Benzazepine derivatives, complexes containing the same and applications thereof

Abstract

The present invention discloses a benzazepine derivative, a conjugate containing the same, and applications thereof. The present invention provides an antibody-immunostimulatory conjugate represented by Formula I or a pharmaceutically acceptable salt thereof. The benzazepine derivative has a good regulatory effect on TLR8 and can effectively treat, alleviate, and / or prevent various related diseases caused by immunosuppression, such as cancer. [Formula 1] JPEG2025537044000630.jpg13169

Description

Detailed Description of the Invention

[0001] [Technical Field] This application claims priority to Chinese Patent Application No. 2022112114506 filed on September 30, 2022, Chinese Patent Application No. 2022114492843 filed on November 18, 2022, and Chinese Patent Application No. 2023112215516 filed on September 20, 2023. This application incorporates the entire text of the above Chinese patent applications by reference.

[0002] The present invention relates to a benzazepine derivative, a complex containing the same, and applications thereof.

[0003] [Background technology] The Toll-like receptor family (TLR) is an important family of proteins that recognize pathogen-associated molecular patterns, sense and initiate innate immune responses, and promote the development of adaptive immune responses. TLRs are primarily expressed on immune cells (e.g., myeloid dendritic cells (mDCs), plasmacytoid dendritic cells (pDCs), monocytes, and B cells (Kawai and Akira, 2010), as well as in the lungs). In humans, more than 10 TLRs are thought to have important functions. TLRs 1, 2, 4, 5, and 6 are located on the cell membrane and their primary function is to recognize extracellular macromolecular ligands from bacteria and fungi. Conversely, TLRs 3, 7, 8, and 9 are located on the intracellular endosomal membrane and their primary function is to recognize exogenous nucleic acids from pathogenic cells. Although most TLRs act through specific signaling pathways (mainly MyD88-dependent pathways), different TLRs can regulate different downstream molecules. The addition of specific TLRs leads to the activation of distinct cell populations (Schreibelt et al., 2010) and distinct patterns of cytokine and other inflammatory mediator production (Ghosh et al., 2006), thereby triggering distinct immune responses. For example, after ligand binding, TLR8 dimerizes and undergoes a conformational change that leads to the engagement of the adaptor protein MyD88, which recruits interleukin-1 receptor-associated kinase and activates downstream signaling pathways, including mitogen-related protein kinase and the transcription factor NF-kB.

[0004] Endosomal TLRs, primarily TLR7 / 8 / 9, are considered attractive new targets for anti-cancer immunotherapy (Kanzler et al., 2007; Kreig 2008; Smits et al., 2008; Hennessy et al., 2010; Kaczanowska et al., 2013; Beesu et al., 2016). For example, TLR7 activates pDCs to respond to viral infection, inducing high levels of interferon-α and inducing adaptive T cell responses against endogenous viral antigens (Liu et al., 2009). Compared with TLR7 / 9, TLR8 is more widely expressed on different subtypes of immune cells. Regulatory T cells (Tregs) have potent immune response suppression capabilities, presenting a major obstacle to effective cancer immunotherapy. The TLR8 signaling pathway has been shown to be necessary and sufficient to reverse the suppressive function of Treg cells, resulting in potent tumor suppression. TLR8-selective agonists can effectively activate various immune cells, including mDCs and monocytes (Gorden et al., 2005), promoting the generation of adaptive immune responses against cancer cells (Krug et al., 2003; Schnurr et al., 2005). Activated mDCs phagocytose apoptotic and dead tumor cells and cross-present tumor-associated antigens to CD8+ CTLs more efficiently than pDCs (Berard et al., 2000; Dalgaard et al., 2005). Furthermore, mDC activation triggers the release of tumor necrosis factor (TNFα) and interleukin-12 (IL-12), which can stimulate the activation of T cells and NK cells. NK cell activation is the primary mechanism of antibody-mediated cytotoxicity (ADCC). Therefore, enhanced ADCC killing of tumor cells may provide an important therapeutic opportunity for TLR8-selective inhibitors (Lu et al., 2011). Several monoclonal antibody therapies, such as rituximab and trastuzumab, are widely used to treat cancer patients and can play a therapeutic role through ADCC (Ferris, et al., 2010). Indeed, the addition of a TLR8 agonist to mAb therapy enhances ADCC, thereby increasing the efficacy of mAb treatment (Ferris, et al., 2015).Recent studies have also shown that TLR8 agonists can exert direct antitumor effects independent of their immunomodulatory function (Ignatz-Hoover, et al., 2015). Therefore, TLR8 agonists can not only function as monotherapies but also improve the efficacy of various chemotherapeutics and targeted anticancer drugs by enhancing the host immune response.

[0005] Among the members of the TLR family that recognize nucleic acids from pathogenic microorganisms, TLR7 and TLR8 share high homology and can recognize several synthetic small molecules with antiviral effects, such as imidazoquinolines (TLR7 and TLR8 ligands). Imidazoquinolines have been studied in a guinea pig genital herpes model infected with HSV. These compounds have been found to have a minimal effect on viral replication in vitro but a strong effect in vivo, indicating that these compounds promote the production of proinflammatory and regulatory cytokines by immune cells, triggering an antiviral response (Int Immunopharmacol 2002;2:443-451). More importantly, TLR7 and TLR8 can recognize viral ssRNA. Studies have demonstrated that ssRNA viruses, such as human immunodeficiency virus type 1 (HIV), influenza virus, Sendai virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), hepatitis B virus (HBV), and hepatitis C virus (HCV), are natural ligands for TLR7 and TLR8. TLR8 can recognize antiviral compounds, ssRNA viruses, and synthetic oligonucleotides, and induces Th1 responses through the MyD88-dependent signaling pathway, suppresses Th2 cytokine secretion, and suppresses Treg proliferation, mediating antiviral immunity and exerting anti-infective and anti-allergic effects.

[0006] Therefore, TLR8 is currently an attractive therapeutic target. Although much research has been conducted on TLRs, there is still a great opportunity to further expand their uses and benefits. The compounds and applications described in this invention will contribute to the development of TLR8 agonists and fulfill unmet clinical needs.

[0007] Summary of the Invention The technical problem that the present invention aims to solve is that conventional TLR8 agonists have a single structure, therefore the present invention provides benzazepine derivatives, conjugates containing the same, and applications thereof, which have good regulatory effects on TLR8 and can effectively treat, alleviate, and / or prevent various related diseases caused by immunosuppression, such as cancer.

[0008] The present invention provides an antibody-immunostimulatory complex according to formula I, or a pharmaceutically acceptable salt thereof:

[0009] [ka]

[0010] wherein Ab is an antibody; t is any value between 1 and 8, D is a benzazepine group as shown below:

[0011] [ka]

[0012] m is 0 or 1, R is -C(O)-NR9-L1-R7, -C(S)-NR9-L1-R7, or -NR9-C(O)-L1-R7; R1, R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkyl halide, -L2-OR a or -L2-NR a R b and R4 and R 4’ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, and R or R 4’ is unsubstituted or optionally halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b or R and R 4’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, and the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with halogen, cyano, -L2-OR a , -L2-OC(O)R a , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b and further substituted at any position with 1 to 3 substituents selected from R5 is hydrogen, -OR a, -C(O)R a , -C(O)OR a or -C(O)NR a R b and R 5’ Ga-R c and R7 is phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, or an 8- to 12-membered fused ring group, and said R7 is unsubstituted or optionally -L3-W, -R c substituted at any position by one or more substituents selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R8 and R 8’ are each independently hydrogen, halogen or alkyl, and said R or R 8’ is unsubstituted or optionally substituted at any position by one or more substituents selected from -L3-W, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide, and alkylamino; R8 and R 8’ are each an independent substituent, or R and R 8’ Both of them are connected to carbon atoms, and oxo, thio, C 1~6 Alkylidene, C 3~10 cycloalkyl or 3- to 10-membered heterocycloalkyl, 1~6 Alkylidene, C 3~10 The cycloalkyl or 3- to 10-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkyl halide, -L2-OR a and -L2-NR a R b and substituted at any position by one or more substituents selected from R9 is hydrogen, alkyl, halogenated alkyl, -L2-OR a or -L2-NR a R b and W is Cy 1 , -SR d , -OR d , -OC(O)R e , -OC(O)NR e R e’ , -C(O)OR e , -C(O)R e , -C(O)NR e R e’ , -C(O)NR e S(O)2R e , -NR d R e , -NR d C(O)R e , -N(R d )C(O)OR e , -N(R d )C(O)NR e R e’ , -NR d S(O)2R e , -NR d S(O)NR e R e’ , -S(O) 1-2 R e , -S(O)NR e R e’ , -S(O)(=NR d )R e , -S(O)2N(R e )C(O)R e’ , -P(O)(OR e )2, -P(O)(OR e )R e’ , -OP(O)(OR e )2 or -B(OR e )2, Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and said Cy 1 is unsubstituted or optionally substituted with halogen, alkyl, halogenated alkyl, halogenated alkoxyl, alkenyl, alkynyl, cyano, -R c , -L4-SR d , -L4-OC(O)R e , -L4-C(O)OR e , -L4-C(O)R e, -L4-C(O)NR e R e’ , -L4-NR d C(O)R e , -L4-NR d S(O)2R e , -L4-S(O) 1-2 R e , -L4-S(O)2NR e R e’ , -L4-OR d and -L4-NR e R e’ and substituted at any position by one or more substituents selected from Each R a , R b , R d , R e and R e’ are each independently -R c , Amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl C 1~6 Alkyl, 3-10 membered heterocycloalkylC 1~6 Alkyl, Phenyl C 1~6 Alkyl or 5-10 membered heteroarylC 1~6 alkyl, and the R a , R b , R d , R e or R e’ is unsubstituted or optionally -L4-OR f , -OC(O)-L4-R f , -L4-NR f R f’ , halogen, cyano, nitro, C 1~6 Alkyl, halogenated C 1~6 Alkyl and halogenated C 1~6 substituted at any position by 1 to 3 substituents selected from alkoxyl; L1, L2, L3 and L4 are each independently a bond, C 1~6Alkylidene, C 2~6 Alkenylene, C 2~6 alkynylene or a polyethylene glycol fragment containing 1 to 20 -OCH2CH2- units, wherein said L1, L2, L3 or L4 is unsubstituted or optionally substituted at any position with one or more substituents selected from oxo, hydroxyl, amino, halogen, cyano, alkyl, halogenated alkyl, alkoxyl and halogenated alkoxyl; Each R f and R f are each independently -R c , -NHR c or C 1~6 is alkyl, R g is a phosphoryl-containing prodrug group; Each R c are each independently hydrogen or a bond connected to L, and at least one R in D c is a bond connected to L, Also, as shown in Formula D, the benzazepine group satisfies one or two of the following conditions: (1) m is 1, (2) R4 and R 4’ At least one of the following is halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-C(O)OR b -L2-NR a C(O)NR a R b and -L2-NR b C(NR b )NR a R b and substituted at any position by one or more substituents selected from L is -M-(T) w -PEG-(T) o - * , -M-PEG- * , -M-(T) w - * , -M-(T) w -(A) v -(T) o -PEG- * , -M-(T) w -(A) v -(T) o - * , -M-(T) w -L5- * , -M-(T) w -PEG-L5- * , -M-(T) w -PEG-(A) v -L5- * , -M-(T) w -PEG-(A) v -(T) o - * ,-M-PEG-(T) o -PEG- * or -M-(T) w -(A) v -L5- * wherein v is an arbitrary integer of 1 to 5, w is an arbitrary integer of 1 to 10, o is an arbitrary integer of 0 to 10, and * is a linking site between L and D; Each T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -Arylene-(CH2) y -, -(CH2) x -Heteroarylene-(CH2) y -, -(CH2) x -Cycloalkylene-(CH2) y -, -(CH2) x -Heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) xCH(NHR h )-C(O)-, -(CH2) x -SS-alkylidene-, alkylidene, or alkenylene, and x and y are each independently any integer of 0 to 10; R h is hydrogen, alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is any integer from 1 to 50, and u is any integer from 0 to 5; Each A is independently an amino acid residue, or -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n is an amino acid residue modified by -CH3, L5 is the self-sacrificing group, M is a bond or connector that is attached to the antibody.

[0013] In some embodiments, in the antibody-immunostimulatory complex of Formula I, or a pharmaceutically acceptable salt thereof, some groups are defined as follows, and the remaining groups are defined as described in any other embodiment (hereinafter referred to as "some embodiments"):

[0014] [ka]

[0015] wherein Ab is an antibody; t is any value between 1 and 8, L is a linker that connects said Ab and said D; D is a group in which one hydrogen atom has been removed from the compound represented by formula D',

[0016] [ka]

[0017] wherein R is -L'-L1-R7, L' is -C(=O)-, -C(=O)-NR9- or -C(=S)-NR9-; R9 is independently hydrogen, C 1~6 Alkyl or halogenated C 1~6 is alkyl, L1 is independently a bond, C 1~6 Alkylidene or C 2~6 is alkenylene, R7 is independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, or one, two, or three R 7-1 phenyl substituted with one, two or three R 7-2 5-6 membered heteroaryl substituted with one, two or three R 7-3 or one, two, or three R 7-4 is an 8- to 12-membered fused ring group substituted with In R7, the 5- to 6-membered heteroaryl and the one, two, or three R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; and the 3- to 8-membered heterocycloalkyl and the 1, 2, or 3 R 7-3 In the "3- to 8-membered heterocycloalkyl" in the 3- to 8-membered heterocycloalkyl substituted by, the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; In R7, the 8- to 12-membered fused ring group and the one, two, or three R 7-4the 8- to 12-membered fused ring groups among the 8- to 12-membered fused ring groups substituted with are independently ring A and fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R 7-1 , R 7-2 , R 7-3 and R 7-4 are independently amino, -L3-NH2, -L3-OH, -C(=O)-L3-OH or -C(=O)-L3-NH2, and L3 is independently C 1~6 Alkylidene or -(CH2CH2O) m’ -C 1~6 alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1, R8 and R 8’ are independently hydrogen or C 1~6 alkyl, or R and R 8’ carbonyl, C, along with both of their connecting carbon atoms 3~10 forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R1, R2, and R3 are independently hydrogen, deuterium, or halogen; R4 and R 4’ independently C 1~6 Alkyl, C 1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R 4-1 are independently hydroxyl, amino, -OC(=O)NR a R b or

[0018] [ka]

[0019] and R a and R b are independently hydrogen, C 1~6 Alkyl or C 3~10 is cycloalkyl, R i is hydrogen, C 1~6 alkyl or benzyl, and R k is hydrogen, halogen or C 1~6 alkyl, and R i C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~6 Alkyl, 3-10 membered heterocycloalkyl-C 1~6 Alkyl, C 6~10 Aryl-C 1~6 Alkyl or 5-10 membered heteroaryl-C 1~6 is alkyl, R j In the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C 1~6 In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C 1~6 In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R4 and R 4’ At least one of the 1~6 Alkoxyl, or one, two or three R 4-1 C replaced by 1~6 is alkyl, Also, the antibody-immunostimulating complex shown in Formula I is not the antibody-immunostimulating complex shown in Table 1, where the mAb is trastuzumab.

[0020] [Table 1] TIFF2025537044000008.tif232169 TIFF2025537044000009.tif234169

[0021] In some embodiments, the antibody-immunostimulatory complex shown in Formula I is not an antibody-immunostimulatory complex shown in Table 2, where mAb is a monoclonal antibody and t is any value between 1 and 8.

[0022] [Table 2] TIFF2025537044000011.tif255169 TIFF2025537044000012.tif194169

[0023] In some embodiments, the compound shown in Formula D' is not a compound shown in Table 3.

[0024] [Table 3] TIFF2025537044000014.tif55169

[0025] In some embodiments, the compound of Formula D' satisfies one, two, or three of the following conditions: (1) L1 is independent and C1~6 Alkylidene or C 2~6 is alkenylene, (2) R7 is independently phenyl substituted with one amino group, 5- to 6-membered heteroaryl substituted with one amino group, 3- to 8-membered heterocycloalkyl substituted with one amino group, or 8- to 12-membered fused ring group substituted with one amino group; (3) R4 and R 4’ At least one of the 1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R 4-1 are independently -OC(=O)NR a R b or

[0026] [ka]

[0027] is.

[0028] In some embodiments, the linker is not one of the structures shown in Table 4.

[0029] [Table 4]

[0030] In some embodiments, L is -M-(T) w -PEG-(T) o - * , -M-PEG- * , -M-(T) w -(A) v -(T) o -PEG- * , -M-(T) w -(A) v -(T) o - * , -M-(T) w -L5- * , -M-(T) w -PEG-L5-* , -M-(T) w -PEG-(A) v -L5- * , -M-(T) w -PEG-(A) v -(T) o - * or -M-PEG-(T) o -PEG- * * is the linking site between L and D, M is a bond or connector that is linked to Ab; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~14 Arylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~6 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, -(CH2) x -SSC 1~6 Alkylidene-, C 1~6 Alkylidene or C 2~6 alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and the -(CH) x -5-6 membered heteroarylene-(CH2) yIn the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, the number of the heteroatoms is 1, 2, or 3, and the -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3; R h are independently hydrogen, C 1~6 Alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R A and R is an amino acid residue substituted with A are independently -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n-CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L5 is the self-sacrificing group.

[0031] In some embodiments, the antibody may comprise one or more antigen-binding domains capable of binding to an antigen.

[0032] In some embodiments, the antibody may comprise only one or two antigen-binding domains capable of binding to an antigen.

[0033] In some embodiments, the antibody may comprise one antigen-binding domain capable of binding to an antigen.

[0034] In some embodiments, the antibody may comprise only one antigen-binding domain capable of binding to an antigen.

[0035] In some embodiments, the antibody may comprise an Fc terminus.

[0036] In some embodiments, the antibody may comprise only one Fc terminus.

[0037] In some embodiments, the antibody may comprise only one antigen-binding domain capable of binding to an antigen and an Fc terminus.

[0038] In some embodiments, the antibody may be a monoclonal antibody.

[0039] In some embodiments, the antibody may be an anti-HER2 antibody.

[0040] In some embodiments, the anti-HER2 monoclonal antibodies include, but are not limited to, trastuzumab, trastuzumab biosimilar, pertuzumab, pertuzumab biosimilar, margetuximab, HT-19, etc.

[0041] In some embodiments, the antibody may be an anti-5T4 antibody.

[0042] In some embodiments, the anti-5T4 antibody includes, but is not limited to, huA1.

[0043] In some embodiments, the antibody may be a Claudin18.2 antibody.

[0044] In some embodiments, the antibody may be an anti-EGFR antibody.

[0045] In some embodiments, the antibody can be an anti-CEACAM5 antibody.

[0046] In some embodiments, the antibody may be an anti-Nectin-4 antibody.

[0047] In some embodiments, the antibody may be an anti-Trop-2 antibody.

[0048] In some embodiments, the antibody is trastuzumab, pertuzumab, margetuximab, or HT-19.

[0049] In some embodiments, the antibody is cetuximab, huA1, sacituzumab, zolbetuximab, labetuzumab, or enfortumab.

[0050] In the antibody-immunostimulating complex shown in formula I or a pharmaceutically acceptable salt thereof, t is an integer or a non-integer. When t is a non-integer, it means that the antibody-immunostimulating complex shown in formula I is a mixture of antibody-immunostimulating complexes having different binding ratios. When t is an integer, it can mean that the antibody-immunostimulating complex shown in formula I is a single antibody-immunostimulating complex having a fixed binding ratio, or it can mean that the antibody-immunostimulating complex shown in formula I is a mixture of antibody-immunostimulating complexes having different binding ratios.

[0051] In some embodiments, t can be any value from 2 to 5, In some embodiments, t can be any value from 3 to 5, In the antibody-immunostimulatory complex shown in Formula I or a pharmaceutically acceptable salt thereof, the left or right end of L' is linked to L1.

[0052] In some embodiments, L' is -C(=O)-, -C(=O)-NR9-, or -C(=S)-NR9-, and the right end thereof is connected to L1.

[0053] In some embodiments, R is —C(O)—NR 9 —L 1 —R 7 .

[0054] In some embodiments, R9 is hydrogen, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a or -L2-NR a R b is.

[0055] In some embodiments, R9 is hydrogen.

[0056] In some embodiments, in L1, the C 1~6 The alkylidene is methylene or ethylidene.

[0057] In some embodiments, L is a bond or C 1~6alkylidene, wherein L1 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0058] In some embodiments, L1 is a bond or -CH2-.

[0059] In some embodiments, R7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl, or 8-12 membered fused ring group, wherein said R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with one or more substituents selected from:

[0060] In some embodiments, R7 is an 8-12 membered fused ring group, and said R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with one or more substituents selected from:

[0061] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein the 5- to 6-membered heteroaryl has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and the 5- to 6-membered heteroalkenyl ring has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0062] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, which is connected to L1 via ring A; in the 5- to 6-membered heteroaryl, the heteroatom is N and the number of heteroatoms is 1 or 2; and in the 5- to 6-membered heteroalkenyl ring, the heteroatom is N and the number of heteroatoms is 1 or 2.

[0063] In some embodiments, in R7, the 5- to 6-membered heteroaryl may have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms may be 1, 2, or 3.

[0064] In some embodiments, in R7, the heteroatom in the 5- to 6-membered heteroaryl can be N, and the number of heteroatoms can be one or two.

[0065] In some embodiments, for R7, the 5-6 membered heteroaryl may be pyridyl, pyrazinyl, or pyridazinyl, or may be pyridin-3-yl, pyrazin-2-yl, or pyridazin-3-yl.

[0066] In some embodiments, R7 is

[0067] [ka]

[0068] wherein R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with 1 to 3 substituents selected from alkylamino.

[0069] In some embodiments, in D, R7 is

[0070] [ka]

[0071] wherein R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with 1 to 3 substituents selected from alkylamino.

[0072] In some embodiments, R7 is

[0073] [ka]

[0074] is.

[0075] In some embodiments, R is —C(O)—NR9-L1-R7 or —C(S)—NR9-L1-R7, where R9 is hydrogen, L1 is a bond, and R7 is an unsubstituted 8-12 membered fused ring group, an 8-12 membered fused ring group substituted with one —L3-W, or a 5-6 membered heteroaryl substituted with one —L3-W, and L3 is a bond or C 1~6 alkylidene, and W is -NR d R e and R d is H and R e Ga-R c is.

[0076] In some embodiments, R7 is

[0077] [ka]

[0078] is.

[0079] In some embodiments, R7 is

[0080] [ka]

[0081] may be.

[0082] In some embodiments, R7 is

[0083] [ka]

[0084] may be.

[0085] In some embodiments, in R7, the 5-6 membered heteroaryl substituted with one -L3-W is

[0086] [ka]

[0087] may be

[0088] [ka]

[0089] may be

[0090] [ka]

[0091] may be.

[0092] In some embodiments, in R7, the 5-6 membered heteroaryl substituted with one -L3-W is

[0093] [ka]

[0094] may be

[0095] [ka]

[0096] may be

[0097] [ka]

[0098] may be.

[0099] In some embodiments, R7 is

[0100] [ka]

[0101] and R c is the bond connected to L.

[0102] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N.

[0103] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2.

[0104] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, said 5- to 6-membered heteroaryl may be pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0105] In some embodiments, in ring A, the heteroatom in said 5-6 membered heteroaryl ring is N.

[0106] In some embodiments, in ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2.

[0107] In some embodiments, in ring A, the 5- to 6-membered heteroaryl ring can be a pyridine ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring.

[0108] In some embodiments, in Ring B, the heteroatom in said 5-6 membered heteroalkenyl ring is N.

[0109] In some embodiments, in ring B, the number of heteroatoms in the 5- to 6-membered heteroalkenyl ring is 1 or 2.

[0110] In some embodiments, R7 is

[0111] [ka]

[0112] is.

[0113] In some embodiments, the one hydrogen atom missing from the compound of formula D' is located on a secondary or primary amine of R7.

[0114] In some embodiments, R7 is

[0115] [ka]

[0116] is.

[0117] In some embodiments, the one hydrogen atom missing from the compound of formula D' is located on the hydroxyl of R7.

[0118] In some embodiments, m is 1.

[0119] In some embodiments, R and R 8’ are each independently hydrogen, halogen or C 1~6 alkyl, 1~6 The alkyl is unsubstituted or optionally substituted with -L3-W, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6Alkoxy and C 1~6 and alkylamino, substituted at any position with 1 to 3 substituents selected from alkylamino.

[0120] In some embodiments, R and R 8’ are each independently C 1~6 alkyl, 1~6 Alkyl is preferably methyl.

[0121] In some embodiments, R and R 8’ Both of them are connected to carbon atoms, and oxo, thio, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 3~6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a and -L2-NR a R b is substituted at any position with 1 to 3 substituents selected from:

[0122] In some embodiments, R and R 8’ together with both of their connecting carbon atoms form oxo, thio, cyclopropyl, cyclobutyl, azetidinyl or oxetanyl, wherein said cyclopropyl, cyclobutyl, azetidinyl or oxetanyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-ORa and -L2-NRaR b is substituted at any position with 1 to 3 substituents selected from:

[0123] In some embodiments, R and R 8’ are each independently unsubstituted C 1~6 alkyl, or R and R 8’Both of the carbon atoms to which they are attached are oxo or unsubstituted C 3~6 Forms a cycloalkyl.

[0124] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form oxo, cyclopropyl or cyclobutyl.

[0125] In some embodiments, R and R 8’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0126] In some embodiments, R and R 8’ C together with both of the carbon atoms that connect them 3~10 Form a cycloalkylene, 3~10 The cycloalkylene can be cyclopropyl or cyclobutyl.

[0127] In some embodiments, R and R 8’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in the 3- to 10-membered heterocycloalkylene is N or O.

[0128] In some embodiments, R and R 8’ together with the carbon atoms to which they are both connected to form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in the 3- to 10-membered heterocycloalkylene is 1 or 2.

[0129] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, which can be oxycyclopropyl, azacyclopropyl, oxacyclobutylene, or azetidine.

[0130] In some embodiments, R1, R2, and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a or -L2-NR a R b is.

[0131] In some embodiments, preferably, R1, R2, and R3 are each independently F, Cl, Br, -CH3, -OCH3, -CF3, -CH2F, -CHF2, -OCF3, -CN, or -(CH2) 0-5 -NH2.

[0132] In some embodiments, R1 is H, R2 is H, and R3 is H or F.

[0133] In some embodiments, for R1, R2, and R3, the halogen is F, Cl, or Br.

[0134] In some embodiments, R and R 4’ are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl C 1~6 Alkyl, 3-8 membered heterocycloalkylC 1~6 Alkyl, C 6~10 Aryl C 1~6 Alkyl or 5-10 membered heteroarylC 1~6 alkyl, and R or R 4’ is unsubstituted or optionally halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b, -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b or R4 and R 4’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, said 3- to 8-membered heterocycloalkyl being unsubstituted or optionally substituted with halogen, cyano, -L2-OR a , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b and substituted at any position with 1 to 3 substituents selected from In some embodiments, R and R 4’ are each independently hydrogen or C 1~6 alkyl, and R or R 4’ is unsubstituted or optionally -OR a , -OR g , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NRb )NR a R b and -C(O)OR b is substituted at any position with 1 to 3 substituents selected from:

[0135] In some embodiments, R4 is hydrogen or C 1~6 alkyl, wherein R4 is unsubstituted or optionally -OR a , -OR g , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b and -C(O)OR b and R 4’ C 1~6 alkyl, and the R 4’ is unsubstituted or optionally halogen, -OR a and -NR a R b is substituted at any position with 1 to 3 substituents selected from:

[0136] In some embodiments, R and R 4’ are each independently hydrogen or C 1~6 alkyl, and R or R 4’ is unsubstituted or optionally halogen, -OR a and -NR a R b and is substituted at any position by one substituent selected from:

[0137] In some embodiments, R and R 4’ are each independently C1~6 alkyl, and R and R 4’ is substituted at any position with one substituent selected from hydroxyl and amino.

[0138] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R or R 4’ is substituted at any position by one hydroxyl.

[0139] In some embodiments, R4 is -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3, and R 4’ is -CH2CH2OH or -CH2CH2CH3.

[0140] In some embodiments, R4 is -CH2CH2OH or -CH2CH2CH3, and R 4’ is -CH2CH2OH or -CH2CH2CH3.

[0141] In some embodiments, R5 is H.

[0142] In some embodiments, R g In the case where the prodrug group containing phosphoryl is

[0143] [ka]

[0144] and R i is hydrogen, C 1~6 alkyl (e.g., methyl, ethyl, isobutyl) or benzyl, and R j C 1~6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, isobutyl), C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 1~6Alkyl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~6 Alkyl, 3-10 membered heterocycloalkyl-C 1~6 Alkyl, C 6~10 Aryl-C 1~6 Alkyl or 5-10 membered heteroaryl-C 1~6 alkyl, and R k is hydrogen, halogen or C 1~6 It is alkyl.

[0145] In some embodiments, R g In the case where the prodrug group containing phosphoryl is

[0146] [ka]

[0147] and R i is methyl and R j is isopropyl or benzyl, and R k is hydrogen.

[0148] In some embodiments, R g but

[0149] [ka]

[0150] is.

[0151] In some embodiments, R and R 4’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0152] In some embodiments, R and R 4’ So, the above C 1~6 The alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl.

[0153] In some embodiments, R and R 4’ So, one, two or three R's? 4-1 The C is substituted with 1~6 C in alkyl 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0154] In some embodiments, R a and R b So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0155] In some embodiments, R a and R b So, the above C 3~10 Cycloalkyl can be cyclopropyl, cyclobutyl or cyclopentyl.

[0156] In some embodiments, R i So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0157] In some embodiments, R k So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0158] In some embodiments, R j So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0159] In some embodiments, R j So, C 6~10 Aryl-C 1~6 In the case of alkyl, the C 6~10 The aryl can be phenyl.

[0160] In some embodiments, R j So, C 6~10Aryl-C 1~6 In the case of alkyl, the C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0161] In some embodiments, R and R 4’ are independently -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3.

[0162] In some embodiments, R and R 4’ At least one of is —OCH2CH3, —CH2CH2NH2, or —CH2CH2OH.

[0163] In some embodiments, R5 is H.

[0164] In some embodiments, R 5’ is H.

[0165] In some embodiments, Cy 1 C 3~8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6~10 aryl or 5- to 10-membered heteroaryl, 1 is unsubstituted or optionally substituted with halogen, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxyl, C 2~6 Alkenyl, C 2‘6 Alkynyl, -L4-SR d , -L4-OC(O)R e , -L4-C(O)OR e , -L4-C(O)R e , -L4-C(O)NR e R e’ , -L4-NR d C(O)R e , -L4-NR d S(O)2R e , -L4-S(O) 1-2 R e , -L4-S(O)2NRe R e’ , -L4-OR d or -L4-NR e R e’ and optionally substituted with one or three substituents selected from:

[0166] In some embodiments, L2 is a bond or C 1~6 alkylidene, wherein L2 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0167] In some embodiments, L2 includes C 1~6 Alkylidene is C 1~3 It may be alkylidene.

[0168] In some embodiments, L2 is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0169] In some embodiments, L2 is a bond or -CH2CH2-.

[0170] In some embodiments, L3 is a bond or C 1~6 alkylidene, wherein L3 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0171] In some embodiments, in L3, C 1~6 Alkylidene is C 1~3 It may be alkylidene.

[0172] In some embodiments, L3 is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2C(CH3)2-, -CH2CH2CH2CH2-, or -CH2CH(CH3)CH2-.

[0173] In some embodiments, L3 is a bond or -CH2-.

[0174] In some embodiments, L4 is a bond or C 1~6 alkylidene, wherein L4 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0175] In some embodiments, each R c are each independently hydrogen or a bond connected to L, and only one R in D c is the bond connected to L. In some embodiments, D is

[0176] [ka]

[0177] and During the ceremony,

[0178] [ka]

[0179] is absent and is -CH2- or -CH2-CH2-, Z1, Z2 and Z3 are each independently N or CH; R c is a bond connected to L, R1, R2, R3, R4, R 4’ , R5, R8, R 8’ and R a The definition of is as above.

[0180] In some embodiments, Z1 is CH, Z2 is CH, and Z3 is N or CH.

[0181] In some embodiments, Formula D' is any one of the general formulae D'-1 through D'-6:

[0182] [ka]

[0183] In some embodiments, D is a structure shown in Table 5.

[0184] [Table 5] TIFF2025537044000039.tif240169 TIFF2025537044000040.tif165169

[0185] In some embodiments, L is -M-(T) w -PEG-(T) o - * , -M-PEG- * , -M-(T) w - * , -M-(T) w -(A) v -(T) o -PEG- * , -M-(T) w -(A) v -(T) o - * , -M-(T) w -L5- * , -M-(T) w -PEG-L5- * , -M-(T) w -PEG-(A) v -L5-* , -M-(T) w -PEG-(A) v -(T) o - * ,-M-PEG-(T) o -PEG- * or -M-(T) w -(A) v -L5- * * is the linking site between L and D, M is a bond or connector that is linked to Ab; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~14 Arylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~6 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, -(CH2) x -SSC 1~6 Alkylidene-, C 1~6 Alkylidene or C 2~6 alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and the -(CH) x -5-6 membered heteroarylene-(CH2) yIn the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, the number of the heteroatoms is 1, 2, or 3, and the -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3; R h are independently hydrogen, C 1~6 Alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R A and R is an amino acid residue substituted with A are independently -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n-CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L5 is the self-sacrificing group.

[0186] In some embodiments, M is a group in which the connector is formed via click chemistry ligation, click-like chemistry ligation, thiol ligation, amine ligation, oxime ligation, or hydrazone ligation.

[0187] In some embodiments, M is a group in which the connector is formed by thiol ligation at the side chain of a cysteine ​​residue or amino ligation at the side chain of a lysine residue of the antibody.

[0188] In some embodiments, M is a group in which the connector is formed by thiol ligation, preferably

[0189] [ka]

[0190] and R o is hydrogen or C 1~4 alkyl, and said connector is linked to the remainder of L via the c-terminus.

[0191] In some embodiments, R o is hydrogen or methyl.

[0192] In some embodiments, M is a group in which the connector is formed by thiol ligation, preferably

[0193] [ka]

[0194] and the connector is linked to the remainder of L via its c-terminus.

[0195] In some embodiments, M is a group in which the connector is formed by oxime ligation, preferably

[0196] [ka]

[0197] and the connector is linked to the remainder of L via its c-terminus.

[0198] In some embodiments, M is a group in which the connector is formed by hydrazone ligation, preferably

[0199] [ka]

[0200] and the connector is linked to the remainder of L via its c-terminus.

[0201] In some embodiments, in M, the connector is a group formed by amino ligation, preferably, said group formed by amino ligation is a group formed by amino ligation at a lysine side chain, more preferably

[0202] [ka]

[0203] is.

[0204] In some embodiments, the connector is a group formed by click chemistry ligation or click-like chemistry ligation, preferably

[0205] [ka]

[0206] and the connector is linked to the remainder of L via its c-terminus.

[0207] In some embodiments, M has a connector [ka] and the connector is linked to the remainder of L via its c-terminus.

[0208] In some embodiments, each A is independently

[0209] [ka]

[0210] and each R 11 are each independently an amino acid side chain, or -C(O)(CH2CH2O) n CH3 or -(CH2CH2O) n an amino acid side chain modified at CH3, or R 11 and the adjacent nitrogen atom form a five-membered heterocycle.

[0211] In some embodiments, in A, the amino acid is a natural amino acid or an unnatural amino acid.

[0212] In some embodiments, the

[0213] [ka]

[0214] but

[0215] [ka]

[0216] and

[0217] [ka]

[0218] may be.

[0219] In some embodiments, in A, each R 11 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, -SO3H,

[0220] [ka]

[0221] or R 11 and the adjacent nitrogen atom form a five-membered heterocycle.

[0222] In some embodiments, -(A) v -but

[0223] [ka]

[0224] and each R 11 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, -SO3H,

[0225] [ka]

[0226] or R 11 and the adjacent nitrogen atom form a 5-membered heterocycle, and v is an integer of 1 to 4, preferably 1 or 2.

[0227] In some embodiments, v is 3 or 4.

[0228] In some embodiments, A is linked via the carbonyl terminus to -(T) o -or -L5-.

[0229] In some embodiments, L5

[0230] [ka]

[0231] is.

[0232] In some embodiments, L5 [ka] is.

[0233] In some embodiments, L5

[0234] [ka]

[0235] is.

[0236] In some embodiments, -L5- is linked to D via the carbonyl terminus.

[0237] In some embodiments, each T is independently (CH) x-C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~10 Arylene-(CH2) y -, -(CH2) x -5-10 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~10 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 10-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, C 1~20 Alkylidene or C 2~20 It is alkenylene, and x and y are each independently any integer of 0 to 10.

[0238] In some embodiments, each T is independently -(CH) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -phenylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~8 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 8-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)- or C 1~6アルケニレンx and y are each independently any integer from 0 to 10; In some embodiments, R h is hydrogen or C 1~6 alkyl, and R h is preferably hydrogen or C 1~3 It is alkyl.

[0239] In some embodiments, -(T) w -but

[0240] [ka]

[0241] and -(T) w - is linked to the -M- via the terminal a. In some embodiments, each x is independently an integer of 0 to 10, and the x is more preferably an integer of 0 to 6.

[0242] In some embodiments, each y is independently an integer of 0-10, and the y is more preferably an integer of 0-6.

[0243] In some embodiments, -(T) o -but

[0244] [ka]

[0245] and -(T) o - is linked to the -PEG- or D via the b-terminus.

[0246] In some embodiments, each x is independently an integer from 0 to 10, and more preferably an integer from 0 to 6.

[0247] In some embodiments, PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2)u -C(O)-, n is any integer from 1 to 30, and u is any integer from 1 to 5; In some embodiments, L is -M-(T) w -(A) v -L5- * In the case of -M-, -(T) w -, -(A) v - and -L5- do not simultaneously satisfy the following conditions, and -M- is succinimidyl (

[0248] [ka]

[0249] ) and -(T) w - is caproyl, -(A) v - is -Val-Cit-, -Val-Ala-, or -Gly-Gly-Phe-Gly-, and -L5- is PABC(

[0250] [ka]

[0251] )

[0252] In some embodiments, L is -M-(T) w -(A) v -L5- * In this case, the L is preferably M-CH2-(C 5~6 Cycloalkylene)-C(=O)-(A) v -L5-, -M-CH2-(5- to 6-membered heterocyclylene)-C(=O)-(A) v -L5-, -M-(phenylene)-CH2-C(=O)-(A) v -L5- or -M-(CH2) x -C(=O)NH-CH2-CH(NHR h )-C(O)-(A) v -L5-.

[0253] In some embodiments, L is -M-(T) w -PEG-(A) v -L5- * and L is preferably -M-(CH2) x -C(=O)NH-PEG-(A) v -L5-, -M-(phenylene)-CH2-C(=O)NH-PEG-(A) v -L5-, -M-CH2-(C 5~6 Cycloalkylene)-C(=O)NH-PEG-(A) v -L5- or -M-CH2-(5- to 6-membered heterocyclylene)-C(=O)NH-PEG-(A) v -L5-.

[0254] In some embodiments, L is -M-(T) w -(A) v -(T) o - * and L is preferably -M-(CH2) x -C(=O)NH-(A) v -NH-CH2-.

[0255] In some embodiments, L is any one combination of the following: a)-M-PEG-, b) -M-(CH2) x -, c) -M-(CH2) x -C(O)-, d) -M-(CH2) x -(C 5~6 Cycloalkylene)-(CH2) y -C(O)NH-PEG-, e)-M-(CH2) x -(5-6 membered heterocyclylene)-(CH2) y -C(O)NH-PEG-, f)-M-(CH2) x -(phenylene)-(CH2) y -C(O)NH-PEG-, g)-M-(CH2) x -C(O)NH-PEG-, h)-M-(CH2) x -C(O)NH-(CH2) x -C(O)NH-PEG-, i)-M-(CH2) x -C(O)NH-(CH2) x -C(O)NH-PEG-NH-(CH2) x -C(O)-, j)-M-(CH2) x -(C 5~6 Cycloalkylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, k)-M-(CH2) x -(5-6 membered heterocyclylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, l)-M-(CH2) x -(phenylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, m)-M-(CH2) x -C(O)NH-(CH2) x -C(O)-L5-, n)-M-(CH2) x -C(O)NH-PEG-L5-, o)-M-(CH2) x -(phenylene)-(CH2) y -C(O)-(A) v -, p)-M-(CH2) x -C(O)NH-(C 3~6 Cycloalkylene)-C(O)-(A) v -, q)-M-(CH2) x -C(O)NH-PEG-(A) v -, r)-M-(CH2) x -C(O)NH-PEG-(A) v -L5-, s)-M-(CH2) x -(C 5~6 cycloalkylene)-C(O)-, t)-M-(CH2) x -(5- to 6-membered heterocyclylene)-C(O)-, u)-M-(phenylene)-(CH2) y -C(O)-, v) -M-(CH2) x -C(O)-(A) v -NH-PEG-, w)-M-(CH2) x -C(O)-(A) v -NH-(CH2) x -C(O)-, x)-M-(CH2) x -C(O)-(A) v -, y)-M-(CH2) x -(5-6 membered heterocyclylene)-C(O)-(A) v -, z)-M-(CH2) x -C(O)NH-CH2-CH(NHR h )-C(O)-(A) v -, aa)-M-(phenylene)-(5- to 6-membered heterocyclylene)-C(O)-, ab)-M-(phenylene)-(CH2) y -C(O)NH-(CH2)x-PEG-(A) v -, ac)-M-(phenylene)-C(O)NH-(CH2)x-(A) v -L5- or ad)-M-(CH2) x -PEG-(A) v -.

[0256] In some embodiments, L is

[0257] [ka] JPEG2025537044000063.jpg245169 JPEG2025537044000064.jpg251169 JPEG2025537044000065.jpg214169 JPEG2025537044000066.jpg223169 JPEG2025537044000067.jpg242169 JPEG2025537044000068.jpg217169

[0258] is.

[0259] In some embodiments, L is

[0260] [ka] JPEG2025537044000070.jpg100169

[0261] is.

[0262] In some embodiments, the antibody-immunostimulatory complex of formula I or a pharmaceutically acceptable salt thereof comprises:

[0263] [ka]

[0264] wherein Ab is pertuzumab, cetuximab, huA1, hRS7, zolbetuximab, labetuzumab, or enfortumab; t is any value between 1 and 8, L is a linker (e.g., -M-(CH2) x -C(O)-(A) v -L5-, -M-(CH2) x -C(O)NH-PEG-, -M-(CH2) x -C(O)-(A) v - or -M-(phenylene)-(5- to 6-membered heterocyclylene)-C(O)-), which is linked to Ab and D; D is a group in which one hydrogen atom has been removed from the compound represented by formula D',

[0265] [ka]

[0266] In the formula, R is -L'-L1-R7, L' is -C(=O)-NR9-, R9 is hydrogen, and L1 is independently a bond; R7 is independently an 8- to 12-membered fused ring group or one, two, or three R 7-4 is an 8- to 12-membered fused ring group substituted with R 7-4 are independently -C(=O)-L3-NH2, and L3 is independently C 1~6 Alkylidene or -(CH2CH2O) m’ -C 1~6 alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0267] In some embodiments, the antibody-immunostimulating complex of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Tables 10, 11, 12, 13, or 14.

[0268] The present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof:

[0269] [ka]

[0270] wherein D is a benzazepine group as shown below:

[0271] [ka]

[0272] m is 0 or 1, R is -C(O)-NR9-L1-R7, -C(S)-NR9-L1-R7, or -NR9-C(O)-L1-R7; R1, R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkyl halide, -L2-OR a or -L2-NR a R b and R4 and R 4’ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, and R or R 4’ is unsubstituted or optionally halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b or R and R 4’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, and the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with halogen, cyano, -L2-OR a , -L2-OC(O)R a , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NRa R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b and further substituted at any position with 1 to 3 substituents selected from R5 is hydrogen, -OR a , -C(O)R a , -C(O)OR a or -C(O)NR a R b and R 5’ Ga-R c and R7 is phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, or an 8- to 12-membered fused ring group, and said R7 is unsubstituted or optionally -L3-W, -R c substituted at any position by one or more substituents selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R8 and R 8’ are each independently hydrogen, halogen or alkyl, and said R or R 8’ is unsubstituted or optionally substituted at any position by one or more substituents selected from -L3-W, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide, and alkylamino; R8 and R 8’ are each an independent substituent, or R and R 8’ Both of them are connected to carbon atoms, and oxo, thio, C 1~6 Alkylidene, C 3~10 cycloalkyl or 3- to 10-membered heterocycloalkyl, 1~6 Alkylidene, C 3~10The cycloalkyl or 3- to 10-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkyl halide, -L2-OR a and -L2-NR a R b and substituted at any position by one or more substituents selected from R9 is hydrogen, alkyl, halogenated alkyl, -L2-OR a or -L2-NR a R b and W is Cy 1 , -SR d , -OR d , -OC(O)R e , -OC(O)NR e R e’ , -C(O)OR e , -C(O)R e , -C(O)NR e R e’ , -C(O)NR e S(O)2R e , -NR d R e , -NR d C(O)R e , -N(R d )C(O)OR e , -N(R d )C(O)NR e R e’ , -NR d S(O)2R e , -NR d S(O)NR e R e’ , -S(O) 1-2 R e , -S(O)NR e R e’ , -S(O)(=NR d )R e , -S(O)2N(R e )C(O)R e’ , -P(O)(OR e )2, -P(O)(OR e )R e’ , -OP(O)(OR e )2 or -B(OR e)2, Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and said Cy 1 is unsubstituted or optionally substituted with halogen, alkyl, halogenated alkyl, halogenated alkoxyl, alkenyl, alkynyl, cyano, -R c , -L4-SR d , -L4-OC(O)R e , -L4-C(O)OR e , -L4-C(O)R e , -L4-C(O)NR e R e’ , -L4-NR d C(O)R e , -L4-NR d S(O)2R e , -L4-S(O) 1-2 R e , -L4-S(O)2NR e R e’ , -L4-OR d and -L4-NR e R e’ and substituted at any position by one or more substituents selected from Each R a , R b , R d , R e and R e’ are each independently -R c , Amino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl C 1~6 Alkyl, 3-10 membered heterocycloalkylC 1~6 Alkyl, Phenyl C 1~6 Alkyl or 5-10 membered heteroarylC 1~6 alkyl, and the R a , R b , R d , R e or R e’is unsubstituted or optionally -L4-OR f , -OC(O)-L4-R f , -L4-NR f R f’ , halogen, cyano, nitro, C 1~6 Alkyl, halogenated C 1~6 Alkyl and halogenated C 1~6 substituted at any position by 1 to 3 substituents selected from alkoxyl; L1, L2, L3 and L4 are each independently a bond, C 1~6 Alkylidene, C 2~6 Alkenylene or C 2~6 alkynylene, wherein L1, L2, L3 or L4 is unsubstituted or optionally substituted at any position by one or more substituents selected from oxo, hydroxyl, amino, halogen, cyano, alkyl, halogenated alkyl, alkoxyl and halogenated alkoxyl; Each R f and R f are each independently -R c , -NHR c or C 1~6 is alkyl, R g is a phosphoryl-containing prodrug group; Each R c are each independently hydrogen or a bond connected to L, and at least one R in D c is a bond connected to LX, Also, as shown in Formula D, the benzazepine group satisfies one or two of the following conditions: (1) m is 1, (2) R4 and R 4’ At least one of the following is halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b , -L2-NR a R b, -L2-NR a C(O)OR b , -L2-C(O)OR b -L2-NR a C(O)NR a R b and -L2-NR b C(NR b )NR a R b and substituted at any position by one or more substituents selected from LX is M'-(T) w -PEG-(T) o - * , M'-PEG- * , M'-(T) w - * , M'-(T) w -(A) v -(T) o -PEG- * , M'-(T) w -(A) v -(T) o - * , M'-(T) w -L5- * , M'-(T) w -PEG-L5- * , M'-(T) w -PEG-(A) v -L5- * , M'-(T) w -PEG-(A) v -(T) o - * , M'-PEG-(T) o -PEG- * or M'-(T) w -(A) v -L5- * wherein v is an integer of 1 to 5, w is an integer of 1 to 10, o is an integer of 0 to 10, and * is a linking site between LX and D; Each T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -Arylene-(CH2) y -, -(CH2) x -Heteroarylene-(CH2)y -, -(CH2) x -Cycloalkylene-(CH2) y -, -(CH2) x -Heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, -(CH2) x -SS-alkylidene-, alkylidene, or alkenylene, and x and y are each independently any integer of 0 to 10; R h is hydrogen, alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is any integer from 1 to 50, and u is any integer from 0 to 5; Each A is independently an amino acid residue, or -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n is an amino acid residue modified by -CH3, L5 is the self-sacrificing group, M' is a connector precursor or a connector linked to 1 to 2 amino acids.

[0273] In some embodiments, in the compound of Formula II or a pharmaceutically acceptable salt thereof, some groups are defined as follows, and the remaining groups are defined as described in any other embodiment (hereinafter referred to as "some embodiments"):

[0274] [ka]

[0275] wherein LX is a linker precursor; D is a group in which one hydrogen atom has been removed from the compound represented by formula D',

[0276] [ka]

[0277] wherein R is -L'-L1-R7, L' is -C(=O)-, -C(=O)-NR9- or -C(=S)-NR9-; R9 is independently hydrogen, C 1~6 Alkyl or halogenated C 1~6 is alkyl, L1 is independently a bond, C 1~6 Alkylidene or C 2~6 is alkenylene, R7 is independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, or one, two, or three R 7-1 phenyl substituted with one, two or three R 7-2 5-6 membered heteroaryl substituted with one, two or three R 7-3 or one, two, or three R 7-4 is an 8- to 12-membered fused ring group substituted with In R7, the 5- to 6-membered heteroaryl and the one, two, or three R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; and the 3- to 8-membered heterocycloalkyl and the 1, 2, or 3 R 7-3In the "3- to 8-membered heterocycloalkyl" in the 3- to 8-membered heterocycloalkyl substituted by, the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; In R7, the 8- to 12-membered fused ring group and the one, two, or three R 7-4 the 8- to 12-membered fused ring groups among the 8- to 12-membered fused ring groups substituted with are independently ring A and fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R 7-1 , R 7-2 , R 7-3 and R 7-4 are independently amino, -L3-NH2, -L3-OH, -C(=O)-L3-OH or -C(=O)-L3-NH2, and L3 is independently C 1~6 Alkylidene or -(CH2CH2O) m’ -C 1~6 alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1, R8 and R 8’ are independently hydrogen or C 1~6 alkyl, or R and R 8’ carbonyl, C, along with both of their connecting carbon atoms 3~10 forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R1, R2, and R3 are independently hydrogen, deuterium, or halogen; R4 and R 4’ independently C1~6 Alkyl, C 1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R 4-1 are independently hydroxyl, amino, -OC(=O)NR a R b or

[0278] [ka]

[0279] and R a and R b are independently hydrogen, C 1~6 Alkyl or C 3~10 is cycloalkyl, R i is hydrogen, C 1~6 alkyl or benzyl, and R k is hydrogen, halogen or C 1~6 alkyl, and R i C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~6 Alkyl, 3-10 membered heterocycloalkyl-C 1~6 Alkyl, C 6~10 Aryl-C 1~6 Alkyl or 5-10 membered heteroaryl-C 1~6 is alkyl, R j In the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C 1~6 In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C 1~6In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R4 and R 4’ At least one of the 1~6 Alkoxyl, or one, two or three R 4-1 C replaced by 1~6 is alkyl, Furthermore, the compound represented by formula II does not have a structure shown in Table 6.

[0280] [Table 6] TIFF2025537044000079.tif253169 TIFF2025537044000080.tif235169

[0281] In some embodiments, the compound shown in Formula D' is not a compound shown in Table 3.

[0282] In some embodiments, the compound of Formula D' satisfies one, two, or three of the following conditions: (1) L1 is independent and C 1~6 Alkylidene or C 2~6 is alkenylene, (2) R7 is independently phenyl substituted with one amino group, 5- to 6-membered heteroaryl substituted with one amino group, 3- to 8-membered heterocycloalkyl substituted with one amino group, or 8- to 12-membered fused ring group substituted with one amino group; (3) R4 and R 4’ At least one of the 1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R4-1 are independently -OC(=O)NR a R b or

[0283] [ka]

[0284] is.

[0285] In some embodiments, the LX is not of the structure:

[0286] [ka]

[0287] In some embodiments, the LX is M'-(T) w -PEG-(T) o - * , M'-PEG- * , M'-(T) w -(A) v -(T) o -PEG- * , M'-(T) w -(A) v -(T) o - * , M'-(T) w -L5- * , M'-(T) w -PEG-L5- * , M'-(T) w -PEG-(A) v -L5- * , M'-(T) w -PEG-(A) v -(T) o - * or M'-PEG-(T) o -PEG- * , * is the linking site between LX and D, M' is hydrogen, a connector precursor, or a connector linked to 1 to 2 amino acids; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~14 Arylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~6 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, -(CH2) x -SSC 1~6 Alkylidene-, C 1~6 Alkylidene or C 2~6 alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and the -(CH) x -5-6 membered heteroarylene-(CH2) y In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, the number of the heteroatoms is 1, 2, or 3, and the -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3; R h are independently hydrogen, C 1~6 Alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O)n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R A and R is an amino acid residue substituted with A are independently -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L5 is the self-sacrificing group.

[0288] In the compound of Formula II or a pharmaceutically acceptable salt thereof, the left or right end of L' is linked to L1.

[0289] In some embodiments, L' is -C(=O)-, -C(=O)-NR9-, or -C(=S)-NR9-, and the right end thereof is connected to L1.

[0290] In some embodiments, in L1, the C 1~6 The alkylidene is methylene or ethylidene.

[0291] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N.

[0292] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2.

[0293] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, said 5- to 6-membered heteroaryl may be pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0294] In some embodiments, in ring A, the heteroatom in said 5-6 membered heteroaryl ring is N.

[0295] In some embodiments, in ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2.

[0296] In some embodiments, in ring A, the 5- to 6-membered heteroaryl ring can be a pyridine ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring.

[0297] In some embodiments, in Ring B, the heteroatom in said 5-6 membered heteroalkenyl ring is N.

[0298] In some embodiments, in ring B, the number of heteroatoms in the 5- to 6-membered heteroalkenyl ring is 1 or 2.

[0299] In some embodiments, R7 is

[0300] [ka]

[0301] is.

[0302] In some embodiments, the one hydrogen atom missing from the compound of formula D' is located on a secondary or primary amine of R7.

[0303] In some embodiments, R7 is

[0304] [ka]

[0305] is.

[0306] In some embodiments, the one hydrogen atom missing from the compound of formula D' is located on the hydroxyl of R7.

[0307] In some embodiments, R and R 8’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0308] In some embodiments, R and R 8’ C together with both of the carbon atoms that connect them 3~10 Form a cycloalkylene, 3~10The cycloalkylene can be cyclopropyl or cyclobutyl.

[0309] In some embodiments, R and R 8’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in the 3- to 10-membered heterocycloalkylene is N or O.

[0310] In some embodiments, R and R 8’ together with the carbon atoms to which they are both connected to form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in the 3- to 10-membered heterocycloalkylene is 1 or 2.

[0311] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, which can be oxycyclopropyl, azacyclopropyl, oxacyclobutylene, or azetidine.

[0312] In some embodiments, for R1, R2, and R3, the halogen is F, Cl, or Br.

[0313] In some embodiments, R and R 4’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0314] In some embodiments, R and R 4’ So, the above C 1~6 The alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl.

[0315] In some embodiments, R and R 4’ So, one, two or three R's? 4-1 The C is substituted with 1~6 C in alkyl 1~6Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0316] In some embodiments, R a and R b So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0317] In some embodiments, R a and R b So, the above C 3~10 Cycloalkyl can be cyclopropyl, cyclobutyl or cyclopentyl.

[0318] In some embodiments, R i So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0319] In some embodiments, R k So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0320] In some embodiments, R j So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0321] In some embodiments, R j So, C 6~10 Aryl-C 1~6 In the case of alkyl, the C 6~10 The aryl can be phenyl.

[0322] In some embodiments, R j So, C 6~10 Aryl-C 1~6 In the case of alkyl, the C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0323] In some embodiments, R and R 4’ are independently -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3.

[0324] In some embodiments, R and R 4’ At least one of is —OCH2CH3, —CH2CH2NH2, or —CH2CH2OH.

[0325] In some embodiments, m is 1.

[0326] In some embodiments, R is —C(O)—NR 9 —L 1 —R 7 .

[0327] In some embodiments, R1, R2, and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a or -L2-NR a R b is.

[0328] In some embodiments, preferably, R1, R2, and R3 are each independently F, Cl, Br, -CH3, -OCH3, -CF3, -CH2F, -CHF2, -OCF3, -CN, or -(CH2) 0-5 -NH2.

[0329] In some embodiments, R1 is H, R2 is H, and R3 is H or F.

[0330] In some embodiments, R g In the case where the prodrug group containing phosphoryl is

[0331] [ka]

[0332] and R i is hydrogen, C1~6 Alkyl (e.g., methyl, ethyl, isobutyl), C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 1~6 Alkyl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~6 Alkyl, 3-10 membered heterocycloalkyl-C 1~6 Alkyl, C 6~10 Aryl-C 1~6 Alkyl or 5-10 membered heteroaryl-C 1~6 alkyl, and R j is C 1-6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, isobutyl) or benzyl; R k is hydrogen, halogen or C 1~6 It is alkyl.

[0333] In some embodiments, R g In the case where the prodrug group containing phosphoryl is

[0334] [ka]

[0335] and R i is methyl and R j is isopropyl or benzyl, and R k is hydrogen.

[0336] In some embodiments, R g but

[0337] [ka]

[0338] is.

[0339] In some embodiments, R and R 4’ are independently hydrogen, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~8 Cycloalkyl C 1~6 Alkyl, 3-8 membered heterocycloalkylC 1~6 Alkyl, C 6~10 Aryl C 1~6 Alkyl or 5-10 membered heteroarylC 1~6 alkyl, and R or R 4’ is unsubstituted or optionally halogen, cyano, -L2-OR a , -L2-OR g , -L2-OC(O)R a , -L2-OC(O)OR a , -L2-OC(O)NR a R b , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R b and -L2-C(O)OR b or R4 and R 4’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, said 3- to 8-membered heterocycloalkyl being unsubstituted or optionally substituted with halogen, cyano, -L2-OR a , -L2-NR a R b , -L2-NR a C(O)OR b , -L2-NR a C(O)NR a R b , -L2-NR b C(NR b )NR a R band -L2-C(O)OR b and substituted at any position with 1 to 3 substituents selected from In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R or R 4’ is unsubstituted or optionally -OR a , -OR g , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b and -C(O)OR b is substituted at any position with 1 to 3 substituents selected from:

[0340] In some embodiments, R4 is C 1~6 alkyl, wherein R4 is unsubstituted or optionally -OR a , -OR g , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b and -C(O)OR b and R 4’ C 1~6 alkyl, and the R4’ is unsubstituted or optionally halogen, -OR a and -NR a R b is substituted at any position with 1 to 3 substituents selected from:

[0341] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R or R 4’ is unsubstituted or optionally halogen, -OR a and -NR a R b and is substituted at any position by one substituent selected from:

[0342] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R and R 4’ is substituted at any position with one substituent selected from hydroxyl and amino.

[0343] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R or R 4’ is substituted at any position by one hydroxyl.

[0344] In some embodiments, R4 is -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3, and R 4’ is -CH2CH2OH or -CH2CH2CH3.

[0345] In some embodiments, R4 is -CH2CH2OH or -CH2CH2CH3, and R 4’ is -CH2CH2OH or -CH2CH2CH3.

[0346] In some embodiments, R5 is H.

[0347] In some embodiments, R 5’ is H.

[0348] In some embodiments, R and R 8’ are each independently hydrogen, halogen or C 1~6 alkyl, 1~6 The alkyl is unsubstituted or optionally substituted with -L3-W, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with 1 to 3 substituents selected from alkylamino.

[0349] In some embodiments, R and R 8’ are each independently C 1~6 alkyl, 1~6 Alkyl is preferably methyl.

[0350] In some embodiments, R and R 8’ Both of them are connected to carbon atoms, and oxo, thio, C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 3~6 The cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a and -L2-NR a R b is substituted at any position with 1 to 3 substituents selected from:

[0351] In some embodiments, R and R 8’together with both of their connecting carbon atoms form oxo, thio, cyclopropyl, cyclobutyl, azetidinyl or oxetanyl, wherein said cyclopropyl, cyclobutyl, azetidinyl or oxetanyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-ORa and -L2-NRaR b is substituted at any position with 1 to 3 substituents selected from:

[0352] In some embodiments, R and R 8’ are each independently unsubstituted C 1~6 alkyl, or R and R 8’ Both of the carbon atoms to which they are attached are oxo or unsubstituted C 3~10 Forms a cycloalkyl.

[0353] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form oxo, cyclopropyl or cyclobutyl.

[0354] In some embodiments, R9 is hydrogen, C 1~6 Alkyl, halogenated C 1~6 Alkyl, -L2-OR a or -L2-NR a R b is.

[0355] In some embodiments, R9 is hydrogen.

[0356] In some embodiments, Cy 1 C 3~8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6~10 aryl or 5- to 10-membered heteroaryl, 1 is unsubstituted or optionally substituted with halogen, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, halogenated C1~6 Alkoxyl, C 2~6 Alkenyl, C 2‘6 Alkynyl, -L4-SR d , -L4-OC(O)R e , -L4-C(O)OR e , -L4-C(O)R e , -L4-C(O)NR e R e’ , -L4-NR d C(O)R e , -L4-NR d S(O)2R e , -L4-S(O) 1-2 R e , -L4-S(O)2NR e R e’ , -L4-OR d or -L4-NR e R e’ and substituted at any position by one or three substituents selected from In some embodiments, L is a bond or C 1~6 alkylidene, wherein L1 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0357] In some embodiments, L1 is a bond or -CH2-.

[0358] In some embodiments, L2 is a bond or C 1~6 alkylidene, wherein L2 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0359] In some embodiments, L2 includes C 1~6Alkylidene is C 1~3 It may be alkylidene.

[0360] In some embodiments, L2 is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0361] In some embodiments, L2 is a bond or -CH2CH2-.

[0362] In some embodiments, L3 is a bond or C 1~6 alkylidene, wherein L3 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0363] In some embodiments, in L3, C 1~6 Alkylidene is C 1~3 It may be alkylidene.

[0364] In some embodiments, L3 is a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2C(CH3)2-, -CH2CH2CH2CH2-, or -CH2CH(CH3)CH2-.

[0365] In some embodiments, L3 is a bond or -CH2-.

[0366] In some embodiments, L4 is a bond or C 1~6 alkylidene, wherein L4 is unsubstituted or optionally oxo, halogen, hydroxyl, amino, cyano, C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 1~6 Alkoxy or halogenated C 1~6 It is substituted at any position with 1 to 3 substituents selected from alkoxyl.

[0367] In some embodiments, each R c are each independently hydrogen or a bond connected to LX, and only one R in D c is a bond connected to LX, In some embodiments, R7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl, or 8-12 membered fused ring group, wherein said R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with one or more substituents selected from:

[0368] In some embodiments, R7 is an 8-12 membered fused ring group, and said R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with one or more substituents selected from:

[0369] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein the 5- to 6-membered heteroaryl has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and the 5- to 6-membered heteroalkenyl ring has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0370] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, which is connected to L1 via ring A; in the 5- to 6-membered heteroaryl, the heteroatom is N and the number of heteroatoms is 1 or 2; and in the 5- to 6-membered heteroalkenyl ring, the heteroatom is N and the number of heteroatoms is 1 or 2.

[0371] In some embodiments, in R7, the 5- to 6-membered heteroaryl may have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms may be 1, 2, or 3.

[0372] In some embodiments, in R7, the heteroatom in the 5- to 6-membered heteroaryl can be N, and the number of heteroatoms can be one or two.

[0373] In some embodiments, for R7, the 5-6 membered heteroaryl may be pyridyl, pyrazinyl, or pyridazinyl, or may be pyridin-3-yl, pyrazin-2-yl, or pyridazin-3-yl.

[0374] In some embodiments, in D, R7 is

[0375] [ka]

[0376] wherein R7 is unsubstituted or optionally -L3-W, -R c , halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxyl, halogenated C 1~6 Alkyl, halogenated C 1~6 Alkoxy and C 1~6 and alkylamino, substituted at any position with 1 to 3 substituents selected from alkylamino.

[0377] In some embodiments, R7 is

[0378] [ka]

[0379] is.

[0380] In some embodiments, R is —C(O)—NR9-L1-R7 or —C(S)—NR9-L1-R7, where R9 is hydrogen, L1 is a bond, and R7 is an unsubstituted 8-12 membered fused ring group, an 8-12 membered fused ring group substituted with one —L3-W, or a 5-6 membered heteroaryl substituted with one —L3-W, and L3 is a bond or C 1~6 alkylidene, and W is -NR d R e and R d is H and R e Ga-R c is.

[0381] In some embodiments, R7 is

[0382] [ka]

[0383] is.

[0384] In some embodiments, R7 is

[0385] [ka]

[0386] may be.

[0387] In some embodiments, R7 is

[0388] [ka]

[0389] may be.

[0390] In some embodiments, in R7, the 5-6 membered heteroaryl substituted with one -L3-W is

[0391] [ka]

[0392] may be

[0393] [ka]

[0394] may be

[0395] [ka]

[0396] may be.

[0397] In some embodiments, in R7, the 5-6 membered heteroaryl substituted with one -L3-W is

[0398] [ka]

[0399] may be

[0400] [ka]

[0401] may be

[0402] [ka]

[0403] may be.

[0404] In some embodiments, R7 is

[0405] [ka]

[0406] and R c is the bond connected to L.

[0407] In some embodiments, D is

[0408] [ka]

[0409] and During the ceremony,

[0410] [ka]

[0411] is absent and is -CH2- or -CH2-CH2-, Z1, Z2 and Z3 are each independently N or CH; R c is a bond connected to L, R1, R2, R3, R4, R 4’ , R5, R8, R 8’ and R a The definition of is as above.

[0412] In some embodiments, Z1 is CH, Z2 is CH, and Z3 is N or CH.

[0413] In some embodiments, R5 is H.

[0414] In some embodiments, Formula D' is any one of the general formulae D'-1 through D'-6:

[0415] [ka]

[0416] In the formula, R 7-1 , R 7-2 , R 7-4 , R4, R 4’ , R8 and R 8’ The definition of is as above.

[0417] In some embodiments, D is any structure shown in Table 5.

[0418] In some embodiments, the LX is M'-(T) w -PEG-(T) o - * , M'-PEG- * , M'-(T) w - * , M'-(T) w -(A) v -(T) o -PEG- * , M'-(T) w -(A) v -(T) o - * , M'-(T) w-L5- * , M'-(T) w -PEG-L5- * , M'-(T) w -PEG-(A) v -L5- * , M'-(T) w -PEG-(A) v -(T) o - * , M'-PEG-(T) o -PEG- * or M'-(T) w -(A) v -L5- * * is the linking site between LX and D, M' is hydrogen, a connector precursor, or a connector linked to 1 to 2 amino acids; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T independently -(CH2) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~14 Arylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~6 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, -(CH2) x -SSC 1~6 Alkylidene-, C 1~6 Alkylidene or C 2~6alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and the -(CH) x -5-6 membered heteroarylene-(CH2) y In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, the number of the heteroatoms is 1, 2, or 3, and the -(CH2) x -3 to 6-membered heterocycloalkylene-(CH2) y In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3; R h are independently hydrogen, C 1~6 Alkyl, -PO(OH)2, -PO(OCH3)2, -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R A and R is an amino acid residue substituted withA are independently -C(O)-(CH2CH2O) n -CH3 or -(CH2CH2O) n -CH3, and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L5 is the self-sacrificing group.

[0419] In LX, M'-(T) w -PEG-(T) o - * , M'-PEG- * , M'-(T) w - * , M'-(T) w -(A) v -(T) o -PEG- * , M'-(T) w -(A) v -(T) o - * , M'-(T) w -L5- * , M'-(T) w -PEG-L5- * , M'-(T) w -PEG-(A) v -L5- * , M'-(T) w -PEG-(A) v -(T) o - * , M'-PEG-(T) o -PEG- * and M'-(T) w -(A) v -L5- * wherein w can be further substituted independently with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0420] If w is 0, LX is further M'-(A) v -(T) o -PEG-* , M'-(A) v -(T) o - * or M'-(A) v -L5- * where * is the linking site between LX and D, and M' is hydrogen.

[0421] In some embodiments, M' is a connector precursor for reacting with a side chain of an antibody amino acid residue, preferably a connector precursor that reacts with an amino or thiol in the side chain of an antibody amino acid residue, more preferably a connector precursor that reacts with a thiol in the side chain of an antibody amino acid residue.

[0422] In some embodiments, M' is ethynyl, vinyl, hydroxylamine,

[0423] [ka]

[0424] and R o is hydrogen or C 1~4 is alkyl, Each R 12 and R 12’ are each independently a halogen (e.g., bromine or iodine), nitro, or -SO3-; R 13 and R 13’ are independently hydrogen, halogen (e.g., bromine), phenylthio, or pyridylthio; R 13 and R 13’ But at the same time it is not hydrogen.

[0425] In some embodiments, M' is

[0426] [ka]

[0427] In some embodiments, M' is

[0428] [ka]

[0429] is.

[0430] In some embodiments, M' is a connector having 1-2 amino acids attached thereto, the amino acids being covalently bonded to the connector via amino acid side chains.

[0431] In some embodiments, LX is M'-(T) w -PEG-(T) o -*, M'-PEG- * , M'-(T) w * -, M'-(T) w -(A) v - * , M'-(T) w -PEG-(A) v - * or M'-PEG-(T) o -PEG-* and M' is

[0432] [ka]

[0433] is.

[0434] In some embodiments, LX is M'-(T) w -(A) v -L5- * and M' is

[0435] [ka]

[0436] is.

[0437] In some embodiments, LX is M'-(T) w -PEG-(T)o - * , M'-PEG- * , M'-(T) w - * , M'-(T) w -(A) v -(T) o -PEG- * , M'-(T) w -(A) v -(T) o - * , M'-(T) w -L5- * , M'-(T) w -PEG-L5- * , M'-(T) w -PEG-(A) v -L5- * , M'-(T) w -PEG-(A) v -(T) o - * , M'-PEG-(T) o -PEG- * , M'-(T) w -(A) v -L5- * , M'-(A) v -(T) o -PEG- * , M'-(A) v -(T) o - * or M'-(A) v -L5- * where * is the linking site between LX and D, and M' is hydrogen.

[0438] In some embodiments, each A is independently

[0439] [ka]

[0440] and each R 11 are each independently an amino acid side chain, or -C(O)(CH2CH2O) n CH3 or -(CH2CH2O) nan amino acid side chain modified at CH3, or R 11 and the adjacent nitrogen atom form a 5-membered heterocycle. In some embodiments, in A, the amino acid is a natural amino acid or an unnatural amino acid.

[0441] In some embodiments, the

[0442] [ka]

[0443] but

[0444] [ka]

[0445] and

[0446] [ka]

[0447] may be.

[0448] In some embodiments, in A, each R 11 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, -SO3H, [ka] or R 11 and the adjacent nitrogen atom form a five-membered heterocycle.

[0449] In some embodiments, -(A) v -but

[0450] [ka]

[0451] and each R 11 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, -SO3H,

[0452] [ka]

[0453] or R 11 and the adjacent nitrogen atom form a 5-membered heterocycle, and v is an integer of 1 to 4, preferably 1 or 2.

[0454] In some embodiments, A is linked via the carbonyl terminus to -(T) o -or -L5-.

[0455] In some embodiments, L5

[0456] [ka]

[0457] is.

[0458] In some embodiments, L5

[0459] [ka]

[0460] is.

[0461] In some embodiments, L5

[0462] [ka]

[0463] is.

[0464] In some embodiments, -L5- is linked to D via the carbonyl terminus.

[0465] In some embodiments, each T is independently (CH) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -C 6~10 Arylene-(CH2) y -, -(CH2) x -5-10 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~10 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 10-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x -C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)-, C 1~20 Alkylidene or C 2~20 It is alkenylene, and x and y are each independently any integer of 0 to 10.

[0466] In some embodiments, each T is independently -(CH) x -C(O)-, -NR h -, -O-, -S-, -(CH2) x -phenylene-(CH2) y -, -(CH2) x -5-6 membered heteroarylene-(CH2) y -, -(CH2) x -C 3~8 Cycloalkylene-(CH2) y -, -(CH2) x -3 to 8-membered heterocycloalkylene-(CH2) y -, -NR h -(CH2) x -C(O)-, -O-(CH2) x-C(O)-, -S-(CH2) x -C(O)-, -(CH2) x CH(NHR h )-C(O)- or C 1~6 It is alkenylene, and x and y are each independently any integer of 0 to 10.

[0467] In some embodiments, R h is hydrogen or C 1~6 alkyl, and R h is preferably hydrogen or C 1~3 It is alkyl.

[0468] In some embodiments, -(T) w -but

[0469] [ka]

[0470] and -(T) w - is linked to M' via the a-terminus. In some embodiments, each x is independently an integer of 0 to 10, and x is more preferably an integer of 0 to 6.

[0471] In some embodiments, each y is independently an integer of 0-10, and the y is more preferably an integer of 0-6.

[0472] In some embodiments, -(T) o -but

[0473] [ka]

[0474] and -(T) o - is linked to the -PEG- or D via the b-terminus.

[0475] In some embodiments, each x is independently an integer from 0 to 10, and more preferably an integer from 0 to 6.

[0476] In some embodiments, PEG is -(CH2CH2O) n -(CH2) u -or-(CH2CH2O) n -(CH2) u It is —C(O)—, n is an arbitrary integer of 1 to 30, and u is an arbitrary integer of 1 to 5.

[0477] In some embodiments, LX is M'-(T) w -(A) v -L5- * If M', -(T) w -, -(A) v - and -L5- do not simultaneously satisfy the following conditions, and M' is maleimide (

[0478] [ka]

[0479] ) and -(T)w- is caproyl, and -(A) v - is -Val-Cit-, -Val-Ala, or -Gly-Gly-Phe-Gly-, and -L5- is PABC(

[0480] [ka]

[0481] )

[0482] In some embodiments, LX is M'-(T) w -(A) v -L5- * and LX is preferably M'-CH2-(C 5~6 Cycloalkylene)-C(=O)-(A) v -L5-, M'-(CH2) x -C(=O)NH-CH2-CH(NHR h )-C(=O)-(A) v-L5-, M'-(phenylene)-CH2-C(=O)-(A) v -L5- or M'-CH2-(5- to 6-membered heterocyclylene)-C(=O)-(A) v -L5-.

[0483] In some embodiments, LX is M'-(T) w -PEG-(A) v -L5- * and LX is preferably M'-(CH2) x -C(=O)NH-PEG-(A) v -L5-, M'-(phenylene)-CH2-C(=O)NH-PEG-(A) v -L5-, M'-CH2-(C 5~6 Cycloalkylene)-C(=O)NH-PEG-(A) v -L5- or M'-CH2-(5- to 6-membered heterocyclylene)-C(=O)NH-PEG-(A) v -L5-.

[0484] In some embodiments, LX is M'-(T) w -(A) v -(T) o - * and LX is preferably M'-(CH2) x -C(=O)NH-(A) v -NH-CH2-.

[0485] In some embodiments, LX is any one combination of the following: A) M'-PEG-, B) M'-(CH2) x -, C) M'-(CH2) x -C(O)-, D) M'-(CH2) x -(C 5~6 Cycloalkylene)-(CH2) y -C(O)NH-PEG-, E) M'-(CH2) x -(5-6 membered heterocyclylene)-(CH2) y-C(O)NH-PEG-, F)M'-(CH2) x -(phenylene)-(CH2) y -C(O)NH-PEG-, G) M'-(CH2) x -C(O)NH-PEG-, H)M'-(CH2) x -C(O)NH-(CH2) x -C(O)NH-PEG-, I) M'-(CH2) x -C(O)NH-(CH2) x -C(O)NH-PEG-NH-(CH2) x -C(O)-, J)M'-(CH2) x -(C 5~6 Cycloalkylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, K)M'-(CH2) x -(5-6 membered heterocyclylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, L)M'-(CH2) x -(phenylene)-(CH2) y -C(O)NH-(CH2) x -NHC(O)-, M)M'-(CH2) x -C(O)NH-(CH2) x -C(O)-L5-, N)M'-(CH2) x -C(O)NH-PEG-L5-, O)M'-(CH2) x -(phenylene)-(CH2) y -C(O)-(A) v -, P)M'-(CH2) x -C(O)NH-(C 3~6 Cycloalkylene)-C(O)-(A) v -, Q) M'-(CH2) x -C(O)NH-PEG-(A) v-, R)M'-(CH2) x -C(O)NH-PEG-(A) v -L5-, S)M'-(CH2) x -(C 5~6 cycloalkylene)-C(O)-, T)M'-(CH2) x -(5- to 6-membered heterocyclylene)-C(O)-, U) M'-(phenylene)-(CH2) y -C(O)-, V) M'-(CH2) x -C(O)-(A) v -NH-PEG, W)M'-(CH2) x -C(O)-(A) v -NH-(CH2) x -C(O)-, X)M'-(CH2) x -C(O)-(A) v -, Y)M'-(CH2) x -(5-6 membered heterocyclylene)-C(O)-(A) v -, Z)M'-(CH2) x -C(O)NH-CH2-CH(NHR h )-C(O)-(A) v -or AA) M'-(phenylene)-(5-6 membered heterocyclylene)-C(O)-, AB) M'-(phenylene)-(CH2) y -C(O)NH-(CH2)x-PEG-(A) v -, AC)M'-(phenylene)-C(O)NH-(CH2)x-(A) v -L5-, or AD)M'-(CH2) x -PEG-(A) v -.

[0486] In some embodiments, LX is

[0487] [ka] JPEG2025537044000123.jpg244169 JPEG2025537044000124.jpg251169 JPEG2025537044000125.jpg225169 JPEG2025537044000126.jpg235169 JPEG2025537044000127.jpg240169 JPEG2025537044000128.jpg118169

[0488] is.

[0489] In some embodiments, LX is

[0490] [ka] JPEG2025537044000130.jpg102169

[0491] is.

[0492] In some embodiments, the compound of Formula II is any one of the following compounds:

[0493] [ka] JPEG2025537044000132.jpg250169 JPEG2025537044000133.jpg216169 JPEG2025537044000134.jpg232169 JPEG2025537044000135.jpg253169 JPEG2025537044000136.jpg241169 JPEG2025537044000137.jpg235169 JPEG2025537044000138.jpg240169 JPEG2025537044000139.jpg242169 JPEG2025537044000140.jpg252169 JPEG2025537044000141.jpg236169 JPEG2025537044000142.jpg236169 JPEG2025537044000143.jpg249169 JPEG2025537044000144.jpg230169

[0494] or a pharmaceutically acceptable salt thereof.

[0495] In some embodiments, the compound of Formula II is any one of the following compounds:

[0496] [ka] JPEG2025537044000146.jpg232169 JPEG2025537044000147.jpg236169 JPEG2025537044000148.jpg235169 JPEG2025537044000149.jpg247169 JPEG2025537044000150.jpg238169 JPEG2025537044000151.jpg250169 JPEG2025537044000152.jpg21169

[0497] or a pharmaceutically acceptable salt thereof.

[0498] In some embodiments, the compound of formula II is compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, or A-27.

[0499] In some embodiments, the compound according to formula II is compound B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, or B-11.

[0500] The present invention further provides a compound of formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0501] [ka]

[0502] wherein R is -L'-L1-R7, L' is -C(=O)-, -C(=O)-NR9- or -C(=S)-NR9-; R9 is independently hydrogen, C 1~6 Alkyl or halogenated C 1~6 is alkyl, L1 is independently a bond, C 1~6 Alkylidene or C 2~6 is alkenylene, R7 is independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, or one, two, or three R 7-1 phenyl substituted with one, two or three R 7-2 5-6 membered heteroaryl substituted with one, two or three R 7-3 or one, two, or three R 7-4 is an 8- to 12-membered fused ring group substituted with In R7, the 5- to 6-membered heteroaryl and the one, two, or three R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; and the 3- to 8-membered heterocycloalkyl and the 1, 2, or 3 R 7-3 In the "3- to 8-membered heterocycloalkyl" in the 3- to 8-membered heterocycloalkyl substituted by, the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; In R7, the 8- to 12-membered fused ring group and the one, two, or three R 7-4 the 8- to 12-membered fused ring groups among the 8- to 12-membered fused ring groups substituted with are independently ring A and fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R 7-1 , R 7-2 , R 7-3 and R 7-4 are independently amino, -L3-NH2, -L3-OH, -C(=O)-L3-OH or -C(=O)-L3-NH2, and L3 is independently C 1~6 Alkylidene or -(CH2CH2O) m’ -C 1~6 alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 0 or 1, R8 and R 8’ are independently hydrogen or C 1~6 alkyl, or R and R 8’ carbonyl, C, along with both of their connecting carbon atoms3~10 forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R1, R2, and R3 are independently hydrogen, deuterium, or halogen; R4 and R 4’ independently C 1~6 Alkyl, C 1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R 4-1 are independently hydroxyl, amino, -OC(=O)NR a R b or

[0503] [ka]

[0504] and R a and R b are independently hydrogen, C 1~6 Alkyl or C 3~10 is cycloalkyl, R i is hydrogen, C 1~6 alkyl or benzyl, and R k is hydrogen, halogen or C 1~6 alkyl, and R i C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~6 Alkyl, 3-10 membered heterocycloalkyl-C 1~6 Alkyl, C 6~10 Aryl-C 1~6 Alkyl or 5-10 membered heteroaryl-C 1~6 is alkyl, R jIn the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C 1~6 In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C 1~6 In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R4 and R 4’ At least one of the 1~6 Alkoxyl, or one, two or three R 4-1 C replaced by 1~6 is alkyl, Also, the compound shown in formula D' is not a compound shown in Table 3.

[0505] In some embodiments, the compound of Formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein some groups are defined as follows, and the remaining groups are defined as described in any other embodiment (hereinafter referred to as "some embodiments"); The compound of formula D' satisfies one, two or three of the following conditions: (1) L1 is independent and C 1~6 Alkylidene or C 2~6 is alkenylene, (2) R7 is independently phenyl substituted with one amino group, 5- to 6-membered heteroaryl substituted with one amino group, 3- to 8-membered heterocycloalkyl substituted with one amino group, or 8- to 12-membered fused ring group substituted with one amino group; (3) R4 and R 4’ At least one of the1~6 Alkoxyl or one, two or three R 4-1 C replaced by 1~6 alkyl, and the R 4-1 are independently -OC(=O)NR a R b or

[0506] [ka]

[0507] is.

[0508] In the compound represented by formula D' or a pharmaceutically acceptable salt thereof, the left or right end of L' is linked to L1.

[0509] In some embodiments, L' is -C(=O)-, -C(=O)-NR9-, or -C(=S)-NR9-, and the right end thereof is connected to L1.

[0510] In some embodiments, R is —C(O)—NR 9 —L 1 —R 7 .

[0511] In some embodiments, R9 is hydrogen.

[0512] In some embodiments, in L1, the C 1~6 The alkylidene is methylene or ethylidene.

[0513] In some embodiments, L1 is a bond or -CH2-.

[0514] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein the 5- to 6-membered heteroaryl has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and the 5- to 6-membered heteroalkenyl ring has heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0515] In some embodiments, in R7, the 8- to 12-membered fused ring group can be ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl or phenyl, and ring B is a 5- to 6-membered heteroalkenyl ring, which is connected to L1 via ring A; in the 5- to 6-membered heteroaryl, the heteroatom is N and the number of heteroatoms is 1 or 2; and in the 5- to 6-membered heteroalkenyl ring, the heteroatom is N and the number of heteroatoms is 1 or 2.

[0516] In some embodiments, in R7, the 5- to 6-membered heteroaryl may have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms may be 1, 2, or 3.

[0517] In some embodiments, in R7, the heteroatom in the 5- to 6-membered heteroaryl can be N, and the number of heteroatoms can be one or two.

[0518] In some embodiments, for R7, the 5-6 membered heteroaryl may be pyridyl, pyrazinyl, or pyridazinyl, or may be pyridin-3-yl, pyrazin-2-yl, or pyridazin-3-yl.

[0519] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N.

[0520] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2.

[0521] In some embodiments, R7 is selected from the group consisting of the 5- to 6-membered heteroaryl and one, two, or three of the R 7-2 In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, said 5- to 6-membered heteroaryl may be pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0522] In some embodiments, in ring A, the heteroatom in said 5-6 membered heteroaryl ring is N.

[0523] In some embodiments, in ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2.

[0524] In some embodiments, in ring A, the 5- to 6-membered heteroaryl ring can be a pyridine ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring.

[0525] In some embodiments, in Ring B, the heteroatom in said 5-6 membered heteroalkenyl ring is N.

[0526] In some embodiments, in ring B, the number of heteroatoms in the 5- to 6-membered heteroalkenyl ring is 1 or 2.

[0527] In some embodiments, R7 is

[0528] [ka]

[0529] is.

[0530] In some embodiments, R7 is

[0531] [ka]

[0532] is.

[0533] In some embodiments, m is 1.

[0534] In some embodiments, R and R 8’ are each independently C 1~6 alkyl, 1~6 Alkyl is preferably methyl.

[0535] In some embodiments, R and R 8’ are each independently unsubstituted C 1~6 alkyl, or R and R 8’ Both of the carbon atoms to which they are attached are oxo or unsubstituted C 3~6 Forms a cycloalkyl.

[0536] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form oxo, cyclopropyl or cyclobutyl.

[0537] In some embodiments, R and R 8’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0538] In some embodiments, R and R 8’ C together with both of the carbon atoms that connect them 3~10 Form a cycloalkylene, 3~10The cycloalkylene can be cyclopropyl or cyclobutyl.

[0539] In some embodiments, R and R 8’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in the 3- to 10-membered heterocycloalkylene is N or O.

[0540] In some embodiments, R and R 8’ together with the carbon atoms to which they are both connected to form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in the 3- to 10-membered heterocycloalkylene is 1 or 2.

[0541] In some embodiments, R and R 8’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, which can be oxycyclopropyl, azacyclopropyl, oxacyclobutylene, or azetidine.

[0542] In some embodiments, R1 is H, R2 is H, and R3 is H or F.

[0543] In some embodiments, for R1, R2, and R3, the halogen is F, Cl, or Br.

[0544] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R and R 4’ is substituted at any position with one substituent selected from hydroxyl and amino.

[0545] In some embodiments, R and R 4’ are each independently C 1~6 alkyl, and R or R 4’ is substituted at any position by one hydroxyl.

[0546] In some embodiments, R4 is -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3, and R 4’ is -CH2CH2OH or -CH2CH2CH3.

[0547] In some embodiments, R and R 4’ So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0548] In some embodiments, R and R 4’ So, the above C 1~6 The alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl.

[0549] In some embodiments, R and R 4’ So, one, two or three R's? 4-1 The C is substituted with 1~6 C in alkyl 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0550] In some embodiments, R i So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0551] In some embodiments, R k So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0552] In some embodiments, R j So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0553] In some embodiments, R j So, C 6~10Aryl-C 1~6 In the case of alkyl, the C 6~10 The aryl can be phenyl.

[0554] In some embodiments, R j So, C 6~10 Aryl-C 1~6 In the case of alkyl, the C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0555] In some embodiments,

[0556] [ka]

[0557] So, R i is methyl and R j is isopropyl or benzyl, and R k is hydrogen.

[0558] In some embodiments,

[0559] [ka]

[0560] but

[0561] [ka]

[0562] is.

[0563] In some embodiments, R a and R b So, the above C 1~6 Alkyl can be methyl, ethyl, n-propyl or isopropyl.

[0564] In some embodiments, R aand R b So, the above C 3~10 Cycloalkyl can be cyclopropyl, cyclobutyl or cyclopentyl.

[0565] In some embodiments, R and R 4’ are independently -OCH2CH3, -CH2CH2NH2, -CH2CH2OH, or -CH2CH2CH3.

[0566] In some embodiments, R and R 4’ At least one of is —OCH2CH3, —CH2CH2NH2, or —CH2CH2OH.

[0567] In some embodiments, in L3, C 1~6 Alkylidene is C 1~3 It may be alkylidene.

[0568] In some embodiments, m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0569] In some embodiments, the compound of formula D' is Any one of compounds 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31 and 32.

[0570] The present invention provides a pharmaceutical composition comprising substance K and pharmaceutically acceptable excipients, the substance K is substance K-1, substance K-2 or substance K-3, the substance K-1 is an antibody-immunostimulating complex shown in formula I above or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound represented by the above formula II or a pharmaceutically acceptable salt thereof, The substance K-3 is a compound represented by the above formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; In some embodiments, the compound of formula II is compound 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, or 32.

[0571] In some embodiments, the dose of substance K can be a therapeutically effective amount.

[0572] In some embodiments, the antibody-immunostimulatory complex of formula I or a pharmaceutically acceptable salt thereof, the compound of formula II or a pharmaceutically acceptable salt thereof, or the compound of formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.

[0573] In some embodiments, the antibody-immunostimulatory complex of Formula I or a pharmaceutically acceptable salt thereof, the compound of Formula II or a pharmaceutically acceptable salt thereof, or compound 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, or 32, or a pharmaceutically acceptable salt thereof, may be a therapeutically effective amount.

[0574] In the pharmaceutical composition, the pharmaceutically acceptable excipient may comprise a pharmaceutically acceptable carrier, diluent and / or excipient.

[0575] The pharmaceutical compositions may be administered via conventional routes, including, but not limited to, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, topical administration (eg, intratumoral injection), and the like.

[0576] The present invention further provides the use of substance K or the above pharmaceutical composition in the preparation of a drug for regulatory T cells and other immune cells, wherein the substance K is substance K-1, substance K-2 or substance K-3; the substance K-1 is an antibody-immunostimulating complex shown in formula I above or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound represented by the above formula II or a pharmaceutically acceptable salt thereof, The substance K-3 is a compound represented by the above formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; In some embodiments, the compound of formula II is compound 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, or 32.

[0577] In some embodiments, the dose of substance K can be a therapeutically effective amount.

[0578] The present invention provides the use of substance K or the above pharmaceutical composition in the preparation of a drug for treating and / or alleviating tumors, wherein the substance K is substance K-1, substance K-2 or substance K-3; the substance K-1 is an antibody-immunostimulating complex shown in formula I above or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound represented by the above formula II or a pharmaceutically acceptable salt thereof, The substance K-3 is a compound represented by the above formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; In some embodiments, the compound of formula II is compound 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, or 32.

[0579] In some embodiments, the dose of substance K can be a therapeutically effective amount.

[0580] The present invention provides a use of substance K or the above pharmaceutical composition in preparing a medicament for treating, alleviating and / or preventing a TLR8-mediated related disease, wherein the substance K is substance K-1, substance K-2 or substance K-3; the substance K-1 is an antibody-immunostimulating complex shown in formula I above or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound represented by the above formula II or a pharmaceutically acceptable salt thereof, The substance K-3 is a compound represented by the above formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; In some embodiments, the compound of formula II is compound 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, or 32.

[0581] In some embodiments, the TLR8-mediated related disease refers to a tumor or a viral infection.

[0582] In some embodiments, the dose of substance K can be a therapeutically effective amount.

[0583] The tumor may be a malignant tumor, including metastatic and non-metastatic cancers, as well as familial and sporadic cancers, and may include solid and non-solid tumors.

[0584] The present invention further provides a therapeutic method for treating or preventing a disease, which comprises administering the above-mentioned substance K-1, the above-mentioned substance K-2, or the above-mentioned substance K-3 to a subject; The disease is a disease associated with regulatory T cells and other immune cells, a tumor, or a TLR8-mediated disease.

[0585] In the present invention, the terms "tumor" and "cancer" have the same meaning, and include eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma and medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including adenocarcinoma and nephroblastoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, These include, but are not limited to, one or more of bile duct cancer, cervical cancer, liver cancer, sarcoma, skin cancer, lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell chronic lymphocytic leukemia, and B-cell chronic lymphocytic leukemia), myeloid leukemia (including acute myeloid leukemia and chronic myeloid leukemia), and AIDS-related leukemia.

[0586] In the present invention, the tumor is preferably a tumor with HER2 expression (which may be a high HER2-expressing tumor or a low HER2-expressing tumor). In the present invention, the tumor is more preferably a high HER2-expressing tumor.

[0587] In the present invention, unless otherwise specified, the term "optionally substituted at any position with one or more groups" means that any one or more hydrogen atoms of one or more designated atoms on that group are replaced with the designated group, provided that the proviso does not exceed the normal valence of the designated atom, and that the substitution at any position is a common and reasonable substitution in the art.

[0588] In the present invention, when a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any available ring atom in the ring.

[0589] In the present invention, any combination of variables is permissible only if such combination results in a stable compound.

[0590] For purposes of the present invention, when any variable occurs more than once in any composition or structure of a compound, its definition at each occurrence is independent. For example, when R is substituted with one or more groups, each substituent is an independent substituent and may be the same or different.

[0591] Unless otherwise stated, the following terms appearing in the present specification and claims have the following meanings.

[0592] The term "antibody" refers to any form that exhibits a desired biological activity (e.g., by inhibiting binding of a ligand to its receptor or by inhibiting receptor signaling induced by a ligand). Therefore, "antibody" is used in the broadest sense and explicitly includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (including bispecific antibodies). Naturally occurring "antibodies" are glycoproteins comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region and a light chain constant region. The light chain constant region contains a CL domain. The variable regions of the heavy and light chains contain a binding domain (antigen-binding domain) that interacts with an antigen. The antigen-binding domain can be provided by one or more variable regions on an antibody. Specifically, the antigen-binding domain comprises an antibody light chain variable domain (VL) and an antibody heavy chain variable domain (VH). The antibody can be a monoclonal antibody, a human antibody, a humanized antibody, or a chimeric antibody. These antibodies can have any type (IgG, IgE, IgM, IgD, IgA, and IgY) or subtype (IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). The present invention includes not only intact antibodies, but also immunologically active antibody fragments (including Fab, F(ab')2, scFv, or Fv fragments) or fusion proteins formed from antibodies and other sequences. Therefore, the term "antibody" as used herein further includes the antibody fragments, derivatives, and analogs. In some specific examples, the antibody binds to any antigen or combination of antigens, including, but not limited to, the following:HER2, 5T4(TPBG), Trop-2, FZD10, GCC, PTK7, Balloon H, LIVI, HER3, CD142(Tissue factor) ROR1, ROR2, P-cadherin, IGF-1R, AXL, NaPi2b, EpCAM, Nectin-4(191P4D12), PSMA, FRα(F olRα), MSLN(mesothelin), c-Met, B7-H3, B7-H4, CEACAM5, EGFR, CD70, CD71, CD73, CD74, FGFR2, and FGF R4, BCMA, CD25, EphA2, EphB3, c-Kit, CDH6, IL-13Rα2, CD47, SIRPα, CD48, CD40, CD105, CD228, NCAM -1, SEZ6, DPEP3, RNF43, CS1, DLL3, DLL4, EMR2, TNFRSF21, TNFSF9, MMP16, LRRC15, UPK1B, Claudin6. Claudin9, Claudin18.2, MFI2, PRLR, BMPR1B, VEGF, PDGF, PDGFR-α, PAI-1, LING01, KaAG1, Steap1. ASCT2, DLK1, HLL2, MUC1, CA6, ADAM9, PMEL17, DC-SiGN, CCR2, CCR7, BDNF, Notch, EGFRvIII, CD3, IGF 1R, EFNA4, EBD, CDCP1, GD3, 24P4C12, STn, lewisY, NTB-A, 158P1D7, TIGIT, C4.4a, MMP-9, MG7Ag, 4-2. 1BB(CD137), CanAg, cream2, CD19, CD22, CD33, CD37, CD79b, CD30, CD20, CD123, PD-1, and PD-L1.

[0593] In the present invention, the "antibody" may further include engineered antibodies, which 1) comprise one or more non-naturally encoded amino acids incorporated into the heavy chain, light chain, or both the heavy and light chains, including, but not limited to, one or more of the following non-natural amino acids (p-acetylphenylalanine, ortho-acylphenylalanine, meta-acylphenylalanine, p-acetyl-L-phenylalanine, p-acyl-L-phenylalanine, p-propargyloxy-L-phenylalanine, 4-azido-L-phenylalanine, p-azidoethyloxyphenylalanine, p-azidomethylphenylalanine, etc.), and 2) have cysteine ​​residues inserted at different positions in the antibody heavy or light chain, or have cysteine ​​residues substituted for specific amino acid residues in the antibody heavy or light chain to form unpaired cysteines for conjugation.

[0594] In the present invention, the "antibody" or antigen-binding fragment thereof may comprise an Fc region, which may be further modified. In some cases, one or more mutations in the Fc region result in an improvement of a drug containing such a modified Fc region (e.g., reduced effector function, altered metabolic half-life of the drug, or altered stability of the drug). In some cases, the modified Fc region may comprise one or more mutations that reduce or eliminate interactions between the antibody and the immune system. Important interactions may include the interaction of the antibody Fc with the Fcγ receptor and the interaction with C1q of the complement system. When the antibody of the present invention is of IgG1 isotype, effector function can be adjusted by substituting some amino acid residues in the constant region. IgG1 mutants that reduce or weaken effector function include, but are not limited to, IgG1 LALA (IgG1-L234A, L235A), IgG1 LAGA (IgG1-L235A, G237A), and IgG1 AAG (IgG1-L234A, L235A, P329G). The above L234A and L235A indicate alanine substitutions for leucine at positions 234 and 235, as determined by the EU index (Proc. Natl. Acad. Sci. USA, Vol. 63, No. 1 (May 15, 1969), pp. 78-85). G237A indicates alanine substitution for glycine at position 237, as determined by the EU index. P329G indicates alanine substitution for proline at position 329, as determined by the EU index. In some cases, glycosylation modification of the Fc terminus can alter the pharmacodynamic and pharmacokinetic properties of drugs (Journal of Pharmaceutical Sciences. 2015, 104(6), 1866-1884). For example, natural antibodies produced by mammalian cells typically contain branched and biantennary oligosaccharides, which are typically N-linked to Asn297 in the Fc-terminal CH2 domain. Oligosaccharides can contain a variety of carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, sialic acid, and fucose attached to GlcNAc within the stem of the biantennary oligosaccharide structure.Modification of antibody oligosaccharides can produce antibody variants with improved properties. For example, fucosylation can enhance antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP). Decreased terminal sialylation or increased terminal acetylglycosamination can enhance ADCC. Treating CHO cells with mannosidase inhibitors can increase mannosylation and fucosylation, thereby improving ADCC and slightly reducing CDC. Glycosylation can also be modified by mutations such as N297Q, which mutates asparagine at position 297 to glutamine.

[0595] The term "monoclonal antibody," also referred to as "mAb," refers to polypeptides having substantially the same amino acid sequence or derived from the same genetic source. Monoclonal antibodies are highly specific and can be directed against a single antigenic site. In contrast to conventional (polyclonal) antibody preparations, which typically include multiple different antibodies directed against multiple different determinants (epitopes), each monoclonal antibody is directed against only a single determinant on an antigen. Table 7 lists several monoclonal antibodies, their corresponding antigens, and indications, including but not limited to those listed in Table 7 below.

[0596] [Table 7] TIFF2025537044000162.tif219169

[0597] The terms "fragment," "derivative," and "analog" refer to polypeptides that retain substantially the same biological function or activity as an antibody of the invention. A polypeptide fragment, derivative, or analog of the invention can be a) a polypeptide in which one or more conservative or non-conservative amino acid residues (preferably conservative amino acid residues) are substituted (such substituted amino acid residues may or may not be encoded by the genetic code), or b) a polypeptide having substitution groups at one or more amino acid residues, or c) a polypeptide formed by fusing the mature polypeptide with another compound (e.g., a compound that extends the half-life of the polypeptide, such as polyethylene glycol), or d) a polypeptide formed by fusing an additional amino acid sequence to the polypeptide sequence (e.g., a leader sequence or secretory sequence, or a sequence for purifying the polypeptide or a proteolytic sequence, or a fusion protein formed with a 6His tag).

[0598] In the present invention, a biosimilar of the monoclonal antibody refers to a product that has slight differences in clinically inactive components, but is very similar to the monoclonal antibody, with no clinically significant differences in safety and / or efficacy.

[0599] The term "HER2" (also known as ERBB2, NEU, NGL, TKR1, CD340, p185, MLN19, and HER-2 / neu) refers to a transmembrane tyrosine kinase receptor of the epidermal growth factor (EGF) receptor family. HER2 contains an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. HER2 does not possess its own ligand-binding domain and therefore cannot bind to growth factors. However, HER2 tightly binds to other EGF receptor family members (e.g., HER1 or HER3) to form heterodimers, stabilizing ligand binding and enhancing activation of kinase-mediated downstream signaling pathways. In humans, there are HER2 isoforms A, B, C, D, and E. As used herein, "HER2" encompasses all HER2 isoforms.

[0600] The term "anti-HER2 antibody" refers to an antibody that targets HER2, and the anti-HER2 antibody may be derived from any species, such as human, rat, mouse, rabbit, etc. The anti-HER2 antibody is preferably a monoclonal anti-HER2 antibody, and more preferably a humanized anti-HER2 antibody. The anti-HER2 antibodies include, but are not limited to, pertuzumab, trastuzumab, trastuzumab biosimilars (e.g., inetamab, coprelotamab, SIBP-01, HL02, TX05, ALT02, EG12014), pertuzumab biosimilars (e.g., SYSA1901, TQB2440, HLX11, HS627, KM118), margetuximab, HT-19, ambenitamab, zanidatamab, etc.; Trastuzumab (also known as Herceptin or Herclon) is a humanized monoclonal antibody that can bind to the juxtamembrane region of the extracellular structure of the HER2 receptor (Hudis CA, N Engl J Med. 2007;357(1):39-51). The amino acid sequences of the trastuzumab heavy and light chain variable regions are disclosed in U.S. Patent No. 5,821,337. Trastuzumab interacts with the kringle region formed by human HER2 residues 557-561, 570-573, and 593-603 (Cho et al., Nature 421:756-760, 2003). Trastuzumab can disrupt HER2 signaling by preventing HER2 receptor dimerization, promoting HER2 receptor endocytosis, and inhibiting shedding of the extracellular structural domain. Another important mechanism of action of anti-HER2 antibodies is their ability to mediate antibody-dependent cellular cytotoxicity (ADCC). In ADCC, anti-HER2 antibodies bind to tumor cells and recruit immune cells such as macrophages via Fcγ receptor (FcγR) interactions. Trastuzumab contains a conserved human IgG Fc region, allowing it to recruit immune effector cells responsible for antibody-dependent cellular cytotoxicity (Hudis CA, N Engl J Med. 2007;357(1):39-51). Trastuzumab was approved by the US FDA in September 1998 for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who have received one or more chemotherapy regimens. Pertuzumab (also known as Perjeta or Omnitarg) is a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor and inhibits dimerization of HER2 with the HER receptor. The amino acid sequences of the heavy and light chain variable regions of pertuzumab are disclosed in U.S. Patent No. 7,560,111. Pertuzumab interacts primarily with residues 245-333 of human HER2, particularly His245, Val286, Ser288, Leu295, His296, or Lys311 (Franklin et al., Cancer Cell 5:317-328, 2004). Studies have shown that pertuzumab is more effective than trastuzumab in disrupting HER1-HER2 and HER3-HER2 complex formation in breast and prostate cancer cell lines (Agus et al., J Clin Oncol. 2005;23(11):2534-43. Epub Feb 7, 2005). Pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received anti-HER2 therapy or chemotherapy. Margetuximab (MGAH22, also known as Margenza) is an Fc-engineered monoclonal antibody targeting the HER2 protein, binding to the extracellular domain of HER2. Its variable region sequence differs from that of trastuzumab by only a few amino acids. The Fc region contains five mutations (F243L / R292P / Y300L / L235V / P396L) that enhance its affinity for CD16A and enhance its ADCC activity. The modified Fc region of margetuximab increases binding to the activating Fc receptor FCGR3A (CD16A) and decreases binding to the inhibitory Fc receptor FCGR2B (CD32B), resulting in more potent ADCC and NK cell activation (Nordstrom J. et al., Breast Cancer Research, 2011;13:R123). Margetuximab was approved by the U.S. FDA in December 2020 for the treatment of adult patients with metastatic HER2-positive breast cancer (MBC) who have received two or more anti-HER2 targeted therapies, including at least one anti-HER2 targeted therapy, for the treatment of metastatic breast cancer. HT-19 is another anti-HER2 monoclonal antibody whose epitope on human HER2 is distinct from that of trastuzumab or pertuzumab, and its ability to inhibit HER2 signaling has been shown to be equivalent to that of trastuzumab, and it can promote HER2 degradation in combination with trastuzumab and pertuzumab (Bergstrom DA et al., Cancer Res. 2015;75:LB-231).

[0601] Ambenitamab and zanidatamab are bispecific antibodies directed against two different epitopes (ECDII and ECDIV) of Her2.

[0602] In the present invention, the anti-HER2 antibody is not limited to the antibodies listed above, as long as it is an antibody that specifically binds to HER2 (for example, an anti-HER2 antibody that has the activity of binding to HER2 and being internalized into HER2-expressing cells).

[0603] The isotype of the "anti-HER2 antibody" in the present invention includes IgG1, IgG2, IgG3, IgG4, etc., and is preferably IgG1, IgG2, or IgG4.

[0604] The term "low HER2 expression" generally refers to a HER2 expression level that is IHC1+ or IHC2+ / FISH-negative (i.e., IHC2+ and FISH are simultaneously negative) in a clinical test. The terms "high HER2 expression" and "HER2-positive" are used interchangeably and generally refer to a HER2 expression level that is IHC2+ / FISH-positive (i.e., IHC2+ and FISH are simultaneously positive) or IHC3+ in a clinical test. When IHC staining intensity is reported as a range, the term "low HER2-low expression" herein includes the ranges of IHC0-1+ and IHC1+-2+, in addition to IHC1+ or IHC2+ / FISH-negative. The terms "high HER2 expression" and "HER2-positive" respectively include the ranges of IHC2+ to 3+, in addition to IHC2+ / FISH-positive or IHC3+. In the present invention, FISH negative refers to the FISH test result not showing amplification of the HER2 gene, and FISH positive refers to the FISH test result showing amplification of the HER2 gene.

[0605] The term "5T4," also known as 5T4 carcinoembryonic antigen or trophoblast glycoprotein TPBG, is a 72 kDa glycoprotein defined by a monoclonal antibody raised against a glycoprotein isolated from wheat germ agglutinin derived from human placental syncytiotrophoblast microvilli. While its expression is limited in normal tissues, it is overexpressed in many types of cancer cells. Anti-5T4 monoclonal antibodies include, but are not limited to, H8 and its humanized monoclonal antibodies disclosed in WO 2006 / 031653 A1, A1, A2, A3 and their humanized monoclonal antibodies (e.g., huA1) disclosed in US 8,044,178 B2, the engineered A1 monoclonal antibody disclosed in WO 2013068874, and naptumomab.

[0606] The term "Claudin18.2," also known as CLDN18.2, is a highly selective cell lineage marker whose expression in normal tissues is strictly restricted to differentiated epithelial cells of the gastric mucosa, but not in the gastric stem cell region. It is expressed in a significant proportion of primary gastric cancers, and its expression level is maintained in cancer tissues of gastric metastases. In addition to gastric cancer, Claudin18.2 expression is also observed in pancreatic cancer and lung cancer. Anti-Claudin18.2 monoclonal antibodies include, but are not limited to, zolbetuximab, osemitamab, ASKB589, LM-102, MIL93, and NBL-015.

[0607] The term "CEACAM5," abbreviated as CEA and also known as CD66e, is an acidic glycoprotein that is a member of the immunoglobulin superfamily and contains seven structural domains bound to the cell membrane via a glycosylphosphatidylinositol anchor. It is primarily present in adult cancer tissues and fetal gastrointestinal tissues, where it is involved in intercellular adhesion during cancer cell invasion and metastasis, and is a relatively broad-spectrum tumor marker. Anti-CEA monoclonal antibodies include, but are not limited to, labetuzumab, SAR408377 (the antibody portion of tusamitamab ravtansine), and RG6123.

[0608] The term "Trop-2" refers to human trophoblast cell surface antigen 2, a cell surface glycoprotein encoded by the TACSTD2 gene. Trop-2 is rarely or not expressed in normal adult tissues, with low levels of expression limited to cells in epithelial regions. However, it is overexpressed in various epithelial-derived tumors, including gastric cancer, lung cancer, intestinal cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, and liver cancer. Anti-Trop-2 monoclonal antibodies include, but are not limited to, sacituzumab (hRS7, the antibody portion of sacituzumab govitecan) and datopotamab (the antibody portion of Dato-Dxd).

[0609] The term "nectin-4," also known as the 191P4D12 protein, is a cell adhesion molecule belonging to the nectin protein family, which plays an important role in various biological processes during the development and adulthood of epithelial, endothelial, immune, and neural cells. Nectin-4 is a tumor-associated antigen, primarily associated with tumors with poor prognosis. Anti-nectin-4 monoclonal antibodies include, but are not limited to, enfortumab (Ha22-2).

[0610] The term "linker" refers to a degradable or non-degradable linking fragment used to link a small molecule drug D to an antibody. One antibody molecule may be linked to multiple linkers carrying small molecule drugs D, and typically each linker may be linked to one or more small molecule drugs; however, in the present invention, each linker is preferably linked to one small molecule drug D. Typically, each antibody may be linked to multiple linkers, but in the present invention, each antibody is preferably linked to 1 to 10 linkers, more preferably 1 to 8 linkers.

[0611] In the present invention, a non-degradable linker refers to a linker that has enzymatic and / or chemical stability in vivo and in vitro, and the release of small molecule drug D may not depend on the differential enzyme levels in plasma, tumor tissue, and cells. The release of small molecule drug D occurs through antigen-mediated phagocytosis of the antibody-immunostimulatory complex, followed by degradation of the antibody to the amino acid level, thereby releasing a derivative of the small molecule drug D. The derivative of small molecule drug D consists of small molecule drug D, a linker, and amino acid residues, or small molecule drug D and residues covalently bound to the linker. Antibody-immunostimulatory complexes constructed using such non-degradable linkers have superior stability. Non-degradable linkers include alkylene chains and polymers thereof (e.g., alkylene amide polymers, alkylene glycol polymers, or combinations including alkylene glycol and alkylene amide polymer fragments), ethylene glycol fragments, polyethylene glycol fragments, aromatic or non-aromatic rings, and combinations thereof.

[0612] In the present invention, the degradable linker can be degraded in vivo or in vitro, and includes a linker that can be degraded by a specific enzyme in vivo or in vitro, or includes a linker that is itself chemically unstable. The degradable linker can be degraded in a cell to release the small molecule drug D, for example, it can be reduced in the cytoplasm, degraded under the acidic conditions of the lysosome, or degraded by a specific protease or other enzyme in the cell. The degradable linker includes one or more enzyme-degradable linkers, chemically labile linkers, or other degradable linkers, and the other moiety can be a linker that is not enzyme-degradable or is chemically stable. The chemically labile linker can be an oxime, hydrazone, and / or disulfide group (e.g.,

[0613] [ka]

[0614] ). The linker specifically degraded by an enzyme is 1) a linker formed based on an amino acid residue or a peptide. Because the activity of lysosomal protease in the blood is much lower than that of some tumor tissues, the peptide bond has good serum stability, and therefore the linker can be selectively degraded in specific tumor tissues or cells to release the small molecule drug D. The lysosomal enzyme can be selected from cathepsin B, cathepsin S, plasmin, elastase, β-glucuronidase, β-galactosidase, etc. The peptide-formed linker (-(A) v-) includes, but is not limited to, tetrapeptides (-Gly-Phe-Leu-Gly-, -Ala-Leu-Ala-Leu-, -Gly-Gly-Phe-Gly-, -Leu-Ser-Gly-lys-, -Ala-Ala-Pro-Val-, -Glu-Val-Ala-Gly-, -Glu-Val-Cit-Gly-, -Leu-Ala-Glu-Gly-), tripeptides (-Val-Leu-Lys-, -Ala-Pro-Val-, - These include Ala-Ala-Asn-, -Glu-Val-Cit-, -Leu-Ala-Glu-, -Glu-Val-Ala-, -Val-Cit-Gly-, -Val-Ala-Gly-, -Leu-Ala-Glu- (without limitation), dipeptides (-Val-Cit-, -Cit-Val-, -Val-Ala-, -Ala-Val-, -Ala-Cit-, -Cit-Ala-, -Asn-Cit-, -Cit-Asn-, -Cit-Cit-, - Val-Glu-, -Glu-Val-, -Ser-Cit-, -Cit-Ser-, -Lys-Cit-, -Cit-Lys-, -Asp-Cit-, -Cit-Asp-, -Ala-Val-, -Val-Ala-, -Phe- Lys-, -Lys-Phe-, -Val-Lys-, -Lys-Val-, -Ala-Lys-, -Lys-Ala-, -Phe-Cit-, -Cit-Phe-, -Leu-Cit-, -Cit-Leu-, -Ile-Cit- The linker may be a dipeptide, tripeptide, or tetrapeptide linker, and more preferably a dipeptide linker. The linker specifically degraded by an enzyme is 2) a linker formed from a pyrophosphate ester or a phosphate ester. Lysosomal acid pyrophosphate and acid phosphatase are enzymes that hydrolyze pyrophosphate esters and terminal monophosphate esters to their parent alcohols, respectively, in the lysosome.Targeting these enzymes can effectively release small molecule drugs D terminated in alkyl alcohols. Other degradable linkers can include ester bonds formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with hydroxyls on the small molecule drug D. This type of ester bond can be hydrolyzed under physiological conditions to release the small molecule drug D. Hydrolytically degradable bonds include, but are not limited to, carbonate ester bonds, imine bonds resulting from the reaction of an amine with an aldehyde, phosphate ester bonds resulting from the reaction of a hydroxyl with a phosphate group, acetal bonds resulting from the reaction of a hydroxyl with an aldehyde, and orthoester bonds resulting from the reaction of a formate with a hydroxyl. Cleavable linkers can further include non-cleavable fragments, such as alkylene chains and polymers thereof, polyethylene glycol (PEG) and related polymers, aromatic or non-aromatic rings, and combinations thereof.

[0615] In the present invention, the "linker" may further include a spacer group, and the connector may be directly linked to the connector body or may be linked to the linker in the connector body via the spacer group. The spacer group may be polyethylene glycol and its related polymers, alkylene having 1 to 10 carbon atoms, cyclohexyl, phenyl, 1,3-dioxanyl, amide, ester, oxo, substituted amino, triazolyl, or the like.

[0616] [ka]

[0617] , as well as combinations of any one or more of the above spacer groups.

[0618] In the present invention, the "linker" may further comprise a self-immolative group, which spatially separates the small molecule drug D and the enzyme degradation site. A typical self-immolative group usually comprises the following basic structure:

[0619] [ka]

[0620] The self-sacrificing group is the aminomethylene group, amino C 3~5 It can also be linked to a hydroxyl on small molecule D via an alkanoyl group, a phosphate ester, or a pyrophosphate ester.

[0621] [ka]

[0622] In 1), the site marked with an * is the site for linking to small molecule drug D, preferably the site for linking to an amino on small molecule drug D, and in 2), the site marked with an * is the site for linking to small molecule drug D, preferably the site for linking to a hydroxyl on small molecule drug D.

[0623] In the present invention, the "linker" further comprises a connector, which is linked to an antibody, and can be formed by reacting a connector precursor with a group in the antibody, such as a thiol (e.g., cysteine), amino (e.g., lysine), carbonyl (e.g., p-acetylphenylalanine), aldehyde, azide (e.g., p-azidomethylphenylalanine), or phenol group (e.g., tyrosine). In the present invention, the "connector precursor" can react with an antibody to form a connector that can be linked to the antibody.

[0624] In the present invention, the connector precursor can react with thiol (e.g., cysteine), amino (e.g., lysine), carbonyl (e.g., p-acetylphenylalanine), aldehyde, azide (e.g., p-azidomethylphenylalanine), phenolic groups (e.g., tyrosine), etc. in the antibody.

[0625] In the present invention, the connector precursor can react with thiols in an antibody to form a connector that can be linked to the antibody. Preferably, the connector precursor is conjugated to one, two, three, or four cysteine ​​side chain thiols in the antibody, and more preferably, to one or two cysteine ​​side chain thiols in the antibody. The connector precursor includes 1) maleimide-based connector precursors (e.g., i) commercially available ADC drugs such as Enhertu® and Trodelvy®, which do not react with maleimides (

[0626] [ka]

[0627] ) and random conjugation of cysteines, and ii) CN103933575B is a three-tooth connector precursor ( ) containing a maleimide connector precursor that can simultaneously bind to two cysteine ​​side chain sulfhydryls of an antibody.

[0628] [ka]

[0629] ) which can be simultaneously conjugated to two cysteine ​​side chain thiols in an antibody), 2) substituted maleimide (including 3-substituted maleimide or 3-,4-disubstituted maleimide) based connector precursors (e.g., i) CN103933575B and Mol.Pharmaceutics 2015, 12, 3986-3998 disclose bromomaleimide connector precursors (

[0630] [ka]

[0631] ) and ii) Org. Biomol. Chem., 2014, 12, 7261-7269 discloses a phenylthio-substituted maleimide connector precursor (

[0632] [ka]

[0633] ) and iii) WO2014197871A2 discloses 2-pyridylthio-substituted maleimide connector precursors (

[0634] [ka]

[0635] ) and iv) CN111433188B discloses a three-tooth connector precursor (

[0636] [ka]

[0637] ) which can be simultaneously conjugated to two, three, or four cysteine ​​side chain thiols in an antibody), 3) halogenated amide-based connector precursors (e.g., i) Bioconjugate Chem. 2008, 19, 759-765 discloses α-bromoamide linker precursors (

[0638] [ka]

[0639] ) and ii) Bioorganic Med. Chem. Lett., 2017, 27, 1154-1158. discloses an α-iodoamide linker precursor (

[0640] [ka]

[0641] )), 4) methanesulfonyl-substituted heteroaryl ring system connector precursors (e.g., i) WO2016142049A1 and US20220024904A1 disclose methanesulfonyl-substituted oxadiazole connector precursors (

[0642] [ka]

[0643] ) and ii) CN113698414A discloses a methanesulfonyl-substituted pyrimidine connector precursor (

[0644] [ka]

[0645] ) and iii) CN112341521A discloses a methanesulfonyl-substituted pyrrolone [3,4-d] pyrimidine-based connector precursor (

[0646] [ka]

[0647] )), 5) halogenated heteroaryl or halomethyl heteroaryl connector precursors (e.g., CN104379168B discloses a series of bromo(chloro)heteroaryls). aryl or bromo(chloro)methyl heteroaryl connector precursors (

[0648] [ka]

[0649] ) and ii) CN114106088A discloses a bromomethylpyrazine connector precursor (

[0650] [ka]

[0651] )), 6) pyridazinedione-based connector precursors (e.g., RSC Adv., 2017, 7, 9073-9077, Org. biomol. Chem., 2018, 16, 1359-1366, WO2023076848A1 discloses dibromopyridazinedione-based connector precursors (

[0652] [ka]

[0653] )), 7) alkenyl-substituted heteroaryl or dienyl-substituted heterocyclic connector precursors (e.g., i) US20210308275A1 discloses divinylpyrimidine-based connector precursors (

[0654] [ka]

[0655] ) and ii) Org. Biomol. Chem., 2020, 18, 4739-4743 discloses a divinyltriazine-based connector precursor (

[0656] [ka]

[0657] ) and iii) Chem.Sci., 2021, 12, 9060-9068 discloses a vinylpyrimidine (triazine)-based connector precursor (

[0658] [ka]

[0659] ) and iv) US10772965B2 discloses diacetenone-substituted triazine-based connector precursors (

[0660] [ka]

[0661] )), 8) p-toluenesulfonyl-based connector precursors (e.g., WO2005007197A2 and Bioconjugate Chem. 2007, 18, 61-76 disclose p-toluenesulfonyl-based connector precursors (

[0662] [ka]

[0663] )), 9) arylpropinenitrile-based connector precursors (e.g., CN105474015B, Bioconjugate Chem. 2014, 25, 2, 202-206, Med. Chem. Commun., 2018 9, 827-830 discloses arylpropynylnitrile-based connector precursors (

[0664] [ka]

[0665] )), 10) carbonyl acrylic connector precursor (e.g., Nat. Commun., 2016, 7, 13128. discloses carbonyl acrylic connector precursor (

[0666] [ka]

[0667] )), 11) 5-methylenepyrrolone-based connector precursors (e.g., at. Commun., 2020, 11(1015), 1-10 discloses 5-methylenepyrrolidone-based connector precursors (

[0668] [ka]

[0669] ) may be disclosed).

[0670] In the present invention, the connector precursors can react with an amino acid in an antibody to form a connector that links to the antibody. Each connector precursor is preferably conjugated to one lysine side chain amino acid in the antibody, and the conjugation preferably forms an amide bond by reaction of the lysine side chain amino acid with an activated carboxyl in the connector precursor. The connector precursors include: 1) NHS ester-based connector precursors (e.g., commercially available ADC drugs Mylotarg®, Kadcyla®, etc., are NHS-activated esters)

[0671] [ka]

[0672] ) to the lysines in the antibody), 2) phenol ester-based connector precursors (e.g., RSC Advances, 2012, 2, 908-914 and US20120201809A1 describe a series of phenol ester-based connector precursors (

[0673] [ka]

[0674] ) may be disclosed). The connector precursor capable of reacting with thiols on the side chains of amino acid residues of antibodies is vinyl,

[0675] [ka]

[0676] Including, but not limited to, R12 , R 13 , R 13’ and R o The reaction between the connector precursor and a thiol (e.g., cysteine) in an antibody has specificity, and for example, as shown in formulas 1 to 6 and 12 to 16,

[0677] [ka] JPEG2025537044000193.jpg39169

[0678] When the connector is maleimide or succinimide, it can be further hydrolyzed to give a hydrolyzate, for example, as shown in Reaction Scheme 1' or Reaction Scheme 2':

[0679] [ka]

[0680] The connector precursor capable of reacting with the azide of an antibody amino acid residue side chain is ethynyl,

[0681] [ka]

[0682] The click chemistry reaction between the connector precursor and an azide in the antibody (e.g., p-azidomethylphenylalanine) has specificity, for example, as shown in Formula 7:

[0683] [ka]

[0684] The connector precursor capable of reacting with the carbonyl or aldehyde group of the side chain of an antibody amino acid residue includes, but is not limited to, hydroxylamine or hydrazine, and the reaction of the connector precursor with the carbonyl (e.g., p-acetylphenylalanine) or aldehyde in the antibody has specificity, for example, as shown in Schemes 8 and 9:

[0685] [ka]

[0686] The connector precursor capable of reacting with a phenol group of an antibody amino acid residue side chain is

[0687] [ka]

[0688] The click-like chemical reaction of the connector with a phenolic group (e.g., tyrosine) in an antibody has specificity, for example, as shown in Scheme 10:

[0689] [ka]

[0690] The connector precursor, which directly reacts the linker with the amino acid of the antibody amino acid residue side chain, is an activated ester group, which is

[0691] [ka]

[0692] Including, but not limited to, R 12 and R 12’ is as defined above, and the reaction of the connector precursor with an amino acid (e.g., lysine) in the antibody has specificity, for example, as shown in formula 11:

[0693] [ka]

[0694] The term "linker precursor" can react directly with the antibody, or can in turn react with the remaining linker moiety, the antibody, to form a degradable or non-degradable linker for linking the small molecule drug D to the antibody.

[0695] The term "and / or" includes any and all combinations of one or more of the associated items.

[0696] "C A~B " refers to an inclusive range from the beginning to the end, where A and B and each point within the range are integers and represent the number of carbon atoms, e.g., C 1~4 represents the number of carbon atoms as 1, 2, 3, or 4, and C 1~6 represents the number of carbon atoms is 1, 2, 3, 4, 5 or 6, and C 3~8 represents the number of carbon atoms is 3, 4, 5, 6, 7 or 8, and C A~B can be used in combination with any group that contains carbon atoms to limit the number of carbon atoms, for example, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, C 1~4 Alkoxyl, C 3~8 Cycloalkyl C 1~4 Alkyl and the like.

[0697] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms, and representative examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, and the like. and the like, including but not limited to butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 4,4-dimethylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and the various isomers thereof.

[0698] The term "alkenyl" refers to a straight or branched chain non-aromatic hydrocarbon containing at least one carbon-carbon double bond. There may be 1 to 3 carbon-carbon double bonds, and preferably one carbon-carbon double bond. 2~4 The term "alkenyl" refers to an alkenyl having 2 to 4 carbon atoms, and "C 2~6 The term "alkenyl" refers to an alkenyl having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, and 2-methylbutenyl.

[0699] The term "alkynyl" refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon triple bond. There may be one to three carbon-carbon triple bonds, and preferably one carbon-carbon triple bond. 2~6The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.

[0700] The term "alkylene" refers to a saturated, straight or branched, unbridged divalent alkyl containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 8, 1 to 6, or 1 to 4 carbon atoms, examples of which include, but are not limited to, -CH-, -CHCH-, -CHCHCH-, -CHCHCHCH-, -CHCH(CH)-, -CHC(CH)CH-, -CHC(CH)CHCHCH-, =CH, =CHCH, =C(CH)

[0701] The term "alkenylene" refers to a straight or branched chain non-aromatic divalent hydrocarbon containing at least one carbon-carbon double bond, and optionally 1 to 3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond. The alkenylene preferably contains 2 to 10 carbon atoms, more preferably 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0702] The term "alkynylene" refers to a straight or branched chain non-aromatic divalent hydrocarbon containing at least one carbon-carbon triple bond. There may be one to three carbon-carbon triple bonds, and preferably one carbon-carbon triple bond. The alkynylene preferably contains 2 to 10 carbon atoms, more preferably 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0703] The term "cycloalkyl" refers to a saturated or partially unsaturated (containing one or two double bonds), monocyclic or polycyclic group containing 3 to 20 carbon atoms. "Monocyclic cycloalkyl" is preferably a 3- to 10-membered monocyclic alkyl, more preferably a 3' to 8-membered monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octyl, cyclodecyl, cyclododecyl, cyclohexenyl. "Polycyclic cycloalkyl" includes "bridged cycloalkyl," "fused cycloalkyl," and "spirocycloalkyl," and representative examples of "bridged cycloalkyl" include, but are not limited to, bornyl, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, adamantyl, and the like. "Fused cycloalkyl" includes a cycloalkyl ring fused to a phenyl, cycloalkyl, or heteroaryl; fused cycloalkyls include, but are not limited to, benzocyclobutenyl, 2,3-indanyl, decalinyl, and the like. A monocyclic or polycyclic cycloalkyl can be attached to the parent molecule through any carbon atom on the ring.

[0704] The term "cycloalkylene" refers to a divalent cycloalkyl. Thus, "cycloalkylene" includes the definition of cycloalkyl above. A "cycloalkylene group" is preferably C 3~10 Cycloalkylene, more preferably C 3~8 Cycloalkylene or C 3~6 It is a cycloalkylene.

[0705] The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing one or two double bonds) non-aromatic cyclic group consisting of carbon atoms and heteroatoms and / or sulfur-containing heteroatom groups, such as nitrogen, oxygen, sulfur, and boron, which may be monocyclic or polycyclic, and the sulfur-containing heteroatom groups may be selected from, but are not limited to, S(O), S(O)2, and S(O)(NH). In the present invention, the number of heteroatoms and / or heteroatom groups in a heterocycloalkyl is preferably 1, 2, 3, or 4, and the boron, nitrogen, or carbon atoms in the heterocycloalkyl may be optionally oxidized. The nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or a quaternary ammonium salt. A "monocyclic heterocycloalkyl" is preferably a 3- to 10-membered monocyclic heterocycloalkyl, more preferably a 3' or 8-membered monocyclic heterocycloalkyl. For example, pyrrolidinyl, dihydropyrrolidinyl, dihydroimidazolyl, dihydropyrazolyl, tetrahydrofuranyl, tetrahydropyrazinyl, dihydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, piperidinyl, aziridinyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxid-4-yl, piperidinyl, piperaziridinyl nyl, 1,4-dioxanyl, homopiperazinyl, 1-imino-1-tetrahydro-2H-thiopyranyl oxide, 1,1-tetrahydrothiophenyl oxide, 1-imino-1-oxytetrahydrothienyl, 1,1-dioxy-3,4-dihydro-2H-thiopyranyl, 1-imino-1-oxy-3,4-dihydro-2H-thiopyranyl, 1,1-dioxy-2,3-dihydrothienyl, 1-imino-1-oxy-2,3-dihydrothienyl, etc. "Polycyclic heterocycloalkyl" includes "fused heterocycloalkyl", "spiroheterocyclyl" and "bridged heterocycloalkyl"."Fused heterocycloalkyl" includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl group, including, but not limited to, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuryl, indolyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydronaphthyridinyl, 5,6,7,8-tetrahydronaphthyridinyl, 1-hydroxyl-1,3-dihydrobenzo[c][1,2]oxaborolanyl, and the like. Monocyclic and polycyclic heterocycloalkyls can be attached to the parent molecule through any ring atom in the ring. The ring atoms specifically refer to the carbon and / or nitrogen atoms that make up the ring backbone.

[0706] The term "heterocycloalkylene" refers to a divalent heterocycloalkyl. Thus, "heterocycloalkylene" includes the definition of heterocycloalkyl above. "Cycloalkylene" is preferably a 3- to 10-membered heterocycloalkylene, more preferably a 3- to 8-membered heterocycloalkylene or a 3- to 6-membered heterocycloalkylene.

[0707] The term "cycloalkylalkyl" refers to the alkyl linkage between the cycloalkyl and the parent core structure. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl above.

[0708] The term "heterocycloalkylalkyl" refers to an alkyl link between a heterocycloalkyl and a parent core structure. Thus, "heterocycloalkylalkyl" encompasses the definitions of alkyl and heterocycloalkyl above.

[0709] The term "alkoxyl" refers to an alkyloxy having the stated number of carbon atoms attached through an oxygen bridge. "Alkoxyl" therefore encompasses the definition of alkyl above.

[0710] The term "hydroxylalkyl" refers to an alkyl in which any hydrogen atom is replaced with a hydroxyl.

[0711] The term "heterocycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, S), which may include one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 A heterocycloalkenyl has a double bond, is a monocyclic ring, and is not aromatic. A heterocycloalkenyl is linked to the rest of the molecule through a carbon atom or a heteroatom.

[0712] [ka]

[0713] Including, but not limited to, the following:

[0714] The term "heteroalkenyl ring" satisfies any of the following conditions and has the same other definitions as the term "heterocycloalkenyl": It shares two atoms and one bond with the rest of the molecule.

[0715] The term "aryl" refers to any stable 6- to 20-membered monocyclic or polycyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl, or biphenyl.

[0716] The term "arylene" refers to a divalent heteroaryl. Thus, "arylene" includes the definition of aryl above. "Arylene" is preferably C 6~10 It is preferably arylene, more preferably phenylene.

[0717] The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one ring carbon atom with a heteroatom selected from nitrogen, oxygen, or sulfur, which may be a 5- to 7-membered single ring structure or a 7- to 20-membered fused ring structure, preferably a 5- to 6-membered heteroaryl. In the present invention, the number of heteroatoms is preferably 1, 2, or 3, which includes pyridyl, pyridonyl, pyrimidinyl, pyrimidine-2,4(1H,3H)-diketone, pyrimidinone, piperazinyl, pyridazinone, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, These include indazolyl, isoindazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzo[d][1,3]dioxolane, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, isoquinolinonyl, quinazolinyl, 4-hydroxythieno[3,2-c]pyridyl, 4,5-dihydro-4-oxofuran[3,2]pyridyl, 4-hydroxyl-5-azaindolyl, furan[2,3-c]pyridin-7(6H)-one, thiophene[2,3-c]pyridin-7(6H)-one, and the like.

[0718] The term "heteroarylene" refers to a divalent heteroaryl. Thus, "heteroarylene" includes the definition of heteroaryl above. "Heteroarylene" is preferably a 5- to 10-membered heteroarylene, more preferably a 5- or 6-membered heteroarylene.

[0719] The term "fused ring group" refers to a fused ring structure in which two, three, or four ring structures share two adjacent atoms, and the fused ring group may further include one spiro ring or bridged ring group. The fused ring group referred to in the present invention refers to a saturated, unsaturated, or partially saturated fused ring structure, preferably in which at least one ring is an aromatic ring. It is more preferably a bicyclic or tricyclic fused ring group, and at least one ring is an aromatic ring. In the present invention, the fused ring group is a fused ring group having 8 to 20 members, preferably 8 to 12 members, and more preferably 8 to 10 members. Specific examples of fused ring groups are benzocyclobutenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7,8,9-tetrahydro-5H-benzo[7]pholenyl, 6,9-dihydro-5H-benzo[7]weerenyl, 5,6,7,8,9,10-hexahydrobenzo[8]weerenyl, 2,3-cyclopentopyridyl, 5,6-dihydro-4H-cyclopentyl[b]thienyl, 5,6-dihydro-4H-cyclopentyl[b]furyl, 2,3-dihydrobenzofuranyl, 1 ,3-dihydroisobenzofuryl, indolyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1,2,3,4-tetrahydroquinolyl, 2,3-dihydro-1,4-benzodioxanyl, 3,4-dihydro-2H-1,4-benzoxazinyl, naphthyridinyl, naphthyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzothiazolyl, benzoxazolyl, indazolyl, benzopyridazinyl, benzimidazolyl, indolyl, quinolyl, isoquinolinyl, purinyl, pteridinyl,

[0720] [ka]

[0721] and the fused ring groups can be linked to the parent molecule through a ring carbon atom, preferably an aromatic ring carbon atom.

[0722] The term "arylalkyl" refers to the connection between an aryl and a parent core structure via an alkyl. Thus, "arylalkyl" encompasses the definitions of alkyl and aryl above.

[0723] The term "heteroarylalkyl" refers to the connection between a heterocycloalkyl and a parent core structure via an alkyl. Thus, "heteroarylalkyl" encompasses the definitions of alkyl and heteroaryl above.

[0724] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0725] The term "halogenated alkyl" refers to an alkyl that is optionally substituted with a halogen. Thus, "halogenated alkyl" encompasses the definitions of halogen and alkyl above.

[0726] The term "halogenated alkoxyl" refers to an alkoxyl that is optionally substituted with a halogen. Thus, "halogenated alkoxyl" includes the definitions of halogen and alkoxyl above.

[0727] The term "amino" refers to -NH2, and the term "alkylamino" refers to at least one hydrogen atom on the amino being replaced with alkyl, including, but not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, and -N(CH2CH3)2. Thus, "alkylamino" encompasses the definitions of alkyl and amino above.

[0728] The term "nitro" refers to -NO2.

[0729] The term "cyano" refers to -CN.

[0730] The term "oxo" refers to =O.

[0731] In the present invention, the abbreviations of amino acids are conventional abbreviations (see the Chinese Chemical Society's Principles of Organic Chemistry Nomenclature 2017), such as alanine (Ala), arginine (Arg), aspartic acid (Asp), asparagine (Asn), cysteine ​​(Cys), glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), and valine (Val). In the present invention, in the symbolic representation of a peptide (take -Gly-(-NH-CH2-CO-) as an example), when the dash representing the peptide bond is on the right side of Gly, it represents the removal of an OH group from the -COOH group of the amino acid, and when the dash is on the left side of Gly, it represents the removal of one H atom from the amino acid -NH2-.

[0732] "Room temperature" as used in the present invention refers to 15 to 30°C.

[0733] The substituents R, R, R, R, R, R in the "antibody-immunostimulatory complex," "compound," and "pharmaceutically acceptable salt" of the present invention 4’ , R5, R6, R7, R8, R 8’ , R9, R 10 , R 11 , R 12 , R 12’ , R 13 , R 13’ , R a , R b , R d , R e , R e’ , R f , R f’ and L 1~5 When tautomers exist in the compound, it may exist in the form of a single tautomer or in the form of a mixture thereof, preferably in the form of a more stable tautomer.

[0734] The "pharmaceutically acceptable salts" according to the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts," J. Pharm. Sci., 66, 1-19 (1977), and will be clear to medicinal chemists that the salts are substantially non-toxic and can provide desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion, etc. The compounds according to the present invention can have acidic, basic, or amphoteric groups, and typical pharmaceutically acceptable salts include salts obtained by reacting the compounds of the present invention with an acid.

[0735] The above preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention, provided that this does not violate common knowledge in the art.

[0736] All reagents and raw materials used in the present invention are commercially available.

[0737] The positive effects of the present invention are as follows: the nitrogen-containing compound has a good regulatory effect on TLR8, and can effectively treat, alleviate and / or prevent various related diseases caused by immunosuppression, such as cancer.

[0738] [Mode for Carrying Out the Invention] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the described examples. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or product specifications.

[0739] The structures of all compounds of the present invention can be determined by nuclear magnetic resonance ( 1 The identity can be determined by 1 H NMR and / or mass spectrometry (MS).

[0740] 1 H NMR chemical shifts (δ) are in ppm (10 -6) NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents include deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO-d6), and heavy water (DO), with tetramethylsilane as the internal standard (TMS).

[0741] Liquid crystal mass spectrometry (LCMS) was performed using an Agilent 1200 HPLC / 6120 mass spectrometer with an Xtimate C18, 3.0 × 50 mm, 3 μm column at 40 °C, or a Thermo UltiMate 3000 HPLC / MSQ PLUS mass spectrometer with an Xbridge C18, 3.0 × 50 mm, 3.5 μm column at 30 °C. Agilent gradient elution conditions: 1: 95–5% solvent A1 and 5–95% solvent B1 (0–2.0 min), followed by 95% solvent B1 and 5% solvent A1 (hold for 1.1 min), where percentages are the volume percentage of the specific solvent relative to the total volume of solvent. Solvent A1: 0.01% trifluoroacetic acid (TFA) in water. Solvent B1: 0.01% trifluoroacetic acid in acetonitrile. Percentages are the volume percentages of solute in solution. Thermogravimetric gradient elution condition 2: 95% to 5% solvent A2 and 5% to 95% solvent B2 (0-2 min), then 95% solvent B2 and 5% solvent A1 (hold for 1.8 min). Percentages are the volume percentages of the specified solvent out of the total solvent volume. Solvent A2: 10 mM ammonium bicarbonate in water. Solvent B2: acetonitrile.

[0742] Preparative high-performance liquid chromatography (HPLC) was performed using a Gilson GX-281 or Agela FLEXA-HP preparative liquid chromatography column. Chromatography column: Xtimate 21.2 x 250 mm, 10 μm. Separation condition 1: Mobile phase A: 0.05% hydrochloric acid aqueous solution, mobile phase B: acetonitrile. Separation condition 2: Mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile. Separation condition 3: Mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile. Chromatography column: Gemini 5 μm, C18, 150 x 21.2 nm. Mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile. Detection wavelength: 214 nm & 254 nm. Flow rate: 15.0-20.0 mL / min.

[0743] Ultra-performance liquid chromatography (UPLC) was performed using a Waters ACQUITY Hclass column: Waters ACQUITY UPLC BEH Shield RP18 2.1mm x 100mm, 1.7µm, 5µm. Mobile phase A: 5mm potassium dihydrogen phosphate buffer, pH adjusted to 2.5 with phosphoric acid. Mobile phase B: acetonitrile. Gradient elution: 90% to 60% B, elution time: 5 min, 60% to 10% B, elution time: 2 min, hold at 10% B for 6 min, 10% to 90% B, elution time: 0.1 min, hold at 90% B for 1.9 min. Detection wavelength: 214nm & 262nm, column temperature: 40°C. Flow rate: 0.4mL / min.

[0744] Flash column chromatography (flash system / Cheetah™): Agela Technologies MP200, equipped normal phase separation column: Flash column Silica-CS (25 g, 40 g, 80 g, 120 g, or 330 g), Tianjin Bona El, elution system: ethyl acetate / petroleum ether or methylene chloride / methanol, reversed phase separation column: C18 reversed phase column (Spherical C18, 40-75 μm, 100 Å, SepaFlash® type: SW-040), elution system: 10 mM aqueous ammonium bicarbonate / acetonitrile or 0.1% aqueous trifluoroacetic acid / acetonitrile.

[0745] The meanings of the abbreviations used in the examples of the present invention are as follows:

[0746] (Boc)2O: di-tert-butyl dicarbonate, BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, DBAD: di-tert-butyl azodicarboxylate, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, DIC: N,N'-diisopropylcarbodiimide, DIPEA: N,N-diisopropylethylamine, EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EEDQ: 2-ethoxy-1-ethoxycarbonyl 1,2-dihydroquinoline, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, HOBT: 1-hydroxylbenzotriazole, LiHMDS: lithium bistrimethylsilylamide, NHS: N-hydroxylsuccinimide, PdCl2dppf.CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex, Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, TBSCl: tert-butyldimethylsilyl chloride, Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, Xphos: 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, Val-Cit-PAB-OH: (S)-2-((S)-2-amino-3-methylbutylamine) Mc-Val-Cit-PAB-OH: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-(hydroxylmethyl)phenyl))amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide; Fmoc-Cit-OH: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl )amino)-5-ureidopentanoic acid, Fmoc-Val-Cit-OH: (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutyrylamino)-5-ureidopentanoic acid, Fmoc-Val-Ala-OH: (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine-L-alanine, Fmoc-Gly-OH: (((9H-fluoren-9-yl)methoxy)carbonyl)glycine, Fmoc-Leu-OH: (((9H-fluoren-9-yl)methoxy)carbonyl) -9-yl)methoxy)carbonyl)-L-leucine, Fmoc-Ala-OH: (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine, Fmoc-Phe-OSu: 2,5-dioxopyrrolidin-1-yl(((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalanine ester, Fmoc-Ser(tBu)-OH: N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-serine, Fmoc-Asn(Trt)-OH: N; 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 4-trityl-L-asparagine, Boc-Val-Cti-OH: (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutyrylamino)-5-ureidovaleric acid, AMAS: 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetate, BMPS: 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionate, EMCS: 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid.

[0747] Synthesis of intermediates, Synthesis of Intermediate 1.5, ((2-Formyl-1,3-dioxan-5-yl)methyl)carbamic Acid Benzyl Ester

[0748] [ka]

[0749] Step 1: Methanesulfonyl chloride (6.51 g, 56.9 mmol) was added dropwise to a solution of 5-hydroxymethyl-2,2-dimethyl-1,3-dioxane (6.78 g, 47.0 mmol) and triethylamine (7.15 g, 70.7 mmol) in dichloromethane (100 mL) under ice-bath conditions. The reaction was stirred at room temperature for 2 hours. The reaction was then quenched with ice water, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1.1 (10.0 g) as a yellow oil. m / z: [M+H] + 225.2.

[0750] Step 2: To a solution of compound 1.1 (1.0 g, 4.46 mmol) and benzyl carbamate (0.67 g, 4.46 mmol) in DMF (10 mL), cesium carbonate (2.91 g, 8.92 mmol) was added and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and quenched with ice water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give compound 1.2 (0.45 g) as a white solid. m / z: [M+Na] + 302.2.

[0751] Step 3: Compound 1.2 (0.45 g, 1.61 mmol) in a 4 M solution of hydrochloric acid / 1,4-dioxane (5 mL) is stirred at room temperature for 30 minutes. The reaction mixture is then concentrated under reduced pressure, and the residue is purified by flash column chromatography (C18, eluent: 0% to 43% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 1.3 (0.38 g) as a white solid. m / z: [M+H] + 240.2.

[0752] Step 4: Concentrated hydrochloric acid (0.04 mL) was added to a dichloromethane (2 mL) solution, followed by the addition of compound 1.3 (0.38 g, 1.59 mmol) and diethyl acrolein acetate (1.03 g, 7.95 mmol). The reaction was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 51% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give compound 1.4 (316 mg) as a white solid. m / z: [M+Na] + 300.2.

[0753] Step 5: To a solution of compound 1.4 (316 mg, 1.14 mmol) in tetrahydrofuran (9 mL) and water (3 mL), N-methylmorpholine oxide (401 mg, 3.42 mmol) and potassium osmate dihydrate (21 mg, 0.06 mmol) were added, and the reaction mixture was stirred at 35 °C for 16 h. Sodium periodate (1.46 g, 6.84 mmol) was added, and the resulting mixture was stirred at 35 °C for 45 min. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 1.5 (154 mg) as a white solid. m / z: [M+H] + 280.1.

[0754] Synthesis of Intermediate 1.6, (2-((2-(methylsulfonyl)ethyl)amino)ethyl)carbamic acid benzyl ester

[0755] [ka]

[0756] To a solution of 1-bromo-2-(methylsulfonyl)ethane (500 mg, 2.67 mmol) and (2-aminoethyl)carbamic acid benzyl ester in acetonitrile (6 mL) were added potassium carbonate (406 mg, 2.94 mmol) and sodium iodide (200 mg, 1.33 mmol), successively. The reaction was stirred in a sealed tube at 90 °C for 48 h, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (dichloromethane / methanol = 10 / 1) to give intermediate 1.6 (600 mg) as a colorless oil. m / z: [M+H] + 301.2.

[0757] Intermediate 1. Synthesis of 9,7-(2-(methylsulfonyl)ethyl)-3,8-dioxo-1-phenyl-2,9-dioxa-4,7-diazaundecanoic-11-oic acid

[0758] [ka]

[0759] Step 1: To a solution of 2-hydroxylacetic acid tert-butyl ester (300 mg, 2.27 mmol) and bis(p-nitrobenzene)carbonate (760 mg, 2.5 mmol) in DMF (5 mL) was added DIPEA (440 mg, 3.41 mmol). After stirring at room temperature for 4 h, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 10% to 80% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 1.7 (500 mg) as a white solid. m / z: [M+Na] + 320.2.

[0760] Step 2: To a solution of intermediates 1.6 (300 mg, 1 mmol) and 1.7 (300 mg, 1 mmol) in dichloromethane (3 mL) was added DIPEA (258 mg, 2 mmol). After stirring overnight at room temperature, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 10% to 70% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give intermediate 1.8 (400 mg) as a colorless oil. m / z: [M+H] + 482.2.

[0761] Step 3: To a solution of intermediate 1.8 (200 mg, 0.44 mmol) in dichloromethane (4 mL) is added trifluoroacetic acid (1 mL). After stirring at room temperature for 1 h, the reaction mixture is directly concentrated under reduced pressure, and the residue is purified by flash column chromatography (C18, eluent: 10% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 1.9 (100 mg) as a colorless oil. m / z: [M+H] + 403.2.

[0762] Intermediate 2. Synthesis of 6,8-bromo-2-((tert-butoxycarbonyl)amino)-3H-benzo[b]azepine-4-carboxylic acid

[0763] [ka]

[0764] Step 1: Stir a solution of Intermediate 2.1 (20 g, 57.4 mmol) and bromoacetonitrile (6.9 g, 57.4 mmol) in ethyl acetate (200 mL) under reflux for 3 h, filter off the solids, and wash the filter cake with ethyl acetate. Concentrate the filtrate under reduced pressure to give Intermediate 2.2 (17 g) as a pale yellow oil.

[0765] Step 2: A solution of 4-bromo-2-nitrobenzaldehyde (10 g, 43.9 mmol) and intermediate 2.2 (17 g, 43.9 mmol) in toluene (170 mL) was stirred under reflux for 2 hours. After cooling to room temperature, the mixture was filtered through a short silica gel column, eluted with 25% ethyl acetate in petroleum ether, concentrated under reduced pressure to remove most of the eluate, and the remaining solution was allowed to stand at -18 °C for 16 hours. The solid precipitated was filtered, and the filter cake was dried under vacuum to give intermediate 2.3 (8.2 g) as an off-white solid.

[0766] Step 3: A solution of Intermediate 2.3 (4.2 g, 12.4 mmol) in acetic acid (80 mL) was heated to 80 °C. Iron powder (4.1 g, 74.3 mmol) was added to the solution in several portions within 15 minutes, maintaining the internal temperature below 90 °C. After the addition was complete, stirring was continued for 3 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was diluted with cold water. The pH was adjusted to >8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with 10% ethyl acetate / petroleum ether solution, filtered, and the filter cake was dried under vacuum to give Intermediate 2.4 (3 g) as an off-white solid.

[0767] Step 4: To a solution of intermediate 2.4 (3 g, 9.7 mmol) and triethylamine (1.47 g, 14.6 mmol) in dichloromethane (50 mL) was added (BOC)2O (3.2 g, 14.6 mmol). The reaction mixture was stirred at room temperature for 2 days, then diluted with dichloromethane. The organic phase was washed with hydrochloric acid (3 M), saturated aqueous sodium bicarbonate, and saturated brine, respectively. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with 10% ethyl acetate in petroleum ether, filtered, and the filter cake was dried to give intermediate 2.5 (1.6 g) as an off-white solid.

[0768] Step 5: To a solution of intermediate 2.5 (1.6 g, 3.91 mmol) in tetrahydrofuran (50 mL) under ice-bath conditions, add aqueous sodium hydroxide (1.0 M, 5.9 mL). The reaction mixture is stirred at room temperature for 16 hours, then adjusted to pH 6 with hydrochloric acid (0.5 M). The aqueous phase is extracted with ethyl acetate, the combined organic phase is washed with saturated brine, the organic phase is separated, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give intermediate 2.6 (1.1 g) as a pale yellow foamy solid.

[0769] Intermediate 3.1, Synthesis of 8-bromo-2-((tert-butoxycarbonyl)amino)-6-fluoro-3H-benzo[b]azepine-4-carboxylic acid

[0770] [ka]

[0771] Using the synthetic method for intermediate 2.6, substituting 4-bromo-2-fluoro-6-nitrobenzaldehyde for 4-bromo-2-nitrobenzaldehyde in step 2 provides intermediate 3.1.

[0772] Intermediate 3.2, Synthesis of 2-amino-8-bromo-6-fluoro-3H-benzo[b]azepine-4-carboxylic acid

[0773] [ka]

[0774] Using the synthetic methodology in step 5 of intermediate 2.6, reaction of 2-amino-8-bromo-6-fluoro-3H-benzo[b]azepine-4-carboxylic acid ethyl ester gives intermediate 3.2.

[0775] Synthesis of Intermediate 4.1, 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylic acid

[0776] [ka]

[0777] Using the synthesis method in Step 5 of Intermediate 2.6, reaction of Intermediate 2.4 gives Intermediate 4.1.

[0778] Synthesis of L-1, (32-(3-amino-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3,6,9,12,15,18,21,24,27,30-decaoxadodecyl)carbamate tert-butyl ester

[0779] [ka]

[0780] Step 1: To a solution of 3,6,9,12,15,18,21,24,27,30-decasatriaconane-1,32-diol (4.8 g, 9.56 mmol) in tetrahydrofuran (50 mL), triphenylphosphine (3.76 g, 14.3 mmol) and DBAD (3.30 g, 14.3 mmol) were added sequentially, followed by the slow dropwise addition of a tetrahydrofuran solution of phthalimide (0.98 g, 6.69 mmol). The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was directly purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 10 mM aqueous ammonium bicarbonate) to obtain Intermediate 1A (1.5 g) as a pale yellow oil. m / z: [M+NH4] + 649.2.

[0781] Step 2: To a solution of intermediate 1A (1.3 g, 2.06 mmol) in dichloromethane (20 mL), add Dess-Martin oxidant (1.05 g, 2.47 mmol). Stir the reaction mixture at room temperature for 2 hours, filter to remove insoluble material, concentrate the filtrate under reduced pressure, dissolve in ethyl acetate, filter again to remove insoluble material, and concentrate the filtrate under reduced pressure to obtain intermediate 1B (1.5 g, crude product). m / z: [M+H] + 630.3.

[0782] Step 3: To a solution of 3-nitro-5,6,7,8-tetrahydro-1,6-naphthyridine (120 mg, 0.67 mmol) in methanol (5 mL), intermediate 1B (421 mg, 0.67 mmol) and sodium cyanoborohydride (126 mg, 2.01 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 30% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give intermediate 1C (300 mg) as a yellow oil. m / z: [M+H] + 793.4.

[0783] Step 4: To a solution of Intermediate 1C (250 mg, 0.32 mmol) in ethanol (5 mL) was added hydrazine hydrate (48 mg, 0.96 mmol), and the reaction mixture was stirred at 80 °C for 2 h and concentrated under reduced pressure to give Intermediate 1D (210 mg, crude product). m / z: [M+H] + 663.4.

[0784] Step 5: A mixture of Intermediate 1D (210 mg, 0.32 mmol), triethylamine (32 mg, 0.32 mmol), (Boc)2O (70 mg, 0.32 mmol), and dichloromethane (10 mL) was stirred at room temperature for 2 h. The reaction was then directly concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give Intermediate 1E (290 mg) as a yellow oil. m / z: [M+H] + 763.4.

[0785] Step 6: A solution of Intermediate 1E (140 mg, 0.18 mmol) and palladium-carbon (19 mg, 10% wt) in methanol (5 mL) was purged with hydrogen three times and then stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give L-1 (110 mg) as a pale yellow solid. m / z: [M+H] + 733.4.

[0786] Synthesis of L-2,1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12,15,18,21,24,27,30-deca-triacontan-33-oic acid

[0787] [ka]

[0788] Step 1: To a solution of 1-amino-3,6,9,12,15,18,21,24,27,30-decaoxatriacontan-33-oic acid tert-butyl ester (180 mg, 0.31 mmol) in water (5 mL), 2,5-dioxa-2,5-dihydro-1H-pyrrole-1-carboxylic acid methyl ester (57 mg, 0.37 mmol) and sodium bicarbonate (52 mg, 0.62 mmol) were added under ice-bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and the residue was purified by flash column chromatography (C18, eluent: 0% to 70% acetonitrile in 10 mM aqueous ammonium bicarbonate) to obtain Intermediate 2A (170 mg) as a colorless oil. m / z: [M+NH4] + 683.2.

[0789] Step 2: Trifluoroacetic acid (1 mL) was added to a solution of intermediate 2A (160 mg, 0.23 mmol) in dichloromethane (3 mL) under ice-bath conditions. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give L-2 (110 mg) as a colorless oil. m / z: [M+NH4] + 610.4.

[0790] Synthesis of L-3, (12S,15S)-22-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-15-isopropyl-11,14,17-trioxo-12-(3-ureidopropyl)-4,7-dioxa-10,13,16-triazadocodenoic acid

[0791] [ka]

[0792] Step 1 & 2: To a solution of Fmoc-Val-Cit-OH (300 mg, 0.60 mmol) in DMF (5 mL), HATU (251 mg, 0.66 mmol), DIPEA (116 mg, 0.9 mmol), and 3-(2-(2-aminoethoxy)ethoxy)propionic acid tert-butyl ester (154 mg, 0.66 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Diethylamine (1 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 35% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 3B (336 mg) as a yellow oil. m / z: [M+H] + 490.3.

[0793] Step 3: To a solution of intermediate 3B (336 mg, 0.56 mmol) and EMCS (190 mg, 0.62 mmol) in DMF (4 mL), add DIEPA (181 mg, 1.4 mmol). The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is directly purified by flash column chromatography (C18, eluent: 0% to 48% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 3C (297 mg) as a white solid. m / z: [M+H] + 683.4.

[0794] Step 4: Trifluoroacetic acid (1 mL) was added dropwise to a solution of intermediate 3C (297 mg, 0.43 mmol) in dichloromethane (3 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the mixture was purified by flash column chromatography (C18, eluent: 0% to 38% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give L-3 (220 mg) as a white solid. m / z: [M+H] + 627.4.

[0795] Synthesis of L-4, (24S,27S)-34-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-27-isopropyl-23,26,29-trioxo-24-(3-ureidopropyl)- 4,7,10,13,16,19-hexaoxa-22,25,28-triazatriacontan-1-oic acid

[0796] [ka]

[0797] Synthesize L-4 using the synthesis method for L-3. m / z: [M+H] + 803.4.

[0798] Synthesis of L-5,4-((2S,5S)-31-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-4,7,29-trioxo-2-(3-ureidopropyl)-10,13,16,19,22,25-hexaoxa-3,6,28-triazatriacontanylamino)benzyl(4-nitrophenyl)carbonate

[0799] [ka]

[0800] Step 1: To a solution of 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16,19,22-hexa-4-azapentacosane-25-oic acid (120 mg, 0.24 mmol) and Val-Cit-PAB-OH (109 mg, 0.29 mmol) in DMF (3 mL), add HATU (110 mg, 0.29 mmol) and DIPEA (93 mg, 0.72 mmol), respectively. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 5A (110 mg) as a yellow solid. m / z: [M+H] + 866.4.

[0801] Step 2: To a solution of intermediate 5A (110 mg, 0.13 mmol) in DMF (3 mL), bis(4-nitrobenzene) carbonate (59 mg, 0.2 mmol) and DIPEA (42 mg, 0.33 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give L-5 (60 mg) as a pale yellow solid. m / z: [1 / 2M+H] + 516.3.

[0802] Synthesis of L-6, 1-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexyl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azatricosane-23-oic acid

[0803] [ka]

[0804] A solution of 2,5-dioxopyrrolidin-1-yl 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylate (100 mg, 0.3 mmol) and 1-amino-3,6,9,12,15,18-hexaoxaicosan-21-oic acid (106 mg, 0.3 mmol) in DMF (3 mL) was stirred at room temperature for 1 h and then directly purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-6 (75 mg) as a white solid. m / z: [M+H] + 573.2.

[0805] Synthesis of L-7, 3-(2-(2-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-amido)ethoxyethoxy)propionic acid

[0806] [ka]

[0807] Step 1: To a solution of 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-carboxylic acid (237 mg, 1 mmol) in DMF (3 mL), HATU (456 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol), and 3-(2-(2-aminoethoxy)ethoxy)propionic acid tert-butyl ester (256 mg, 1.1 mmol) were added sequentially. The reaction was stirred at room temperature for 2 h and then directly purified by flash column chromatography (C18, eluent: 0% to 80% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give Intermediate 7A (130 mg) as a white solid. m / z: [M+H] + 454.2.

[0808] Step 2: Trifluoroacetic acid (1 mL) was added dropwise to a solution of intermediate 7A (100 mg, 0.22 mmol) in dichloromethane (2 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, L-7 (220 mg) was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid) as a white solid. m / z: [M+H] + 397.2.

[0809] Synthesis of L-8, 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetylamino)ethoxy)ethoxy)propionic acid

[0810] [ka]

[0811] Using the synthesis method for L-7, synthesize L-8 with 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid. m / z: [M+Na] + 393.2.

[0812] Synthesis of L-9, 4-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetamido)butyric acid

[0813] [ka]

[0814] Using the synthesis method for L-7, synthesize L-9 with 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid and 4-aminobutyric acid tert-butyl ester. m / z: [M+Na] + 241.0.

[0815] Synthesis of L-10, 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,7-dioxo-11,14-dioxa-3,8-diazaheptadecan-17-oic acid

[0816] [ka]

[0817] Using the synthesis method for L-7, L-10 was synthesized from L-9. m / z: [M+H] + 400.2.

[0818] Synthesis of L-11, (1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,7-dioxo-11,14-dioxa-3,8-diazaheteroheptadecyl-17-acyl)glycine

[0819] [ka]

[0820] Using the synthesis method for L-7, synthesize L-11 from L-10 and glycine tert-butyl ester. m / z: [M+H] + 457.2.

[0821] Synthesis of L-12, 3-(2-(2-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoylamino)ethoxy)ethoxypropionic acid

[0822] [ka]

[0823] Using the synthesis method for L-7, synthesize L-12 with 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoic acid. m / z: [M+Na] + 391.0.

[0824] Synthesis of L-13, 1-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)phenyl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azatricosane-23-oic acid

[0825] [ka]

[0826] Using the synthesis method for L-7, synthesize L-13 with 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoic acid. m / z: [M+H] + 567.2.

[0827] Synthesis of L-14, 4-(3-(2-(2-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)propionylamino)ethoxy)ethoxy)propionylamino)benzyl(4-nitrophenyl)carbonate

[0828] [ka]

[0829] Step 1: To a solution of 3-(2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionylamino)ethoxy)ethoxy)propionic acid (100 mg, 0.3 mmol) in DMF (3 mL) was added HATU (140 mg, 0.36 mmol) and DIPEA (78 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of (4-aminophenyl)methanol (44 mg, 0.36 mmol). The reaction mixture was stirred for 1 hour and directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give Intermediate 14A (97 mg) as a yellow solid. m / z: [M+Na] + 456.2.

[0830] Step 2: Using the synthesis method in Step 2 of L-5, reaction of 14A gave L-14 (92 mg) as a white solid. m / z: [M+H] + 599.2.

[0831] Synthesis of L-15,32-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionylamino)-26,33-dioxo-2,5,8,11,14,17,20,23-octaxa-27,34-diazatriacontan-37-oic acid

[0832] [ka]

[0833] Step 1: To a solution of 6-amino-2-(((benzyloxy)carbonyl)amino)hexanoic acid methyl ester hydrochloride (900 mg, 2.18 mmol) and 2,5,8,11,14,17,20,23-octaoxa-26-oic acid (793 mg, 2.4 mmol) in DMF (3 mL) was added DIPEA (1.1 g, 8.72 mmol). The reaction was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 70% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give Intermediate 15A (1.1 g) as a colorless oil. m / z: [M+H] + 689.0.

[0834] Step 2: To a solution of Intermediate 15A (1.1 g, 1.6 mmol) in tetrahydrofuran (2.5 mL) was added a solution of lithium hydroxide monohydrate (134 mg, 3.2 mmol) in water (0.5 mL). The reaction was stirred at room temperature for 4 hours. After dilution with water, the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure to give Intermediate 15B (900 mg) as a colorless liquid.

[0835] Step 3: To a solution of intermediate 15B (1 g, 1.48 mmol) and 3-aminopropionic acid tert-butyl ester (210 mg, 1.48 mmol) in DMF (2.5 mL), HATU (619 mg, 1.63 mmol) and DIPEA (770 mg, 5.92 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 15C (1 g) as a colorless liquid. m / z: [M+H] + 802.7.

[0836] Step 4: To a solution of Intermediate 15C (1 g, 1.25 mmol) in methanol (3 mL), add Pd / C (10% wt, 100 mg). After purging with hydrogen, the reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give Intermediate 15D (850 mg) as a colorless oil. m / z: [M+H]+ 668.6.

[0837] Step 5: A solution of intermediate 15D (450 mg, 0.67 mmol) and BMPS (180 mg, 0.67 mmol) in DMF (2.5 mL) was stirred at room temperature for 4 h and directly concentrated under reduced pressure to give intermediate 15E (350 mg) as a colorless liquid. m / z: [M+H] + 818.9.

[0838] Step 6: To intermediate 15E (350 mg, 0.43 mmol), trifluoroacetic acid (1 mL) and dichloromethane (15 mL) are added. The reaction mixture is stirred at room temperature for 4 hours and then directly concentrated under reduced pressure. The residue is purified by flash column chromatography (C18, eluent: 0% to 55% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-15 (180 mg) as a colorless viscous liquid. m / z: [M+H] + 762.9, 1 H NMR(400MHz,DMSO-d6):δ12.17(s,1H),8.02(d,J=8.0Hz,1H),7.89(t,J=5.6Hz,1H),7.74(t,J=5.2Hz ,1H),6.97(s,2H),4.10-4.04(m,1H),3.58-3.52(m,5H),3.49-3.48(m,1H),3.46-3.45(m,7H),3.45- 3.41(m,4H),3.41-3.37(m,2H),3.30(s,13H),3.25-3.12(m,5H),2.99-2.92(m,2H),2.37-2.31(m,4H) ),2.25(t,J=6.8Hz,2H),1.57-1.46(m,1H),1.45-1.35(m,1H),1.34-1.26(m,2H),1.21-1.08(m,2H).

[0839] Synthesis of L-16,32-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionylamino)-26,33-dioxo-2,5,8,11,14,17,20,23,37,40-deca-27,34-diazatetrasan-43-oic acid

[0840] [ka]

[0841] Using the synthesis method for L-15, synthesize L-16 from 3-(2-(2-aminoethoxy)ethoxy)propionic acid tert-butyl ester and 15B. m / z: [M+H] + 850.9. 1 H NMR(400MHz,DMSO-d6):δ12.12(br.s,1H),8.02(d,J=8.4Hz,1H),7.87(t,J=5.6Hz,1H),7.74(t,J=5.6Hz,1H),6 .97(s,2H),4.13-4.07(m,1H),3.57-3.52(m,7H),3.49-3.48(m,1H),3.47-3.46(m,10H),3.46-3.45(m,6H),3.45 -3.41(m,10H),3.40-3.37(m,3H),3.44(t,J=6.0Hz,2H),3.20(s,3H),3.18-3.11(m,2H),2.99-2.92(m,2H),2.41 -2.34(m,5H),2.25(t,J=6.4Hz,2H),1.57-1.48(m,1H),1.45-1.36(m,1H),1.34-1.26(m,2H),1.22-1.07(m,2H).

[0842] Synthesis of L-17, 1-(2,5-dioxo-3,4-bis(pyridin-2-ylmercapto)-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16,19,22-hexaoxa-4-azapentacosane-25-oic acid

[0843] [ka]

[0844] Step 1: A solution of 3,4-dibromofuran-2,5-dione (900 mg, 3.41 mmol) and 3-aminopropionic acid (320 mg, 3.41 mmol) in acetic acid (10 mL) was stirred at 100°C for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was slurried in a mixture of petroleum ether and ethyl acetate (5 / 1), filtered, and the filter cake was dried under vacuum to give Intermediate 17A (1.2 g) as a pale yellow solid. m / z: [M+H] + 349.8.

[0845] Step 2: To a solution of 1-amino-3,6,9,12,15,18-hexaoxaicosan-21-oic acid tert-butyl ester (99 mg, 0.23 mmol) in DMF (2 mL) was added HATU (107 mg, 0.28 mmol), DIPEA (45.5 mg, 0.35 mmol), and intermediate 17A (75 mg, 0.23 mmol) sequentially under ice-bath conditions. The reaction mixture was stirred at room temperature for 1 h and then directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 17B (126 mg) as a yellow solid. m / z: [M+H] + 717.2.

[0846] Step 3: To a solution of intermediate 17B (126 mg, 0.18 mmol) in dichloromethane (2 mL) is added trifluoroacetic acid (1 mL). The reaction is stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue is purified by flash column chromatography (C18, eluent: acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 17C (60 mg) as a yellow solid. m / z: [M+H] + 661.2.

[0847] Step 4: Under ice-bath conditions, a solution of intermediate 17C (18 mg, 0.03 mmol) in DMF (1 mL) was added, followed by 2-mercaptopyridine (63 mg, 0.06 mmol) and triethylamine (4.8 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 1 h and then directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate L-17 (16 mg) as a yellow solid. m / z: [M+H] + 723.2.

[0848] Synthesis of L-18, 3-(2-(2-(3-(2,5-dioxo-3,4-bis(pyridin-2-ylmercapto))-2,5-dihydro-1H-pyrrol-1-yl)propanol acylamino)ethoxy)ethoxy)propionic acid

[0849] [ka]

[0850] Synthesize L-18 using the synthesis method for L-17. m / z: [M+H] + 547.2.

[0851] Synthesis of L-19, (24S,27S)-34-(2,5-dioxo-3,4-bis(pyridin-2-ylmercapto)-2,5-dihydro-1H-pyrrol-1-yl)-27-isopropyl-23,26,29-trioxo-24-(3-ureidopropyl)-4,7,10,13,16,19-hexaoxa-22,25,28-triazatriacontan-1-oic acid

[0852] [ka]

[0853] Step 1: Using the synthetic method for 17A, obtain 19A by reaction of 3,4-dibromofuran-2,5-dione and 6-aminocaproic acid.

[0854] Step 2: To a solution of intermediate 19A (300 mg, 0.81 mmol) and 2-mercaptopyridine (189 mg, 1.7 mmol) in dichloromethane (5 mL) under ice bath conditions, triethylamine (180 mg, 1.78 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure at low temperature, the mixture was purified by flash column chromatography (C18, eluent: 0% to 49% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 19B (370 mg) as a yellow solid. m / z: [M+H] + 430.0.

[0855] Steps 3 & 4: Reaction of 19B using the synthetic method of 17C gives L-19 as a white solid. m / z: [1 / 2M+H] + 511.3.

[0856] Synthesis of L-20, (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-(2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)acetylamino)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0857] [ka]

[0858] Step 1: To a solution of β-D-galactose pentaacetate (3.1 g, 7.94 mmol) in dichloromethane (30 mL) was added dropwise a solution of hydrobromic acid and acetic acid (33%, 15 mL) under ice-bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice-water (300 mL) and extracted with ice-cold dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate. The organic phase was separated and concentrated under reduced pressure to give Intermediate 20A (3.2 g) as a white solid. m / z: [M+Na] + 433.0.

[0859] Step 2: To a solution of intermediate 20A (1 g, 2.4 mmol) and 4-hydroxyl-3-nitrobenzaldehyde (0.45 g, 2.67 mmol) in acetonitrile (15 mL) was added silver oxide (2 g, 8.6 mmol). The reaction mixture was stirred overnight at room temperature in the dark. The reaction mixture was then filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give intermediate 20B (1.10 g) as a white solid. m / z: [M+Na] + 520.2.

[0860] Step 3: Dissolve intermediate 20B (1.1 g, 2.21 mmol) in methanol (110 mL). Add palladium on carbon (550 mg, 10% wt). Purge the reaction mixture three times with hydrogen and stir under a hydrogen atmosphere for 3 hours. The reaction mixture is then filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to give intermediate 20C (1.02 g) as a white solid. m / z: [M+H] + 470.2.

[0861] Step 4: To a solution of 2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)acetic acid (200 mg, 0.75 mmol) in DMF (3 mL), HATU (314 mg, 0.83 mmol), DIPEA (194 mg, 1.50 mmol), and intermediate 20C (352 mg, 0.75 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 37% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 20D (160 mg) as a white solid. m / z: [M+Na] + 742.2.

[0862] Step 5: To a solution of intermediate 20D (160 mg, 0.22 mmol) in DMF (3 mL), bis(p-nitrobenzene) carbonate (134 mg, 0.44 mmol) and DIPEA (85.3 mg, 0.66 mmol) were added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 58% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give L-20 (130 mg) as a white solid. m / z: [M+Na] + 907.2.

[0863] Synthesis of L-21, (2S,3R,4S,5S,6S)-2-(2-(2-((tert-butoxycarbonyl)amino)hexanoylamino)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetic acid

[0864] [ka]

[0865] Using the synthesis method for intermediate L-20, L-21 was synthesized using 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid methyl ester as the starting material, substituting N-tert-butoxycarbonylglycine for 2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)acetic acid in step 4. m / z: [M+H] + 778.2.

[0866] Synthesis of L-22, 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2-oxo-6,9,12,15,18,21-hexa-3-azatetracosan-24-oic acid

[0867] [ka]

[0868] Using the synthesis method for L-7, synthesize L-22 with 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid. m / z: [M+H] + 491.2.

[0869] Synthesis of L-23, 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)-3-methylbutyrylamino)-5-ureidopentaloylamino)benzyl (4-nitrobenzene) carbonate

[0870] [ka]

[0871] Using the synthesis method in Step 2 of L-14, L-23 was synthesized from Mc-Val-Cit-PAB-OH. m / z: [M+H] + 738.1.

[0872] Synthesis of L-24, (E)-4,7,11-trioxo-3,15,18,21,24,27,30-heptaoxa-8,12-diazatriacont-5-en-33-oic acid

[0873] [ka]

[0874] Step 1: To a solution of monoethyl fumarate (900 mg, 6.24 mmol) and tert-butyl 3-aminopropionic acid (906 mg, 6.24 mmol) in DMF (10 mL) was added HATU (3.6 g, 9.36 mmol) and DIPEA (1.6 g, 12.5 mmol) sequentially under ice-bath conditions. The reaction mixture was stirred at room temperature for 1.5 h and then directly purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give Intermediate 24A (1.2 g) as a pale yellow solid. m / z: [M+H] + 294.2.

[0875] Step 2: Trifluoroacetic acid (5 mL) is added to a solution of Intermediate 24A (1 g, 3.69 mmol) in dichloromethane (15 mL) under ice-bath conditions. After the addition is complete, the reaction is stirred at room temperature for 1 h and then directly purified by flash column chromatography (C18, eluent: 0% to 30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give Intermediate 24B (1.2 g) as a yellow solid. m / z: [M+H] + 216.2.

[0876] Steps 3-4: Using the synthesis method for L-7C, L-24 is obtained by reaction of 24B. m / z: [1 / 2M+H] + 551.2.

[0877] Synthesis of L-25, 2-(4,6-divinylpyridin-2-yl)-4-oxo-8,11,14,17,20,23-hexaoxa-2,5-diazahexadecano-26-oic acid

[0878] [ka]

[0879] Using the synthesis method for L-7, synthesize L-25 with N-(4,6-divinylpyridin-2-yl)-N-methylglycine. m / z: [M+H] + 555.3.

[0880] Synthesis of L-26, 1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azatricosane-23-oic acid

[0881] [ka]

[0882] Using the synthesis method for L-7, synthesize L-26 from 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid. m / z: [M+H] + 553.2.

[0883] L-27, Method for synthesizing 2-(4,6-divinylpyridin-2-yl)-4-oxo-8,11-dioxa-2,5-diazatetradecanoic acid

[0884] [ka]

[0885] Using the synthesis method for L-7, synthesize L-27 with N-(4,6-divinylpyridin-2-yl)-N-methylglycine. m / z: [M+H] + 379.2.

[0886] Synthesis of L-28, (3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetylamino)ethoxy)ethoxy)propionyl)glycine

[0887] [ka]

[0888] Using the synthesis method for L-7, synthesize L-28 in L-8. m / z: [M+H] + 372.2.

[0889] Synthesis of L-29, 3-(2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)acetylamino)-4-((1-methyl-2-nitro-1H-imidazol-5-yl)methoxy)benzyl (4-nitrophenyl)carbonate

[0890] [ka]

[0891] Step 1: To a solution of 4-hydroxyl-3-nitrobenzyl alcohol (2 g, 11.8 mmol) in dichloromethane (100 mL) was added 3,4-dihydro-2H-pyran (1.02 g, 12.2 mmol) and p-toluenesulfonic acid pyridine salt (0.3 g, 1.18 mmol). The reaction mixture was stirred at room temperature for 16 hours. The organic phase was then washed with saturated aqueous sodium bicarbonate and water, concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give Intermediate 29A (2.5 g) as a yellow oil. m / z: [M+Na] + 276.0.

[0892] Step 2: Under nitrogen protection, to a solution of Intermediate 29A (1.25 g, 4.94 mmol) in methanol (120 mL) was added palladium on carbon (10% wt, 165 mg), and the mixture was purged with hydrogen three times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give Intermediate 29B (1 g) as a yellow solid. m / z: [M+Na] + 246.2.

[0893] Step 3: To a solution of 3-methyl-2-nitroimidazole-4-methanol (600 mg, 3.82 mmol), Intermediate 29B (929 mg, 4.16 mmol), and triphenylphosphine (1.5 g, 5.73 mmol) in tetrahydrofuran (10 mL) under ice bath conditions, add DBAD (1.32 g, 5.73 mmol). The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is directly purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain Intermediate 29C (0.51 g) as a yellow solid. m / z: [M+Na] + 385.2.

[0894] Step 4: Trifluoroacetic acid (2 mL) was added dropwise to a solution of intermediate 29C (510 mg, 1.41 mmol) in dichloromethane (6 mL) under ice bath conditions, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography (C18, eluent: 0% to 25% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 29D (391 mg) as a yellow solid. m / z: [M+H] + 279.0.

[0895] Step 5: To a solution of N-tert-butoxycarbonylglycine (214 mg, 1.22 mmol) in DMF (5 mL) under ice bath conditions, HATU (510 mg, 1.34 mmol), DIPEA (315 mg, 2.44 mmol), and intermediate 29D (340 mg, 1.22 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 44% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 29E (150 mg) as a yellow solid. m / z: [M+Na] + 458.2.

[0896] Step 6: Trifluoroacetic acid (1 mL) was added dropwise to a solution of intermediate 29E (150 mg, 0.34 mmol) in dichloromethane (3 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the mixture was purified by flash column chromatography (C18, eluent: 0% to 27% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 29F (70 mg) as a yellow solid. m / z: [M+H] + 336.2.

[0897] Step 7: To a solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid (38 mg, 0.18 mmol) in DMF (2 mL) under ice bath conditions, add HATU (75.3 mg, 0.20 mmol), DIPEA (46.5 mg, 0.36 mmol), and intermediate 29F (60 mg, 0.18 mmol). The reaction mixture is stirred at room temperature for 1 h and directly purified by flash column chromatography (C18, eluent: 0% to 41% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 29G (60 mg) as a yellow solid. m / z: [M+H] + 529.2.

[0898] Step 8: To a solution of intermediate 29G (50 mg, 0.1 mmol) in DMF (2 mL), add bis(p-nitrobenzene)carbonate (57.8 mg, 0.19 mmol) and DIPEA (36.8 mg, 0.29 mmol). The reaction mixture is stirred at room temperature for 2 h and directly purified by flash column chromatography (C18, eluent: 0% to 54% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-29 (60 mg) as a white solid. m / z: [M+H] + 694.2.

[0899] Synthesis of L-30, 1-(4,5-dibromo-2-ethyl-3,6-dioxo-3,6-dihydropyridazin-1(2H)-yl)-3-oxo-7,10,13,16,19,22-hexaoxa-4-azapentacosane-25-oic acid

[0900] [ka]

[0901] Using the synthesis method for L-7, synthesize L-30 with 3-(4,5-dibromo-2-ethyl-3,6-dioxo-3,6-dihydropyridazin-1(2H)-yl)propionic acid. m / z: [M+H] + 704.0.

[0902] Synthesis of L-31, 2-((2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionylamino)ethyl)dimercapto)-2-methylpropyl(4-nitrophenyl)carbonate

[0903] [ka]

[0904] Step 1: To a solution of 2-mercapto-2-methylpropan-1-ol (100 mg, 0.83 mmol) in dichloromethane (4 mL) and methanol (0.2 mL), add 1,2-bis(pyridin-2-yl) disulfide (274 mg, 1.24 mmol). The reaction mixture is stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue is purified by flash column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 3) to obtain Intermediate 31A (300 mg) as a colorless liquid. m / z: [M+H] + 215.6.

[0905] Step 2: To a solution of Intermediate 31A (1.9 g, 8.82 mmol) in methanol (15 mL) was added 2-aminoethanethiol (820 mg, 10.6 mmol). The reaction mixture was stirred at 70 °C for 4 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 1 to 4 / 1) to give Intermediate 31B (1.3 g) as a pale yellow oil. m / z: [M+H] + 181.9.

[0906] Step 3: A solution of intermediate 31B (500 mg, 1.88 mmol), BMPS (310 mg, 1.71 mmol), and N-methylmorpholine (360 mg, 2.82 mmol) in dichloromethane (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give intermediate 31C (232 mg) as a yellow oil.

[0907] Step 4: To a solution of intermediate 31C (50 mg, 0.15 mmol) in DMF (2 mL), bis(p-nitrobenzene) carbonate (68.5 mg, 0.22 mmol) and DIPEA (48.5 mg, 0.38 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-31 (38 mg) as a white solid. m / z: [M+H] + 498.0.

[0908] Synthesis of L-32, (E)-3,6,10-trioxo-2,14,17,20,23,26,29-heptaoxa-7,11-diazatriadec-4-en-32-oic acid

[0909] [ka]

[0910] Step 1: To a solution of intermediate 24C (300 mg, 0.49 mmol) in ethanol (5 mL) under ice-bath conditions, add aqueous lithium hydroxide (1 M, 1.5 mL) and stir the reaction mixture at room temperature for 2 h. Adjust the pH to 2-3 with 3 M hydrochloric acid at 0 °C, concentrate under reduced pressure, and purify the residue by flash column chromatography (C18, eluent: 0%-30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain intermediate 32A (230 mg) as a white solid. m / z: [M+H] + 579.4.

[0911] Step 2: Under ice-bath conditions, a solution of trimethylsilylated diazomethane in n-hexane (2 M, 3 mL) was slowly added to a solution of intermediate 32A (230 mg, 0.4 mmol) in methanol (8 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 8 h and then directly concentrated under reduced pressure to give intermediate 32B (250 mg) as a yellow solid.

[0912] Step 3: To a solution of Intermediate 32B (250 mg, 0.42 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 h and then directly concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-32 (110 mg) as a pale yellow solid. m / z: [M+H] + 537.2.

[0913] Synthesis of L-33, 2,5-dioxopyrrolidin-1-yl 6-(3-bromo-5-methylene-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid

[0914] [ka]

[0915] Step 1: Acetic anhydride (3.46 g, 33.9 mmol) was added dropwise to a solution of (4-bromofuran-2-yl)methanol (1.5 g, 8.47 mmol) in pyridine (12 mL) under ice-bath conditions. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give Intermediate 33A (1.4 g) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.35(d,J=0.7Hz,1H),6.39(s,1H),4.94(s,2H),2.01(s,3H).

[0916] Step 2: NBS (1.36 g, 7.67 mmol) was added to a solution of Intermediate 33A (1.4 g, 6.39 mmol) in tetrahydrofuran (9 mL) and water (1 mL) under ice bath conditions. The reaction mixture was stirred at 0°C for 4 hours, and then 6-aminocaproic acid (1.01 g, 7.67 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give Intermediate 33B (600 mg) as a yellow oil. m / z: [M+H] + 288.0.

[0917] Step 3: To a solution of intermediate 33B (600 mg, 2.08 mmol) in dichloromethane (4 mL) was added NHS (250 mg, 2.18 mmol) and DIC (280 mg, 2.18 mmol) sequentially under ice bath conditions. The reaction solution was stirred at 0 °C for 3 h. Diluted with ethyl acetate, the organic phase was washed with saturated brine, separated, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give L-33 (176 mg) as a yellow oil. m / z: [M+H] + 384.8.

[0918] Synthesis of L-34, 6-(4-(3-tosyl-2-(tosylmethyl)propionyl)benzoylamino)caproic acid

[0919] [ka]

[0920] Using the synthesis method for L-7, synthesize L-34 with 4-(3-p-toluenesulfonyl-2-(toluenesulfonylmethyl)propionyl)benzoic acid. m / z: [M+H] + 614.2.

[0921] Synthesis of L-35, 1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-2-oxo-6,9,12,15,18,21-hexaoxa-3-aza-24 acid

[0922] [ka]

[0923] Using the synthesis method for L-7, synthesize L-35 with 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetic acid. m / z: [M+H] + 567.2.

[0924] Synthesis of L-36, 2-(2-((tert-butoxycarbonyl)amino)acetylamino)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenylneopentyl sulfate

[0925] [ka]

[0926] Step 1: In an ice bath, neopentyl chlorosulfonate (2.87 g, 15.4 mmol) was slowly added dropwise to a solution of 4-(hydroxymethyl)-2-nitrophenol (2 g, 11.8 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 g, 15.4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 to 2 / 1) to obtain Intermediate 36A (960 mg) as a yellow oil. m / z: [M+Na] + 342.0.

[0927] Step 2: Under ice-bath conditions, zinc powder (1.4 g, 21.9 mmol) was slowly added to a solution of intermediate 36A (700 mg, 2.19 mmol) and ammonium chloride (1.17 g, 21.9 mmol) in a mixture of methanol (3 mL), tetrahydrofuran (6 mL), and water (8 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 36B (240 mg) as a yellow solid. m / z: [M+H] + 290.1.

[0928] Using the synthesis method in steps 3-4 and 7-8 of L-29, reaction of intermediate 36B gives L-36 as a white solid. m / z: [M+Na] + 634.2.

[0929] Synthesis of L-37, (S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)-5-ureidopentanoic acid

[0930] [ka]

[0931] To a solution of EMCS (300 mg, 0.97 mmol) and L-citrulline (170 mg, 0.97 mmol) in DMF (3 mL) was added DIPEA (251 mg, 1.94 mmol). The reaction mixture was stirred at room temperature for 3 days and then purified by flash column chromatography (C18, eluent: 0% to 45% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-37 (169 mg) as a white solid. m / z: [M+H] + 369.2.

[0932] Synthesis of L-38, 2-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)-3-methylbutyrylamino)-5-ureidopentaloylamino)acetic acid

[0933] [ka]

[0934] Using the synthesis method for L-3, synthesize L-38 with Fmoc-Val-Cit-OH and 2-aminoacetyl tert-butyl ester. m / z: [M+H] + 525.2.

[0935] Synthesis of L-39, 1-(3,5-diacryloyl-1,3,5-triazin-1-yl)-1,6-dioxo-10,13,16,19,22,25-hexa-4-thia-7-azaoctadecanoic acid

[0936] [ka]

[0937] Step 1: Under ice bath conditions and nitrogen protection, triethylamine (0.15 g, 1.5 mmol) and 2-mercaptoacetic acid (280 mg, 3 mmol) were added to a solution of compound 1,1',1''-(1,3,5-triazine-1,3,5-triyl)tris(prop-2-en-1-one) (3.74 g, 15.0 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 1) to give Intermediate 39A (400 mg) as a white solid. m / z: [M+H] + 342.0.

[0938] Step 2: To a solution of intermediate 39A (80 mg, 0.23 mmol) and 1-amino-3,6,9,12,15,18-hexaoxaicosan-21-oic acid tert-butyl ester (94 mg, 0.23 mmol) in DMF (3 mL) was added DIPEA (44.6 mg, 0.35 mmol), EDCI (52.9 mg, 0.28 mmol), and HOBT (37.3 mg, 0.28 mmol) sequentially under ice-bath conditions. The reaction mixture was stirred overnight at room temperature, filtered, and the filtrate was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 39B (56 mg) as a colorless oil. m / z: [M+H] + 733.4.

[0939] Step 3: Trifluoroacetic acid (1 mL) was added to a solution of intermediate 39B (56 mg, 0.08 mmol) in dichloromethane (3 mL) under ice-bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h and then directly purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-39 (30 mg) as a colorless oil. m / z: [M+H] + 677.3.

[0940] Synthesis of L-40, (9H-fluoren-9-yl)methyl(2-(3-((1-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-2-methylprop-2-yl)dimercapto)propionamido)ethyl)carbamate

[0941] [ka]

[0942] Step 1: A solution of 3-(2-pyridyldimercapto)propionic acid N-hydroxylsuccinimide ester (1.8 g, 5.76 mmol), Fmoc-ethylenediamine (1.79 g, 6.34 mmol), and N-methylmorpholine (1.17 g, 11.5 mmol) in dichloromethane (15 mL) was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with dichloromethane. The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane / methanol = 20 / 1) to give Intermediate 40A (2.01 g) as a white solid.

[0943] Step 2: A solution of intermediate 40A (1.0 g, 2.09 mmol) and 2-mercapto-2-methylpropan-1-ol (0.21 g, 1.99 mmol) in methanol (12 mL) was stirred at 60 °C for 6 hours. The mixture was concentrated under reduced pressure to remove the methanol, diluted with water, and extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give intermediate 40B (686 mg) as a white solid. m / z: [M+Na] + 497.0.

[0944] Step 3: Under nitrogen protection, N,N'-disuccinimidyl carbonate (64.6 mg, 0.25 mmol) and pyridine (20.8 mg, 0.26 mmol) were sequentially added to a solution of intermediate 40B (100 mg, 0.21 mmol) in acetonitrile (3 mL). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred overnight at room temperature. The reaction mixture was directly concentrated under reduced pressure and purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give L-40 (61 mg) as a white solid. m / z: [M+Na] + 638.2.

[0945] Synthesis of L-41A, 2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxane-5-carboxylic acid, isomer 1 and L-41B, 2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxane-5-carboxylic acid, isomer 2

[0946] [ka]

[0947] Step 1: To a solution of 2,2-dimethoxyeth-1-amine (2 g, 19.0 mmol) and DIPEA (7.37 g, 57.1 mmol) in dichloromethane (20 mL) was added benzyl chloroformate (3.41 g, 20.0 mmol) under ice-bath conditions. The reaction mixture was stirred at room temperature for 3 hours, washed with water and saturated brine, and the organic phase was separated and concentrated under reduced pressure to give Intermediate 41A (2.7 g) as a colorless oil.

[0948] Step 2: To a solution of intermediate 41A (1.3 g, 5.43 mmol) in toluene (40 mL) was added methyl 3-hydroxyl-2-(hydroxylmethyl)propionate (1.18 g, 7.06 mmol) and p-toluenesulfonic acid (18.7 mg, 0.11 mmol). The reaction was stirred at 110 °C for 2 h, sodium bicarbonate (100 mg) was added, and stirring was continued for 0.5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 41B (2.1 g) as a pale yellow oil. m / z: [M+H] + 310.1.

[0949] Step 3: Add Intermediate 41B (2.1 g, 5.43 mmol) to a solution of lithium hydroxide in tetrahydrofuran and water (0.75%, 60 mL, 1 / 1). Stir the reaction mixture at room temperature for 6 hours, adjust the pH to 5-6 with HCl (1 M), extract with dichloromethane, and concentrate the combined organic phase under reduced pressure to give Intermediate 41C (1.25 g) as a pale yellow solid.

[0950] Step 4: To a solution of Intermediate 41C (380 mg, 1.29 mmol) in methanol (20 mL), add Pd / C (10% wt, 38 mg), purge the reaction mixture with nitrogen three times, then purge again three times with nitrogen and increase the pressure to 14.5 psi, stir at room temperature for 1 hour, and concentrate under reduced pressure to give Intermediate 41D (200 mg) as a black solid. m / z: [M+H] + 162.0.

[0951] Step 5: To a mixture of Intermediate 41D (200 mg, 1.24 mmol) and 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylic acid methyl ester (190 mg, 1.24 mmol) in water (2 mL) and tetrahydrofuran (4 mL) was added sodium bicarbonate (210 mg, 2.48 mmol) under ice-bath conditions. The reaction mixture was stirred at 0 °C for 2 h, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure to give L-41. L-41 was separated by preparative HPLC (Separation Condition 4, eluent: 0% to 28% acetonitrile in 0.1% aqueous formic acid, 20 min) to give L-41A (14 mg) and L-41B (16.5 mg), both of which were white solids.

[0952] L-41A: 1 H NMR(400MHz,DMSO-d6):δ12.45(s,1H),7.04(s,2H),4.72(t,J=5.2Hz,1H),4.31 (d,J=11.2Hz,2H),3.80-3.84(m,2H),3.41(d,J=5.2Hz,2H),3.31-3.25(m,1H).

[0953] L-41B: 1 H NMR (400MHz, CDCl3): δ6.73 (s, 1H), 4.70 (t, J=5.2Hz, 1H), 4.30-4.34 (m, 1H), 3.71-3.75 (m, 2H), 3.07 (m, 1H).

[0954] Synthesis of L-42, 1-(2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxan-5-yl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azatricosane-23-oic acid

[0955] [ka]

[0956] Using the synthesis method for L-7, synthesize L-42 from L-41. m / z: [M+H]+ 577.2.

[0957] Synthesis of L-43, tert-butyl 2-(3-((1-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-2-methylpropan-2-yl)dimercapto)propionyl)carbazate

[0958] [ka]

[0959] Step 1: To a solution of 3-mercaptopropionic acid (5.0 g, 47.1 mmol) in DMF (50 mL) was added HOBT (8.28 g, 61.2 mmol), EDCI (9.93 g, 51.8 mmol), carbazic acid tert-butyl ester (9.34 g, 70.7 mmol), and DIPEA (12.2 g, 94.2 mmol) in an ice bath. The reaction mixture was purged with nitrogen three times and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 1) to give Intermediate 43A (3.0 g) as a colorless oil. m / z: [M-56+H] + 164.9.

[0960] Step 2: Under nitrogen protection, 1,2-bis(pyridin-2-yl) disulfide (2.34 g, 10.6 mmol) was added to a solution of intermediate 43A (3.0 g, 8.17 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain intermediate 43B (1.0 g) as a colorless oil. m / z: [M+H] + 330.0.

[0961] Steps 3-4: Using the synthesis method in Steps 2-3 of L-40, reaction of 43B gives L-43. m / z: [M+Na] + 488.0.

[0962] Synthesis of L-44, (S)-2-(1-(ethoxycarbonyl)cyclobutylformylamino)-5-ureidopentanoic acid

[0963] [ka]

[0964] A mixture of L-citrulline (1.5 g, 8.56 mmol) and sodium bicarbonate (1.5 g, 8.56 mmol) in dimethyl ether (20 mL) and water (40 mL) was stirred at room temperature for 15 minutes. After the reaction became cloudy, 1-(2,5-dioxopyrrolidin-1-yl)1-ethylcyclobutane-1,1-dicarboxylate (3.46 g, 12.8 mmol) was added and the reaction was stirred at room temperature for 4 days. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 0-30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-44 (2.3 g) as a white solid. m / z: [M+H] + 330.2.

[0965] Synthesis of L-45, N-(2-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-amido)ethyl)-4-formylbenzamide

[0966] [ka]

[0967] Step 1 & 2: Using the synthesis method of L-7, synthesize 45B with 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylic acid and (2-aminoethyl)carbamate tert-butyl ester. m / z: [M+H] + 280.2.

[0968] Step 3: To a solution of 4-formylbenzoic acid (41.3 mg, 0.28 mmol), HATU (124 mg, 0.33 mmol), and DIPEA (97 mg, 0.75 mmol) in DMF (3 mL) was added intermediate 45B (100 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 3 h and then directly purified by flash column chromatography (C18, eluent: 0% to 45% acetonitrile in 10 mmol / L aqueous ammonium bicarbonate) to give L-45 (85 mg) as a white solid. m / z: [M+H] + 412.2.

[0969] Synthesis of L-46, 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylacetylamino)-N-methylacetylacylamino)acetylamino)propionic acid

[0970] [ka]

[0971] Step 1: To a solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetic acid (1.5 g, 4.82 mmol) in DMF (20 mL), DIPEA (1.8 g, 14.5 mmol) and HATU (1.83 g, 4.82 mmol) were added. The reaction mixture was stirred at room temperature for 10 min. 2-(methylamino)acetic acid tert-butyl ester (1.06 g, 5.78 mmol) was then added. The reaction mixture was stirred at room temperature for 40 min. The mixture was then diluted with ethyl acetate and the organic phase was washed with water and saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 9 to 3 / 7) to give Intermediate 46A (1.5 g) as a yellow solid. m / z: [M+Na] + 461.1.

[0972] Step 2: To a solution of Intermediate 46A (3 g, 6.84 mmol) in dichloromethane (5 mL) under ice bath conditions, add a solution of hydrogen chloride in 1,4-dioxane (2 M, 30 mL). The reaction mixture is stirred at room temperature for 6 hours and then directly concentrated under reduced pressure to give Intermediate 46B (3 g) as a yellow solid. m / z: [M+H] + 383.0.

[0973] Step 3: Using the synthesis method of 46A, reaction of 46B gives 46C as a yellow solid. m / z: [M+H] + 510.1.

[0974] Step 4: Intermediate 46C (900 mg, 1.77 mmol) was added to a solution of diethylamine in dichloromethane (30%, 3 mL). The reaction mixture was stirred at room temperature for 2 h, then directly concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol / dichloromethane = 0 to 1 / 10) to give Intermediate 46D (490 mg) as a yellow solid.

[0975] Step 5: To a solution of intermediate 46D (490 mg, 1.7 mmol) and 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid (330 mg, 2.13 mmol) in DMF (4 mL), HOBT (370 mg, 2.77 mmol), EDCI (530 mg, 2.77 mmol), and DIPEA (830 mg, 6.39 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 h, diluted with ethyl acetate, and the organic phase was washed with water and saturated brine. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give intermediate 46E (310 mg) as a yellow solid. m / z: [M+H] + 425.1.

[0976] Step 6: To a solution of intermediate 46E (310 mg, 0.73 mmol) in dichloromethane (3.5 mL), add trifluoroacetic acid (0.5 mL), stir the reaction at room temperature for 6 h, and then directly concentrate under reduced pressure. Purify the residue by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain L-46 (60 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ12.27(s,1H),8.25-7.74(m,1H),7.10(d,J=2.4Hz,2H),4.43-4.29(m,1H),4.17(d,J=15.8Hz,1H),3.91 (dd,J=19.8,13.4Hz,2H),3.29(d,J=10.2Hz,4H),2.98(dd,J=27.4,15.2Hz,2H),2.82-2.76(m,4H),2.40(dd,J=13.6,6.0Hz,3H).

[0977] Synthesis of L-47, 4-((S)-2-((S)-2-(2-((3-(3,5-diacryloyl-1,3,5-triazin-1-yl))-3-oxopropyl)mercapto)acetylamino)-3-methylbutyrylamino)-5-ureidopentaloylamino)benzyl (4-nitrobenzene) carbonate

[0978] [ka]

[0979] Using the synthesis method for L-5, synthesize L-47 with Val-Cit-PAB-OH and 39A. m / z: [M+H] + 868.2.

[0980] Synthesis of L-48, 4-((S)-2-((S)-2-(2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxane-5amido)-3-methylbutyrylamino)-5-ureidopentaloylamino)benzyl (4-nitrobenzene) carbonate

[0981] [ka]

[0982] Using the synthesis method for L-5, synthesize L-47 using Val-Cit-PAB-OH and L-41. m / z: [M+H] + 768.2.

[0983] Synthesis of L-49, 4-((S)-2-((S)-2-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetyl(amino)-3-methylbutyrylamino)-5-ureidopentaloylamino)benzyl(4-nitrobenzene)carbonate

[0984] [ka]

[0985] Using the synthesis method for L-5, synthesize L-49 with 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetic acid. m / z: [M+H] + 758.2.

[0986] Synthesis of L-50, 4-((S)-2-((S)-2-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoylamino))-3-methylbutyrylamino)-5-ureidopentaloylamino)benzyl (4-nitrobenzene) carbonate

[0987] [ka]

[0988] Using the synthetic method for L-5, synthesize L-50 with Val-Cit-PAB-OH and 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid. m / z: [M+H] + 744.2.

[0989] Synthesis of L-51, (R)-2-((tert-butoxycarbonyl)amino)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetylamino)propanoic acid

[0990] [ka]

[0991] Using the synthesis method in Step 1 of L-7, synthesize L-51 from 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid and (R)-3-amino-2-((tert-butoxycarbonyl)amino)propionic acid. m / z: [M+Na] + 364.0.

[0992] Synthesis of L-52, 4-((S)-4-amino-2-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) )hexanoylamino)propionylamino)propionylamino)-4-oxobutyrylamino)benzyl(4-nitrobenzene)carbonate

[0993] [ka]

[0994] Step 1: To a solution of Fmoc-Ala-Ala-Asn(Trt)-OH (150 mg, 0.2 mmol) in tetrahydrofuran (2 mL), add (4-aminophenyl)methanol (29.6 mg, 0.24 mmol) and EEDQ (79.1 mg, 0.32 mmol). The reaction mixture is stirred overnight at room temperature and concentrated under reduced pressure to give Intermediate 52A (171 mg) as a yellow solid. m / z: [M+H] + 844.3.

[0995] Steps 2-4: Using the synthesis method in Steps 2-4 of L-3, 52A is reacted to give 52D. m / z: [M+H]+ 573.2.

[0996] Step 5: Using the synthesis method in Step 2 of L-14, reaction of 52D gives L-52. m / z: [M+H] + 738.2.

[0997] Synthesis of L-53, (10S,13S)-20-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-13-isopropyl-6,9,12,15-tetraoxo-10-(3-ureidopropyl))-3-oxa-5,8,11,14-tetraazaeicosan-1-oic acid

[0998] [ka]

[0999] Using the synthesis method in Step 1, Step 2 of L-3, reaction of (9H-fluoren-9-yl)methyl(2-(((benzyloxy)methyl)amino)-2-oxoethyl)carbamate ester gives 53A. m / z: [M+H] + 253.2.

[1000] Using the synthesis method in steps 2-3 and 1-2 of L-3, 53A is reacted to give 53C. m / z: [M+H] + 509.2.

[1001] Step 4: To a solution of Intermediate 53C (30 mg, 0.06 mmol) in methanol (3 mL) was added palladium on carbon (10% wt, 10 mg). The reaction mixture was purged with nitrogen and then hydrogen three times, then stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtration, the filtrate was directly concentrated under reduced pressure to give Intermediate 53D (25 mg) as a yellow solid. m / z: [M+H] + 419.2.

[1002] Step 5: Using the synthesis method in Step 3 of L-3, reaction of 53D with L-53 gives L-53. m / z: [M+Na] +634.2.

[1003] Synthesis of L-54, (2S,3R,4S,5S,6S)-2-(2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutyramido)-5-ureidopentaloylamino)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-tolyltriacetate

[1004] [ka]

[1005] Using the synthesis method for intermediate L-20, L-54 was synthesized using 1,2,3,4-tetra-O-acetyl-β-D-glucuronic acid methyl ester as the starting material, substituting Fmoc-Val-Cit-OH for 2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)acetic acid in step 4. m / z: [M+H] + 1099.2.

[1006] L-55, N 2 -N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)-O-(tert-butyl)-L-serylglycyl-N 6 Synthesis of -((allyloxy)carbonyl)-L-lysine

[1007] [ka]

[1008] Step 1: Weigh 2-chlorotrityl chloride resin (1.0 g) into a reaction column, then add dichloromethane (15 mL) until the reaction column swells for 10 minutes, drain the waste, and wash twice with dichloromethane.

[1009] Add a DMF (8 mL) solution of Fmoc-Lys(Alloc)-OH (1.1 g, 2.5 mmol) and DIPEA (2 mL) to the reaction column obtained in step 1. Place the reaction column flat on a shaker and shake at 150-180 r. Allow to react with the resin for 2 h at room temperature. Remove the reaction solution and wash with DMF and dichloromethane 2-3 times, draining the waste until no liquid flows out. Add DIPEA (1 mL), methanol (3 mL), and dichloromethane (12 mL) for end-capping and wash to obtain 55A.

[1010] Step 2: Add 10 mL of 20% piperidine in DMF to the reaction column, washing twice for 10 minutes each time. Add 10 mL of DIPEA and dichloromethane, wash three times, and drain the waste. Weigh out Fmoc-Gly-OH (742.5 mg, 2.5 mmol) and HATU (1.07 g, 2.75 mmol), add 2 mL of DIPEA, and add 10 mL of DMF to the reaction column. Shake on a shaker and react for 30 minutes at room temperature. Remove the reaction solution, wash three times with 10 mL of DMF and 10 mL of dichloromethane, and drain the waste until no more liquid flows out. This affords 55B.

[1011] Step 3: Following Step 2, Fmoc-Gly-OH is replaced with Fmoc-Ser(tBu)-OH and the reaction gives 55C.

[1012] Step 4: Following Step 2, Fmoc-Gly-OH is replaced with Fmoc-Leu-OH and reacted to give 55D.

[1013] Step 5: Add the dried resin 55D to cutting fluid (trifluoroacetic acid / dichloromethane mixture, 8 mL, 1 / 100), shake on a shaker for 30 minutes, filter, wash the resin once with cutting fluid, combine the filtrate, remove most of the dichloromethane under reduced pressure, add it to 10 volumes of ice-cold ether, centrifuge, and wash twice with ether. Vacuum-dry the solid for 2 hours to obtain L-55 as a white solid. m / z: [M+H] + 766.4.

[1014] Synthesis of L-56, allyl((5S,11S,14S)-11-(tert-butoxymethyl)-21-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-14-isobutyl-5-((4-(((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)-7,10,13,16-tetraoxa-6,9,12,15-tetrazabinodecyl)carbamate

[1015] [ka]

[1016] Using the synthetic method of steps 1-3 and 5 of L-52, L-55 is reacted to give L-56. m / z: [M+H] + 1007.3.

[1017] Synthesis of L-57, 4-((S)-2-((S)-2-((R)-2-((dimethoxyphosphoryl)amino)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetylamino)propionylamino)-3-methylbutyroylamino)-5-ureidopentaloylamino)benzyl(4-nitrobenzene)carbonate

[1018] [ka]

[1019] Step 1: To a solution of intermediate 57A (700 mg, 1 mmol) (obtained by the reaction of L-51 and Val-Cit-PAB-OH using the synthesis method in Step 1 of L-5) in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, then directly concentrated under reduced pressure. The residue was diluted with methanol and adjusted to neutral pH with ammonia in methanol (7 M). It was then purified by preparative HPLC (eluent: 0-35% acetonitrile in 0.1% aqueous trifluoroacetic acid, 25 min) to give intermediate 57B (250 mg) as a yellow solid. m / z: [M+H] + 603.2.

[1020] Step 2: Under ice-bath conditions, O,O-dimethylphosphoryl chloride (65.2 mg, 0.45 mmol) was added to a solution of intermediate 57B (250 mg, 0.41 mmol) and triethylamine (104 mg, 1.02 mmol) in DMF (8 mL). The reaction mixture was stirred at 0 °C for 2 h, then directly concentrated under reduced pressure. The residue was purified by preparative HPLC (eluent: 10–65% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give intermediate 57C (200 mg) as a white solid. m / z: [M+H] + 711.2.

[1021] Step 3: Using the synthesis method in Step 2 of L-5, reaction of 57C gives L-57 as a white solid. m / z: [M+H] + 876.2.

[1022] Synthesis of L-58, (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(aminomethyl)phenyl)amino)-1-oxo-5-ureido)pent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

[1023] [ka]

[1024] Step 1: To a solution of Fmoc-Val-Cit-OH (500 mg, 1.01 mmol) and 4-(N-Boc-aminomethyl)aniline (200 mg, 1.01 mmol) in DMF (5 mL), EDCI (232 mg, 1.21 mmol) and HOBT (164 mg, 1.21 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to water (40 mL) and stirred for 20 minutes. The precipitated solid was filtered and the filter cake was dried to give Intermediate 58A (1 g) as a yellow solid. m / z: [M+H] + 701.4.

[1025] Step 2: To a solution of intermediate 58A (350 mg, 0.5 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 h and then directly concentrated under reduced pressure. The residue was adjusted to pH 7 with 7M ammonia-methanol solution, then concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 50% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give L-58 (60 mg) as a white solid. m / z: [M+H] + 601.4.

[1026] L-59, N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanyl-L-alanyl-N 4 Synthesis of -trityl-L-asparagine

[1027] [ka]

[1028] Using the solid phase synthesis method of L-55, pretreat 2-chlorotrityl chloride resin using the method in step 1, then repeat the method in step 2, adding Fmoc-Asn(Trt)-OH, Fmoc-Ala-OH, and Fmoc-Ala-OH sequentially, and then use the cleavage method in step 5 of L-55 to obtain L-59 as a white solid. m / z: [M+Na] + 761.3.

[1029] Synthesis of L-60, (10S,13S)-20-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-13-isopropyl-6,9,12,15-tetraoxo-10-(3-ureidopropyl))-3-oxa-5,8,11,14-tetraazaeicosan-1-oic acid

[1030] [ka]

[1031] Step 1: To a solution of intermediate 53A (150 mg, 0.59 mmol) and Fmoc-Phe-OSu (314 mg, 0.65 mmol) in DMF (3 mL), DIPEA (114 mg, 0.89 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and then directly purified by preparative HPLC (eluent: 10% to 75% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give intermediate 60A (280 mg) as a white solid. m / z: [M+Na] + 644.2.

[1032] Using the synthesis method for L-53 in steps 2-6, L-60 is obtained by the reaction of 60A. m / z: [M+Na] + 639.2.

[1033] Synthesis of L-61, (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((3-(aminomethyl)phenyl)amino)-1-oxo-5-ureido)pent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate

[1034] [ka]

[1035] Using the synthesis method for L-58, the reaction of Fmoc-Val-Cit-OH and 3-(N-Boc-aminomethyl)aniline affords L-61 as a white solid. m / z: [M+H] +601.3.

[1036] Synthesis of L-62, (S)-11-benzyl-1-(9H-fluoren-9-yl)-3,6,9,12,15-pentaoxo-2,18,21,24-tetraoxa-4,7,10,13,16-pentaazaheptacosane-27-oic acid

[1037] [ka]

[1038] Step 1: A solution of Fmoc-Gly-Gly-OH (10 g, 28.2 mmol) and lead tetraacetate (17.5 g, 39.5 mmol) in tetrahydrofuran (240 mL) and toluene (80 mL) was stirred at 80 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate / methyl tert-butyl ether (20%, 300 mL), filtered, and the filter cake was dried under vacuum to give Intermediate 62A (9.5 g) as a white solid. m / z: [M+Na] + 391.2.

[1039] Steps 2-3: Using the synthesis method in Steps 1-2 of L-60, reaction of 62A gave 62C as a colorless liquid. m / z: [M+H] + 321.2.

[1040] Using the synthesis method in steps 4-6 and 1-3 of L-60, 62C is reacted to give 62F as a colorless liquid. m / z: [M+Na] + 826.3.

[1041] Step 7: Under ice-bath conditions, a mixture of trifluoroacetic acid (2 mL) and dichloromethane (10 mL) is slowly added to a solution of Intermediate 62F (400 mg, 0.5 mmol) in dichloromethane (10 mL). The reaction mixture is stirred at room temperature for 1 hour and then directly concentrated under reduced pressure to give L-62 (350 mg) as a colorless oil. m / z: [M+Na] + 770.2.

[1042] Synthesis of L-63, (4S,7S)-1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-4-isopropyl-2,5,8-trioxo-7-(3-ureidopropyl)-12,15,18,21,24,27-hexaoxa-3,6,9-triazatriacan-30-oic acid

[1043] [ka]

[1044] Using the synthesis method for L-7, synthesize L-63 with 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoic acid and intermediate 3B. m / z: [M+H] + 823.4.

[1045] Synthesis of L-64, 4-((26S,29S)-1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-26-isopropyl-2,24,27-trioxo-29-(3-ureidopropyl)-6,9,12,15,18,21-hexaoxa-3,25,28-triazatriacan-30-amino)benzyl(4-nitrobenzene)carbonate

[1046] [ka]

[1047] Using the synthesis method for L-5, synthesize L-64 with Val-Cit-PAB-OH and L-35. m / z: [M+H] + 1093.5.

[1048] Synthesis of L-65, 4-((25S,28S)-1-(2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxan-5-yl)-25-isopropyl-1,23,26-trioxo-28-(3-ureidopropyl)-5,8,11,14,17,20-hexaoxa-2,24,27-triazanonacan-29-amino)benzyl(4-nitrobenzene)carbonate

[1049] [ka]

[1050] Using the synthesis method for L-5, synthesize L-65 using Val-Cit-PAB-OH and L-42. m / z: [1 / 2M+H] + 552.3.

[1051] Synthesis of L-66, (2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)ethylacyl)glycylglycyl-L-phenylalanylglycine

[1052] [ka]

[1053] Step 1: To a solution of Cbz-Gly-Gly-Phe-Gly-OtBu (350 mg, 0.66 mmol) in 15 mL of methanol and 5 mL of dichloromethane, add palladium on carbon (70 mg, 10% wt). The reaction mixture was purged with hydrogen three times and then stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 66A (250 mg) as a yellow oil. m / z: [M+H] + 393.2.

[1054] Steps 2-3: Using the synthesis method for L-58, L-66 is obtained by the reaction of 66A. m / z: [M+H] + 550.2.

[1055] Synthesis of L-67, t-butyl (S)-4-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoylamino)-5-(((S)-3-methyl-1-(((S)-1-((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)amino)-5-oxopentanoate

[1056] [ka]

[1057] Step 1-2: Under ice bath conditions, EDCI (0.68 g, 3.53 mmol) and HOBT (0.48 g, 3.53 mmol) were added to a DMF (10 mL) solution of Fmoc-Glu(OtBu)-OH (1.0 g, 2.35 mmol) and Val-Cit-PAB-OH (0.89 g, 2.35 mmol), and the reaction mixture was stirred at room temperature for 2 h. Diethylamine (2 mL) was added to the mixture, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by flash column chromatography (C18, eluent: 0% to 35% acetonitrile in 0.05% aqueous trifluoroacetic acid) to obtain Glu(OtBu)-Val-Cit-PAB-OH (67B, 1.02 g) as a white solid. m / z: [M+H] + 565.4.

[1058] Step 3: Using the synthesis method in Step 3 of L-3, reaction of 67B gives 67C. m / z: [M+H] + 758.4.

[1059] Step 4: Using the synthesis method in Step 2 of L-5, reaction of 67C gives L-67. m / z: [M+H] + 923.4.

[1060] Synthesis of L-68, 4-((S)-4-amino-2-((S)-2-((S)-2-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetylamino)propionylamino)-4-oxobutyroamino)benzyl(4-nitrobenzene)carbonate

[1061] [ka]

[1062] Step 1: To a solution of 52B (153 mg, 0.25 mmol) in DMF (2 mL), EDCI (71.9 mg, 0.38 mmol) and HOBT (50.7 mg, 0.38 mmol) were added sequentially under ice bath conditions, followed by the slow dropwise addition of a solution of 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoic acid (57.8 mg, 0.25 mmol) in DMF (0.4 mL). The reaction mixture was stirred at room temperature for 5 h and directly purified by flash column chromatography (C18, eluent: 0% to 57% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give 68A (40 mg) as a white solid. m / z: [M+H] + 835.3.

[1063] Using the synthesis method described in steps 2-3 and 4-5 of L-52, reaction of 68A gives L-68. m / z: [M+H] + 758.2.

[1064] L-69, (Z)-3,6-dioxo-2,10,13,16,19,22,25-heptaoxa-7-azaoctaco-4-en-28-oic acid

[1065] [ka]

[1066] Step 1: Under ice-bath conditions, 2,5-dihydrofuran-2,5-dione (125 mg, 1.27 mmol) was added to a solution of 1-amino-3,6,9,12,15,18-hexaoxaicosan-21-oic acid tert-butyl ester (300 mg, 0.85 mmol) in acetic acid (5 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give 69A (400 mg) as a white solid. m / z: [M+H] + 508.2.

[1067] Step 2: Methyl iodide (147 mg, 1.03 mmol) was added dropwise to a solution of 69A (350 mg, 0.69 mmol) and potassium carbonate (190 mg, 1.38 mmol) in DMF (5 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 3 h and directly purified by flash column chromatography (C18, eluent: 0% to 45% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give 69B (300 mg) as a white solid. m / z: [M+H] + 522.2.

[1068] Step 3: Stir 69B (300 mg, 0.58 mmol) in 8 mL of dichloromethane and 3 mL of trifluoroacetic acid at room temperature for 2 h under ice-bath conditions. The reaction mixture is concentrated under reduced pressure, and the residue is purified by flash column chromatography (C18, eluent: 0% to 30% acetonitrile in 0.1% aqueous trifluoroacetic acid) to obtain L-69 (120 mg) as a white solid. m / z: [M+H] + 466.2.

[1069] Synthesis of L-70, t-butyl (S)-1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-26-(((S)-3-methyl-1-(((S)-1-((4-(((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropyl-2-yl)amino)-1-oxobutan-2-yl)carbamoyl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3,25-diazanonacan-29-oic acid ester

[1070] [ka]

[1071] For the synthesis of Intermediate 70A, using the synthetic method for Intermediate 67B, the reaction of Fmoc-Glu(OtBu)-OH and Val-Ala-PAB-OH affords Glu(OtBu)-Val-Ala-PAB-OH (Intermediate 70A) as a white solid. m / z: [M+H] + 479.2.

[1072] Using the synthesis method for L-5, L-70 was synthesized using intermediates 70A and L-35. m / z: [M+H] + 1192.4.

[1073] Synthesis of L-71, 4-((26S,29S,32S)-1-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)phenyl)-26,29-dimethyl-2,24,27,30-tetrahydroxo-32-(2-oxo-2-(triphenylmethylamino)ethyl)-6,9,12,15,18,21-hexaoxa-3,25,28,31-tetraazatridecan-33-amido)benzyl(4-nitrophenyl)carbonate

[1074] [ka]

[1075] Using the synthesis method for L-5, L-71 is synthesized using intermediates 52B and L-35. m / z: [M+H] + 1192.4.

[1076] Synthesis of L-72, (2-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxane-5-carbonyl)glycine

[1077] [ka]

[1078] Using the synthesis method for L-7, synthesize L-72 from L-41 and glycine tert-butyl ester. m / z: [M+H] + 299.0.

[1079] Synthesis of L-73, 1-(9H-fluoren-9-yl)-3,10-dioxo-2,14,17,20,23,26,29-heptaoxa-4,11-diazatridodecan-32-oic acid

[1080] [ka]

[1081] Using the synthesis method for L-7, synthesize L-73 with 1-amino-3,6,9,12,15,18-hexaoxaicosan-21-oic acid tert-butyl ester and 6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)hexanoic acid. m / z: [M+H] + 688.9.

[1082] Synthesis of L-74, 3-(2-(2-(6-(11,12-didehydrodibenzo[b,f]azelatin-5(6H)-yl)-6-oxohexanamido)ethoxy)ethoxy)propionic acid

[1083] [ka]

[1084] Using the synthesis method for L-7, synthesize L-74 using DBCO-C6-COOH (CAS: 1425485-72-8) and 3-(2-(2-aminoethoxy)ethoxy)propionic acid tert-butyl ester. m / z: [M+H] + 493.2.

[1085] Synthesis of L-75, 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1,3-dioxane-5-carboxylic acid

[1086] [ka]

[1087] Step 1: To a solution of methyl 3-hydroxyl-2-(hydroxylmethyl)propionate (1.5 g, 11.2 mmol) and 4-nitrobenzaldehyde (1.69 g, 11.2 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (210 mg, 1.12 mmol). The reaction mixture was stirred at 110 °C for 2 h, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 75A (1.5 g) as a pale yellow solid. m / z: [M+H] + 268.2.

[1088] Step 2: To a solution of 75A (1.4 g, 5.24 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added lithium hydroxide monohydrate (440 mg, 10.5 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was adjusted to pH 3 with 2 M hydrochloric acid. Filtered, and the filter cake was dried under vacuum to give 75B (1.42 g) as a pale yellow solid. m / z: [M+H] + 254.1.

[1089] Step 3: To a solution of 75B (300 mg, 1.18 mmol) in ethyl acetate (20 mL) was added palladium on carbon (10% wt, 299 mg). The reaction mixture was purged with hydrogen and stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give 75C (300 mg) as a yellow solid. m / z: [M+H] + 224.2.

[1090] Step 4: To a solution of 75C (300 mg, 1.34 mmol) in DMF (3 mL) was added 2,5-dihydrofuran-2,5-dione (171 mg, 1.74 mmol). The reaction was stirred at room temperature for 1 h, concentrated under reduced pressure, and the residue was purified by flash column chromatography (C18, eluent: 10% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give 75D (150 mg) as an orange solid. m / z: [M+H] + 322.2.

[1091] Step 5: To a solution of 75D (150 mg, 0.47 mmol) in acetic anhydride (480 mg, 4.7 mmol), sodium acetate (38.6 mg, 0.47 mmol) was added. The reaction was stirred at 50 °C for 0.5 h. After cooling to room temperature, the reaction was purified by flash column chromatography (C18, eluent: 10%-60% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-75 (30 mg) as a yellow solid. m / z: [M+H] + 304.2.

[1092] Synthesis of L-76, (32S,35S,38S)-32-(2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetylamino)-35-isopropyl-38-methyl-26,33,36,39,42-pentaoxo-2,5,8,11,14,17,20,23,45-nonaoxa-27,34,37,40,43-pentaazaterraheptadecan-47-oic acid

[1093] [ka]

[1094] Step 1: To a solution of 15B (195 mg, 0.29 mmol) and 76A (123 mg, 0.29 mmol) (see the synthesis of intermediate 53C, replacing Fmoc-Val-Cit-OH with Fmoc-Val-Ala-OH) in DMF (3 mL) under ice-bath conditions, add HATU (132 mg, 0.35 mmol) and DIPEA (56.2 mg, 0.43 mmol), and stir the reaction mixture at 0 °C for 1 h. The reaction mixture is directly purified by flash column chromatography (C18, eluent: 0% to 52% acetonitrile in 0.05% aqueous trifluoroacetic acid) to obtain 76B (177 mg) as a white solid. m / z: [1M+H] + 1079.5.

[1095] Step 2: To a solution of 76B (100 mg, 0.093 mmol) in methanol (5 mL), palladium on carbon (29.7 mg, 10% wt) is added and the reaction is stirred under a hydrogen atmosphere for 4 h. The reaction mixture is then filtered through diatomaceous earth and concentrated under reduced pressure to give 76C (76.4 mg) as a white solid. m / z: [M+H] + 855.6.

[1096] Step 3: To a solution of 76C (66 mg, 0.077 mmol) in anhydrous DMF (2 mL) under ice bath conditions, add 2-(4-maleimidophenyl)acetate (N-hydroxylsuccinimide) ester (27.8 mg, 0.085 mmol) and DIPEA (19.9 mg, 0.15 mmol). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is directly purified by flash column chromatography (C18, eluent: 0% to 41% acetonitrile in 0.05% aqueous trifluoroacetic acid) to obtain L-76 (18.2 mg) as a white solid. m / z: [M+Na] + 1090.5.

[1097] Synthesis of L-77, 2-(4-(3-methylbenzenesulfonyl-2-(methylbenzenesulfonylmethyl)propionyl)phenyl)-1,3-dioxane-5-carboxylic acid

[1098] [ka]

[1099] Step 1: To a solution of 4-(3-(p-tolylmercapto)-2-((p-tolylmercapto)methyl)propionyl)benzoic acid (CAS: 124242-93-9) (1 g, 2.29 mmol) and dimethylhydroxylamine hydrochloride (335 mg, 3.44 mmol) in DMF (1 mL) was added HATU (1.1 g, 2.98 mmol) and DIPEA (592 mg, 4.58 mmol). The reaction was stirred at room temperature for 1 h, quenched by the addition of water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 77A (1.1 g) as a colorless oil. m / z: [M+H] + 480.2.

[1100] Step 2: At -78°C under nitrogen protection, diisobutylaluminum hydride (290 mg, 2.06 mmol) was added to a solution of 77A (620 mg, 1.29 mmol) in tetrahydrofuran (8 mL). The reaction was stirred at -78°C for 1 hour, then slowly warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 77B (420 mg) as a yellow oil. m / z: [M+H] + 421.0.

[1101] Step 3: To a solution of 77B (320 mg, 0.76 mmol) and methyl 3-hydroxyl-2-(hydroxymethyl)propionate (133 mg, 0.99 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (14.5 mg, 0.08 mmol). The reaction was stirred at 110 °C for 2 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 77C (450 mg) as a pale yellow solid. m / z: [M+H] + 537.2.

[1102] Step 4: To a solution of 77C (320 mg, 0.6 mmol) in tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (32.7 mg, 0.78 mmol) under ice-bath conditions. The reaction mixture was stirred at 0 °C for 1 h, adjusted to pH 3 with 1 M hydrochloric acid, and then directly purified by flash column chromatography (C18, eluent: 10% to 95% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give 77D (40 mg) as a white solid. m / z: [M+H] + 523.2.

[1103] Step 5: To a solution of 77D (120 mg, 0.23 mmol) in dichloromethane (10 mL) was added metachloroperbenzoic acid (234 mg, 1.15 mmol) under ice-bath conditions. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure at low temperature. The residue was purified by flash column chromatography (C18, eluent: 10% to 60% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give L-77 (120 mg) as a white solid. m / z: [M+H] + 587.2.

[1104] Synthesis of L-78, 6-(3,5-dichloro-2,6-bis(methylsulfonyl)isonicotinamido)hexanoic acid

[1105] [ka]

[1106] Step 1: To a solution of 2,3,5,6-tetrachloroisonicotinic acid (1 g, 3.83 mmol) in DMF (10 mL), sodium methyl mercaptide (670 mg, 9.57 mmol) was added in several portions. The reaction mixture was stirred overnight at 50 °C under nitrogen protection and then directly purified by flash column chromatography (C18, eluent: 0% to 55% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give 78A (480 mg) as a white solid. m / z: [M+H] + 284.0.

[1107] Step 2: To a solution of 78A (75.4 mg, 0.27 mmol) in dichloromethane (3 mL) was added DMF (4 mg, 0.054 mmol) and oxalyl chloride (41.1 mg, 0.32 mmol) sequentially under ice-bath conditions. The reaction mixture was stirred at room temperature for 2 h. After cooling the reaction mixture to 0 °C, pyridine (70.5 mg, 0.89 mmol) and 6-aminocaproic acid tert-butyl ester (55.6 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 78B (42.3 mg) as a white solid. m / z: [M+Na] + 475.0.

[1108] Step 3: To a solution of 78B (42.3 mg, 0.093 mmol) in dichloromethane (10 mL) was added metachloroperbenzoic acid (113 mg, 0.56 mmol) under ice bath conditions. The reaction was stirred at room temperature for 2 days, quenched by the addition of ice water, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to give 78C (48 mg) as a white solid. m / z: [M+Na] + 539.0.

[1109] Step 4: Trifluoroacetic acid (0.5 mL) is added to a solution of intermediate 78C (48 mg, 0.093 mmol) in dichloromethane (10 mL) under ice bath conditions. The reaction mixture is stirred at 0 °C for 2 h and then directly purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give L-78 (37.5 mg) as a white solid. m / z: [M+H] + 461.0.

[1110] Synthesis of L-79, 4-((S)-2-((S)-2-(2-(4-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetylamino)-3-methylbutyroylamino)-5-ureidopentaloylamino)benzyl(4-nitrobenzene)carbonate

[1111] [ka]

[1112] Step 1: To a solution of para-aminophenylacetic acid (300 mg, 1.98 mmol) and DIEPA (380 mg, 2.97 mmol) in dichloromethane (5 mL), add 3-bromo-1H-pyrrole-2,5-dione (350 mg, 1.98 mmol). Stir the reaction mixture overnight at room temperature and then purify it directly by flash column chromatography (C18, eluent: 0% to 35% acetonitrile in 0.05% aqueous trifluoroacetic acid) to obtain 79A (350 mg) as a yellow solid. m / z: [M+H] + 328.0.

[1113] A solution of 79A (200 mg, 0.61 mmol) in acetic acid (3 mL) was stirred in a sealed tube at 80 °C for 4 h. The reaction mixture was cooled to room temperature and then directly purified by flash column chromatography (C18, eluent: 10% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid) to give L-79 (120 mg) as a yellow solid. m / z: [M+H] + 310.1.

[1114] Synthesis of L-80, 4-((S)-2-((S)-2-(2-(4-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetylamino)-3-methylbutyroylamino)-5-ureidopentaloylamino)benzyl(4-nitrobenzene)carbonate

[1115] [ka]

[1116] Using the synthesis method for L-5, synthesize L-80 with Val-Cit-PAB-OH and L-79. m / z: [M+H] + 836.2.

[1117] Synthesis of L-81, 1-oxo-1-(4-(3-toluenesulfonyl-2-(toluenesulfonylmethyl)propionyl)phenyl)-5,8,11,14,17,20-hexaoxa-2-azatricosane-23-oic acid

[1118] [ka]

[1119] Using the synthesis method for L-7, synthesize L-81 with 4-(3-p-toluenesulfonyl-2-(toluenesulfonylmethyl)propionyl)benzoic acid. m / z: [M+H] + 836.2.

[1120] Synthesis of L-82, t-butyl (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(((S)-3-methyl-1-(((S)-1-((4-(((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropyl-2-yl)amino)-1-oxobutan-2-yl)amino)-5-oxopenrate

[1121] [ka]

[1122] Using the synthesis method in Step 2 of L-5, L-82 is synthesized from Intermediate 70A. m / z: [M+H] + 866.2.

[1123] Synthesis of L-83, 3-(2-(2-(((1,3-diacryloyltetrahydropyrimidine-5(2H)-methylene)amino)oxy)ethoxy)ethoxy)propionic acid

[1124] [ka]

[1125] Step 1: To a suspension of sodium bicarbonate (21.9 g, 549 mmol) in tetrahydrofuran (1.5 L) was added N,N'-methylenediethylamide (34 g, 261 mmol), followed by the dropwise addition of 3-chloro-2-(chloromethyl)prop-1-ene (34.3 g, 274 mmol). The reaction was heated to reflux and stirred for 48 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give 83A (31.7 g) as a yellow oil. m / z: [M+H] + 183.2.

[1126] Steps 2 & 3: 83A (14.4 g, 79 mmol) in 75 mL of sodium hydroxide (15.8 g, 395 mmol) was stirred overnight at 110 °C. The reaction mixture was cooled to room temperature, solid sodium hydroxide (1.6 g) was added, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to 250 mL under reduced pressure. HOBT (39.1 g, 289 mmol), EDCI (55.5 g, 289 mmol), DIPEA (46.8 g, 362 mmol), and 2-(diethoxyphosphoryl)acetic acid (46.3 g, 236 mmol) were added sequentially to the dichloromethane solution containing 83B under ice-bath conditions. The reaction mixture is stirred overnight at room temperature, diluted with dichloromethane (200 mL), washed with water, the organic phase separated and concentrated under reduced pressure, and the residue purified by flash column chromatography (C18, eluent: 0% to 40% acetonitrile in 0.05% aqueous trifluoroacetic acid) to give 83C (4.5 g) as a colorless oil. m / z: [M+H] + 455.2.

[1127] Step 4: In a dry ice-ethyl acetate bath, ozone was introduced into a solution of 83C (1 g, 2.2 mmol) in dichloromethane (20 mL) and methanol (5 mL) until the reaction mixture turned light blue (approximately 5 min). After stirring for 5 min, nitrogen was introduced to blow off excess ozone. Dimethyl sulfide (3.58 g, 57.6 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature with stirring and concentrated under reduced pressure to give 83D (1 g) as a yellow liquid. m / z: [M+H] + 457.2.

[1128] Step 5: To a solution of 83D (1 g, 2.19 mmol) in methanol (10 mL), 3-(2-(2-(aminooxy)ethoxy)ethoxy)propionic acid (800 mg, 4.16 mmol) and sodium acetate (900 mg, 11 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature. After adding water (3 mL), the mixture was purified directly by preparative HPLC (eluent: 0% to 35% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give 83E (412 mg) as a yellow oil. m / z: [M+H]+ 632.2.

[1129] Step 6: Under ice bath conditions, sodium tert-butoxide (92.3 mg, 0.96 mmol) was added to a solution of 83E (150 mg, 0.24 mmol) in tetrahydrofuran (2.5 mL). The reaction mixture was stirred at 0 °C for 30 min. A solution of formaldehyde (13 mg) in tetrahydrofuran was added dropwise to the above reaction mixture, and the resulting mixture was directly lyophilized to obtain the crude product. The crude product was further purified by preparative HPLC (eluent: 0% to 35% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to obtain L-83 (90 mg) as a colorless oil. m / z: [M+H] + 384.2.

[1130] Synthesis of L-84, 6-(2-(methanesulfonyl)pyrimidine-5-carboxamido)hexanoic acid

[1131] [ka]

[1132] Using the synthesis method described in steps 2-4 of L-78, synthesize L-84 from 2-(methylthio)pyrimidine-5-carboxylic acid. m / z: [M+H] + 316.0.

[1133] Synthesis of L-85, 3-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)(methyl)amino)propionic acid

[1134] [ka]

[1135] Step 1: To a solution of 3-(methylamino)propionic acid tert-butyl ester (300 mg, 1.88 mmol) and (2-bromoethyl)benzylcarbamate (437 mg, 1.69 mmol) in DMF (8 mL), potassium carbonate (260 mg, 1.88 mmol) and sodium iodide (28 mg, 0.19 mmol) were added. The reaction was stirred overnight at room temperature and quenched by the addition of water (6 mL). The mixture was directly purified by preparative HPLC (eluent: 10% to 50% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give 85A (550 mg) as a colorless oil. m / z: [M+H] + 337.2.

[1136] Step 2: To a solution of 85A (550 mg, 1.63 mmol) in methanol (8 mL) was added Pd / C (10%, 170 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give 85B (300 mg) as a colorless oil. m / z: [M+H] + 203.2.

[1137] To a solution of 85B (270 mg, 1.33 mmol) and triethylamine (270 mg, 2.66 mmol) in dichloromethane (3 mL) was added maleic anhydride (196 mg, 2.0 mmol). The reaction was stirred at room temperature for 1 h and directly purified by preparative HPLC (eluent: 10% to 60% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give 85C (220 mg) as a colorless oil. m / z: [M+H] + 301.2.

[1138] Step 4: To a solution of 85C (190 mg, 0.63 mmol) in acetonitrile (5 mL), add acetic anhydride (129 mg, 1.26 mmol) and sodium acetate (8 mg, 0.1 mmol). Stir the reaction at 85 °C for 2 h. Cool the reaction to room temperature and purify directly by preparative HPLC (eluent: 10% to 45% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to obtain 85D (160 mg) as a colorless oil. m / z: [M+H] + 283.2.

[1139] Step 5: To a solution of 85D (110 mg, 0.39 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (eluent: 10% to 30% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give L-85 (100 mg) as a colorless oil. m / z: [M+H] + 227.2.

[1140] Synthesis of L-86, 2-((3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3-dioxane-5-carboxylic acid

[1141] [ka]

[1142] Step 1: To a solution of 41D (450 mg, 2.79 mmol) and DIPEA (721 mg, 5.58 mmol) in a tetrahydrofuran / water (20 mL, 1 / 1) mixture, slowly add bromaleic anhydride (642 mg, 3.63 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was then directly purified by preparative HPLC (eluent: 10% to 45% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give 86A (450 mg) as a yellow oil. m / z: [M+H] + 338.2.

[1143] Step 2: To a solution of 86A (200 mg, 0.59 mmol) in acetic acid (4 mL), add acetic anhydride (60.2 mg, 0.59 mmol). The reaction mixture is stirred in a sealed tube at 110 °C for 3 h. After cooling to room temperature, it is directly purified by preparative HPLC (eluent: 10% to 45% acetonitrile in 0.1% aqueous trifluoroacetic acid, 20 min) to give L-86 (45 mg) as a brown solid. m / z: [M+H] + 320.2.

[1144] Synthesis of L-87, 3-(2-(4-(3-tosyl-2-(tosylmethyl)propionyl)benzoylamino)ethoxy)propionic acid

[1145] [ka]

[1146] Using the synthesis method for L-7, synthesize L-87 with 4-(3-p-toluenesulfonyl-2-(toluenesulfonylmethyl)propionyl)benzoic acid. m / z: [M+H] + 616.2.

[1147] Compound synthesis Example 1 Synthesis of 2-amino-N,N-dipropyl-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 1)

[1148] [ka]

[1149] Step 1: A solution of compound 2.6 (1.1 g, 2.8 mmol), HATU (1.6 g, 4.33 mmol), dipropylamine (580 mg, 22 mmol), and DIPEA (560 mg, 4.37 mmol) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and saturated brine, respectively. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol / dichloromethane = 1 / 20) to give compound 2.7 (500 mg, 39% yield) as a pale yellow solid.

[1150] Step 2: Compound 2.7 (2 g, 4.31 mmol), Xphos (0.2 g), and Pd2(dba)3 (0.2 g) were dissolved in a freshly prepared solution of (1-(methoxycarbonyl)cyclopropyl)zinc bromide in tetrahydrofuran (30 mL) (see WO2018 / 138356A1). The reaction mixture was purged with nitrogen three times, then stirred at 75 °C under nitrogen protection for 2 h. The mixture was cooled to room temperature and quenched by the addition of ice water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 2.8 (500 mg, 24% yield) as a pale yellow solid. m / z: [M+H] + 484.2.

[1151] Step 3: To a solution of compound 2.8 (500 mg, 1.03 mmol) in tetrahydrofuran (5 mL), methanol (0.5 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (130 mg, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then neutralized with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2.9 (400 mg, 82% yield) as an off-white solid. m / z: [M+H] + 484.2.

[1152] Step 4: To a solution of compound 2.9 (100 mg, 0.21 mmol) in DMF (1 mL), 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (64 mg, 0.25 mmol), HATU (97 mg, 0.25 mmol), and DIPEA (55 mg, 0.42 mmol) were added sequentially and stirred at room temperature for 4 h. The resulting mixture was then directly purified by flash column chromatography (C18, eluent: 0% to 85% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 2.10 (28 mg, 19% yield) as a white solid. m / z: [M+H] + 701.3.

[1153] Step 5: To a solution of compound 2.10 (28 mg, 0.4 mmol) in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then directly concentrated under reduced pressure. The residue was neutralized with ammonia-methanol solution (7 M) and purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 1 (17 mg, 85% yield) as a white solid. m / z: [M+H] + 501.3, 1 H NMR (400MHz, DMSO-d6): δ9.19(s,1H),8.42(s,1H),7.63(s,1H),7.25(d,J=7.6Hz,1H),7.00(s,1H),6.91( d,J=8.4Hz,1H),6.74(s,2H),6.69(s,1H),3.78(s,2H),2.97(br.s,2H),2.63(s,6H),1.55-0.74(m,17H).

[1154] Example 2 Synthesis of 2-amino-N-(2-hydroxylethyl)-N-propyl-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 2)

[1155] [ka]

[1156] Using the synthesis method for compound 1, replace dipropylamine in step 1 with 2-(propylamino)ethanol to give compound 2 as a white solid. m / z: [M+H] + 503.3, 1H NMR(400MHz,CD3OD):δ8.40(s,1H),7.68(s,1H),7.38(d,J=8.0Hz,1H),7.26(s,1H),7.16(d,J=8.0Hz,1H),6.94(s,1H),3.94(s,2H),3.77(br.s, 2H),3.62(t,J=8.0Hz,2H),3.50(t,J=8.0Hz,2H),3.16(t,J=8.0Hz,2H), 2.93-2.80(m,3H),1.78-1.50(m,4H),1.44-1.15(m,3H),0.90(br.s,3H).

[1157] Example 3 Synthesis of 2-amino-6-fluoro-N,N-dipropyl-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 3)

[1158] [ka]

[1159] Using the synthesis method for compound 1, substitute intermediate 3.1 for intermediate 2.6 in step 1 to give compound 3 as a white solid. m / z: [M+H] + 519.1.

[1160] Example 4 Synthesis of 2-amino-8-(2-oxo-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)acetyl)-N,N-dipropyl-3H-benzo[b]azepine-4-formamide (Compound 4)

[1161] [ka]

[1162] Step 1: Using the synthesis method for compound 2.7, compound 4.1 is reacted to give compound 4.2.

[1163] Step 2: A mixture of compound 4.2 (2 g, 5.49 mmol), hexamethylditin (1.89 g, 5.76 mmol), and Pd(PPh3)4 (127 mg, 0.11 mmol) in toluene (25 mL) was purged with nitrogen three times and the reaction mixture was stirred at 100 °C under nitrogen protection for 6 h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 4.3 (1.45 g, 59% yield) as a light brown solid. m / z: [M+H] + 450.2.

[1164] Step 3: To a solution of compound 4.3 (1.45 g, 3.24 mmol) in dichloromethane (30 mL), triethylamine (0.98 g, 9.71 mmol), 4-dimethylaminopyridine (79 mg, 0.65 mmol), and (Boc)2O (2.12 g, 9.71 mmol) were added. The reaction solution was stirred overnight at room temperature and then directly concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 4.4 (1.2 g, 57% yield) as a pale yellow solid. m / z: [M+H] + 650.0.

[1165] Step 4: In an ice bath, a solution of compound 4.4 (400 mg, 0.62 mmol), DIPEA (120 mg, 0.92 mmol), and potassium carbonate (17 mg, 0.12 mmol) in anhydrous tetrahydrofuran (6 mL) was added with Pd2(dba)3 (33 mg, 0.06 mmol). The reaction mixture was purged with nitrogen three times, and then a solution of oxalyl monomethyl chloride (113 mg, 0.92 mmol) in tetrahydrofuran (1 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature, quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 4.5 (145 mg, 58% yield) as a pale yellow solid. m / z: [M+H] + 594.3.

[1166] Step 5: Under ice-bath conditions, a solution of compound 4.5 (145 mg, 0.44 mmol) in tetrahydrofuran (5 mL) is added to an aqueous solution (2 mL) of lithium hydroxide monohydrate (289 mg, 0.88 mmol). The reaction mixture is stirred at 0 °C for 1 h. Next, the pH is adjusted to 7 with hydrochloric acid (1 M), and the mixture is directly purified by flash column chromatography (C18, eluent: 0% to 85% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 4.6 (90 mg, 31% yield) as a light brown solid. m / z: [M+H] + 558.3.

[1167] Step 6: To a solution of compound 4.6 (80 mg, 0.14 mmol) in DMF (4 mL), 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (43 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol), and DIPEA (22 mg, 0.17 mmol) were added sequentially, and the reaction mixture was microwaved at 50 °C for 1 h. The reaction was then quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1 / 2) to give compound 4.7 (39 mg, 34% yield) as a pale yellow solid. m / z: [M+H] + 789.5.

[1168] Step 7: To a solution of compound 4.7 (39 mg, 0.05 mmol) in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then directly concentrated under reduced pressure. The residue was neutralized with ammonia-methanol solution (7 M) and purified by flash column chromatography (C18, eluent: 0% to 60% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 4 (15 mg, 62% yield) as a yellow solid. m / z: [M+H] + 489.3.

[1169] Example 5 Synthesis of 2-amino-8-(2-methyl-1-oxo-1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)amino)propan-2-yl)-N,N-dipropyl-3H-benzo[b]azepine-4-formamide (Compound 5)

[1170] [ka]

[1171] Using the synthesis method for compound 1, substituting (1-(methoxycarbonyl)cyclopropyl)zinc bromide with (1-methoxy-2-methyl-1-oxopropyl-2-yl)zinc bromide in step 2, compound 5 is obtained as a white solid. m / z: [M+H] + 503.3, 1 H NMR(400MHz,CD3OD):δ8.45(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),7.31(d,J=8.4Hz,1H),7.20(d,J=1.6Hz,1H),7.09-7.05(m, 1H),6.82(s,1H),3.96(s,2H),3.44-3.37(m,4H),3.19-3.14(m,2H),2.94-2.73(m,4H),1.75-1.56(m,10H),1.05-0.78(m,6H).

[1172] Example 6 Synthesis of 2-amino-6-fluoro-N-(2-hydroxylethyl)-N-propyl-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 6)

[1173] [ka]

[1174] Step 1: Compound 6.1 (obtained by the synthesis of Compound 2.7 via the reaction of Intermediate 3.1 with 2-(propylamino)ethanol) (1 g, 2.06 mmol), Xphos (0.1 g), and Pd2(dba) (0.2 g) were dissolved in a freshly prepared solution of (1-(methoxycarbonyl)cyclopropyl)zinc bromide in tetrahydrofuran (35 mL). The reaction mixture was purged with nitrogen three times and then stirred at 75 °C under nitrogen protection for 2 h. After cooling to room temperature, the reaction was quenched with 1 mL of 4 M hydrogen chloride in methanol and directly purified by flash column chromatography (C18, eluent: 0% to 70% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give Compound 6.2 (600 mg, 72% yield) as an off-white solid. m / z: [M+H] + 404.2.

[1175] Step 2: To a solution of compound 6.2 (500 mg, 1.24 mmol) in DMF (5 mL), imidazole (422 mg, 6.2 mmol) and TBSCl (561 mg, 3.72 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 h and then directly purified by flash column chromatography (C18, eluent: 0% to 85% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 6.3 (510 mg, 79% yield) as a white solid. m / z: [M+H] + 518.2.

[1176] Step 3: To a solution of compound 6.3 (500 mg, 0.97 mmol) in dichloromethane (15 mL), triethylamine (220 mg, 2.18 mmol) and (Boc)2O (285 mg, 1.31 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 12 h. Water was added to quench the reaction, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 6.4 (510 mg, 85% yield) as an off-white solid. m / z: [M+H] + 618.3.

[1177] Step 4: To a solution of compound 6.4 (500 mg, 0.81 mmol) in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL), lithium hydroxide monohydrate (102 mg, 2.43 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then adjusted to pH 6 with 1 M hydrochloric acid and directly purified by flash column chromatography (C18, eluent: 0% to 55% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 6.5 (330 mg, 68% yield) as a white solid. m / z: [M+H] + 604.3.

[1178] Step 5: To a solution of compound 6.5 (50 mg, 0.08 mmol) in DMF (5 mL), HATU (46 mg, 0.12 mmol) and DIPEA (31 mg, 0.24 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (25 mg, 0.1 mmol). The resulting reaction mixture was stirred at room temperature for 16 h and then directly purified by flash column chromatography (C18, eluent: 0% to 85% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 6.6 (35 mg, 52% yield) as a white solid. m / z: [M+H] + 835.4.

[1179] Step 6: To a solution of compound 6.6 (30 mg, 0.04 mmol) in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ammonia-methanol (7 M) solution was added. The mixture was then directly purified by flash column chromatography (C18, eluent: 0% to 35% acetonitrile in 10 mM ammonium bicarbonate solution) to give compound 6 (12 mg, 58% yield) as a white solid. m / z: [M+H] + 521.3, 1H NMR(400MHz,CD3OD):δ8.40(d,J=2.4Hz,1H),7.69(d,J=2.0Hz,1H),7.06(s,1H),7.01(d,J=1.2Hz,1H),6.90(dd,J=1.6,10.8Hz,1H) ,3.94(s,2H),3.45-3.75(m,6H),3.13(t,J=6.4Hz,2H),2.85-2.90(m,3H),1.58-1.70(m,4H),1.21-1.28(m,3H),0.84-0.96(m,3H).

[1180] Example 7 Synthesis of 2-amino-8-(1-((5-(aminomethyl)pyridin-3-yl)carbamoyl)cyclopropyl)-N-(2-hydroxylethyl)-N-propyl-3H-benzo[b]azepine-4-formamide (Compound 7)

[1181] [ka]

[1182] Using the synthesis method for compound 1, but substituting 2-(propylamino)ethanol for dipropylamine in step 1 and ((5-aminopyridin-3-yl)methyl)carbamic acid tert-butyl ester for 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester in step 3, compound 7 is obtained as a white solid. m / z: [M+H] + 477.3, 1 H NMR (400 MHz, CD3OD): δ 8.59 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.33 (t, J = 2.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.52-7.44 (m, 2H), 7.11 (s, 1H), 4.90 (overlapped with solvent, 2H), 4.18 (s, 2H), 3.83-3.42 (m, 6H), 1.77-1.60 (m, 4H), 1.33-1.27 (m, 2H), 1.06-0.81 (m, 3H).

[1183] Example 8, 2-amino-N 4-(2-hydroxyethyl)-N 4 -Propyl-N 8 Synthesis of -(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-3H-benzo[b]azepine-4,8-diacetamide (Compound 8)

[1184] [ka]

[1185] Step 1: To a solution of compound 2.6 (8.8 g, 23.1 mmol) in DMF (100 mL), DIPEA (8.9 g, 69.2 mmol), 2-(propylamino)ethanol (2.9 g, 27.7 mmol), and HATU (13.2 g, 34.63 mmol) were added sequentially. After the addition was complete, the reaction was stirred at room temperature for 2 hours. Water was then added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 7.7 (10 g, 93% yield) as an off-white solid. m / z: [M+H] + 466.2.

[1186] Step 2: Compound 7.7 (600 mg, 1.29 mmol), potassium phosphate (820 mg, 3.86 mmol), palladium acetate (29 mg, 0.13 mmol), and Xantphos (37 mg, 0.06 mmol) were dissolved in tetrahydrofuran (10 mL) and water (5 mL). The mixture was purged with nitrogen and carbon monoxide three times, respectively, and stirred at 70 °C under a carbon monoxide atmosphere for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was dispersed in methanol, filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and directly purified by flash column chromatography (C18, eluent: 0% to 70% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 7.8 (100 mg, 18% yield) as a light brown solid. m / z: [M+H] + 432.2.

[1187] Step 3: To a solution of compound 7.8 (50 mg, 0.11 mmol), HATU (49 mg, 0.13 mmol), and DIPEA (17 mg, 0.13 mmol) in DMF (3 mL), 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (32 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure. The residue was purified by flash column chromatography (C18, eluent: 0% to 70% acetonitrile in 10 mM aqueous ammonium bicarbonate) to give compound 7.9 (25 mg, 32% yield) as a light brown solid. m / z: [M+H] + 663.2.

[1188] Step 4: A solution of compound 7.9 (25 mg, 0.04 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 h, concentrated directly under reduced pressure, and the residue was purified by preparative HPLC (Separation Condition 2) to give compound 8 (16 mg, 94% yield) as a white solid. m / z: [M+H] + 463.2, 1 H NMR(400MHz,DMSO-d6):δ10.36(s,1H),8.69(d,J=2.0Hz,1H),8.00(s,1H) ,7.69(s,1H),7.53-7.45(m,1H),7.42(d,J=8.4Hz,1H),6.99-6.76(m,2H) ,4.81(s,1H),4.01(s,2H),3.55(br.s,4H),3.38(m,5H),3.17(t,J=6.0Hz ,3H),2.83(t,J=6.0Hz,2H),2.73(s,2H),1.67-1.43(m,2H),0.86(s,3H).

[1189] Example 9 Synthesis of 2-amino-N,N-bis(2-hydroxylethyl)-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 9)

[1190] [ka]

[1191] Using the synthesis method for compound 1, replace dipropylamine in step 1 with bis(2-((tert-butyldimethylsilyl)oxy)ethyl)amine to give compound 9 as a white solid. m / z: [M+H] + 505.2, 1 H NMR(400MHz,CD3OD):δ8.38(d,J=2.4Hz,1H),7.68(d,J=2.0Hz,1H),7.37(d,J=8.0Hz,1H),7.24(d,J=1.6Hz,1H),7.17-7.11(m,1H),7.00(s,1H), 3.94(s,2H),3.86-3.69(m,4H),3.69-3.57(m,4H),3.18-3.11(m,2H),3. 07-2.95(m,1H),2.90-2.79(m,3H),1.63-1.56(m,2H),1.26-1.19(m,2H).

[1192] Example 10 Synthesis of 2-amino-6-fluoro-N,N-bis(2-hydroxylethyl)-8-(1-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)carbamoyl)cyclopropyl)-3H-benzo[b]azepine-4-formamide (Compound 10)

[1193] [ka]

[1194] Using the synthesis method for compound 1, bis(2-((tert-butyldimethylsilyl)oxy)ethyl)amine in step 1 and 6.1 as starting materials, compound 10 is obtained as a white solid. m / z: [M+H] + 523.1, 1H NMR(400MHz,CD3OD):δ8.42(d,J=2.4Hz,1H),7.72(d,J=2.4Hz,1H),7.12(d,J=1.6Hz,1H),7.08(s,1H),6.92(dd,J=1.2,10.8Hz,1 H),3.97(s,2H),3.68-3.81(m,8H),3.32-3.34(m,2H),3.17-3.20(m,2H),2.88-2.91(m,2H),1.60-1.62(m,2H),1.23-1.26(m,2H).

[1195] Example 11 Synthesis of 2-amino-8-(1-((5-(aminomethyl)pyridin-3-yl)carbamoyl)cyclopropyl)-N,N-bis(2-hydroxylethyl)-3H-benzo[b]azepine-4-formamide (Compound 11)

[1196] [ka]

[1197] Using the synthesis method for compound 1, but substituting bis(2-((tert-butyldimethylsilyl)oxy)ethyl)amine for dipropylamine in step 1 and ((5-aminopyridin-3-yl)methyl)carbamic acid tert-butyl ester for 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester in step 3, compound 11 is obtained as a white solid. m / z: [M+H] + 479.2, 1 H NMR(400MHz,CD3OD):δ8.53(d,J=2.4Hz,1H),8.24(d,J=2.0Hz,1H),7.93(t,J=2.4Hz,1H),7.37(d,J=8.0Hz,1H),7.24(d,J=2.0Hz) ,1H),7.14(dd,J=1.8,8.0Hz,1H),7.00(s,1H),4.62(s,2H),3.81(s,2H),3.79-3.61(m,8H),1.65-1.58(m,2H),1.27-1.19(m,2H).

[1198] Example 12 Synthesis of 2-amino-8-(1-((5-(aminomethyl)pyridin-3-yl)carbamoyl)cyclopropyl)-6-fluoro-N-(2-hydroxylethyl)-N-propyl-3H-benzo[b]azepine-4-formamide (Compound 12)

[1199] [ka]

[1200] Using the synthesis method for compound 6, substituting ((5-aminopyridin-3-yl)methyl)carbamic acid tert-butyl ester for 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester in step 5, compound 12 is obtained as a white solid. m / z: [M+H] + 495.2, 1 HNMR(400MHz,CD3OD):δ8.55(d,J=2.4Hz,1H),8.24(d,J=1.6Hz,1H),7.93(t,J= 2.4Hz,1H),7.07(s,1H),7.01(d,J=2.0Hz,1H),6.90(dd,J=2.0,10.8Hz,1H),4. 64(br.s,1H)3.84-3.64(m,4H),3.63-3.55(m,2H),3.51-3.42(m,2H),2.91(s,1 H),1.73-1.63(m,2H),1.62-1.58(m,2H),1.26-1.20(m,2H),1.02-0.77(m,3H).

[1201] Example 13 Synthesis of 2-amino-8-(1-((5-(aminomethyl)pyridin-3-yl)carbamoyl)cyclopropyl)-6-fluoro-N,N-dipropyl-3H-benzo[b]azepine-4-formamide (Compound 13)

[1202] [ka]

[1203] Using the synthesis method for compound 1, intermediate 3.2 is used as the starting material, substituting ((5-aminopyridin-3-yl)methyl)carbamic acid tert-butyl ester for 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester in step 3 to g...

Claims

1. An antibody-immunostimulating complex according to formula I, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein Ab is an antibody; t is any value from 1 to 8, D is a benzazepine group shown below, 【Chemistry 2】 m is 0 or 1; R is —C(O)—NR ９ -L １ -R ７ , -C(S)-NR ９ -L １ -R ７ or -NR ９ -C(O)-L １ -R ７ and R １ , R ２ and R ３ each independently represents hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkyl halide, -L ２ -OR ａ or -L ２ -NR ａ R ｂ and R ４ and R ４’ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; ４ or R ４’ is unsubstituted or optionally halogen, cyano, -L ２ -OR ａ , -L ２ -OR ｇ , -L ２ -OC(O)R ａ , -L ２ -OC(O)OR ａ , -L ２ -OC(O)NR ａ R ｂ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -NR ａ C(O)NR ａ R ｂ , -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and -L ２ -C(O)OR ｂ or substituted at any position by one or more substituents selected from R ４ and R ４’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, said 3- to 8-membered heterocycloalkyl being unsubstituted or substituted with halogen, cyano, -L ２ -OR ａ , -L ２ -OC(O)R ａ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -NR ａ C(O)NR ａ R ｂ , -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and -L ２ -C(O)OR ｂ is further substituted at any position with 1 to 3 substituents selected from R ５ is hydrogen, -OR ａ , -C(O)R ａ , -C(O)OR ａ or -C(O)NR ａ R ｂ and R ５’ Ga-R ｃ and R ７ is phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, or 8- to 12-membered fused ring group, and ７ is unsubstituted or optionally -L ３ -W, -R ｃ substituted at any position by one or more substituents selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R ８ and R ８’ are each independently hydrogen, halogen or alkyl, and ８ or R ８’ is unsubstituted or optionally -L ３ -substituted at any position by one or more substituents selected from W, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R ８ and R ８’ are each independently a substituent, or R ８ and R ８’ together with the carbon atoms to which they are attached, oxo, thio, C １～６ Alkylidene, C ３～１０ cycloalkyl or 3- to 10-membered heterocycloalkyl, １～６ Alkylidene, C ３～１０ The cycloalkyl or 3- to 10-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkyl halide, -L ２ -OR ａ and -L ２ -NR ａ R ｂ and substituted at any position by one or more substituents selected from R ９ is hydrogen, alkyl, halogenated alkyl, -L ２ -OR ａ or -L ２ -NR ａ R ｂ and WがCy １ 、-SR ｄ 、-OR ｄ 、-OC(O)R ｅ 、-OC(O)NR ｅ R ｅ’ 、-C(O)OR ｅ 、-C(O)R ｅ 、-C(O)NR ｅ R ｅ’ 、-C(O)NR ｅ S(O) ２ R ｅ 、-NR ｄ R ｅ 、-NR ｄ C(O)R ｅ 、-N(R ｄ )C(O)OR ｅ 、-N(R ｄ )C(O)NR ｅ R ｅ’ 、-NR ｄ S(O) ２ R ｅ 、-NR ｄ S(O) ２ NR ｅ R ｅ’ 、-S(O) １－２ R ｅ 、-S(O) ２ NR ｅ R ｅ’ 、-S(O)(=NR ｄ )R ｅ 、-S(O) ２ N(R ｅ )C(O)R ｅ’ 、-P(O)(OR ｅ ) ２ 、-P(O)(OR ｅ )R ｅ’ 、-OP(O)(OR ｅ ) ２ または-B(OR ｅ ) ２ であり、 Cy １ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and said Cy １ is unsubstituted or optionally substituted with halogen, alkyl, halogenated alkyl, halogenated alkoxyl, alkenyl, alkynyl, cyano, -R ｃ , -L ４ -SR ｄ , -L ４ -OC(O)R ｅ , -L ４ -C(O)OR ｅ , -L ４ -C(O)R ｅ , -L ４ -C(O)NR ｅ R ｅ’ , -L ４ -NR ｄ C(O)R ｅ , -L ４ -NR ｄ S (O) ２ R ｅ , -L ４ -S(O) １－２ R ｅ , -L ４ -S(O) ２ NR ｅ R ｅ’ , -L ４ -OR ｄ and -L ４ -NR ｅ R ｅ’ and substituted at any position by one or more substituents selected from Each R ａ , R ｂ , R ｄ , R ｅ and R ｅ’ are each independently -R ｃ , Amino, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～１０ Cycloalkyl C １～６ Alkyl, 3- to 10-membered heterocycloalkylC １～６ Alkyl, phenyl C １～６ Alkyl or 5-10 membered heteroaryl C １～６ alkyl, and the R ａ , R ｂ , R ｄ , R ｅ or R ｅ’ is unsubstituted or optionally -L ４ -OR ｆ , -OC(O)-L ４ -R ｆ , -L ４ -NR ｆ R ｆ’ , halogen, cyano, nitro, C １～６ Alkyl, halogenated C １～６ Alkyl and halogenated C １～６ substituted at any position by 1 to 3 substituents selected from alkoxyl; L １ , L ２ , L ３ and L ４ are each independently a bond, C １～６ Alkylidene, C ２～６ Alkenylene, C ２～６ Alkynylene or 1 to 20 —OCH ２ CH ２ -unit, and said L １ , L ２ , L ３ or L ４ is unsubstituted or optionally substituted at any position with one or more substituents selected from oxo, hydroxyl, amino, halogen, cyano, alkyl, halogenated alkyl, alkoxyl and halogenated alkoxyl; Each R ｆ and R ｆ are each independently -R ｃ , -NHR ｃ or C １～６ is alkyl, R ｇ is a phosphoryl-containing prodrug group; Each R ｃ are each independently hydrogen or a bond connected to L, and at least one R ｃ is a bond connected to L, Also, as shown in Formula D, the benzazepine group satisfies one or two of the following conditions: (1) m is 1, (2) R ４ and R ４’ At least one of the groups is halogen, cyano, -L ２ -OR ａ , -L ２ -OR ｇ , -L ２ -OC(O)R ａ , -L ２ -OC(O)OR ａ , -L ２ -OC(O)NR ａ R ｂ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -C(O)OR ｂ -L ２ -NR ａ C(O)NR ａ R ｂ and -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and substituted at any position by one or more substituents selected from L is -M- (T) ｗ -PEG-(T) ｏ - ＊ , -M-PEG- ＊ , -M-(T) ｗ - ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , -M-(T) ｗ -L ５ - ＊ , -M-(T) ｗ -PEG-L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ , -M-PEG-(T) ｏ -PEG- ＊ or -M-(T) ｗ -(A) ｖ -L ５ - ＊ wherein v is an integer of 1 to 5, w is an integer of 1 to 10, o is an integer of 0 to 10, * is a linking site between L and D, Each T is independently -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-alkylidene-, alkylidene, or alkenylene, and x and y are each independently any integer from 0 to 10; R ｈ is hydrogen, alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is any integer from 1 to 50, and u is any integer from 0 to 5; Each A is independently an amino acid residue or —C(O)—(CH ２ CH ２ O) ｎ -CH ３ Or -(CH ２ CH ２ O) ｎ -CH ３ is an amino acid residue modified by L ５ is a self-sacrificing group, An antibody-immunostimulatory complex or a pharmaceutically acceptable salt thereof, wherein M is a bond or connector that is linked to the antibody. 【Request Item 2】 【Chemistry 3】 wherein Ab is an antibody; t is any value from 1 to 8, L is a linker that connects said Ab and said D; D is a group obtained by removing one hydrogen atom from the compound represented by formula D', 【Chemistry 4】 In the formula, R is -L'-L １ -R ７ and L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ - and R ９ are independently hydrogen, C １～６ Alkyl or halogenated C １～６ is alkyl, L １ are independently bonded bonds, C １～６ Alkylidene or C ２～６ is alkenylene, R ７ are independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, one, two, or three R ７－１ phenyl substituted with one, two or three R ７－２ 5-6 membered heteroaryl substituted with one, two or three R ７－３ or one, two or three R ７－４ is an 8- to 12-membered fused ring group substituted with R ７ wherein the 5- to 6-membered heteroaryl and the one, two, or three R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O and S, the number of heteroatoms is independently 1, 2 or 3, and the 3- to 8-membered heterocycloalkyl and the 1, 2 or 3 R ７－３ In the "3- to 8-membered heterocycloalkyl" in 3- to 8-membered heterocycloalkyl substituted with, said heteroatoms are independently selected from one or more of N, O and S, and the number of said heteroatoms is independently 1, 2 or 3; R ７ the 8- to 12-membered fused ring group and the one, two, or three R ７－４ wherein the 8- to 12-membered fused ring group in the 8- to 12-membered fused ring group substituted with is independently ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R ７－１ , R ７－２ , R ７－３ and R ７－４ are independently amino, -L ３ -NH ２ , -L ３ -OH, -C(=O)-L ３ -OH or -C(=O)-L ３ -NH ２ and L ３ became independent and became C １～６ Alkylidene or -(CH ２ CH ２ O) ｍ’ -C １～６ alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0 or 1; R ８ and R ８’ are independently hydrogen or C １～６ alkyl, or R ８ and R ８’ together with both of the carbon atoms to which they are attached, form a carbonyl, C ３～１０ forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R １ , R ２ and R ３ are independently hydrogen, deuterium, or halogen; R ４ and R ４’ became independent and became C １～６ Alkyl, C １～６ Alkoxyl or one, two or three R ４－１ C substituted with １～６ alkyl, and the R ４－１ are independently hydroxyl, amino, or —OC(═O)NR ａ R ｂ or 【Transformation 5】 and R ａ and R ｂ are independently hydrogen, C １～６ Alkyl or C ３～１０ is cycloalkyl, R ｉ is hydrogen, C １～６ alkyl or benzyl, and R ｋ is hydrogen, halogen or C １～６ alkyl, and R ｉ is C １～６ Alkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～１０ Cycloalkyl-C １～６ Alkyl, 3- to 10-membered heterocycloalkyl-C １～６ Alkyl, C ６～１０ Aryl-C １～６ Alkyl or 5- to 10-membered heteroaryl-C １～６ is alkyl, R ｊ In the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C １～６ In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C １～６ In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ is alkyl, The antibody-immunostimulating complex of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the antibody-immunostimulating complex of formula I is not an antibody-immunostimulating complex shown in Table 1, and wherein the mAb is trastuzumab. Table 1 【change】 【change】

3. Meet one or more of the following conditions: (1) The antibody-immunostimulating complex shown in Formula I is not an antibody-immunostimulating complex shown in Table 2, wherein mAb is a monoclonal antibody and t is any value between 1 and 8; Table 2 (2) the compound represented by formula D' is not a compound represented by Table 3, Table 3 、 (3) The antibody-immunostimulating complex of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the linker is not one of the structures shown in Table 4. Table 4

4. The following conditions (1) and / or (2) are satisfied: (1) The compound represented by D' satisfies one, two or three of the following conditions: (a) L １ became independent and became C １～６ Alkylidene or C ２～６ alkenylene, and (b) R ７ are independently phenyl substituted with one amino, 5-10 membered heteroaryl substituted with one amino, 3-8 membered heterocycloalkyl substituted with one amino, or 8-12 membered fused ring group substituted with one amino; (c) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ alkyl, and the R ４－１ are independently -OC(=O)NR ａ R ｂ or 【Transformation 6】 and (2) The L is -M-(T) ｗ -PEG-(T) ｏ - ＊ , -M-PEG- ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , -M-(T) ｗ -L ５ - ＊ , -M-(T) ｗ -PEG-L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ or -M-PEG-(T) ｏ -PEG- ＊ * is the linking site between L and D, M is a bond or connector that is linked to Ab; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T is independent -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -C ６～１４ Arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -C ３～６ Cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-C １～６ Alkylidene-, C １～６ Alkylidene or C ２～６ alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3, and the -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, or S, and the number of the heteroatoms is 1, 2, or 3; R ｈ are independently hydrogen, C １～６ Alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R Ａ and R is an amino acid residue substituted with Ａ are independently —C(O)—(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L ５ 4. The antibody-immunostimulating complex of formula I according to claim 3, or a pharmaceutically acceptable salt thereof, wherein is a self-immolative group.

5. Meet one or more of the following conditions: (1) the antibody comprises one or more antigen-binding domains capable of binding to an antigen; (2) the antibody comprises an Fc terminus; (3) The antibody is a monoclonal antibody, (4) The t is any value between 2 and 5, In formula (5), L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ -, and its right end is L １ is connected to (6) R ９ is hydrogen, (7) L １ So, the above C １～６ alkylidene is methylene or ethylidene; (8) R ７ In the formula, the 8- to 12-membered fused ring group is ring A and fused ring B, ring A is a 5- to 6-membered heteroaryl or phenyl, ring B is a 5- to 6-membered heteroalkenyl ring, and ring A is connected to L via ring A. １ wherein the heteroatom in said 5- to 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, and the heteroatom in said 5- to 6-membered heteroalkenyl ring is N and the number of heteroatoms is 1 or 2; (9) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N; (10) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2, (11) In ring A, the heteroatom in the 5- to 6-membered heteroaryl ring is N; (12) In ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2, (13) In ring B, the heteroatom in the 5- to 6-membered heteroalkenyl ring is N; (14) One hydrogen atom lost from the compound represented by formula D′ is R ７ or one hydrogen atom lost from the compound of formula D' is located on a secondary or primary amine of R ７ Located on the hydroxyl of (15) m is 1, (16) R ８ and R ８’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (17) R ８ and R ８’ together with both of the carbon atoms to which they are attached, ３～１０ Form a cycloalkylene, ３～１０ cycloalkylene is cyclopropyl or cyclobutyl; (18) R ８ and R ８’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in said 3- to 10-membered heterocycloalkylene is N or O; (19) R ８ and R ８’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in said 3- to 10-membered heterocycloalkylene is 1 or 2; (20) R １ , R ２ and R ３ wherein the halogen is F, Cl or Br; (21) R ４ and R ４’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (22) R ４ and R ４’ So, the above C １～６ alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl; (23) R ４ and R ４’ So, one, two or three Rs? ４－１ The C substituted with １～６ C in alkyl １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (24) R ａ and R ｂ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (25) R ａ and R ｂ So, the above C ３～１０ cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl; (26) R ｉ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (27) R ｋ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (28) R ｊ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (29) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C ６～１０ aryl is phenyl; (30) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (31) The L is -M-(T) ｗ -PEG-(T) ｏ - ＊ , -M-PEG- ＊ , -M-(T) ｗ - ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , -M-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , -M-(T) ｗ -L ５ - ＊ , -M-(T) ｗ -PEG-L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , -M-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ , -M-PEG-(T) ｏ -PEG- ＊ or -M-(T) ｗ -(A) ｖ -L ５ - ＊ * is the linking site between L and D, M is a bond or connector that is linked to Ab; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T is independent -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -C ６～１４ Arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -C ３～６ Cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-C １～６ Alkylidene-, C １～６ Alkylidene or C ２～６ alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3, and the -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, or S, and the number of the heteroatoms is 1, 2, or 3; R ｈ are independently hydrogen, C １～６ Alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R Ａ and R is an amino acid residue substituted with Ａ are independently —C(O)—(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L ５ 3. The antibody-immunostimulating complex of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is a self-immolative group.

6. Meet one or more of the following conditions: (1) The antibody is an anti-HER2 antibody such as trastuzumab, trastuzumab biosimilar, pertuzumab, pertuzumab biosimilar, margetuximab, or HT-19; (2) the antibody is an anti-5T4 antibody such as huA1; (3) The antibody is an anti-EGFR antibody such as cetuximab, (4) The antibody is an anti-Trop-2 antibody such as sacituzumab; (5) The antibody is an anti-Claudin18.2 antibody such as zolbetuximab, (6) The antibody is an anti-CEACAM5 antibody such as labetuzumab, (7) The antibody is an anti-Nectin-4 antibody such as enfortumab, (8) R ７ but 【Transformation 7】 and (9) In M, the connector 【Transformation 8】 wherein the connector is linked via the c-terminus to the remainder of L; (10)-(A) ｖ -but 【Chemistry 9】 and each R １１ are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, —SO ３ H. 【Chemistry 10】 or R １１ and the adjacent nitrogen atom form a 5-membered heterocycle, v is an integer of 1 to 4, preferably 1 or 2, or 3 or 4, (11) A is -(T) through the carbonyl terminal ｏ - or -L ５ - is connected to (12) L ５ but 【Chemistry 11】 and (13)-L ５ - is linked to D via the carbonyl terminus, (14)-(T) ｗ -but 【Chemistry 12】 and -(T) ｗ - is linked to the -M- via the a-terminus, (15)-(T) ｏ -but 【Chemistry 13】 and (T) ｏ - is linked to the -PEG- or D via the b-terminus, (16) L is any one of the following combinations: a) -M-PEG-, b) -M-(CH ２ ) ｘ -, c) -M-(CH ２ ) ｘ -C(O)-,d)-M-(CH ２ ) ｘ -(C ５～６ cycloalkylene)-(CH ２ ) ｙ -C(O)NH-PEG-,e)-M-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-(CH ２ ) ｙ -C(O)NH-PEG-, f)-M-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)NH-PEG-,g)-M-(CH ２ ) ｘ -C(O)NH-PEG-,h)-M-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)NH-PEG-,i)-M-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)NH-PEG-NH-(CH ２ ) ｘ -C(O)-,j)-M-(CH ２ ) ｘ -(C ５～６ cycloalkylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,k)-M-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,l)-M-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,m)-M-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)-L ５ -, n) -M-(CH ２ ) ｘ -C(O)NH-PEG-L ５ -, o) -M-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)-(A) ｖ -, p) -M-(CH ２ ) ｘ -C(O)NH-(C ３～６ cycloalkylene)-C(O)-(A) ｖ -, q) -M-(CH ２ ) ｘ -C(O)NH-PEG-(A) ｖ -, r) -M-(CH ２ ) ｘ -C(O)NH-PEG-(A) ｖ -L ５ -, s) -M-(CH ２ ) ｘ -(C ５～６ cycloalkylene)-C(O)-, t)-M-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-C(O)-, u)-M-(phenylene)-(CH ２ ) ｙ -C(O)-,v)-M-(CH ２ ) ｘ -C(O)-(A) ｖ -NH-PEG-,w)-M-(CH ２ ) ｘ -C(O)-(A) ｖ -NH-(CH ２ ) ｘ -C(O)-,x)-M-(CH ２ ) ｘ -C(O)-(A) ｖ -,y)-M-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-C(O)-(A) ｖ -, z) -M-(CH ２ ) ｘ -C(O)NH-CH ２ -CH(NHR ｈ )-C(O)-(A) ｖ -, aa)-M-(phenylene)-(5- to 6-membered heterocyclylene)-C(O)-, ab)-M-(phenylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ )x-PEG-(A) ｖ -, ac)-M-(phenylene)-C(O)NH-(CH ２ ) x-(A) ｖ -L ５ - or ad)-M-(CH ２ ) ｘ -PEG-(A) ｖ - and Or, L is -M-(T) ｗ -(A) ｖ -L ５ - ＊ and L is -M- (T) ｗ -(A) ｖ -L ５ - ＊ In the case of -M-, -(T) ｗ -, -(A) ｖ - and -L ５ - does not simultaneously satisfy the following conditions, -M- is succinimidyl, and -(T) ｗ - is caproyl, -(A) ｖ - is -Val-Cit-, -Val-Ala- or -Gly-Gly-Phe-Gly-, and -L ５ - is PABC, and preferably L is -M-CH ２ -(C ５～６ cycloalkylene)-C(═O)-(A) ｖ -L ５ -, -M-CH ２ -(5- to 6-membered heterocyclylene)-C(=O)-(A) ｖ -L ５ -, -M-(phenylene)-CH ２ -C(=O)-(A) ｖ -L ５ - or -M-(CH ２ ) ｘ -C(=O)NH-CH ２ -CH(NHR ｈ )-C(O)-(A) ｖ -L ５ - and L is -M- (T) ｗ -PEG-(A) ｖ -L ５ - ＊ In the case where L is -M-(CH ２ ) ｘ -C(=O)NH-PEG-(A) ｖ -L ５ -, -M-(phenylene)-CH ２ -C(=O)NH-PEG-(A) ｖ -L ５ -, -M-CH ２ -(C ５～６ cycloalkylene)-C(═O)NH-PEG-(A) ｖ -L ５ -or-M-CH ２ -(5- to 6-membered heterocyclylene)-C(═O)NH-PEG-(A) ｖ -L ５ - and L is -M- (T) ｗ -(A) ｖ - (T) ｏ - ＊ In the case where L is -M-(CH ２ ) ｘ -C(=O)NH-(A) ｖ -NH-CH ２ 6. The antibody-immunostimulating complex of formula I according to claim 5, wherein: - or a pharmaceutically acceptable salt thereof.

7. Meet one or more of the following conditions: (1) The antibody is trastuzumab, pertuzumab, cetuximab, huA1, sacituzumab, zolbetuximab, labetuzumab, or enfortumab; (2) D is a structure shown in Table 5; Table 5 【change】 【change】 、 (3) L is 【Chemistry 14】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 7. The antibody-immunostimulatory complex of claim 6, wherein:

8. D is in situation 1 or 2, In situation 1, D is formula (D-1) or formula (D-2), 【Chemistry 15】 During the ceremony, 【Chemistry 16】 does not exist, and -CH ２ - or -CH ２ -CH ２ - and Z １ , Z ２ and Z ３ are each independently N or CH; R ｃ is a bond connected to L, R １ , R ２ , R ３ , R ４ , R ４’ , R ５ , R ８ , R ８’ and R ａ is defined as in any one of claims 1 to 7, Situation 2: D is a formula D', and the formula D' is any one of general formulas D'-1 to D'-6; 【Chemistry 17】 R ４ , R ４’ , R ８ and R ８’ is defined as in any one of claims 1 to 7, and R ７－１ , R ７－２ , R ７－４ and R ８ is defined as in any one of claims 2 to 7, Alternatively, the antibody-immunostimulating complex of formula I or a pharmaceutically acceptable salt thereof may comprise: [Chemistry 18] the Ab is pertuzumab, cetuximab, huA1, hRS7, zolbetuximab, labetuzumab, or enfortumab; t is any value from 1 to 8, L is a linker that connects said Ab and said D; D is a group obtained by removing one hydrogen atom from the compound represented by formula D', 【Chemistry 19】 In the formula, R is -L'-L １ -R ７ and L' is -C(=O)-NR ９ - and R ９ is hydrogen, and L １ are independently bonds, R ７ are independently an 8- to 12-membered fused ring group or one, two, or three R ７－４ is an 8- to 12-membered fused ring group substituted with R ７－４ are independently -C(=O)-L ３ -NH ２ and L ３ became independent and became C １～６ Alkylidene or -(CH ２ CH ２ O) ｍ’ -C １～６ The antibody-immunostimulatory complex of formula I according to any one of claims 1 to 7, wherein m' is alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically acceptable salt thereof.

9. The antibody-immunostimulating complex of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the antibody-immunostimulating complex is any one of the following complexes, wherein antibody 1 is trastuzumab, antibody 2 is pertuzumab, antibody 4 is trastuzumab (HC-s239.5), antibody 6 is cetuximab, antibody 7 is huA1, antibody 8 is sacituzumab, antibody 9 is zolbetuximab, antibody 10 is labetuzumab, or antibody 11 is enfortumab. Table 6 Table 7 Table 8 Table 9 Table 10

10. A compound of formula II or a pharmaceutically acceptable salt thereof: 【Chemistry 20】 wherein D is a benzazepine group as shown below: 【Chemistry 21】 m is 0 or 1; R is —C(O)—NR ９ -L １ -R ７ , -C(S)-NR ９ -L １ -R ７ or -NR ９ -C(O)-L １ -R ７ and R １ , R ２ and R ３ each independently represents hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkyl halide, -L ２ -OR ａ or -L ２ -NR ａ R ｂ and R ４ and R ４’ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; ４ or R ４’ is unsubstituted or optionally halogen, cyano, -L ２ -OR ａ , -L ２ -OR ｇ , -L ２ -OC(O)R ａ , -L ２ -OC(O)OR ａ , -L ２ -OC(O)NR ａ R ｂ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -NR ａ C(O)NR ａ R ｂ , -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and -L ２ -C(O)OR ｂ or substituted at any position by one or more substituents selected from R ４ and R ４’ together with the N atoms to which they are both attached form a 3- to 8-membered heterocycloalkyl, said 3- to 8-membered heterocycloalkyl being unsubstituted or substituted with halogen, cyano, -L ２ -OR ａ , -L ２ -OC(O)R ａ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -NR ａ C(O)NR ａ R ｂ , -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and -L ２ -C(O)OR ｂ is further substituted at any position with 1 to 3 substituents selected from R ５ is hydrogen, -OR ａ , -C(O)R ａ , -C(O)OR ａ or -C(O)NR ａ R ｂ and R ５’ Ga-R ｃ and R ７ is phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, or 8- to 12-membered fused ring group, and ７ is unsubstituted or optionally -L ３ -W, -R ｃ substituted at any position by one or more substituents selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R ８ and R ８’ are each independently hydrogen, halogen or alkyl, and ８ or R ８’ is unsubstituted or optionally -L ３ -substituted at any position by one or more substituents selected from W, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxyl, alkyl halide, alkoxyl halide and alkylamino; R ８ and R ８’ are each independently a substituent, or R ８ and R ８’ together with the carbon atoms to which they are attached, oxo, thio, C １～６ Alkylidene, C ３～１０ cycloalkyl or 3- to 10-membered heterocycloalkyl, １～６ Alkylidene, C ３～１０ The cycloalkyl or 3- to 10-membered heterocycloalkyl is unsubstituted or optionally substituted with deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkyl halide, -L ２ -OR ａ and -L ２ -NR ａ R ｂ and substituted at any position by one or more substituents selected from R ９ is hydrogen, alkyl, halogenated alkyl, -L ２ -OR ａ or -L ２ -NR ａ R ｂ and WがCy １ 、-SR ｄ 、-OR ｄ 、-OC(O)R ｅ 、-OC(O)NR ｅ R ｅ’ 、-C(O)OR ｅ 、-C(O)R ｅ 、-C(O)NR ｅ R ｅ’ 、-C(O)NR ｅ S(O) ２ R ｅ 、-NR ｄ R ｅ 、-NR ｄ C(O)R ｅ 、-N(R ｄ )C(O)OR ｅ 、-N(R ｄ )C(O)NR ｅ R ｅ’ 、-NR ｄ S(O) ２ R ｅ 、-NR ｄ S(O) ２ NR ｅ R ｅ’ 、-S(O) １－２ R ｅ 、-S(O) ２ NR ｅ R ｅ’ 、-S(O)(=NR ｄ )R ｅ 、-S(O) ２ N(R ｅ )C(O)R ｅ’ 、-P(O)(OR ｅ ) ２ 、-P(O)(OR ｅ )R ｅ’ 、-OP(O)(OR ｅ ) ２ または-B(OR ｅ ) ２ であり、 Cy １ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and said Cy １ is unsubstituted or optionally substituted with halogen, alkyl, halogenated alkyl, halogenated alkoxyl, alkenyl, alkynyl, cyano, -R ｃ , -L ４ -SR ｄ , -L ４ -OC(O)R ｅ , -L ４ -C(O)OR ｅ , -L ４ -C(O)R ｅ , -L ４ -C(O)NR ｅ R ｅ’ , -L ４ -NR ｄ C(O)R ｅ , -L ４ -NR ｄ S (O) ２ R ｅ , -L ４ -S(O) １－２ R ｅ , -L ４ -S(O) ２ NR ｅ R ｅ’ , -L ４ -OR ｄ and -L ４ -NR ｅ R ｅ’ and substituted at any position by one or more substituents selected from Each R ａ , R ｂ , R ｄ , R ｅ and R ｅ’ are each independently -R ｃ , Amino, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～１０ Cycloalkyl C １～６ Alkyl, 3- to 10-membered heterocycloalkylC １～６ Alkyl, phenyl C １～６ Alkyl or 5-10 membered heteroaryl C １～６ alkyl, and the R ａ , R ｂ , R ｄ , R ｅ or R ｅ’ is unsubstituted or optionally -L ４ -OR ｆ , -OC(O)-L ４ -R ｆ , -L ４ -NR ｆ R ｆ’ , halogen, cyano, nitro, C １～６ Alkyl, halogenated C １～６ Alkyl and halogenated C １～６ substituted at any position by 1 to 3 substituents selected from alkoxyl; L １ , L ２ , L ３ and L ４ are each independently a bond, C １～６ Alkylidene, C ２～６ Alkenylene or C ２～６ alkynylene, and １ , L ２ , L ３ or L ４ is unsubstituted or optionally substituted at any position with one or more substituents selected from oxo, hydroxyl, amino, halogen, cyano, alkyl, halogenated alkyl, alkoxyl and halogenated alkoxyl; Each R ｆ and R ｆ are each independently -R ｃ , -NHR ｃ or C １～６ is alkyl, R ｇ is a phosphoryl-containing prodrug group; Each R ｃ are each independently hydrogen or a bond connected to L, and at least one R ｃ is a bond connected to LX, Also, as shown in Formula D, the benzazepine group satisfies one or two of the following conditions: (1) m is 1, (2) R ４ and R ４’ At least one of the groups is halogen, cyano, -L ２ -OR ａ , -L ２ -OR ｇ , -L ２ -OC(O)R ａ , -L ２ -OC(O)OR ａ , -L ２ -OC(O)NR ａ R ｂ , -L ２ -NR ａ R ｂ , -L ２ -NR ａ C(O)OR ｂ , -L ２ -C(O)OR ｂ -L ２ -NR ａ C(O)NR ａ R ｂ and -L ２ -NR ｂ C (NR ｂ ) NR ａ R ｂ and substituted at any position by one or more substituents selected from LX is M'-(T) ｗ -PEG-(T) ｏ - ＊ , M'-PEG- ＊ , M'-(T) ｗ - ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , M'-(T) ｗ -L ５ - ＊ , M'-(T) ｗ -PEG-L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ , M'-PEG-(T) ｏ -PEG- ＊ or M'-(T) ｗ -(A) ｖ -L ５ - ＊ wherein v is an integer of 1 to 5, w is an integer of 1 to 10, o is an integer of 0 to 10, * is a linking site between LX and D, Each T is independently -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-alkylidene-, alkylidene, or alkenylene, and x and y are each independently any integer from 0 to 10; R ｈ is hydrogen, alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is any integer from 1 to 50, and u is any integer from 0 to 5; Each A is independently an amino acid residue or —C(O)—(CH ２ CH ２ O) ｎ -CH ３ Or -(CH ２ CH ２ O) ｎ -CH ３ is an amino acid residue modified by L ５ is a self-sacrificing group, A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein M' is a connector precursor or a connector linked to 1 to 2 amino acids. 【Request Item 11】 【Chemistry 22】 wherein LX is a linker precursor; D is a group obtained by removing one hydrogen atom from the compound represented by formula D', 【Chemistry 23】 In the formula, R is -L'-L １ -R ７ and L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ - and R ９ are independently hydrogen, C １～６ Alkyl or halogenated C １～６ is alkyl, L １ are independently bonded bonds, C １～６ Alkylidene or C ２～６ is alkenylene, R ７ are independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, one, two, or three R ７－１ phenyl substituted with one, two or three R ７－２ 5-6 membered heteroaryl substituted with one, two or three R ７－３ or one, two or three R ７－４ is an 8- to 12-membered fused ring group substituted with R ７ wherein the 5- to 6-membered heteroaryl and the one, two, or three R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O and S, the number of heteroatoms is independently 1, 2 or 3, and the 3- to 8-membered heterocycloalkyl and the 1, 2 or 3 R ７－３ In the "3- to 8-membered heterocycloalkyl" in 3- to 8-membered heterocycloalkyl substituted with, said heteroatoms are independently selected from one or more of N, O and S, and the number of said heteroatoms is independently 1, 2 or 3; R ７ the 8- to 12-membered fused ring group and the one, two, or three R ７－４ wherein the 8- to 12-membered fused ring group in the 8- to 12-membered fused ring group substituted with is independently ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R ７－１ , R ７－２ , R ７－３ and R ７－４ are independently amino, -L ３ -NH ２ , -L ３ -OH, -C(=O)-L ３ -OH or -C(=O)-L ３ -NH ２ and L ３ became independent and became C １～６ Alkylidene or -(CH ２ CH ２ O) ｍ’ -C １～６ alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0 or 1; R ８ and R ８’ are independently hydrogen or C １～６ alkyl, or R ８ and R ８’ together with both of the carbon atoms to which they are attached, form a carbonyl, C ３～１０ forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R １ , R ２ and R ３ are independently hydrogen, deuterium, or halogen; R ４ and R ４’ became independent and became C １～６ Alkyl, C １～６ Alkoxyl or one, two or three R ４－１ C substituted with １～６ alkyl, and the R ４－１ are independently hydroxyl, amino, or —OC(═O)NR ａ R ｂ or 【Chemistry 24】 and R ａ and R ｂ are independently hydrogen, C １～６ Alkyl or C ３～１０ is cycloalkyl, R ｉ is hydrogen, C １～６ alkyl or benzyl, and R ｋ is hydrogen, halogen or C １～６ alkyl, and R ｉ is C １～６ Alkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～１０ Cycloalkyl-C １～６ Alkyl, 3- to 10-membered heterocycloalkyl-C １～６ Alkyl, C ６～１０ Aryl-C １～６ Alkyl or 5- to 10-membered heteroaryl-C １～６ is alkyl, R ｊ In the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C １～６ In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C １～６ In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ is alkyl, 11. The compound of formula II or a pharmaceutically acceptable salt thereof according to claim 10, wherein the compound of formula II is not a structure shown in Table 6. Table 11 【change】 【change】

12. Meet one or more of the following conditions: (1) the compound shown in D' is not a compound shown in Table 3, Table 12 【change】 、 (2) The compound of formula II according to claim 10 or 11, wherein LX is not the following structure, or a pharmaceutically acceptable salt thereof. 【Chemistry 25】

13. (1) the compound represented by D′ satisfies one, two, or three of the following conditions: (a) L １ became independent and became C １～６ Alkylidene or C ２～６ alkenylene, and (b) R ７ are independently phenyl substituted with one amino group, 5- to 10-membered heteroaryl substituted with one amino group, 3- to 8-membered heterocycloalkyl substituted with one amino group, or 8- to 12-membered fused ring group substituted with one amino group; (c) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ alkyl, and the R ４－１ are independently -OC(=O)NR ａ R ｂ or 【Chemistry 26】 and (2) The LX is M'-(T) ｗ -PEG-(T) ｏ - ＊ , M'-PEG- ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , M'-(T) ｗ -L ５ - ＊ , M'-(T) ｗ -PEG-L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ or M'-PEG-(T) ｏ -PEG- ＊ , * is the linking site between LX and D, M' is hydrogen, a connector precursor, or a connector linked to 1-2 amino acids; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or w is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T is independent -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -C ６～１４ Arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -C ３～６ Cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-C １～６ Alkylidene-, C １～６ Alkylidene or C ２～６ alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3, and the -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, or S, and the number of the heteroatoms is 1, 2, or 3; R ｈ are independently hydrogen, C １～６ Alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R Ａ and R is an amino acid residue substituted with Ａ are independently —C(O)—(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L ５ 13. The compound of formula II according to claim 12, or a pharmaceutically acceptable salt thereof, wherein is a self-immolative group.

14. Meet one or more of the following conditions: In formula (1), L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ -, and its right end is L １ is connected to (2) R ９ is hydrogen, (3) L １ So, the above C １～６ alkylidene is methylene or ethylidene; (4) R ７ In the formula, the 8- to 12-membered fused ring group is ring A and fused ring B, ring A is a 5- to 6-membered heteroaryl or phenyl, ring B is a 5- to 6-membered heteroalkenyl ring, and ring A is connected to L via ring A. １ wherein the heteroatom in said 5- to 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, and the heteroatom in said 5- to 6-membered heteroalkenyl ring is N and the number of heteroatoms is 1 or 2; (5) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N; (6) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2, (7) In ring A, the heteroatom in the 5- to 6-membered heteroaryl ring is N; (8) In ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2, (9) In ring B, the heteroatom in the 5- to 6-membered heteroalkenyl ring is N; (10) One hydrogen atom lost from the compound represented by formula D′ is R ７ or one hydrogen atom lost from the compound of formula D' is located on a secondary or primary amine of R ７ Located on the hydroxyl of (11) m is 1, (12) R ８ and R ８’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (13) R ８ and R ８’ together with both of the carbon atoms to which they are attached, ３～１０ Form a cycloalkylene, ３～１０ cycloalkylene is cyclopropyl or cyclobutyl; (14) R ８ and R ８’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in said 3- to 10-membered heterocycloalkylene is N or O; (15) R ８ and R ８’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in said 3- to 10-membered heterocycloalkylene is 1 or 2; (16) R １ , R ２ and R ３ wherein the halogen is F, Cl or Br; (17) R ４ and R ４’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (18) R ４ and R ４’ So, the above C １～６ alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl; (19) R ４ and R ４’ So, one, two or three Rs? ４－１ The C substituted with １～６ C in alkyl １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (20) R ａ and R ｂ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (21) R ａ and R ｂ So, the above C ３～１０ cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl; (22) R ｉ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (23) R ｋ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (24) R ｊ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (25) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C ６～１０ aryl is phenyl; (26) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (27) The LX is M′-(T) ｗ -PEG-(T) ｏ - ＊ , M'-PEG- ＊ , M'-(T) ｗ - ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ -PEG- ＊ , M'-(T) ｗ -(A) ｖ - (T) ｏ - ＊ , M'-(T) ｗ -L ５ - ＊ , M'-(T) ｗ -PEG-L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ , M'-(T) ｗ -PEG-(A) ｖ - (T) ｏ - ＊ , M'-PEG-(T) ｏ -PEG- ＊ or M'-(T) ｗ -(A) ｖ -L ５ - ＊ * is the linking site between LX and D, M' is hydrogen, a connector precursor, or a connector linked to 1-2 amino acids; w is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or w is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; T is independent -(CH ２ ) ｘ -C(O)-, -NR ｈ -, -O-, -S-, -(CH ２ ) ｘ -C ６～１４ Arylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -C ３～６ Cycloalkylene-(CH ２ ) ｙ -, -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ -, -NR ｈ - (CH ２ ) ｘ -C(O)-, -O-(CH ２ ) ｘ -C(O)-, -S-(CH ２ ) ｘ -C(O)-, -(CH ２ ) ｘ CH (NHR ｈ )-C(O)-,-(CH ２ ) ｘ -S-S-C １～６ Alkylidene-, C １～６ Alkylidene or C ２～６ alkenylene, wherein x and y are independently any integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; ２ ) ｘ -5- to 6-membered heteroarylene-(CH ２ ) ｙ In the "5- to 6-membered heteroarylene" in -, the heteroatom is selected from one or more of N, O, and S, and the number of the heteroatoms is 1, 2, or 3, and the -(CH ２ ) ｘ -3 to 6-membered heterocycloalkylene-(CH ２ ) ｙ In the "3- to 6-membered heterocycloalkylene" in -, the heteroatoms are selected from one or more of N, O, or S, and the number of the heteroatoms is 1, 2, or 3; R ｈ are independently hydrogen, C １～６ Alkyl, -PO(OH) ２ , -PO(OCH ３ ) ２ , -C(O)-(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; PEG is -(CH ２ CH ２ O) ｎ - (CH ２ ) ｕ - or - (CH ２ CH ２ O) ｎ - (CH ２ ) ｕ -C(O)-, n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; and u is independently 0, 1, 2, 3, 4, or 5; v is independently 1, 2, 3, 4, or 5; A is independently an amino acid residue or one R Ａ and R is an amino acid residue substituted with Ａ are independently —C(O)—(CH ２ CH ２ O) ｎ -CH ３ or -(CH ２ CH ２ O) ｎ -CH ３ and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; L ５ 12. The compound of formula II according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, wherein is a self-immolative group.

15. Meet one or more of the following conditions: (1) R ７ but 【Chemistry 27】 and (2) M' is 【Chemistry 28】 and (3)-(A) ｖ -but 【Chemistry 29】 and each R １１ are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, —SO ３ H. 【Transformation 30】 or R １１ and the adjacent nitrogen atom form a 5-membered heterocycle, v is an integer of 1 to 4, preferably 1 or 2, (4) A is -(T) through the carbonyl terminal ｏ - or -L ５ - is connected to (5) L ５ but 【Chemistry 31】 and (6)-L ５ - is linked to D via the carbonyl terminus, (7)-(T) ｗ -but 【Chemistry 32】 and -(T) ｗ - is linked to said M' via the a-terminus, (8)-(T) ｏ -but 【Transformation 33】 and (T) ｏ - is linked to the -PEG- or D via the b-terminus, (9) LX is any one of the following combinations: A) M'-PEG-, B) M'-(CH ２ ) ｘ -, C)M'-(CH ２ ) ｘ -C(O)-,D)M'-(CH ２ ) ｘ -(C ５～６ cycloalkylene)-(CH ２ ) ｙ -C(O)NH-PEG-,E)M'-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-(CH ２ ) ｙ -C(O)NH-PEG-,F)M'-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)NH-PEG-,G)M'-(CH ２ ) ｘ -C(O)NH-PEG-, H)M'-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)NH-PEG-, I)M'-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)NH-PEG-NH-(CH ２ ) ｘ -C(O)-, J)M'-(CH ２ ) ｘ -(C ５～６ cycloalkylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,K)M'-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,L)M'-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ ) ｘ -NHC(O)-,M)M'-(CH ２ ) ｘ -C(O)NH-(CH ２ ) ｘ -C(O)-L ５ -, N)M'-(CH ２ ) ｘ -C(O)NH-PEG-L ５ -, O)M'-(CH ２ ) ｘ -(phenylene)-(CH ２ ) ｙ -C(O)-(A) ｖ -, P)M'-(CH ２ ) ｘ -C(O)NH-(C ３～６ cycloalkylene)-C(O)-(A) ｖ -, Q)M'-(CH ２ ) ｘ -C(O)NH-PEG-(A) ｖ -, R)M'-(CH ２ ) ｘ -C(O)NH-PEG-(A) ｖ -L ５ -, S)M'-(CH ２ ) ｘ -(C ５～６ Cycloalkylene)-C(O)-, T)M'-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-C(O)-, U)M'-(phenylene)-(CH ２ ) ｙ -C(O)-,V)M'-(CH ２ ) ｘ -C(O)-(A) ｖ -NH-PEG-, W)M'-(CH ２ ) ｘ -C(O)-(A) ｖ -NH-(CH ２ ) ｘ -C(O)-,X)M'-(CH ２ ) ｘ -C(O)-(A) ｖ -, Y)M'-(CH ２ ) ｘ -(5- to 6-membered heterocyclylene)-C(O)-(A) ｖ -, or Z)M'-(CH ２ ) ｘ -C(O)NH-CH ２ -CH(NHR ｈ )-C(O)-(A) ｖ -, AA) M'-(phenylene)-(5- to 6-membered heterocyclylene)-C(O)-, AB) M'-(phenylene)-(CH ２ ) ｙ -C(O)NH-(CH ２ )x-PEG-(A) ｖ -, AC)M'-(phenylene)-C(O)NH-(CH ２ ) x-(A) ｖ -L ５ - or AD)M'-(CH ２ ) ｘ -PEG-(A) ｖ - and Alternatively, LX is M'-(T) ｗ -(A) ｖ -L ５ - ＊ and LX is M'-(T) ｗ -(A) ｖ -L ５ - ＊ In the case of M', -(T) ｗ -, -(A) ｖ - and -L ５ - does not simultaneously satisfy the following conditions, M' is maleimide, and -(T) ｗ - is caproyl, -(A) ｖ - is -Val-Cit-, -Val-Ala or -Gly-Gly-Phe-Gly-, and -L ５ - is PABC, and preferably L is M'-CH ２ -(C ５～６ cycloalkylene)-C(═O)-(A) ｖ -L ５ -, M'-CH ２ -(5- to 6-membered heterocyclylene)-C(=O)-(A) ｖ -L ５ -, M'-(phenylene)-CH ２ -C(=O)-(A) ｖ -L ５ - or -M-(CH ２ ) ｘ -C(=O)NH-CH ２ -CH(NHR ｈ )-C(O)-(A) ｖ -L ５ - and LX is M'-(T) ｗ -PEG-(A) ｖ -L ５ - ＊ In the case where LX is M'-(CH ２ ) ｘ -C(=O)NH-PEG-(A) ｖ -L ５ -, M'-(phenylene)-CH ２ -C(=O)NH-PEG-(A) ｖ -L ５ -, M'-CH ２ -(C ５～６ cycloalkylene)-C(═O)NH-PEG-(A) ｖ -L ５ - or M'-CH ２ -(5- to 6-membered heterocyclylene)-C(═O)NH-PEG-(A) ｖ -L ５ - and LX is M'-(T) ｗ -(A) ｖ - (T) ｏ - ＊ In the case where LX is M'-(CH ２ ) ｘ -C(=O)NH-(A) ｖ -NH-CH ２ 15. The compound of formula II according to claim 14, wherein: - or a pharmaceutically acceptable salt thereof.

16. Meet one or more of the following conditions: (1) D is a structure shown in Table 5, Table 13 【change】 【change】 、 (2) LX 【Transformation 34】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 16. The compound of formula II according to claim 15, wherein: or a pharmaceutically acceptable salt thereof.

17. 13. The compound of formula II according to claim 12, wherein said compound of formula II is any one of the following compounds: 【Chemistry 35】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

18. A compound of formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, 【Transformation 36】 In the formula, R is -L'-L １ -R ７ and L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ - and R ９ are independently hydrogen, C １～６ Alkyl or halogenated C １～６ is alkyl, L １ are independently bonded bonds, C １～６ Alkylidene or C ２～６ is alkenylene, R ７ are independently phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 8- to 12-membered fused ring group, one, two, or three R ７－１ phenyl substituted with one, two or three R ７－２ 5-6 membered heteroaryl substituted with one, two or three R ７－３ or one, two or three R ７－４ is an 8- to 12-membered fused ring group substituted with R ７ wherein the 5- to 6-membered heteroaryl and the one, two, or three R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the heteroatoms are independently selected from one or more of N, O and S, the number of heteroatoms is independently 1, 2 or 3, and the 3- to 8-membered heterocycloalkyl and the 1, 2 or 3 R ７－３ In the "3- to 8-membered heterocycloalkyl" in 3- to 8-membered heterocycloalkyl substituted with, said heteroatoms are independently selected from one or more of N, O and S, and the number of said heteroatoms is independently 1, 2 or 3; R ７ the 8- to 12-membered fused ring group and the one, two, or three R ７－４ wherein the 8- to 12-membered fused ring group in the 8- to 12-membered fused ring group substituted with is independently ring A fused ring B, wherein ring A is a 5- to 6-membered heteroaryl ring or a benzene ring, and ring B is a 5- to 6-membered heteroalkenyl ring, wherein in the 5- to 6-membered heteroaryl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and in the 5- to 6-membered heteroalkenyl ring, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; R ７－１ , R ７－２ , R ７－３ and R ７－４ are independently amino, -L ３ -NH ２ , -L ３ -OH, -C(=O)-L ３ -OH or -C(=O)-L ３ -NH ２ and L ３ became independent and became C １～６ Alkylidene or -(CH ２ CH ２ O) ｍ’ -C １～６ alkylidene- and m' is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0 or 1; R ８ and R ８’ are independently hydrogen or C １～６ alkyl, or R ８ and R ８’ together with both of the carbon atoms to which they are attached, form a carbonyl, C ３～１０ forming a cycloalkylene or a 3- to 10-membered heterocycloalkylene, wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R １ , R ２ and R ３ are independently hydrogen, deuterium, or halogen; R ４ and R ４’ became independent and became C １～６ Alkyl, C １～６ Alkoxyl or one, two or three R ４－１ C substituted with １～６ alkyl, and the R ４－１ are independently hydroxyl, amino, or —OC(═O)NR ａ R ｂ or 【Chemistry 37】 and R ａ and R ｂ are independently hydrogen, C １～６ Alkyl or C ３～１０ is cycloalkyl, R ｉ is hydrogen, C １～６ alkyl or benzyl, and R ｋ is hydrogen, halogen or C １～６ alkyl, and R ｉ is C １～６ Alkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, C ３～１０ Cycloalkyl-C １～６ Alkyl, 3- to 10-membered heterocycloalkyl-C １～６ Alkyl, C ６～１０ Aryl-C １～６ Alkyl or 5- to 10-membered heteroaryl-C １～６ is alkyl, R ｊ In the above, the 3- to 10-membered heterocycloalkyl and the 3- to 10-membered heterocycloalkyl-C １～６ In the "3- to 10-membered heterocycloalkyl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl-C １～６ In the "5- to 10-membered heteroaryl" in alkyl, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Also, as shown in formula D', the compound satisfies one or two of the following conditions: (1) m is 1, (2) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ is alkyl, Also, a compound of formula D', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the compound of formula D' is not a compound shown in Table 3. Table 14 【change】

19. Meet one, two or three of the following conditions: (1) L １ became independent and became C １～６ Alkylidene or C ２～６ is alkenylene, (2) R ７ are independently phenyl substituted with one amino, 5- to 6-membered heteroaryl substituted with one amino, 3- to 8-membered heterocycloalkyl substituted with one amino, or 8- to 12-membered fused ring group substituted with one amino; (3) R ４ and R ４’ At least one of the １～６ Alkoxyl, or one, two or three R ４－１ C substituted with １～６ is alkyl, The R ４－１ are independently -OC(=O)NR ａ R ｂ or 【Transformation 38】 19. The compound of formula D' according to claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein:

20. Meet one or more of the following conditions: In formula (1), L' is -C(=O)-, -C(=O)-NR ９ - or -C(=S)-NR ９ -, and its right end is L １ is connected to (2) R ９ is hydrogen, (3) L １ So, the above C １～６ alkylidene is methylene or ethylidene; (4) R ７ In the formula, the 8- to 12-membered fused ring group is ring A and fused ring B, ring A is a 5- to 6-membered heteroaryl or phenyl, ring B is a 5- to 6-membered heteroalkenyl ring, and ring A is connected to L via ring A. １ wherein the heteroatom in said 5- to 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, and the heteroatom in said 5- to 6-membered heteroalkenyl ring is N and the number of heteroatoms is 1 or 2; (5) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted by, the heteroatoms are independently N; (6) R ７ wherein the 5- to 6-membered heteroaryl and one, two or three of the R ７－２ In the "5- to 6-membered heteroaryl" in the 5- to 6-membered heteroaryl substituted with, the number of said heteroatoms is independently 1 or 2, (7) In ring A, the heteroatom in the 5- to 6-membered heteroaryl ring is N; (8) In ring A, the number of heteroatoms in the 5- to 6-membered heteroaryl ring is 1 or 2, (9) In ring B, the heteroatom in the 5- to 6-membered heteroalkenyl ring is N; (10) One hydrogen atom lost from the compound represented by formula D′ is R ７ or one hydrogen atom lost from the compound of formula D' is located on a secondary or primary amine of R ７ Located on the hydroxyl of (11) m is 1, (12) R ８ and R ８’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (13) R ８ and R ８’ together with both of the carbon atoms to which they are attached, ３～１０ Form a cycloalkylene, ３～１０ cycloalkylene is cyclopropyl or cyclobutyl; (14) R ８ and R ８’ together with both of the carbon atoms to which they are attached form a 3- to 10-membered heterocycloalkylene, and the heteroatom in said 3- to 10-membered heterocycloalkylene is N or O; (15) R ８ and R ８’ together with the carbon atoms to which they are both attached form a 3- to 10-membered heterocycloalkylene, and the number of heteroatoms in said 3- to 10-membered heterocycloalkylene is 1 or 2; (16) R １ , R ２ and R ３ wherein the halogen is F, Cl or Br; (17) R ４ and R ４’ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (18) R ４ and R ４’ So, the above C １～６ alkoxyl is methoxyl, ethoxyl, n-propoxyl or isopropoxyl; (19) R ４ and R ４’ So, one, two or three Rs? ４－１ The C substituted with １～６ C in alkyl １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (20) R ａ and R ｂ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (21) R ａ and R ｂ So, the above C ３～１０ cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl; (22) R ｉ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (23) R ｋ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (24) R ｊ So, the above C １～６ alkyl is methyl, ethyl, n-propyl or isopropyl; (25) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C ６～１０ aryl is phenyl; (26) R ｊ So, C ６～１０ Aryl-C １～６ In the case of alkyl, the C １～６ 19. The compound of formula D' according to claim 18, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein alkyl is methyl, ethyl, n-propyl, or isopropyl.

21. Meet one or more of the following conditions: (1) R ７ but 【Chemistry 39】 and (2) R １ H, R ２ H, R ３ is H or F, (3) R ４ and R ４’ is independently -OCH ２ CH ３ , -CH ２ CH ２ NH ２ , -CH ２ CH ２ OH or -CH ２ CH ２ CH ３ 21. The compound of formula D' according to claim 20, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein:

22. The compound of formula D' according to any one of claims 18 to 21, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound of formula D' is any one of the following compounds: 【Chemistry 40】 【change】

23. A pharmaceutical composition comprising substance K and a pharmaceutically acceptable excipient, the substance K is substance K-1, substance K-2, or substance K-3, The substance K-1 is an antibody-immunostimulating complex according to formula I of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound of formula II according to any one of claims 10 to 17 or a pharmaceutically acceptable salt thereof; A pharmaceutical composition, characterized in that the substance K-3 is a compound represented by formula D' according to any one of claims 18 to 22, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

24. 23. The use of substance K or the pharmaceutical composition according to claim 22 in the preparation of a drug, the drug is a drug for regulatory T cells and other immune cells, a drug for treating and / or alleviating tumors, or a drug for treating, alleviating and / or preventing related diseases mediated by TLR8; the substance K is substance K-1, substance K-2, or substance K-3, The substance K-1 is an antibody-immunostimulating complex according to formula I of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof; The substance K-2 is a compound of formula II according to any one of claims 10 to 17 or a pharmaceutically acceptable salt thereof; The substance K-3 is a compound represented by formula D' according to any one of claims 18 to 22, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The application, characterized in that the tumor is preferably a malignant tumor.

25. A therapeutic method for treating or preventing a disease, comprising administering to a subject the substance K-1 according to claim 24, the substance K-2 according to claim 24, or the substance K-3 according to claim 24; the disease is a disease associated with regulatory T cells and other immune cells, a tumor, or a TLR8-mediated related disease; A method of treatment, characterized in that the tumor is preferably a malignant tumor.

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