups thereon are each optionally selected independently from halogens, hydroxyl groups, -OR groups, etc. 15 -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR mR n ) s -NR 16c -S(O) p R 15 、-NR 16c -C(O)R 15 、-NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b One or more identical or different substituents are substituted in R; where R 14 R 15 R 16a R 16b R 16c R m R n p, m and s are as defined in general formula (I).

[0201] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; wherein R 29 R 30 R 31 R 32 p is as defined in general formula (I).

[0202] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 6 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 6 It is a hydrogen atom.

[0203] 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 and Y 2 Whether the same or different, and each independently constitutes a CR 6 , where R 6 As defined in general formula (I); preferably, Y 1 and Y 2 All are CH.

[0204] 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 hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1- 6-Haloalkoxy; preferably, R 7 It is a hydrogen atom or a halogen; more preferably, R 7 It consists of hydrogen or fluorine atoms.

[0205] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 It is a halogen; preferably, R 7 It is a fluorine atom.

[0206] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 C 1-6 Alkoxy; preferably, R 7 It is a methoxy group.

[0207] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7 It is a hydrogen atom.

[0208] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in the preceding one, wherein Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms, where R 7 As defined in general formula (I); preferably, Z 2 Z3 and Z 4 All are CR 7 , where R 7 As defined in general formula (I).

[0209] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described in any of the preceding embodiments, wherein U is -O-.

[0210] 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):

[0211] Where R 7a R 7b and R 7c In the same general formula (I) R 7 Defined;

[0212] Rings A, X, Z 1 V, R 1 To R 4 And t are as defined in general formula (I).

[0213] 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 5- to 10-membered heteroaryl group; preferably, ring A is a 5- or 6-membered heteroaryl group; more preferably, ring A is a pyrazolyl group.

[0214] In some implementations, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in the preceding one, wherein for Where R 4 And t are as defined in general formula (I).

[0215] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described in any of the preceding embodiments, wherein X is a chemical bond or -(CH2). n - where n is as defined in general formula (I); preferably, X is a chemical bond.

[0216] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein V is -(CR e R f ) j -, where R e R f And j is as defined in general formula (I); preferably, V is -(CH2). j- 1-CR e R f -, where R e Rf And j is as defined in general formula (I); more preferably, V is -CH2-CR e R f -, where R e and R f As defined in general formula (I).

[0217] 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, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (I); preferably, R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (I).

[0218] 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 group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups are each independently selected from C. 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (I).

[0219] 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, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, -OR groups, etc. 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (I).

[0220] 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 group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (I).

[0221] 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, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-hydroxyalkyl and -OR 14 , where R 14 As defined in general formula (I).

[0222] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4 C 1-6 Alkyl or C 1-6 Hydroxyalkyl.

[0223] 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):

[0224] Where R 4a R 4b and R 4c In the same general formula (I) R 4 Defined; R 7a R 7b and R 7c In the same general formula (I) R 7 Defined;

[0225] Z 1 R 1 To R 3 R e R f And n is as defined in general formula (I).

[0226] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in the preceding one, wherein Z 1 For CR 7 , where R 7 As defined in general formula (I); preferably, Z 1 For CH.

[0227] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7a It is a hydrogen atom or a halogen; preferably, R 7a It is a hydrogen atom.

[0228] 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-III-H):

[0229] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0230] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0231] R 4a and R 4bIn the same general formula (I) R 4 Defined;

[0232] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0233] R 1 To R 3 R e R f And n is as defined in general formula (I).

[0234] 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-III-SH):

[0235] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0236] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0237] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0238] R 1 To R 3 R e R f And n is as defined in general formula (I).

[0239] 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-III-RH):

[0240] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0241] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0242] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0243] R 1 To R3 R e R f And n is as defined in general formula (I).

[0244] 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

[0245] 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 0 to 20;

[0246] 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)[[ID=P34]] 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)-, -NR18 -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 0 to 20 and p1 is an integer from 0 to 20;

[0247] L 3 Selected from peptide residues consisting of 1 to 12 amino acid residues,

[0248] 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, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, and -(CR) groups. 22a R 22b ) p2 -cycloalkyl, -(CR 22a R 22b ) p2 -heterocyclic group, -(CR) 22a R 22b ) p2 -Aryl, -(CR 22a R 22b )p2 -Heteroaryl, -(CR 22a R 22b ) p2 -SR 25 、-(CR 22a R 22b ) p2 -COOR 25 、-(CR 22a R 22b ) p2 -NR 23 R 24 、-(CR 22a R 22b ) p2 -C(O)-NR 23 R 24 、-(CR 22a R 22b ) p2 -NR 25 -C(=NR 25 )-NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally replaced by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy groups; wherein p2 is an integer from 0 to 20, and *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0249] 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;

[0250] W2 The group is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from oxo groups, halogens, sugars (e.g., sugars). It is substituted by one or more of the same or different substituents from nitro, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0251] 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;

[0252] W 4 For -NR 28 C(O)- or -C(O)NR 28 -;

[0253] R 27 and R 28 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl;

[0254] 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;

[0255] 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;

[0256] 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.

[0257] R 20a R 20b R 20c R 20d R 21a R21b 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;

[0258] 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.

[0259] 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

[0260] 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 0 to 20;

[0261] 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 -W1 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-NR 18 -、-W 1 -C(O)-、-NR 18 -W 1 -C(O)-NR 18 -、-S-(CR 21e R 21f ) p1 -C(O)-、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -O-W 1 -C(O)-NR 18 -、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-、-NR 18 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -O-W 1 -NR 18 -C(O)-、-NR 18 -W 1 -W 2 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR18 -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 0 to 20 and p1 is an integer from 0 to 20;

[0262] L 3 Selected from peptide residues consisting of 1 to 12 amino acid residues,

[0263] 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, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, and -(CR) groups. 22a R 22b ) p2 -cycloalkyl, -(CR 22a R 22b ) p2 -heterocyclic group, -(CR) 22a R 22b ) p2 -Aryl, -(CR 22a R 22b ) p2 -Heteroaryl, -(CR 22a R 22b ) p2 -SR 25 、-(CR 22a R 22b ) p2 -COOR 25 、-(CR 22a R 22b ) p2 -NR 23 R 24 、-(CR 22a R 22b ) p2 -C(O)-NR 23 R 24、-(CR 22a R 22b ) p2 -NR 25 -C(=NR 25 )-NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R 24 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally replaced by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy groups; wherein p2 is an integer from 0 to 20, and *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0264] 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;

[0265] 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.

[0266] 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;

[0267] W 4 For -NR28 C(O)- or -C(O)NR 28 -;

[0268] R 27 and R 28 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, haloalkyl and hydroxyalkyl;

[0269] 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;

[0270] 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;

[0271] 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.

[0272] 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;

[0273] Or R 20a and R20b 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.

[0274] The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

[0275] 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):

[0276] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0277] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0278] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0279] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0280] Ab、R 1 To R 3 R e R f L 2 To L 4 W1 , q, n and y are as defined in general formula (I).

[0281] 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):

[0282] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0283] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0284] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0285] Ab、R 1 To R 3 R e R f L 2 To L 4 W 1 , q, n and y are as defined in general formula (I).

[0286] 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):

[0287] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0288] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0289] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0290] Ab、R 1 To R 3 R e R f L 2 To L 4 W 1 , q, n and y are as defined in general formula (I).

[0291] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 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 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups are optionally selected from oxo, halogen, cyano, amino, hydroxyl, 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, R 1 and R 2 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 Haloalkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; more preferably, R 1 and R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0292] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0293] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; preferably, R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a 3- to 6-membered cycloalkyl group; more preferably, R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a cyclopropyl group; most preferably, R 1 and R 2 All are hydrogen atoms.

[0294] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; preferably, R 1 and R 2 Together with the carbon atoms attached to them, they form cyclopropyl groups.

[0295] 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 atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 The alkyl group may optionally be replaced by a 3- to 6-membered cycloalkyl group; preferably, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 3 C 1-6 Alkyl; more preferably, R 3 It is a methyl group.

[0296] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms bonded to them together form 3- to 6-membered heterocyclic groups; said 3- to 6-membered heterocyclic groups are optionally selected from oxo groups, halogens, cyano groups, amino groups, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 It is substituted by one or more identical or different substituents in the haloalkoxy group.

[0297] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form 3 to 6-membered heterocyclic groups.

[0298] In some implementations, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, as described in the preceding one, wherein for Where R 1 and R 2 As defined in general formula (I).

[0299] 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 Any one of them and R 3 The carbon and nitrogen atoms bonded to them together form 3- to 6-membered heterocyclic groups; said 3- to 6-membered heterocyclic groups are optionally selected from oxo groups, halogens, cyano groups, amino groups, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 It is substituted by one or more identical or different substituents in the haloalkoxy group.

[0300] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R e and R f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, cyano groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; or R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups are optionally selected from oxo, halogen, cyano, amino, hydroxyl, 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, R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom.1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0301] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R e and R f They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0302] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; preferably, R e and R f Together with the carbon atoms attached to them, they form cyclopropyl groups.

[0303] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4c Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (I); preferably, R 4c Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6Alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups are each independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (I); more preferably, R 4c C 1-6 Hydroxyalkyl.

[0304] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4c Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-hydroxyalkyl, -OR 14 3 to 6-membered cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, -OR groups, etc. 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (I); preferably, R 4c Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1- Each of the 6 alkyl groups is independently selected from hydroxyl, C... 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (I); more preferably, R 4c C 1-6 Hydroxyalkyl.

[0305] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 4a and R 4b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 4a and R 4bThe same or different, and each independently is C. 1-6 alkyl.

[0306] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 7b and R 7c They may be the same or different, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy group; preferably, R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen; more preferably, R 7b and R 7c They may be the same or different, and each is independently a halogen; more preferably, R 7b and R 7c All are fluorine atoms.

[0307] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 Alkyl; more preferably, R k It is tert-butyl.

[0308] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein D is as shown in general formula (D-III-H), general formula (D-III-SH), or general formula (D-III-RH), wherein R k C 1- 6-alkyl group.

[0309] 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 (IN), general formula (IN-S), or general formula (IN-R), wherein R k C 1-6 alkyl.

[0310] 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 or 1; preferably, n is 0.

[0311] 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 All are hydrogen atoms.

[0312] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein j is 1, 2, 3 or 4; preferably, j is 2.

[0313] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 14 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0314] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 15 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 15 C 1-6 alkyl.

[0315] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R c and R d All are hydrogen atoms.

[0316] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R g and R h All are hydrogen atoms.

[0317] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R i and R j All are hydrogen atoms.

[0318] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R m and R n All are hydrogen atoms.

[0319] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 8 R 16c and R 32 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 8 R 16c and R 32 All are hydrogen atoms.

[0320] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 5 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0321] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 9 R 10 R 13 R 14 and R 29 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0322] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 11 and R 12 All are hydrogen atoms.

[0323] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein 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; preferably, R 16a and R 16b All are hydrogen atoms.

[0324] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 30 and R 31 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 30 and R 31 All are hydrogen atoms.

[0325] 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 1, 2, 3 or 4; preferably, t is 3.

[0326] 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 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, where W 1 R 20a R 20b R 20c R 20d And q are as defined in general formula (I).

[0327] 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).

[0328] 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 2It is a chemical bond.

[0329] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 3 The peptide residues are selected from 1 to 12 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 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -(CR 22a R 22b ) p2 -cycloalkyl, -(CR 22a R 22b ) p2 -heterocyclic group, -(CR) 22a R 22b ) p2 -Aryl, -(CR 22a R 22b ) p2 -Heteroaryl, -(CR 22a R 22b ) p2 -SR 25 、-(CR 22a R 22b ) p2 -COOR 25 、-(CR 22a R 22b ) p2 -NR 23 R 24 、-(CR 22a R 22b ) p2 -C(O)-NR 23 R 24 、-(CR 22a R 22b ) p2 -NR 25 -C(=NR 25 )-NR 23 R 24 and -(CR 22a R 22b ) p2 -NR 25 -C(O)-NR 23 R24 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are selected from 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups, and each is independently 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, wherein 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:1); most preferably, L 3 It is a dipeptide residue represented by valine-citrulline or a tetrapeptide residue represented by GGFG (SEQ ID NO:1).

[0330] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in the preceding one, wherein L3 is Where *1 and L 2 Connect the ends, *2 and L 4 Terminal connection, W 3 As defined in general formula (I).

[0331] 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 W 4 W 5 and R 27 As defined in general formula (I).

[0332] In some implementations, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments, wherein L 4 For chemical bonds or -NR 19 -W 2 -W 1-OC(O)-, where R 19 W 1 and W 2 As defined in general formula (I); preferably, L 4 It is a chemical bond.

[0333] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 19 It is a hydrogen atom.

[0334] 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

[0335] L 1 -(succinimide-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, where R 20a R 20b R 20c and R 20d All are hydrogen atoms; q is 1, 2, 3, 4, 5 or 6;

[0336] L 2 It is a chemical bond;

[0337] L 3 for

[0338] L 4 It is a chemical bond;

[0339] 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;

[0340] W 4 For -NR 28 C(O)- or -C(O)NR 28 -;

[0341] R 27 and R 28 All are hydrogen atoms;

[0342] *1 and L 2 Connect the ends, *2 and L 4 End connected;

[0343] The L of -L- 1 The terminal is connected to Ab, L 4 The terminal is connected to D.

[0344] 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

[0345] 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;

[0346] L 2 It is a chemical bond;

[0347] L 3 It is the tetrapeptide residue shown in GGFG (SEQ ID NO:1);

[0348] L 4 It is a chemical bond;

[0349] The L of -L- 1 The terminal is connected to Ab, L 3 The terminal is connected to D.

[0350] 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

[0351] L 1 -(succinimide-3-yl-N)-W1 -C(O)-;

[0352] L 2 It is a chemical bond;

[0353] L 3 The dipeptide residues represented by valine-citrulline;

[0354] L 4 For -NR 19 -W 2 -W 1 -OC(O)-;

[0355] W 1 -(CR) 26a R 26b ) p3 -;

[0356] 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 groups;

[0357] W 2 It is phenyl;

[0358] R 19 It is a hydrogen atom;

[0359] p3 is 1, 2, 3, 4, 5, or 6;

[0360] The L of -L- 1 The terminal is connected to Ab, L 3 The terminal is connected to D.

[0361] 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 and R 20d All are hydrogen atoms.

[0362] 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 0, 1, 2, 3, 4, 5 or 6; preferably, q is 0 or 2; more preferably, q is 2.

[0363] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in any of the preceding embodiments, wherein W 2The 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, 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 groups, halogens, sugars (e.g., sugars). ), nitro, cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1- The 6-haloalkoxy group is substituted with one or more identical or different substituents; preferably, W 2 The group is selected from 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are optionally selected from sugars (e.g., sugars). ), hydroxyl group, carboxyl group, 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; more preferably, W 2 The group is selected from cyclohexyl, phenyl, and pyridyl, wherein the cyclohexyl, phenyl, and pyridyl groups are optionally selected from sugars (e.g., sugars). ), hydroxyl group, carboxyl group, 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; most preferably, W 2 For phenyl, Substituted phenyl or Substituted phenyl groups.

[0364] In some embodiments, 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, W2 Selected from 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; more preferably, W 2 Selected from cyclohexyl, phenyl, and pyridyl; most preferably, W 2 It is a phenyl group.

[0365] 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 groups and C 1-6 Hydroxyalkyl; preferably, R 17 R 18 R 19 and R 25 All are hydrogen atoms.

[0366] In some embodiments, such as the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described in the preceding one, wherein R 21a R 21b R 21c R 21d R 21e R 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 21a R 21b R 21c R 21d R 21e R 21f R 22a and R 22b All are hydrogen atoms.

[0367] 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 groups and C 1-6 Hydroxyalkyl; preferably, R 23 and R 24They 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.

[0368] 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-Hydroalkyl; preferably, R 26a and R 26b All are hydrogen atoms.

[0369] 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 groups and C 1-6 Hydroxyalkyl; preferably, R 27 and R 28 All are hydrogen atoms.

[0370] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt, as described in any of the preceding embodiments, is selected from the following structures:

[0371] Where Ab represents an antibody;

[0372] y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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-HER2 antibodies, anti-B7H3 antibodies, anti-TROP2 antibodies, and anti-CD20 antibodies.

[0378] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt as described in any of the preceding embodiments is used, wherein the Ab is selected from trastuzumab, ifinatamab, sacituzumab, and rituximab.

[0379] In some embodiments, the ligand-drug conjugate or its pharmaceutically acceptable salt 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.

[0380] 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 1-9, or 1-8, or 1-7, or 1-6, or 1-5, or 1-4, or 1-3, or 2-9, 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 3-5, or 4-9, or 4-8, or 4-7, or 4-6, or 4-5.

[0381] 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 3 to 8.

[0382] 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).

[0383] In some embodiments, 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 or 1-4.

[0384] On the other hand, this disclosure relates to a compound of general formula (D) or a pharmaceutically acceptable salt thereof:

[0385] in:

[0386] X represents a chemical bond or -(CR) a R b ) n -;

[0387] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0388] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0389] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8- and -S(O) p -;

[0390] V represents a chemical bond or -(CR) e R f ) j -;

[0391] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0392] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0393] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0394] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0395] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0396] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0397] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s-NR 16c -S(O) p R 15 、-NR 16c -C(O)R 15 、-NR 16c -S(O) p R 15 、 cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b 、-C(O)-NR 16c -(CR m R n ) s -OR 15 、-C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 、-C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n )s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0398] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0399] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0400] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0401] R a R b R cR d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0402] 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 i and R j 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, 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.

[0403] R 5 R 8 R 16c and R 32 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;

[0404] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0405] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0406] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0407] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0408] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0409] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0410] p is 0, 1, or 2;

[0411] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0412] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0413] t can be 0, 1, 2, 3, 4, 5 or 6.

[0414] In some embodiments, the compound represented by general formula (D) as described above, or a pharmaceutically acceptable salt thereof:

[0415] in:

[0416] X represents a chemical bond or -(CR) a R b ) n -;

[0417] Y 1 and Y 2 Whether the same or different, and each independently constitutes a CR 6 Or nitrogen atoms;

[0418] Z 1 Z 2 Z 3 and Z 4 Whether the same or different, and each independently constitutes a CR 7 Or nitrogen atoms;

[0419] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0420] V represents a chemical bond or -(CR) e R f ) j -;

[0421] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0422] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CR g R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0423] Or R 1 and R 2Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0424] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0425] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0426] Or R a and R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0427] R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 alkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, -OR 15 , cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)p R 15 、 -C(O)-NR 16a R 16b 、 -NR 16a R 16b 、 -C(O)R 15 、 -C(O)OR 15 、 -(CR m R n ) s -NR 16a R 16b 、 -(CR m R n )<D s -NR 16c -C(O)R 15 、 -(CR m R n ) s -NR 16c -S(O) p R 15 、 -NR[[ID=A8]] 16c -C(O)R 15 、 -NR 16c -S(O) p R 15 、 氰基、 -(CR m R n ) s -S(O) p R 15 、 -(CR m R n ) s -C(O)-NR<00D3026>R 16b 、 -C(O)-NR 16c ! -(CR m R n ) s -OR 15 、 -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、 -(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R<0003O47>) ! s ) m 、 -(CR m It should be noted that there may be some inaccuracies in the translation due to the complexity and potential ambiguity of the original text. It is recommended to double-check with the original context for a more accurate understanding.R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5 It is substituted by one or more of the same or different substituents from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0428] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0429] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0430] Or any two adjacent R 7 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, nitro, amino, hydroxy, carboxyl, alkyl, alkenyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0431] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0432] 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 i and R j Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R nTogether 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.

[0433] R 5 R 8 R 16c and R 32 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;

[0434] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0435] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0436] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0437] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0438] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0439] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0440] p is 0, 1, or 2;

[0441] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0442] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0443] t can be 0, 1, 2, 3, 4, 5 or 6.

[0444] In some embodiments, the compound represented by general formula (D) as described above, or a pharmaceutically acceptable salt thereof:

[0445] in:

[0446] X represents a chemical bond or -(CR) a R b ) n -;

[0447] Y 1 and Y 2 Whether the two are the same or different, and each is an independent CR 6 Or nitrogen atoms;

[0448] Z 1 Z 2 Z 3 and Z 4 Whether the two are the same or different, and each is an independent CR 7 Or nitrogen atoms;

[0449] U is selected from -O- and -CR c R d -、-C(O)-、-NR 8 - and -S(O) p -;

[0450] V represents a chemical bond or -(CR) e R f ) j -;

[0451] Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0452] R 1 and R 2 Whether the groups are the same or different, and each is independently selected from hydrogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CR g R h ) k -cycloalkyl, -(CRg R h ) k -heterocyclic group, -(CR) g R h ) k -Aryl and-(CR g R h ) k -Heteroaryl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, cyano, nitro, -OR 9 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0453] Or R 1 and R 2 Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups; said cycloalkyl or heterocyclic groups are optionally substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0454] R 3 Selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -COOR 10 、-(CR i R j ) q -COOR 10 -NR 11 R 12 、-(CR i R j ) q -NR 11 R 12 alkyl, heterocyclic, aryl, and heteroaryl groups; each of the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, cyano, nitro, -OR 13 It is substituted by one or more of the same or different substituents from , oxo, alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0455] Or R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0456] Or R aand R b Any one of them and R 3 The carbon and nitrogen atoms attached to them together form a heterocyclic group; the heterocyclic group may be optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0457] R 4 Selected from hydrogen, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl and -OR 14 The alkyl, alkenyl, and alkynyl groups thereon are each optionally selected independently from halogens, hydroxyl groups, -OR groups, etc. 15 -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c -S(O) p R 15 -NR 16c -C(O)R 15 -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)N((CR) mR n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b One or more identical or different substituents are substituted in the substance;

[0458] R 6 Selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, and hydroxyalkyl groups;

[0459] R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31-NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0460] R a R b R c R d R e R f R g R h R i R j R m and R n The same or different, and each independently selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more of the same or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy;

[0461] 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 i and R j Together with the carbon atoms attached to them, they form cycloalkyl or heterocyclic groups, or R m and R nTogether 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.

[0462] R 8 R 16c and R 32 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;

[0463] R 9 R 10 R 13 R 14 R 15 and R 29 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;

[0464] R 11 R 12 R 16a R 16b R 30 and R 31 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 11 and R 12 Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 16a and R 16b Together with the nitrogen atoms attached to them, they form heterocyclic groups, or R 30 and R 31 Together with the nitrogen 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, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy.

[0465] j can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0466] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0467] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0468] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0469] p is 0, 1, or 2;

[0470] q can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0471] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

[0472] t can be 0, 1, 2, 3, 4, 5 or 6.

[0473] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 alkyl, heterocyclic, aryl, and heteroaryl groups; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally selected from halogen, hydroxyl, -OR 15 Alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c -S(O) p R 15 -NR 16c -C(O)R 15 -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n )s -C(O)-NR 16a R 16b -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)N((CR) m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, cyano, nitro, amino, carboxyl, oxo, and -OR groups. 5The substituent is one or more of the same or different substituents selected from alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; wherein R 14 R 15 R 16a R 16b R 16c R m R n p, m and s are as defined in general formula (D).

[0474] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl and -OR 14 The alkyl, alkenyl, and alkynyl groups thereon are each optionally selected independently from halogens, hydroxyl groups, -OR groups, etc. 15 -S(O) p R 15 -C(O)-NR 16a R 16b -NR 16a R 16b -C(O)R 15 -C(O)OR 15 、-(CR m R n ) s -NR 16a R 16b 、-(CR m R n ) s -NR 16c -C(O)R 15 、-(CR m R n ) s -NR 16c -S(O) p R 15 -NR 16c -C(O)R 15 -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 、-(CR m R n ) s -C(O)-NR 16a R 16b -C(O)-NR 16c-(CR m R n ) s -OR 15 -C(O)N((CR) m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m 、-(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 -C(O)-N((CR) m R n ) s -O-(CR m R n ) s ) m -OR 15 、-(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b One or more identical or different substituents are substituted in R; where R 14 R 15 R 16a R 16b R 16c R m R n p, m and s are as defined in general formula (D).

[0475] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein R 7 The atom is selected from hydrogen, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and hydroxyalkyl; the alkyl group is optionally selected from halogen, cyano, nitro, hydroxy, and -S(O). p R 29 -S(O) p -NR 30 R 31 -NR 30 R 31 -NR 32 -C(O)R 29 -NR 32 -S(O) p R 29 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each substituted by one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; wherein R 29 R 30 R 31 R 32 p is as defined in general formula (D).

[0476] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 Hydroxyalkyl; preferably, R 6 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 6 It is a hydrogen atom.

[0477] In some embodiments, the compound represented by the general formula (D) as described above, or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 Whether the two are the same or different, and each is an independent CR 6 , where R 6 As defined in general formula (D); preferably, Y 1 and Y 2 All are CH.

[0478] 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 7 Selected from hydrogen atom, halogen, hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, R 7 It is a hydrogen atom or a halogen; more preferably, R 7 It consists of hydrogen or fluorine atoms.

[0479] 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 7 It is a halogen; preferably, R 7 It is a fluorine atom.

[0480] 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 7 C 1-6 Alkoxy; preferably, R 7 It is a methoxy group.

[0481] 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 7 It is a hydrogen atom.

[0482] 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 Z 2 Z 3 and Z 4 Whether the two are the same or different, and each is an independent CR 7 Or nitrogen atoms, where R 7 As defined in general formula (D); preferably, Z 2 Z 3 and Z 4 All are CR 7 , where R 7 As defined in general formula (D).

[0483] In some embodiments, the compound represented by general formula (D) as described in the preceding one, or a pharmaceutically acceptable salt thereof, wherein U is -O-.

[0484] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, represented by general formula (D) as described in any of the preceding embodiments, wherein D is represented by general formula (DI):

[0485] Where R 7a R 7b and R7c For example, R in general formula (D) 7 Defined;

[0486] Rings A, X, Z 1 V, R 1 To R 4 And t are as defined in general formula (D).

[0487] In some embodiments, the compound represented by formula (D) or formula (DI) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroaryl group; preferably, ring A is a 5- or 6-membered heteroaryl group; more preferably, ring A is a pyrazolyl group.

[0488] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein... for Where R 4 And t are as defined in general formula (D).

[0489] In some embodiments, the compound or its pharmaceutically acceptable salt represented by general formula (D) or general formula (DI) as described in any of the preceding embodiments, wherein X is a chemical bond or -(CH2). n - where n is as defined in general formula (D); preferably, X is a chemical bond.

[0490] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein V is -(CR e R f ) j -, where R e R f And j is as defined in general formula (D); preferably, V is -(CH2). j-1 -CR e R f -, where R e R f And j is as defined in general formula (D); more preferably, V is -CH2-CR e R f -, where R e and R f As defined in general formula (D).

[0491] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (D); preferably, R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (D).

[0492] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups are each independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (D).

[0493] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 Selected from hydrogen atom, halogen, cyano, nitro, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, -OR groups, etc. 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (D).

[0494] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (D).

[0495] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl and -OR 14 , where R 14 As defined in general formula (D).

[0496] In some embodiments, a compound of formula (D) or formula (DI) as described in any of the preceding embodiments, wherein R 4 C 1-6 Alkyl or C 1-6 Hydroxyalkyl.

[0497] 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 embodiments, is represented by general formula (D-II):

[0498] Where R 4a R 4b and R 4c In the same formula (D) R 4 Defined; R 7a R 7b and R 7c In the same formula (D) R 7 Defined;

[0499] Z 1 R 1 To R 3 R e R f And n is as defined in general formula (D).

[0500] In some embodiments, a compound of formula (D), formula (DI), or formula (D-II) or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein Z 1 For CR 7 , where R 7 As defined in general formula (D); preferably, Z 1 For CH.

[0501] In some embodiments, a compound of formula (DI) or formula (D-II) as described in any of the preceding embodiments, wherein R 7a It is a hydrogen atom or a halogen; preferably, R 7a It is a hydrogen atom.

[0502] In some embodiments, the compound or a pharmaceutically acceptable salt thereof of general formula (D), general formula (DI), or general formula (D-II) as described in any of the preceding claims, is represented by general formula (D-III):

[0503] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0504] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0505] R 4a and R 4b In the same formula (D) R 4 Defined;

[0506] R 7b and R 7c In the same formula (D) R 7 Defined;

[0507] R1 To R 3 R e R f And n is as defined in general formula (D).

[0508] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by general formula (D), general formula (DI), general formula (D-II) or general formula (D-III) as described in any of the preceding claims, as represented by general formula (D-III-S):

[0509] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0510] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0511] R 4a and R 4b In the same formula (D) R 4 Defined;

[0512] R 7b and R 7c In the same formula (D) R 7 Defined;

[0513] R 1 To R 3 R e R f And n is as defined in general formula (D).

[0514] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by general formula (D), general formula (DI), general formula (D-II) or general formula (D-III) as described in any of the preceding claims, as represented by general formula (D-III-R):

[0515] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl;

[0516] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0517] R 4a and R 4b In the same formula (D) R 4 Defined;

[0518] R 7b and R 7c In the same formula (D) R 7 Defined;

[0519] R1 To R 3 R e R f And n is as defined in general formula (D).

[0520] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 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-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups are optionally selected from oxo, halogen, cyano, amino, hydroxyl, 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, R 1 and R 2 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-acetylinyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; more preferably, R 1 and R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0521] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0522] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; preferably, R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a 3- to 6-membered cycloalkyl group; more preferably, R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a cyclopropyl group; most preferably, R 1 and R 2 All are hydrogen atoms.

[0523] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 Together with the carbon atoms attached to them, they form cyclopropyl groups.

[0524] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 The alkyl group may optionally be replaced by a 3- to 6-membered cycloalkyl group; preferably, R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 3 C1- 6-alkyl; more preferably, R 3 It is a methyl group.

[0525] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms bonded to them together form 3- to 6-membered heterocyclic groups; said 3- to 6-membered heterocyclic groups are optionally selected from oxo groups, halogens, cyano groups, amino groups, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 It is substituted by one or more identical or different substituents in the haloalkoxy group.

[0526] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 1 and R 2 Any one of them and R 3 The carbon and nitrogen atoms attached to them together form 3 to 6-membered heterocyclic groups.

[0527] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by general formula (D), general formula (DI), general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding embodiments, wherein for Where R 1 and R 2 As defined in general formula (I).

[0528] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R a and R b Any one of them and R 3 The carbon and nitrogen atoms bonded to them together form 3- to 6-membered heterocyclic groups; said 3- to 6-membered heterocyclic groups are optionally selected from oxo groups, halogens, cyano groups, amino groups, hydroxyl groups, C-groups, etc. 1-6 Alkyl, C1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 It is substituted by one or more identical or different substituents in the haloalkoxy group.

[0529] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R e and R f They may be the same or different, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, cyano groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; or R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups are optionally selected from oxo, halogen, cyano, amino, hydroxyl, 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, R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

[0530] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R e and R f They may be the same or different, and each is independently a hydrogen atom or a methyl group.

[0531] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; preferably, R e and R f Together with the carbon atoms attached to them, they form cyclopropyl groups.

[0532] In some embodiments, a compound of formula (D-II) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4c Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (D); preferably, R 4c Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups are each independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (D); more preferably, R 4c C 1-6 Hydroxyalkyl.

[0533] In some embodiments, a compound of formula (D-II) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4c Selected from hydrogen atom, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, -OR 14 , 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups are each independently selected from halogens, hydroxyl groups, -OR groups, etc. 15 The alkyl group is substituted with one or more identical or different substituents from 3 to 6 membered cycloalkyl groups and 3 to 6 membered heterocyclic groups, wherein R 14 and R 15 As defined in general formula (D); preferably, R 4c Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -OR 14 and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from hydroxyl, C 1-6 The alkoxy group is substituted with one or more identical or different substituents from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein R 14 As defined in general formula (D); more preferably, R 4c C 1-6 Hydroxyalkyl.

[0534] In some embodiments, the compound represented by general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding claims, wherein R 4a and R 4b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 4a and R 4b The same or different, and each independently is C. 1-6 alkyl.

[0535] In some embodiments, the compound represented by general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding claims, wherein R 7b and R 7cThey may be the same or different, and each is independently selected from hydrogen atoms, halogens, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen; more preferably, R 7b and R 7c They may be the same or different, and each is independently a halogen; more preferably, R 7b and R 7c All are fluorine atoms.

[0536] In some embodiments, a compound of formula (D-III), formula (D-III-S), or formula (D-III-R) or a pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, wherein R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 Alkyl; more preferably, R k It is tert-butyl.

[0537] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding claims, wherein n is 0 or 1; preferably, n is 0.

[0538] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R a and R b All are hydrogen atoms.

[0539] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding claims, wherein j is 1, 2, 3 or 4; preferably, j is 2.

[0540] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 14 Selected from hydrogen atoms, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 14 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0541] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 15 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 15 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 15 C 1-6 alkyl.

[0542] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R c and R d All are hydrogen atoms.

[0543] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R g and R h All are hydrogen atoms.

[0544] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R i and R j All are hydrogen atoms.

[0545] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R m and R n All are hydrogen atoms.

[0546] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 8 R 16c and R 32 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 8 R 16c and R 32 All are hydrogen atoms.

[0547] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 5 It is a hydrogen atom or a carbon atom. 1-6 alkyl.

[0548] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 9 R 10 R 13 R 14 and R 29 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0549] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 11 and R 12 All are hydrogen atoms.

[0550] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein 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; preferably, R 16a and R 16b All are hydrogen atoms.

[0551] In some embodiments, a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein R 30 and R 31 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R 30 and R 31 All are hydrogen atoms.

[0552] In some embodiments, the compound or a pharmaceutically acceptable salt thereof represented by formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, wherein t is 1, 2, 3 or 4; preferably, t is 3.

[0553] In some embodiments, a compound of formula (D-III) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R k C 1-6 Alkyl group; * represents a chiral carbon atom, in either the R or S configuration, or a mixture of both; R 4a and R 4b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen; R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups; n is 0 or 1.

[0554] In some embodiments, a compound of formula (D-III) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R k C 1-6 Alkyl group; * represents a chiral carbon atom, in either the R or S configuration, or a mixture of both; R 4a and R 4b The same or different, and each independently is C. 1-6 Alkyl; R 7b and R 7c They may be the same or different, and each is an independent halogen; R 1 and R 2 All are hydrogen atoms; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups; n is 0 or 1.

[0555] In some embodiments, a compound of formula (D-III) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R k C 1-6 Alkyl group; * represents a chiral carbon atom, in either the R or S configuration, or a mixture of both; R 4a and R 4b The same or different, and each independently is C. 1-6 Alkyl; R 7b and R 7c They may be the same or different, and each is an independent halogen; R 1 and R 2 All are hydrogen atoms; R 3 C 1-6 Alkyl; R e and R f All are hydrogen atoms; n is 0.

[0556] In some embodiments, a compound of formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4bThey may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen; R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups; n is 0 or 1.

[0557] In some embodiments, a compound of formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R k C 1-6 Alkyl; R 4a and R 4b The same or different, and each independently is C. 1-6 Alkyl; R 7b and R 7c They may be the same or different, and each is an independent halogen; R 1 and R 2 All are hydrogen atoms; or R1 and R2 together with the carbon atoms attached to them form 3 to 6-membered cycloalkyl groups; R 3 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups; n is 0 or 1.

[0558] In some embodiments, a compound of formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R k C 1-6 Alkyl; R 4a and R 4b The same or different, and each independently is C. 1-6 Alkyl; R 7b and R 7cThey may be the same or different, and each is an independent halogen; R 1 and R 2 All are hydrogen atoms; R 3 C 1-6 Alkyl; R e and R f All are hydrogen atoms; n is 0.

[0559] In some embodiments, the compounds or pharmaceutically acceptable salts thereof represented by general formula (D), general formula (DI), general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding embodiments have the structures shown in Table 1-1.

[0560] On the other hand, this disclosure relates to a compound of general formula (LN-D-III) or a salt thereof:

[0561] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 alkyl;

[0562] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0563] R 4a and R 4b As in general formula (I) R 4 Defined;

[0564] R 7b and R 7c As in general formula (I) R 7 Defined;

[0565] R 1 To R 3 R e R f L 2 To L 4 W 1 q and n are as defined in general formula (I).

[0566] On the other hand, this disclosure relates to a compound of the general formula (LN-D-III-S) or a salt thereof:

[0567] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 alkyl;

[0568] R4a and R 4b As in general formula (I) R 4 Defined;

[0569] R 7b and R 7c As in general formula (I) R 7 Defined;

[0570] R 1 To R 3 R e R f L 2 To L 4 W 1 q and n are as defined in general formula (I).

[0571] On the other hand, this disclosure relates to a compound of the general formula (LN-D-III-R) or a salt thereof:

[0572] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 alkyl;

[0573] R 4a and R 4b As in general formula (I) R 4 Defined;

[0574] R 7b and R 7c As in general formula (I) R 7 Defined;

[0575] R 1 To R 3 R e R f L 2 To L 4 W 1 q and n are as defined in general formula (I).

[0576] In some embodiments, compounds of the general formula (LN-D-III), general formula (LN-D-III-S) or general formula (LN-D-III-R) as described in any of the preceding claims, or salts thereof, wherein R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 Alkyl; more preferably, R k It is tert-butyl.

[0577] In some embodiments, the compounds or salts thereof represented by the general formula (LN-D-III), (LN-D-III-S) or (LN-D-III-R) as described in any of the preceding claims have structures shown in Tables 1-2.

[0578] 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 to a ligand; wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

[0579] 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 to a ligand via a connector; wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

[0580] 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:

[0581] 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.

[0582] Where R k C 1-6 Alkyl or 3- to 6-membered cycloalkyl; preferably, R k C 1-6 alkyl;

[0583] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0584] R 4a and R 4b In the same general formula (I) R 4 Defined;

[0585] R 7b and R 7c In the same general formula (I) R 7 Defined;

[0586] Ab、R 1 To R 3 R e R f L 2 To L4 W 1 , q, n and y are as defined in general formula (I).

[0587] In some embodiments, compounds of general formula (IN-S) or general formula (IN-R) as described in any of the preceding claims, or pharmaceutically acceptable salts thereof, may be synthesized by means of the above methods, using appropriate chiral starting materials (e.g., general formula (LN-D-III-S) or general formula (LN-D-III-R) instead of general formula (LN-D-III)), or obtained by chiral resolution.

[0588] Table 1-1 Typical compounds disclosed herein include, but are not limited to:

[0589] Table 1-3 lists typical compounds disclosed herein, including but not limited to: Note: In Table 1-3, p is defined as y in general formula (I).

[0590] Table 1-4 lists typical compounds disclosed herein, including but not limited to:

[0591] 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 (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding claims, a compound of formula (LN-D-III), formula (LN-D-III-S) or formula (LN-D-III-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.

[0592] 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.

[0593] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a compound of formula (D), formula (DI), formula (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0594] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a compound of the formula (LN-D-III), (LN-D-III-S), or (LN-D-III-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.

[0595] In some embodiments, based on the total weight of the pharmaceutical composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned ligand-drug conjugate or a pharmaceutically acceptable salt thereof, a compound of general formula (D), general formula (DI), general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding claims, or a compound of general formula (LN-D-III), general formula (LN-D-III-S) or general formula (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0596] 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), (D-II), (D-III), (D-III-S), or (D-III-R) as described in any of the preceding claims, or a compound of formula (LN-D-III), (LN-D-III-S), or (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0597] 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), (D-II), (D-III), (D-III-S), or (D-III-R) as described in any of the preceding claims, or a compound of formula (LN-D-III), (LN-D-III-S), or (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0598] 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), (D-II), (D-III), (D-III-S), or (D-III-R) as described in any of the preceding claims, or a compound of formula (LN-D-III), (LN-D-III-S), or (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0599] 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), (D-II), (D-III), (D-III-S), or (D-III-R) as described in any of the preceding claims, or a compound of formula (LN-D-III), (LN-D-III-S), or (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0600] 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.

[0601] In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable diluent or excipient.

[0602] In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients.

[0603] In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable diluents or excipients.

[0604] In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable diluents or excipients.

[0605] 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 (D-II), formula (D-III), formula (D-III-S) or formula (D-III-R) as described in any of the preceding claims, a compound of formula (LN-D-III), formula (LN-D-III-S) or formula (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutical composition as described above.

[0606] 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.

[0607] 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 (D-II), formula (D-III), formula (D-III-S), or formula (D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0608] 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-III), formula (LN-D-III-S), or formula (LN-D-III-R) as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0609] 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 general formula (D), general formula (DI), general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-R) as described in any of the preceding claims, a compound of general formula (LN-D-III), general formula (LN-D-III-S) or general formula (LN-D-III-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.

[0610] 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 to prevent or treat a disease.

[0611] In some embodiments, this disclosure relates to a compound of general formula (D), general formula (DI), general formula (D-II), general formula (D-III), general formula (D-III-S) or general formula (D-III-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 pharmaceutical medicament is used for the prevention or treatment of a disease.

[0612] In some embodiments, this disclosure relates to a compound of general formula (LN-D-III), general formula (LN-D-III-S), or general formula (LN-D-III-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.

[0613] The disease described in any of the preceding items in this disclosure is a tumor; preferably, the disease is selected from gallbladder cancer, brain tumor, lymphoma, leukemia, blastoma, myeloma, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer, liver cancer, urothelial carcinoma, ovarian cancer, pancreatic cancer, bladder cancer, stomach cancer, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, endometrial cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, and penile cancer.

[0614] the term

[0615] 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.

[0616] The singular forms “a,” “an,” and “the” used in the specification and claims include plural references unless the context clearly indicates otherwise.

[0617] The plural form “multiple” used in the specification and claims has no specific upper or lower limit on the number (except that it must be greater than one), so it naturally includes all numbers greater than one, including 2, 3, 4... up to infinity.

[0618] 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.

[0619] 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.

[0620] 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).

[0621] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem., 243, p3558 (1968).

[0622] 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.

[0623] 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.

[0624] The term "ligand" refers to a macromolecular compound that can recognize and bind to antigens or receptors associated with a target cell.

[0625] 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).

[0626] 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).

[0627] 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.

[0628] "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.

[0629] 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.

[0630] The amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat" numbering rule, the "Chothia" numbering rule, the "ABM" numbering rule, the "contact" numbering rule, and the ImMunoGenTics (IMGT) numbering rule; the correspondence between various numbering systems is well known to those skilled in the art.

[0631] Unless otherwise stated, the variable areas and CDRs in this disclosure embodiment are subject to the "Kabat" numbering rule.

[0632] 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.

[0633] 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.

[0634] 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.

[0635] 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).

[0636] 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.

[0637] 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.

[0638] 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).

[0639] The term "surface plasmon resonance" refers to the optical phenomenon of real-time interactions that is analyzed by detecting changes in protein concentration within a biosensor matrix.

[0640] 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.

[0641] 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.

[0642] 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).

[0643] The term "epitope" refers to a region on an antigen that can specifically bind 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), such as those spatially proximal due to antigen folding (i.e., tertiary folding of antigens as proteins). The difference between conformational and linear epitopes is that antibody binding to a conformational epitope is lost in the presence of a denaturing solvent. Epitopes contain 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, Western blotting, peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen, and cross-blocking.

[0644] 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)).

[0645] 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.

[0646] 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).

[0647] 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.

[0648] 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.

[0649] 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.

[0650] 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.

[0651] 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*, *Pichia membranaefaciens*, *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.

[0652] 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.

[0653] 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.

[0654] 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., C16-64 ... 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.

[0655] 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.

[0656] 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.

[0657] 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.

[0658] 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).

[0659] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0660] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0661] 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:

[0662] Its connection point can be anywhere;

[0663] wait.

[0664] 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:

[0665] Its connection point can be anywhere;

[0666] wait.

[0667] 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:

[0668] Its connection point can be anywhere.

[0669] 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.

[0670] 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 has 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).

[0671] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0672] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0673] 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:

[0674] wait.

[0675] 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:

[0676] wait.

[0677] 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:

[0678] wait.

[0679] 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.

[0680] 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:

[0681] wait.

[0682] 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.

[0683] 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.

[0684] 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.

[0685] 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:

[0686] wait.

[0687] 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.

[0688] 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".

[0689] 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 Or simultaneously include and Two configurations.

[0690] 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.

[0691] 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.

[0692] "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.

[0693] 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.

[0694] 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.

[0695] 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.

[0696] "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.

[0697] 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.

[0698] "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.

[0699] 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.

[0700] Exemplary compounds or their pharmaceutically acceptable salts:

[0701] This disclosure relates to a compound of general formula (D-III) or a pharmaceutically acceptable salt thereof:

[0702] Where R k C 1-6 alkyl;

[0703] * represents a chiral carbon atom, which is either R-configuration, S-configuration, or a mixture of both;

[0704] R 4a and R 4b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0705] R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen;

[0706] R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups;

[0707] R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0708] R e and R f They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups;

[0709] n is 0 or 1.

[0710] This disclosure relates to a compound of formula (D-III-S) or formula (D-III-R) or a pharmaceutically acceptable salt thereof:

[0711] Where R k C 1-6 alkyl;

[0712] R 4a and R 4b They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl;

[0713] R 7b and R 7c They may be the same or different, and each is independently a hydrogen atom or a halogen;

[0714] R 1 and R 2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups;

[0715] R 3 It is a hydrogen atom or a carbon atom. 1-6 alkyl;

[0716] R e and Rf They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; or R e and R f Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups;

[0717] n is 0 or 1. Detailed Implementation

[0718] 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.

[0719] Examples and Test Cases

[0720] I. Antibody Examples

[0721] Example 1, Antibody

[0722] The conjugate antibodies used in this disclosure may be selected from trastuzumab, sacituzumab, and ifinatamab.

[0723] Heavy chains of trastuzumab:

[0724] The light chain of trastuzumab

[0725] heavy chains of sacituzumab

[0726] >sacituzumab's light chain

[0727] heavy chains of ifinatamab

[0728] light chain of ifinatamab

[0729] II. Compound Examples

[0730] 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. -6The 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).

[0731] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Other instruments used included: a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0732] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0733] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0734] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0735] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0736] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0737] 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.

[0738] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0739] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0740] 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, Accela ChemBio Inc, and Darui Chemicals.

[0741] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0742] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0743] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0744] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0745] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0746] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0747] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0748] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0749] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / 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.

[0750] Example 2-1, D-1

[0751] 1-(4-(2-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-1

[0752] first step

[0753] 1-(6-Clomidazolo[1,2-b]pyridazin-3-yl)-N-methylmethylamine 1b

[0754] 6-Clonimidazolo[1,2-b]pyridazine-3-carboxaldehyde 1a (500 mg, 2.75 mmol, Shanghai Haohong Leyan Reagent) was dissolved in methanol (20 mL) in methylamine ethanol solution (777 mg, 8.25 mmol, 30%), and 1 drop of acetic acid was added dropwise. The mixture was stirred for 12 hours. Sodium borohydride (208 mg, 5.49 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using system C as the elution point to give the title compound 1b (500 mg, yield: 92%).

[0755] MS m / z(ESI):197.1[M+1].

[0756] Step 2

[0757] ((6-chloroimidazolo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 1c

[0758] Compound 1b (500 mg, 2.54 mmol) and triethylamine (515 mg, 5.08 mmol) were dissolved in dichloromethane (20 mL). Di-tert-butyl dicarbonate (720 mg, 3.30 mmol, Shanghai Titan) was added under ice-water bath, and the mixture was stirred at room temperature for 3 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 1c (700 mg, yield: 92%).

[0759] MS m / z(ESI):297.5[M+1].

[0760] Step 3

[0761] ((6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 1d

[0762] Compound 1c (500 mg, 1.68 mmol), (3,4-difluoro-2-hydroxyphenyl)boronic acid (300 mg, 1.72 mmol, prepared by the method disclosed in the intermediate on page 67 of patent application WO2017001812A1) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). At room temperature, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (111 mg, 0.17 mmol, Adamas) and potassium phosphate (1075 mg, 5.07 mmol) were added. The mixture was purged with nitrogen three times, heated to 100 °C by microwave, and stirred for 1 hour. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography with elution system B to give the title compound 1d (500 mg, yield: 76%).

[0763] MS m / z(ESI): 391.3 [M+1].

[0764] Step 4

[0765] ((6-(2-(2-(1,5-dimethyl-3-neovaler-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 1f

[0766] 1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylacetone 1e (58 mg, 0.25 mmol, prepared by the method disclosed in Example 12, Intermediate 89, and Step 7, pages 85-86 of patent application WO2024052685A1), compound 1d (100 mg, 0.25 mmol), and cyanomethylenetri-n-butylphosphine (123 mg, 0.51 mmol, BIDE) were dissolved in toluene (5 mL) and reacted at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give title compound 1f (50 mg, yield: 32%). MS m / z(ESI): 597.6 [M+1].

[0767] Step 5

[0768] ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 1g

[0769] Compound 1f (50 mg, 83.70 μmol) was dissolved in methanol (5 mL), and lithium borohydride (10 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography using elution system B to give 1 g (30 mg, yield: 59%) of the title compound.

[0770] MS m / z(ESI): 599.6 [M+1].

[0771] Step 6

[0772] 1-(4-(2-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-1

[0773] 1 g (30 mg, 50 μmol) of the compound was dissolved in methanol (5 mL), and 1 mL of 4 M hydrogen chloride solution of 1,4-dioxane was added. The mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545; column: Sharpsil-T, Prep 30×150 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound D-1 (20 mg, yield: 80%).

[0774] MS m / z(ESI): 499.5 [M+1].

[0775] 1 H NMR (500MHz, CDCl3): δ7.87(d,1H),7.77(s,1H),7.45-7.39(m,1H),7.34(d,1H),7.11-7.04(m,1H),4 .25-4.15(m,3H),4.08(t,2H),3.60(s,3H),2.84-2.75(m,2H),2.50(s,3H),2.00(s,3H),0.9(s,9H).

[0776] Example 2-1-P1, D-1-P1

[0777] Example 2-1-P2, D-1-P2

[0778] (S)-1-(4-(2-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-1-P1

[0779] (R)-1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-1-P2

[0780] Compound D-1 (440 mg, 0.88 mmol) was resolved by a chiral preparative column (instrument: Gilson-281; ​​column: ChiralPak IG, 20 × 250 mm (Daicel), 5 μm; mobile phase: n-hexane and ethanol (0.5% 7M ammonia in methanol); flow rate: 20 mL / min) to give the title compound (110 mg, 25.0% yield) and (110 mg, 25.0% yield).

[0781] Single configuration compound (shorter retention time, 110 mg, yield: 25.0%);

[0782] MS m / z(ESI):499.6[M+1].

[0783] 1 H NMR (500MHz, CDCl3): δ7.87(d,1H),7.77(s,1H),7.46-7.40(m,1H),7.35(d,1H),7.11-7.04(m,1H) ,4.21(s,3H),4.08(t,2H),3.62(s,3H),2.84-2.75(m,2H),2.50(s,3H),2.00(s,3H),0.90(s,9H).

[0784] Chiral HPLC analysis: retention time 12.230 min, purity: 100% (column: CHIRALPAK IG, 150×4.6 mm, 5 μm; mobile phase: ethanol (0.1% diethanolamine) and n-hexane, gradient ratio: ethanol (0.1% diethanolamine): n-hexane = 20%: 80%).

[0785] Single configuration compound (longer retention time, 110 mg, yield: 25.0%).

[0786] MS m / z(ESI): 499.5 [M+1].

[0787] 1 H NMR (500MHz, CDCl3): δ7.87(d,1H),7.77(s,1H),7.46-7.40(m,1H),7.35(d,1H),7.11-7.04(m,1H) ,4.21(s,3H),4.08(t,2H),3.62(s,3H),2.84-2.75(m,2H),2.50(s,3H),2.00(s,3H),0.90(s,9H).

[0788] Chiral HPLC analysis: retention time 15.528 min, purity: 100% (column: CHIRALPAK IG, 150×4.6 mm, 5 μm; mobile phase: ethanol (0.1% diethanolamine) and n-hexane, gradient ratio: ethanol (0.1% diethanolamine): n-hexane = 20%: 80%).

[0789] Example 2-2, D-2

[0790] 1-(4-(1-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)-2-methylpropyl-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-2

[0791] The preparation can be achieved by referring to the synthetic route of D-1 and replacing the reactants in step four.

[0792] Exact Mass: 526.29.

[0793] Examples 2-3, D-3

[0794] 1-(4-(1-((2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)methyl)cyclopropyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-3

[0795] first step

[0796] 2-(3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-1H-pyrazole-4-yl)ethyl acrylate 3b

[0797] 3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-pyrazole 3a (5.0 g, 13.43 mmol, prepared by the method disclosed in intermediate 4 on page 36 of patent application WO2017182625A1) and ethyl 2-bromoacrylate (2.5 g, 13.96 mmol, prepared by the method disclosed in the Journal of Organic Chemistry) The compound IIb was prepared by the method disclosed in SCHEME5 on page 6 of Chemistry, vol. 83, 21, pp. 13217-13227. It was dissolved in tetrahydrofuran (50 mL) and water (10 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.13 g, 1.34 mmol, Adamas) and potassium phosphate (8.55 g, 40.33 mmol) were added at room temperature. The mixture was purged with nitrogen three times, heated to 70 °C, and stirred for 15 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water. It was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3b (3.3 g, yield: 71%).

[0798] MS m / z(ESI): 345.4 [M+].

[0799] Step 2

[0800] 1-(3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid ethyl ester 3c

[0801] Trimethyl sulfoxide (2.75 g, 12.49 mmol) was dissolved in dimethyl sulfoxide (30 mL), and sodium hydride (575 mg, 14.37 mmol, 60% dispersed in mineral oil) was added under an ice-water bath. The mixture was stirred under an ice-water bath for 1 hour. Compound 3b (3.3 g, 9.58 mmol) was dissolved in dimethyl sulfoxide (10 mL) and added dropwise to the reaction mixture. The reaction mixture was heated to room temperature and stirred for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3c (1.8 mg, yield: 52%). MS m / z (ESI): 359.4 [M+1].

[0802] Step 3

[0803] (1-(3-(((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-1H-pyrazole-4-yl)cyclopropyl)methanol3d

[0804] Compound 3c (400 mg, 1.11 mmol) was dissolved in tetrahydrofuran (10 mL), cooled in an ice bath, and lithium aluminum hydride (43 mg, 1.13 mmol, 2.5 M tetrahydrofuran solution) was added dropwise. The reaction mixture was heated to room temperature and stirred for 2 hours. Sodium sulfate decahydrate was added to quench the reaction, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed twice with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 3d (300 mg, yield: 85%).

[0805] MS m / z(ESI): 317.3 [M+1].

[0806] Step 4

[0807] ((6-(3,4-difluoro-2-((1-(3-((((4-methoxybenzyl)oxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)cyclopropyl)methoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 3e

[0808] Compound 3d (260 mg, 0.66 mmol), compound 1d (200 mg, 0.63 mmol), and cyanomethylenetri-n-butylphosphine (403 mg, 1.89 mmol, BIDE) were dissolved in toluene (5 mL) and reacted at 110 °C for 16 h. The reaction mixture was cooled to room temperature, poured into 20 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3e (300 mg, yield: 68%). MS m / z (ESI): 689.7 [M+1].

[0809] Step 5

[0810] ((6-(3,4-difluoro-2-((1-(3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl)cyclopropyl)methoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 3f

[0811] Compound 3e (350 mg, 508 μmol) was dissolved in dichloromethane (10 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (150 mg, 661 μmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 30 mL of water, neutralized with excess saturated sodium bicarbonate solution, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the desiccant was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to give the title compound 3f (200 mg, yield: 69%). MS m / z (ESI): 569.6 [M+1].

[0812] Step 6

[0813] ((6-(3,4-difluoro-2-((1-(3-formyl-1,5-dimethyl-1H-pyrazol-4-yl)cyclopropyl)methoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 3g

[0814] Compound 3f (200 mg, 351 μmol) was dissolved in dichloromethane (10 mL), and Dys-Martin oxidant (150 mg, 353 μmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give the title compound 3 g (100 mg, yield: 50%). MS m / z (ESI): 567.6 [M+1].

[0815] Step 7

[0816] ((6-(3,4-difluoro-2-((1-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)cyclopropyl)methoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 3h

[0817] 3 g (60 mg, 105 μmol) of the compound was dissolved in tetrahydrofuran (3 mL), cooled in an ice bath, and tert-butylmagnesium bromide (86 mg, 533 μmol, 0.5 M tetrahydrofuran solution) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated ammonium chloride solution (15 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give the title compound 3h (30 mg, yield: 69%).

[0818] MS m / z(ESI): 569.6 [M-55].

[0819] Step 8

[0820] 1-(4-(1-((2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)methyl)cyclopropyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-3

[0821] Compound 3h (30 mg, 48 μmol) was dissolved in methanol (5 mL), and 1 mL of 4 M hydrogen chloride solution of 1,4-dioxane was added. The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (HPLC) (instrument: Waters-2545, column: Sharpsil-T, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound D-3 (12 mg, yield: 47%).

[0822] MS m / z(ESI):525.6[M+1](Exact Mass:524.27.).

[0823] 1 H NMR (500MHz, CDCl3): δ7.76(s,1H),7.71(d,1H),7.43-7.37(m,1H),7.25(d,1H),7.04(dd,1H),4.48(s,1H),4.20(s,2H ),4.02(d,1H),3.73(d,1H),3.69(s,3H),2.49(s,3H),2.07(s,3H),1.00(s,9H),0.97-0.81(m,4H),0.75-0.68(m,1H).

[0824] Examples 2-4, D-4

[0825] 1-(4-(2-(2,3-difluoro-6-(3-(1-(methylamino)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-4

[0826] first step

[0827] (6-Clomidazolo[1,2-b]pyridazin-3-yl)methanol4a

[0828] Compound 1a (1.0 g, 5.50 mmol, Shanghai Haohong Leyan Reagent) was dissolved in methanol (30 mL), and sodium borohydride (210 mg, 5.55 mmol) was added at 0 °C. The reaction mixture was then heated to room temperature for 3 hours. The reaction solution was quenched with 30 mL of water, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 4a (750 mg, yield: 74%). The product was used directly in the next step without purification.

[0829] MS m / z(ESI):184.1[M+1].

[0830] Step 2

[0831] 2-(6-Clomidazolo[1,2-b]pyridazin-3-yl)acetonitrile 4b

[0832] Compound 4a (750 mg, 4.08 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.24 g, 12.26 mmol) was added at 0 °C. Methanesulfonyl chloride (888 mg, 7.75 mmol, 600 μL) was added dropwise, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (20 mL), and sodium cyanide (400 mg, 8.16 mmol) was added. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, 20 mL of water was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give the title compound 4b (310 mg, yield: 39%).

[0833] MS m / z(ESI): 193.2 [M+1].

[0834] Step 3

[0835] 1-(6-chloroimidazolo[1,2-b]pyridazin-3-yl)cyclopropane-1-carboxylonitrile 4c

[0836] Compound 4b (160 mg, 0.83 mmol) was dissolved in dimethyl sulfoxide (10 mL), and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (360 mg, 0.99 mmol, Shaoyuan) was added. After stirring at room temperature for 5 minutes, bicyclo[5.4.0]-1,8-diaza-7-nonene (387 mg, 2.54 mmol, 380 μL, Shaoyuan) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with 10 mL of water, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give the title compound 4c (160 mg, yield: 88%).

[0837] MS m / z(ESI):219.2[M+1].

[0838] Step 4

[0839] 1-(6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropane-1-carboxynitrile 4d

[0840] Compound 4c (150 mg, 0.69 mmol), (3,4-difluoro-2-hydroxyphenyl)boronic acid (130 mg, 0.75 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (44 mg, 0.07 mmol, Adamas) and potassium phosphate (435 mg, 2.05 mmol) were added. The mixture was purged three times with nitrogen, microwaved to 110 °C, and reacted for 1 hour. The reaction solution was cooled to room temperature, quenched with 10 mL of water, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 4d (195 mg, yield: 91%).

[0841] MS m / z(ESI): 313.3 [M+1].

[0842] Step 5

[0843] 1-(6-(2-(2-(1,5-dimethyl-3-neovaleryl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropane-1-carboxylonitrile 4e

[0844] Compound 4d (195 mg, 0.62 mmol), compound 1e (154 mg, 0.69 mmol), and cyanomethylenetri-n-butylphosphine (304 mg, 1.26 mmol, BIDE) were dissolved in toluene (10 mL) and the mixture was heated to 110 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give title compound 4e (310 mg, yield: 96%).

[0845] MS m / z(ESI): 519.5 [M+1].

[0846] Step 6

[0847] 1-(6-(2-(2-(1,5-dimethyl-3-neovaleryl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropane-1-carboxylic acid 4f

[0848] Compound 4e (150 mg, 0.29 mmol) was dissolved in methanol (8 mL) and water (5 mL), and sodium hydroxide (260 mg, 6.50 mmol, Sinopharm) was added. The mixture was heated to 100 °C and reacted for 40 hours. The reaction solution was cooled to room temperature, and methanol was evaporated under reduced pressure. The pH of the reaction solution was adjusted to 4 with 1 M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 4f (150 mg). The product was used directly in the next step without purification.

[0849] MS m / z(ESI): 538.6 [M+1].

[0850] Step 7

[0851] (1-(6-(2-(2-(1,5-dimethyl-3-neovaleryl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropyl)tert-butyl carbamate 4g

[0852] Compound 4f (150 mg, 0.28 mmol) was dissolved in tert-butanol (5 mL), and diphenyl azidophosphate (96 mg, 0.35 mmol, 75 μL, Adamas) and triethylamine (55 mg, 0.54 mmol, 75 μL, Sinopharm) were added. The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using system C as the elution medium to give the title compound 4 g (60 mg, yield: 35%).

[0853] MS m / z(ESI): 609.7 [M+1].

[0854] Step 8

[0855] (1-(6-(2-(2-(1,5-dimethyl-3-neovaler-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropyl)(methyl)tert-butyl carbamate 4h

[0856] 4 g (60 mg, 0.10 mmol) of the compound was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (14 mg, 0.35 mmol, 60%) was added at 0 °C. The reaction was carried out at 0 °C for 30 min, followed by the addition of iodomethane (100 mg, 0.71 mmol, 46 μL, Adamas). The reaction was then allowed to return to room temperature for 2 h. The reaction mixture was quenched with 5 mL of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using system C as the elution medium to give the title compound 4h (23 mg, yield: 38%).

[0857] MS m / z(ESI): 623.6 [M+1].

[0858] Step 9

[0859] (1-(6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropyl)(methyl)tert-butyl carbamate 4i

[0860] Compound 4h (23 mg, 0.04 mmol) was dissolved in methanol (2 mL), and sodium borohydride (7 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was quenched with 5 mL of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 4i (23 mg). The product was used directly in the next step without purification.

[0861] MS m / z(ESI): 625.7 [M+1].

[0862] Step 10

[0863] 1-(4-(2-(2,3-difluoro-6-(3-(1-(methylamino)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-4

[0864] Compound 4i (23 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545; column: ODS-BIO C18, Prep 30×250 mm; 5 μm; mobile phase: water (0.1% ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-75%, flow rate: 30 mL / min) to give the title compound D-4 (8 mg, yield: 41%).

[0865] MS m / z(ESI): 525.6 [M+1].

[0866] 1 H NMR (500MHz, CDCl3): δ7.86(d,1H),7.64(s,1H),7.48-7.43(m,1H),7.40(d,1H),7.08(q,1H),4.28(s,1H),4.09(t,2H),3 .66(s,3H),2.91-2.75(m,2H),2.24(s,3H),2.03(s,1H),2.01(s,3H),1.19-1.07(m,2H),1.05-0.97(m,2H),0.92(s,9H).

[0867] Examples 2-5, D-5

[0868] 1-(4-(2-(2,3-difluoro-6-(3-(1-((methylamino)methyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-5

[0869] first step

[0870] 2,3-Difluoro-6-(3-(1-((methylamino)methyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)phenol 5a

[0871] Compound 4d (90 mg, 0.29 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), and methylamine ethanol solution (1.0 g, 10.63 mmol, 33%) and Raney nickel (40 mg, 0.68 mmol) were added. The mixture was purged three times with hydrogen and heated to 60 °C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 5a (50 mg). The product was used directly in the next step without purification.

[0872] MS m / z(ESI): 331.4 [M+1].

[0873] Step 2

[0874] ((1-(6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropyl)methyl)(methyl)tert-butyl carbamate 5b

[0875] Compound 5a (50 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (44 mg, 0.43 mmol, Sinopharm) and di-tert-butyl dicarbonate (48 mg, 0.22 mmol, Adamas) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using system C as the elution medium to give the title compound 5b (40 mg, yield: 61%).

[0876] MS m / z(ESI):431.5[M+1].

[0877] Step 3

[0878] ((1-(6-(2-(2-(1,5-dimethyl-3-neovaleryl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)cyclopropyl)methyl)(methyl)tert-butyl carbamate 5c

[0879] Compound 5b (40 mg, 0.09 mmol), compound 1e (23 mg, 0.10 mmol), and cyanomethylenetri-n-butylphosphine (46 mg, 0.19 mmol, BIDE) were dissolved in toluene (4 mL) and the mixture was heated to 110 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system C to give title compound 5c (30 mg, yield: 51%).

[0880] MS m / z(ESI): 637.7 [M+1].

[0881] Step 4

[0882] ((1-(6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazine-3-yl)cyclopropyl)methyl)(methyl)tert-butyl carbamate 5d

[0883] Compound 5c (30 mg, 0.05 mmol) was dissolved in methanol (2 mL), and sodium borohydride (8 mg, 0.22 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with 5 mL of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 5d (30 mg). The product was used directly in the next step without purification.

[0884] MS m / z(ESI): 639.7 [M+1].

[0885] Step 5

[0886] 1-(4-(2-(2,3-difluoro-6-(3-(1-((methylamino)methyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylprop-1-ol D-5

[0887] Compound 5d (30 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (instrument: Gilson-GX-281; ​​column: Phlex ODS C18, Prep 30×150 mm; 5 μm; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-65%, flow rate: 30 mL / min) to give the title compound D-5 (6 mg, yield: 24%).

[0888] MS m / z(ESI): 539.7 [M+1].

[0889] 1 H NMR (500MHz, CDCl3): δ7.82(d,1H),7.60(s,1H),7.41-7.36(m,1H),7.33(d,1H),7.05(q,1H),4.08(s,1H),3.98-3.86(m,2H),3.64(s,3H) ),2.98(d,1H),2.85-2.78(m,2H),2.76-2.68(m,1H),2.31(s,3H),2.26-2.17(m,1H),2.06-1.98(m,4H),1.08-0.91(m,4H),0.76(s,9H).

[0890] Examples 2-6, D-6

[0891] 1-(3-(2-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-ol D-6

[0892] first step

[0893] 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-one 6b

[0894] 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid 6a (1.5 g, 9.86 mmol, BIDE) was dissolved in dichloromethane (50 mL). Oxaloyl chloride (2.25 g, 17.72 mmol, 1.52 mL) was added in an ice bath, followed by the slow addition of N,N-dimethylformamide (72 mg, 0.98 mmol). The reaction was stirred for 1 hour, and 0.5 M tert-butylmagnesium bromide (3.18 g, 19.71 mmol, 39.4 mL) was added in an ice bath. The mixture was heated to room temperature and stirred for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 6b (350 mg, yield: 18%). MS m / z(ESI): 193.2 [M+].

[0895] Step 2

[0896] 1-(3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-one 6c

[0897] Compound 6b (350 mg, 1.82 mmol) was dissolved in dichloromethane (30 mL), and N-bromosuccinimide (356 mg, 1.82 mmol) was added under ice-water bath conditions. The mixture was heated to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 6c (350 mg, yield: 71%).

[0898] MS m / z(ESI):271.2[M+1].

[0899] Step 3

[0900] (E)-1-(3-(2-ethoxyvinyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-one 6d

[0901] Compound 6c (350 mg, 1.29 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). Pinaryl (E)-1-ethoxyvinyl-2-boronate (511 mg, 2.58 mmol, Adamas), sodium carbonate (410 mg, 3.86 mmol), and tetraphenylphosphine palladium (149 mg, 128 mmol) were added at room temperature. The mixture was purged three times with nitrogen, heated to 100 °C, and stirred for 16 hours. The reaction mixture was cooled to room temperature, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6d (300 mg, yield: 88%).

[0902] MS m / z(ESI):263.0[M+1].

[0903] Step 4

[0904] 2-(2-neovaleryl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)acetaldehyde 6e

[0905] Compound 6d (300 mg, 1.14 mmol) was dissolved in 3 mL of 4 M hydrogen chloride solution of 1,4-dioxane, and the solution was heated to 60 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 20 mL of saturated sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 6e (400 mg). The product was used directly in the next reaction without purification.

[0906] MS m / z(ESI):235.3[M+1].

[0907] Step 5

[0908] 1-(3-(2-hydroxyethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylacetone 6f

[0909] Compound 6e (400 mg, 1.70 mmol) was dissolved in ethanol (5 mL), and sodium borohydride (129 mg, 3.41 mmol) was added under ice bath conditions. The mixture was stirred for 15 minutes. The reaction solution was poured into 20 mL of saturated ammonium chloride solution and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give the title compound 6f (65 mg, yield: 16%).

[0910] MS m / z(ESI):237.3[M+1].

[0911] Step 6

[0912] ((6-(3,4-difluoro-2-(2-(2-neovaleryl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 6g

[0913] Compound 6f (65 mg, 0.28 mmol), compound 1d (107 mg, 0.28 mmol), and cyanomethylenetri-n-butylphosphine (198 mg, 0.82 mmol, BIDE) were dissolved in toluene (5 mL) and reacted at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 6 g (100 mg, yield: 60%).

[0914] MS m / z(ESI): 609.6 [M+1].

[0915] Step 7

[0916] ((6-(3,4-difluoro-2-(2-(2-(1-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 6h

[0917] 6 g (100 mg, 164.29 μmol) of the compound was dissolved in methanol (5 mL), and sodium borohydride (18 mg, 475.78 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the crude title compound 6h (100 mg). The product was used directly in the next reaction without purification.

[0918] MS m / z(ESI): 611.6 [M+1].

[0919] Step 8

[0920] 1-(3-(2-(2,3-difluoro-6-(3-(((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-ol D-6

[0921] Compound 6h (100 mg, 50 μmol) was dissolved in methanol (5 mL), and 1 mL of 4 M hydrogen chloride solution of 1,4-dioxane was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (HPLC) (instrument model: GLLSON-281; ​​column: Phlex ODS, Prep 30×150 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-95%, flow rate: 30 mL / min) to give the title compound D-6 (40 mg, yield: 48%).

[0922] MS m / z(ESI): 511.6 [M+1].

[0923] 1 H NMR (500MHz, CDCl3): δ7.86(d,1H),7.76(s,1H),7.45-7.40(m,1H),7.34(d,1H),7.10-7.03(m,1H),4.30-4.09(m,5H), 3.94-3.87(m,1H),3.75-3.67(m,1H),2.79-2.73(m,2H),2.68-2.54(m,2H),2.50(s,3H),2.43-2.29(m,4H),0.9(s,9H).

[0924] Examples 2-7, D-7

[0925] 1-(6-(2-(2-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)-N-methylmethylamine D-7

[0926] first step

[0927] ((6-(2-(2-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 7b

[0928] 2-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol-1-ol 7a (100 mg, 0.48 mmol, prepared by the method disclosed in step 7 on pages 71-72 of patent application WO2017001812A1), compound 1d (189 mg, 0.48 mmol), and cyanomethylenetri-n-butylphosphine (307 mg, 1.45 mmol, BIDE) were dissolved in toluene (5 mL). The reaction mixture was heated to 110 °C and reacted for 16 hours. The reaction mixture was cooled to room temperature, poured into 20 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give title compound 7b (160 mg, yield: 57%).

[0929] MS m / z(ESI): 581.5 [M+1].

[0930] Step 2

[0931] 1-(6-(2-(2-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)-N-methylmethylamine D-7

[0932] Compound 7b (100 mg, 0.17 mmol) was dissolved in methanol (5 mL), and a 1,4-dioxane solution of 4 M hydrogen chloride (1 mL) was added. The mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545; column: Sharpsil-T, Prep 30×150 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound D-7 (50 mg, yield: 60%).

[0933] MS m / z(ESI):481.5[M+1].

[0934] 1 H NMR (500MHz, CDCl3): δ7.85(d,1H),7.76(s,1H),7.40(t,1H),7.25(d,1H),7.06(q, 1H),4.19(s,2H),4.13(t,2H),3.72(s,3H),2.88(t,2H),2.48(s,3H),2.05(s,3H).

[0935] Examples 2-8, D-8

[0936] 4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxynitrile D-8

[0937] first step

[0938] ((6-(2-(2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 8b

[0939] Compound 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxynitrile 8a (50 mg, 0.31 mmol, prepared by the method disclosed in step 3 on page 73 of patent application WO2017001812A1), compound 1d (130 mg, 0.33 mmol), and cyanomethylenetri-n-butylphosphine (192 mg, 0.91 mmol, BIDE) were dissolved in toluene (5 mL). The reaction mixture was heated to 110 °C and reacted for 16 hours. The reaction mixture was cooled to room temperature, poured into 20 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to give title compound 8b (30 mg, yield: 18%).

[0940] MS m / z(ESI): 538.5 [M+1].

[0941] Step 2

[0942] 4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxynitrile D-8

[0943] Compound 8b (30 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (HPLC) (instrument: Waters-2545; column: Sharpsil-T, Prep 30×150 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to give the title compound D-8 (9 mg, yield: 36%).

[0944] MS m / z(ESI): 438.5 [M+1].

[0945] 1 H NMR (500MHz, CDCl3): δ7.85(d,1H),7.74(s,1H),7.40(t,1H),7.27(d,1H),7 .06(q,1H),4.24(s,4H),3.71(s,3H),2.88(t,2H),2.51(s,3H),2.05(s,3H).

[0946] Examples 2-9, D-9

[0947] Cyclopropyl(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)methanol D-9

[0948] first step

[0949] 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester 9b

[0950] Ethyl 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid 9a (2.5 g, 11.78 mmol, prepared by the method disclosed in intermediate 6 on page 50 of patent application WO2024052685A1) was dissolved in dichloromethane (30 mL), and imidazole (1.6 g, 23.50 mmol) was added in an ice bath, followed by tert-butyldimethylchlorosilane (2.3 g, 15.26 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 9b (3.0 g, yield: 78%). MS m / z (ESI): 327.3 [M+1].

[0951] Step 2

[0952] 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxaldehyde 9c

[0953] Compound 9b (3.0 g, 9.18 mmol) was dissolved in tetrahydrofuran (50 mL), and 1 M diisobutylaluminum hydride (2.59 g, 18.34 mmol, 18.34 mL) was added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 9c (1.0 g, yield: 38%).

[0954] MS m / z(ESI):283.4[M+1].

[0955] Step 3

[0956] (4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)(cyclopropyl)methanol9d

[0957] Compound 9c (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (30 mL), and 1 M cyclopropylmagnesium bromide (1.54 g, 10.60 mmol, 10.6 mL) was added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the title compound 9d (500 mg, yield: 87%).

[0958] MS m / z(ESI): 325.5 [M+1].

[0959] Step 4

[0960] (4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5-dimethyl-1H-pyrazole-3-yl)(cyclopropyl)methyl ketone 9e

[0961] Compound 9d (700 mg, 2.15 mmol) was dissolved in dichloroethane (50 mL), and manganese dioxide (1.87 g, 21.51 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, and insoluble matter was removed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 9e (500 mg, yield: 71%).

[0962] MS m / z(ESI): 323.4 [M+1].

[0963] Step 5

[0964] Cyclopropyl (4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl) methyl ketone 9f

[0965] Compound 9e (500 mg, 1.55 mmol) was dissolved in tetrahydrofuran (20 mL), and 1 M tetrabutylammonium fluoride (698 mg, 3.10 mmol, 3.1 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 9f (300 mg, yield: 93%).

[0966] MS m / z(ESI):209.3[M+1].

[0967] Step 6

[0968] ((6-(2-(2-(3-(cyclopropanecarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 9g

[0969] Compound 9f (100 mg, 0.48 mmol), compound 1d (187 mg, 0.48 mmol), and cyanomethylenetri-n-butylphosphine (347 mg, 1.44 mmol, BIDE) were dissolved in toluene (5 mL), and the reaction mixture was heated to 110 °C and reacted for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography (HPLC) (instrument model: GLLSON-281; ​​column: Phlex ODS, Prep 30 × 150 mm; 5 μm; C18; mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45%-70%, flow rate: 30 mL / min) to give the title compound 9 g (50 mg, yield: 18%).

[0970] MS m / z(ESI): 581.5 [M+1].

[0971] Step 7

[0972] ((6-(2-(2-(3-(cyclopropyl(hydroxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)(methyl)tert-butyl carbamate 9h

[0973] 9 g (50 mg, 0.086 mmol) of the compound was dissolved in methanol (5 mL), and sodium borohydride (10 mg, 0.26 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 10 mL of saturated ammonium chloride solution and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give the crude title compound 9h (50 mg). The product was directly used in the next reaction without purification.

[0974] MS m / z(ESI): 583.5 [M+1].

[0975] Step 8

[0976] Cyclopropyl(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)methanol D-9

[0977] Compound 9h (30 mg, 0.051 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative high-performance liquid chromatography (HPLC) (instrument model: GLLSON-281; ​​column: Phlex ODS, Prep 30 × 150 mm; 5 μm; C18; mobi...

Claims

1. A ligand-drug conjugate or a pharmaceutically acceptable salt thereof, comprising a ligand and a drug linked to the ligand, wherein the drug comprises a structure as shown in general formula (DH): wherein: X is a bond or -(CR a R b ) n -; Y 1 and Y 2 are the same or different and each independently CR 6 or a nitrogen atom; Z 1 , Z 2 , Z 3 and Z 4 are identical or different and each independently CR 7 or a nitrogen atom; U is selected from -O-, -CR c R d -, -C(O)-, -NR 8 - and -S(O) p -; V is a chemical bond or -(CR e R f ) j -; Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR g R h ) k a cycloalkyl group, -(CR g R h ) k a heterocyclyl group, -(CR g R h ) k an aryl group, and -(CR g R h ) k a heteroaryl group; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is independently optionally substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 9 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 10 , -(CR i R j ) q -COOR 10 , -NR 11 R 12 , -(CR i R j ) q -NR 11 R 12 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 13 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and any one of R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R a and R b any one of R 3 and the carbon and nitrogen atom to which they are attached together form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 4 selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, hydroxy, -OR 15 , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) p R 15 , -C(O)-NR 16a R 16b , -NR 16a R 16b , -C(O)R 15 , -C(O)OR 15 , -(CR m R n ) s -NR 16a R 16b , -(CR m R n ) s -NR 16c -C(O)R 15 , -(CR m R n ) s -NR 16c -S(O) p R 15 , -NR 16c -C(O)R 15 , -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 , -(CR m R n ) s -C(O)-NR 16a R 16b , -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 , -(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b , each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, nitro, amino, carboxyl, oxo, -OR 5 , alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; R 6 selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and a hydroxyalkyl group; R 7 selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxyalkyl; said alkyl is optionally substituted with one or more identical or different substituents selected from halogen, cyano, nitro, hydroxyl, -S(O) p R 29 , -S(O) p -NR 30 R 31 , -NR 30 R 31 , -NR 32 -C(O)R 29 , -NR 32 -S(O) p R 29 , cycloalkyl, heterocyclyl, aryl and heteroaryl; each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; or any two adjacent R 7 with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, nitro, amino, hydroxy, carboxy, alkyl, alkenyl, alkynyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R m , and R n are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each of said cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, and a haloalkoxy group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R i and R j together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 5 , R 8 , R 16c and R 32 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 , R 10 , R 13 , R 14 , R 15 , and R 29 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 11 , R 12 , R 16a , R 16b , R 30 and R 31 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R 11 and R 12 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 30 and R 31 together with the nitrogen atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and t is 0, 1, 2, 3, 4, 5, or 6.

2. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of claim 1, wherein the ligand is an antigen-binding molecule; preferably, the ligand is an antibody.

3. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a ligand-drug conjugate represented by general formula (I) or a pharmaceutically acceptable salt thereof: Ab-(L-D) y (I) wherein Ab is an antigen-binding molecule; preferably, Ab is an antibody; L is a linker connecting Ab and D; D a structure according to general formula (D-H): wherein: X is a bond or -(CR a R b ) n -; Y 1 and Y 2 are the same or different and each independently CR 6 or a nitrogen atom; Z 1 , Z 2 , Z 3 and Z 4 are identical or different and each independently CR 7 or a nitrogen atom; U is selected from -O-, -CR c R d -, -C(O)-, -NR 8 - and -S(O) p -; V is a chemical bond or -(CR e R f ) j -; Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR g R h ) k a cycloalkyl group, -(CR g R h ) k a heterocyclyl group, -(CR g R h ) k an aryl group, and -(CR g R h ) k a heteroaryl group; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is independently optionally substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 9 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 10 , -(CR i R j ) q -COOR 10 , -NR 11 R 12 , -(CR i R j ) q -NR 11 R 12 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 13 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and any one of R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R a and any one of R b and R 3 together with the carbon and nitrogen atoms to which they are attached form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 4 selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, hydroxy, -OR 15 , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) p R 15 , -C(O)-NR 16a R 16b , -NR 16a R 16b , -C(O)R 15 , -C(O)OR 15 , -(CR m R n ) s -NR 16a R 16b , -(CR m R n ) s -NR 16c -C(O)R 15 , -(CR m R n ) s -NR 16c -S(O) p R 15 , -NR 16c -C(O)R 15 , -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 , -(CR m R n ) s -C(O)-NR 16a R 16b , -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 , -(CR m R n ) s -C(O)-N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b , each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, nitro, amino, carboxyl, oxo, -OR 5 , alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; R 6 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and a hydroxyalkyl group; R 7 selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxyalkyl; said alkyl is optionally substituted with one or more identical or different substituents selected from halogen, cyano, nitro, hydroxyl, -S(O) p R 29 , -S(O) p -NR 30 R 31 , -NR 30 R 31 , -NR 32 -C(O)R 29 , -NR 32 -S(O) p R 29 , cycloalkyl, heterocyclyl, aryl and heteroaryl; each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; or any two adjacent R 7 with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, nitro, amino, hydroxy, carboxy, alkyl, alkenyl, alkynyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R m and R n are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; each of said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R i and R j together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 5 , R 8 , R 16c and R 32 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 , R 10 , R 13 , R 14 , R 15 and R 29 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 11 , R 12 , R 16a , R 16b , R 30 and R 31 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R 11 and R 12 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 30 and R 31 together with the nitrogen atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; t is 0, 1, 2, 3, 4, 5, or 6; and y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

4. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Y 1 and Y 2 are the same or different and each independently CR 6 wherein R 6 is as defined in claim 1 ; preferably, Y 1 and Y 2 are both CH.

5. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z 2 , Z 3 , and Z 4 are the same or different and each independently CR 7 or a nitrogen atom, wherein R 7 is as defined in claim 1 ; preferably, Z 2 , Z 3 , and Z 4 are each CR 7 , wherein R 7 is as defined in claim 1.

6. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein U is -O-.

7. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein D is represented by the following formula (D-I-H): wherein R 7a , R 7b and R 7c are as defined for R 7 in claim 1 ; ring A, X, Z 1 , V, R 1 to R 4 and t are as defined in claim 1.

8. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein Ring A is 5- to 10-membered heteroaryl; preferably, Ring A is 5- or 6-membered heteroaryl; more preferably, Ring A is pyrazolyl.

9. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein X is a chemical bond or -(CH2) n -, wherein n is as defined in claim 1 ; preferably, X is a chemical bond.

10. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein V is -(CR e R f ) j - wherein R e , R f and j are as defined in claim 1 ; preferably V is -(CH2) j-1 -CR e R f - wherein R e , R f and j are as defined in claim 1 ; more preferably V is -CH2-CR e R f - wherein R e and R f are as defined in claim 1.

11. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, -OR 14 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -OR 15 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 14 and R 15 are as defined in claim 1 ; preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -OR 14 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 14 is as defined in claim 1 ; more preferably, R 4 is C 1-6 alkyl or C 1-6 hydroxyalkyl.

12. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 7 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group; preferably, R 7 is a hydrogen atom or a halogen; more preferably, R 7 is a hydrogen atom or a fluorine atom.

13. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein D is represented by Formula (D-II-H): wherein R 4a , R 4b and R 4c are as defined in claim 1 for R 4 ; R 7a , R 7b and R 7c are as defined in claim 1 for R 7 ; Z 1 , R 1 to R 3 , R e , R f and n are as defined in claim 1.

14. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 13, wherein Z 1 is CR 7 ; wherein R 7 is as defined in claim 1; preferably, Z 1 is CH.

15. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein D is represented by Formula (D-III-H): wherein R k is C 1-6 1-6 alkyl or 3 to 6 membered cycloalkyl; preferably, R k is C 1-6 1-6 alkyl; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; R 4a and R 4b are as defined in claim 1 4 ; R 7b and R 7c are as defined in claim 1 for R 7 . R 1 to R 3 , R e , R f and n are as defined in claim 1.

16. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 15, wherein -L- is -L 1 -L 2 -L 3 -L 4 -, and L 1 -(CR 1 -C(O)-, -(succinimid-3-yl-N)-W 1 -W 2 -C(O)-, -(succinimid-3-yl-N)-W 1 -, 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -W 1 -, 1 -(CR 20a R 20b -CR 20c R 20d -O) q -W 1 -, 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, -(succinimid-3-yl-N)-W 1 -(CR 20a R 20b -CR 20c R 20d -O) q -C(O)-, -(succinimid-3-yl-N)-W 1 -NR 17 -C(O)-, -C(O)-NR 17 -W 1 -C(O)-, -W 1 -C(O)-NR 17 -W 1 -C(O)-, -C(O)-W 1 -C(O)-, wherein q is an integer from 0 to 20; L 2 -NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -NR 18 -C(O)-、-NR 18 -(CR 21a R 21b -CR 21c R 21d -O) v -W 1 -C(O)-NR 18 -、-W 1 -C(O)-、-NR 18 -W 1 -C(O)-NR 18 -、-S-(CR 21e R 21f ) p1 -C(O)-、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -O-W 1 -C(O)-NR 18 -、-NR 18 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-、-NR 18 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -O-W 1 -NR 18 -C(O)-, -NR 18 -W 1 -W 2 -W 1 -(O-CR 21a R 21b -CR 21c R 21d ) v -NR 18 -C(O)-W 1 -O-W 1 -C(O)-, -NR 18 -W 1 -W 2 -W 1 -(CR 21a R 21b -O-CR 21c R 21d ) v -W 1 -W 2 -W 1 -C(O)- and a bond, wherein v is an integer from 0 to 20, pi is an integer from 0 to 20; L 3 a peptide residue consisting of 1 to 12 amino acid residues, wherein the amino acid residues are selected from the group consisting of amino acid residues formed from phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid and asparagine, and are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR 22a R 22b ) p2 - cycloalkyl, -(CR 22a R 22b ) p2 - heterocyclyl, -(CR 22a R 22b ) p2 - aryl, -(CR 22a R 22b ) p2 - heteroaryl, -(CR 22a R 22b ) p2 - SR 25 , -(CR 22a R 22b ) p2 - COOR 25 , -(CR 22a R 22b ) p2 - NR 23 R 24 , -(CR 22a R 22b ) p2 - C(O)-NR 23 R 24 , -(CR 22a R 22b ) p2 - NR 25 - C(=NR 25 )-NR 23 R 24 , and -(CR 22a R 22b ) p2 - NR 25 - C(O)-NR 23 R 24 ; wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halo, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; wherein p2 is an integer from 0 to 20, *1 is attached to the left end of L 2 , and *2 is attached to the right end of L 4 ; L 4 -NR 19 -W 1 -, -C(O)NR 19 -, -NR 19 C(O)-, -NR 19 -W 1 -C(O)-, -C(O)-NR 19 -W 1 -, -NR 19 -W 2 -W 1 -, -NR 19 -W 2 -W 1 -O-C(O)- and a chemical bond; W 2 The group is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from oxo groups, halogens, sugars (e.g., sugars). substituted with one or more identical or different substituents selected from the group consisting of phenyl, nitrile, nitro, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; W 1 , W 3 , and W 5 are the same or different and each independently is -(CR 26a R 26b ) p3 - wherein p3 is an integer from 1 to 20; W 4 -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group; R 17 , R 18 , R 19 and R 25 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; R 23 and R 24 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted with one or more same or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R 23 and R 24 together with the carbon atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 20a , R 20b , R 20c , R 20d , R 21a , R 21b , R 21c , R 21d , R 21e , R 21f , R 22a , R 22b , R 26a and R 26b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group being optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R 20a and R 20b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 20c and R 20d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21a and R 21b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21c and R 21d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 21e and R 21f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 22a and R 22b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R 26a and R 26b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; Preferably, -L- is -L 1 -L 2 -L 3 -L 4 - and L 1 -(succinimid-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, wherein R 20a , R 20b , R 20c and R 20d are each a hydrogen atom; q is 0, 1, 2, 3, 4, 5 or 6; L 2 is a chemical bond; L 3 selected from a monopeptide residue, a dipeptide residue, a tetrapeptide residue, wherein the amino acid residue is selected from the group consisting of an amino acid residue formed from phenylalanine, alanine, glycine, cysteine, valine, lysine, citrulline, serine, glutamine, glutamic acid, aspartic acid, and asparagine; L 4 is a chemical bond or -NR 19 -W 2 -W 1 -O-C(O)-; R 19 is a hydrogen atom; W 1 , W 3 , and W 5 are the same or different and each independently -(CR 26a R 26b ) p3 , R 26a , and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group, and p3 is 1, 2, 3, 4, 5, or 6; W 2 is phenyl; W 4 -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 are each a hydrogen atom; *1 with L 2 connected to the end, *2 with L 4 connected to the end; wherein L of said -L- is 1 attached to Ab, L 4 attached to D; More preferably, -L- is -L 1 -L 2 -L 3 -L 4 - and L 1 -(succinimid-3-yl-N)-W 1 -(O-CR 20a R 20b -CR 20c R 20d -) q -C(O)-, wherein R 20a , R 20b , R 20c and R 20d are each a hydrogen atom; q is 1, 2, 3, 4, 5 or 6; L 2 is a chemical bond; L 3 for L 4 is a chemical bond; W 1 , W 3 , and W 5 are the same or different and each independently -(CR 26a R 26b ) p3 , R 26a , and R 26b are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group, and p3 is 1, 2, 3, 4, 5, or 6; W 4 -NR 28 C(O)- or -C(O)NR 28 -; R 27 and R 28 are each a hydrogen atom; *1 with L 2 connected to the end, *2 with L 4 connected to the end; wherein L of said -L- is 1 attached to Ab, L 4 attached to D.

17. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is a ligand-drug conjugate represented by the general formula (IN) or a pharmaceutically acceptable salt thereof: wherein R k is C 1-6 alkyl or 3- to 6-membered cycloalkyl; preferably, R k is C 1-6 alkyl; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; R 4a and R 4b are as defined in claim 1 for R 4 ​ R 7b and R 7c are as defined in claim 1 for R 7 . R 1 to R 3 , R e , R f , n and y are as defined in claim 1 ; Ab is as defined in claim 3; L 2 to L 4 , W 1 and q are as defined in claim 16.

18. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with one or more same or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; preferably, R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and 3- to 6-membered cycloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; more preferably, R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, and 3- to 6-membered cycloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl.

19. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 3 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with 3- to 6-membered cycloalkyl; preferably, R 3 is a hydrogen atom or C 1-6 alkyl; more preferably, R 3 is C 1-6 alkyl.

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R e and R f are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, and a C 1-6 hydroxyalkyl group; or R e and R f together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group; said 3- to 6-membered cycloalkyl group or 3- to 6-membered heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, a halogen, a cyano group, an amino group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; preferably, R e and R f are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; or R e and R f together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group.

21. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 20, wherein R 4a and R 4b are the same or different and each independently a hydrogen atom or a C 1-6 alkyl group; preferably, R 4a and R 4b are the same or different and each independently a C 1-6 alkyl group.

22. The ligand-drug conjugate or pharmaceutically acceptable salt thereof of any one of claims 1 to 21, selected from the following structures: wherein Ab is an antibody as defined in claim 3; y is 1 to 10; preferably, y is 1 to 8; more preferably, y is 3 to 8.

23. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 22, wherein Ab is selected from the group consisting of an anti-HER2 antibody, an anti-B7H3 antibody, an anti-TROP2 antibody, and an anti-CD20 antibody.

24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 23, wherein Ab is selected from the group consisting of trastuzumab, ifinatamab, sacituzumab, and rituximab.

25. A compound of Formula (D) or a pharmaceutically acceptable salt thereof: ###00019### (D) wherein: X is a bond or -(CR a R b ) n -; Y 1 and Y 2 are the same or different and each independently CR 6 or a nitrogen atom; Z 1 , Z 2 , Z 3 and Z 4 are identical or different and each independently CR 7 or a nitrogen atom; U is selected from -O-, -CR c R d -, -C(O)-, -NR 8 - and -S(O) p -; V is a chemical bond or -(CR e R f ) j -; Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 and R 2 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CR g R h ) k a cycloalkyl group, -(CR g R h ) k a heterocyclyl group, -(CR g R h ) k an aryl group, and -(CR g R h ) k a heteroaryl group; each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is independently optionally substituted with one or more substituents, which are the same or different, selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 9 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, -COOR 10 , -(CR i R j ) q -COOR 10 , -NR 11 R 12 , -(CR i R j ) q -NR 11 R 12 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each of said alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of a halogen, a cyano group, a nitro group, -OR 13 , an oxo group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; or R 1 and any one of R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; or R a and R b any one of R 3 and the carbon and nitrogen atom to which they are attached form a heterocyclyl group; said heterocyclyl group is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 4 selected from hydrogen atom, halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, -OR 14 , cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, -OR 15 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) p R 15 , -C(O)-NR 16a R 16b , -NR 16a R 16b , -C(O)R 15 , -C(O)OR 15 , -(CR m R n ) s -NR 16a R 16b , -(CR m R n ) s -NR 16c -C(O)R 15 , -(CR m R n ) s -NR 16c -S(O) p R 15 , -NR 16c -C(O)R 15 , -NR 16c -S(O) p R 15 , cyano, -(CR m R n ) s -S(O) p R 15 , -(CR m R n ) s -C(O)-NR 16a R 16b , -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m , -(CR m R n ) s -C(O)-NR 16c -(CR m R n ) s -OR 15 , -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 , -(CR m R n ) s -C(O)N((CR m R n ) s -O-(CR m R n ) s ) m -OR 15 and -S(O) p NR 16a R 16b , each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, cyano, nitro, amino, carboxyl, oxo, -OR 5 , alkenyl, alkynyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy; R 6 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and a hydroxyalkyl group; R 7 selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxyalkyl; said alkyl is optionally substituted with one or more identical or different substituents selected from halogen, cyano, nitro, hydroxyl, -S(O) p R 29 , -S(O) p -NR 30 R 31 , -NR 30 R 31 , -NR 32 -C(O)R 29 , -NR 32 -S(O) p R 29 , cycloalkyl, heterocyclyl, aryl and heteroaryl; each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more identical or different substituents selected from oxo, halogen, cyano, amino, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; or any two adjacent R 7 with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, nitro, amino, hydroxy, carboxy, alkyl, alkenyl, alkynyl, alkoxy-alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R m and R n are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; each of said cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxyl, carboxyl, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group; or R a and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R c and R d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R e and R f together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R g and R h together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R i and R j together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, or R m and R n together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, said cycloalkyl or heterocyclyl group being optionally substituted with one or more identical or different substituents selected from oxo, halo, cyano, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy and haloalkoxy; R 5 , R 8 , R 16c and R 32 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 , R 10 , R 13 , R 14 , R 15 and R 29 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 11 , R 12 , R 16a , R 16b , R 30 and R 31 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; or R 11 and R 12 together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 16a and R 16b together with the nitrogen atom to which they are attached form a heterocyclyl group, or R 30 and R 31 together with the nitrogen atom to which they are attached form a heterocyclyl group, which is optionally substituted with one or more identical or different substituents selected from the group consisting of oxo, halogen, cyano, amino, hydroxy, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a haloalkoxy group; j is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and t is 0, 1, 2, 3, 4, 5, or 6.

26. The compound according to claim 25 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 are the same or different and each independently CR 6 wherein R 6 is as defined in claim 25; preferably, Y 1 and Y 2 are both CH.

27. The compound according to claim 25 or 26, represented by the general formula (D) or a pharmaceutically acceptable salt thereof, wherein Z 2 , Z 3 and Z 4 are the same or different and each independently CR 7 or a nitrogen atom, wherein R 7 is as defined in claim 25; preferably, Z 2 , Z 3 and Z 4 are each CR 7 wherein R 7 is as defined in claim 25.

28. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 27, wherein U is -O-.

29. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 28, wherein D is according to Formula (D-I): ###00016### (D-I) ​ wherein R 7a , R 7b and R 7c are as defined for R 7 in claim 25; ring A, X, Z 1 , V, R 1 to R 4 and t are as defined in claim 25.

30. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 29, wherein Ring A is 5- to 10-membered heteroaryl; preferably, Ring A is 5- or 6-membered heteroaryl; more preferably, Ring A is pyrazolyl.

31. The compound according to any one of claims 25 to 30 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein X is a chemical bond or -(CH2) n -, wherein n is as defined in claim 25; preferably, X is a chemical bond.

32. The compound according to any one of claims 25 to 31 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein V is -(CR e R f ) j - wherein R e , R f and j are as defined in claim 25; preferably V is -(CH2) j-1 -CR e R f - wherein R e , R f and j are as defined in claim 25; more preferably V is -CH2-CR e R f - wherein R e and R f are as defined in claim 25.

33. The compound according to any one of claims 25 to 32 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, -OR 14 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -OR 15 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 14 and R 15 are as defined in claim 1 ; preferably, R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -OR 14 , 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein the C 1-6 alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with one or more identical or different substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, C 1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 14 is as defined in claim 25; more preferably, R 4 is C 1-6 alkyl or C 1-6 hydroxyalkyl.

34. The compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 33, wherein R 7 is selected from a hydrogen atom, a halogen, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group; preferably, R 7 is a hydrogen atom or a halogen; more preferably, R 7 is a hydrogen atom or a fluorine atom.

35. The compound of any one of claims 25 to 34, or a pharmaceutically acceptable salt thereof, wherein D is according to Formula (D-II): ###0009### (D-II) 35 wherein R 4a , R 4b and R 4c are as defined for R 4 in claim 25; R 7a , R 7b , and R 7c are as defined in claim 25 for R 7 . Z 1 , R 1 to R 3 , R e , R f and n are as defined in claim 25.

36. The compound according to any one of claims 25 to 35 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein Z 1 is CR 7 ; and R 7 is as defined in claim 25; preferably, Z 1 is CH.

37. The compound of any one of claims 25 to 36, or a pharmaceutically acceptable salt thereof, wherein D is according to Formula (D-III): ###0010### (D-III) ​ wherein R k is C 1-6 1-6 alkyl or 3 to 6 membered cycloalkyl; preferably, R k is C 1-6 1-6 alkyl; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; R 4a and R 4b R in claim 25 4 Defined; R 7b and R 7c are as defined in claim 25 7 ; R 1 to R 3 , R e , R f and n are as defined in claim 25.

38. The compound of general formula (D) according to any one of claims 25 to 37, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 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 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups; said 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic groups are optionally selected from oxo, halogen, cyano, amino, hydroxyl, 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, R 1 and R 2 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 Haloalkyl, C 1-6 Hydroxyalkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3- to 6-membered cycloalkyl groups; more preferably, R 1 and R 2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and 3- to 6-membered cycloalkyl; or R 1 and R 2 Together with the carbon atoms attached to them, they form 3 to 6-membered cycloalkyl groups.

39. The compound according to any one of claims 25 to 38 of general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl, wherein said C 1-6 alkyl is optionally substituted with 3- to 6-membered cycloalkyl; preferably, R 3 is a hydrogen atom or C 1-6 alkyl; more preferably, R 3 is C 1-6 alkyl.

40. The compound according to any one of claims 25 to 39, represented by the general formula (D) or a pharmaceutically acceptable salt thereof, wherein R e and R f are the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, and a C 1-6 hydroxyalkyl group; or R e and R f together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group; said 3- to 6-membered cycloalkyl group or 3- to 6-membered heterocyclyl group is optionally substituted with one or more same or different substituents selected from the group consisting of an oxo group, a halogen, a cyano group, an amino group, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 hydroxyalkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; preferably, R e and R f are the same or different, and each independently a hydrogen atom or a C 1-6 alkyl group; or R e and R f together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group.

41. The compound according to any one of claims 33 to 40 represented by the general formula (D) or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b are identical or different and each independently a hydrogen atom or a C 1-6 alkyl group; preferably, R 4a and R 4b are identical or different and each independently a C 1-6 alkyl group.

42. The compound of any one of claims 25 to 41, or a pharmaceutically acceptable salt thereof, of Formula (D) selected from the following structures:

43. A compound of the formula (LN-D-III) or a salt thereof: ###00019### (LN-D-III) wherein R k is C 1-6 alkyl or 3- to 6-membered cycloalkyl; preferably, R k is C 1-6 alkyl; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; R 4a and R 4b are as defined in claim 1 for R 4 ​ R 7b and R 7c are as defined in claim 1 7 R R 1 to R 3 , R e , R f and n are as defined in claim 1 ; L 2 to L 4 , W 1 and q are as defined in claim 16.

44. The compound of Formula (LN-D-III) or a salt thereof according to claim 43, selected from the following structures:

45. A method of preparing the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, comprising the step of linking a compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 42 to a ligand; preferably, comprising the step of linking a compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 42 to a ligand via a linker; wherein the ligand is an antigen binding molecule; preferably, the ligand is an antibody.

46. A method of making a ligand-drug conjugate of the formula (IN) or a pharmaceutically acceptable salt thereof, comprising the steps of: Ab is reduced, and a coupling reaction occurs with a compound of Formula (LN-D-III) or a salt thereof to obtain a ligand-drug conjugate of Formula (IN) or a pharmaceutically acceptable salt thereof; wherein R k is C 1-6 alkyl or 3- to 6-membered cycloalkyl; preferably, R k is C 1-6 alkyl; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; * represents a chiral carbon atom, in R configuration or in S configuration or a mixture of both; R 4a and R 4b are as defined in claim 1 for R 4 . R 7b and R 7c are as defined in claim 1 for R 7 ; R 1 to R 3 , R e , R f , n and y are as defined in claim 1 ; Ab is as defined in claim 3; L 2 to L 4 , W 1 and q are as defined in claim 16.

47. A pharmaceutical composition comprising the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, the compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 42, the compound of Formula (LN-D-III) or a salt thereof according to claim 43 or 44, and one or more pharmaceutically acceptable carriers, diluents or excipients.

48. A method of preventing or treating a disease, the method comprising administering to a subject the ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, the compound of Formula (D) or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 42, the compound of Formula (LN-D-III) or a salt thereof according to claim 43 or 44, or the pharmaceutical composition according to claim 47; preferably, the disease is a tumor; more preferably, the disease is selected from the group consisting of gallbladder cancer, brain tumor, lymphoma, leukemia, blastoma, myeloma, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer, liver cancer, urothelial cancer, ovarian cancer, pancreatic cancer, bladder cancer, stomach cancer, cervical cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, endometrial cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, and penile cancer.

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