Heterocyclic amide compounds, ligand drug conjugates thereof, and uses thereof

Abstract

This disclosure relates to heterocyclic amide compounds, their ligand-drug conjugates, and their uses. Specifically, this disclosure relates to a compound of general formula (I) and its ligand-drug conjugate, pharmaceutical compositions containing such compounds and their ligand-drug conjugates, and their use as therapeutic agents, particularly as STING agonists, and for the treatment and / or prevention of STING-mediated diseases or conditions, including cancer, inflammation, infectious diseases, and immune-related diseases.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to interferon gene-stimulating protein (STING) agonists for the treatment and / or prevention of STING-mediated diseases or conditions, such as cancer, inflammation, infectious diseases, and immune-related diseases. Background Technology

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

[0003] The cyclic GMP-AMP synthase (cGAS)-interferon gene-stimulating factor (STING) signaling pathway is a cytoplasmic DNA sensing pathway that plays a crucial role in the innate immune response. When tumor-derived DNA is recognized by the cytoplasmic DNA receptor cGAS, cGAS catalyzes the linkage of two nucleotides to generate cyclic dinucleotides (CDNs, such as 2′,3′-cGAMP). Subsequently, CDNs, acting as second messengers, bind to STING and activate its function. Activation of STING leads to the activation of downstream IRF3 and NF-κB pathways, thereby activating the immune system. Activation of the NF-κB pathway leads to the activation of a series of downstream pro-inflammatory cytokines, while activation of the IRF3 pathway leads to the activation and release of type I interferon (IFN-α / β). The combined action of these cytokines can promote the activation of dendritic cells, cytotoxic cells, NK cells, etc., thereby exerting an anti-tumor effect.

[0004] The scientific community generally believes that exogenous STING agonists have significant potential for activating innate immunity and can be used as monotherapy or in combination with checkpoint inhibitors to control tumor growth. This makes STING agonists a promising cancer immunotherapy strategy. However, new drug development is usually accompanied by challenges. Early clinical studies of STING agonists showed limited efficacy, low response rates, and significant limitations. Specifically, CDN molecules are easily degraded by ENPP phosphodiesterases in the body, leading to loss of activity. They have a short half-life in the circulatory system and low bioavailability, making clinical use highly dependent on intratumoral administration. However, intratumoral administration often causes pain and inconvenience to patients, and this approach is not suitable for all tumors. While non-CDN molecules are more stable, systemic administration may trigger systemic cytokine responses, leading to inflammation in normal tissues or even a cytokine storm.

[0005] Therefore, there is an urgent need to develop a novel therapy that can precisely deliver STING agonists to the tumor environment while prolonging efficacy and reducing systemic toxicity. Summary of the Invention

[0006] This disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof. in: It can be a single bond or a double bond; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 1 and R 2 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 Replace; or, R 1 and R 2 Together with the carbon atom attached thereto, it forms a cycloalkyl, heterocyclic, or phenyl group, which may optionally be influenced by one or more R groups. 10 replace; X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; L 1Selected from alkylene, alkylene-O-alkylene, alkenyl, and ynylene, wherein the alkylene and alkenyl groups are each independently and optionally influenced by one or more R groups. 13 replace, L 2 Selected from =NC(=O)-、-NR 11 -C(=O)-、-C(=O)-NR 11 - Cycloalkylene, heterocyclic, aryl, heteroaryl, alkenyl, and alkyneyl groups, each of which is independently optionally influenced by one or more R groups. 13 replace; Each R B and R 7 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 and -NR 17 S(=O)2R 14 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; R 5 and R 6Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 and -NR 17 S(=O)2R 14 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; Each R 11 Independently selected from hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -alkylene-C(=O)OH, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl and heterocyclic alkyl; R 8 Selected from -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 and -NR 17 C(=O)OR 14 ; R 9Selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; Each R 14 R 15 R 16 and R 17 Each of the following is independently selected from hydrogen atoms, deuterium atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, and alkylheteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected by one or more R atoms. 13 replace; Each R 10 and R 13 Each is independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, -NR 15 R 16 -N(alkyl)-NR 15 R 16 -C(=O)O alkyl, -C(=O)OH, -C(=O)NR 15R 16 -C(=O)N(alkyl)-NR 15 R 16 -C(=O)NH-alkylene-NR 15 R 16 -C(=O)N(alkyl)-alkylene-NR 15 R 16 -C(=O)NH-alkylene-OH, -C(=O)N(alkyl)-alkylene-OH, -C(=O)halogen, -C(=O)alkyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, -O-alkylene-NR 15 R 16 alkoxyalkyl, oxo, =S, =CR a R b , , , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkoxy, aryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroaryloxy and heteroarylalkoxy; R 12 R a and R b Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, hydroxyl, cyano, amino, cycloalkyl and cycloalkylalkyl; or R a and R b Together with the carbon atom attached to it, it forms a cycloalkyl group or C=O; R c and R d Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, hydroxyl, cyano, amino, cycloalkyl and cycloalkylalkyl; or R c and R d Together with the carbon atom attached to it, it forms a cycloalkyl group or C=O; n B It can be 1, 2, or 3; The condition is that when R 1 and R 2 For a phenyl group to form with the carbon atom it is attached to, one of the following conditions must be met: (i) R on the phenyl group 10 for ; (ii) Ring B is a 6-7 membered heteroaryl group; (iii) L2 It is an acetylinyl group or -C(=O)-NR 11 -; The condition is that the compound represented by the general formula (I) is not one of the following compounds: and .

[0007] This disclosure also provides a ligand-drug conjugate of general formula (I') or a pharmaceutically acceptable salt thereof. (I') in, Ab is a ligand unit; L represents the connecting subunit; n is a decimal or integer between 1 and 10; D is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. in, R 1 and R 2 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups.13 Replace; or, R 1 and R 2 Together with the carbon atom attached thereto, it forms a cycloalkyl, heterocyclic, or phenyl group, which may optionally be influenced by one or more R groups. 10 replace; The condition is that one of the following conditions must be met: (i)R 8 for , where # represents the connection point with the connecting subunit; and R 9 and R 10 As defined in general formula (I); (ii)R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; and R 8 and R 10 As defined in general formula (I); (iii) R 10 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; and R 8 and R 9 As defined in general formula (I); Ring B, X 1 L 1 L 2 R 5 R 6 R 7 R 13 R 14 R 15 R 16 R 17 Ra R b R c R d R B and n B As defined in general formula (I).

[0008] In some embodiments, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. in, X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 3 and R 4 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; n 1 It can be 0, 1, or 2; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; X 1 L 2 R 1 R 2 R 5 R 6 R 7 R 11 R 12 R a and R b As defined in general formula (I); R 9 and R 10 As defined in general formula (I) or general formula (I'); R 15 and R 16 As defined in general formula (I), or, for , where # represents the connection point with the connecting subunit.

[0009] In some embodiments, R is present in a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. 1 and R 2 Together with the carbon atom attached thereto, they form a 3-8 membered heterocyclic group, preferably... , where X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 n 5 0, 1, or 2, preferably , , , , , or ;or R 1 and R 2 It forms together with the carbon atoms attached to it. ;or R 1 and R 2 It forms together with the carbon atoms attached to it. n 6 It can be 0, 1, or 2; or R 1 and R 2 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Deuterated alkoxy, C 1-6 aminoalkyl, C 1-6 Alkylamino, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 and ; in, Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl group, cyano group, nitro group, -NR 15 R 16 -N(C 1-6 alkyl)-NR 15 R 16 -C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NR 15 R 16 -C(=O)N(C 1-6 alkyl)-NR 15 R 16 -C(=O)NH-C 1-6 Alkylene-NR 15 R 16 -C(=O)N(C 1-6 alkyl)-C 1-6 Alkylene-NR 15 R 16 -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)N(C 1-6 alkyl)-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NR 15 R 16 C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 alkyl; n 2 It can be 1, 2, or 3.

[0010] In some embodiments, R is present in a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. 1 and R 2 It forms together with the carbon atoms attached to it. , , , , , , , , , , , , or ;or R 1 and R 2 Each is independently selected from hydrogen atoms and -C(=O)NH2.

[0011] In some embodiments, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-1), or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; X 2 Selected from O, S, N, NR 11 CR12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 5 It can be 0, 1, or 2; The condition is that the compound represented by the general formula (III-1) is not one of the following compounds: and .

[0012] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-1-1) or a pharmaceutically acceptable salt thereof. Among them, X 4 X 5 X6 R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 5 As defined in general formula (III-1); The condition is that the compound represented by the general formula (III-1-1) is not one of the following compounds: and .

[0013] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-1) or general formula (III-1-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-1-1A) or general formula (III-1-1B), or a pharmaceutically acceptable salt thereof. , Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined in general formula (III-1); The condition is that the compound represented by the general formula (III-1-1A) or general formula (III-1-1B) is not one of the following compounds: and .

[0014] In some embodiments, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; X2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 5 It can be 0, 1, or 2.

[0015] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III-2), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-2-1), or a pharmaceutically acceptable salt thereof. Among them, X 4 X 5 X 6 R 3 R 4 R5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 5 As defined in general formula (III-2).

[0016] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-2) or general formula (III-2-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-2-1A) or general formula (III-2-1B), or a pharmaceutically acceptable salt thereof. , Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined by general formula (III-2).

[0017] In some embodiments, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-3) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR4 and CR a R b ; L 2 Selected from =NC(=O)-、-NR 11 -C(=O)-、-C(=O)-NR 11 -and C 2-6 Ethyne group; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; The condition is that one of the following conditions must be met: (i) R on the phenyl group 10 for ; (ii) Ring B is a 6-7 membered heteroaryl group, preferably pyrimidinyl, pyridinyl or pyrazinyl; (iii) L 2 C 2-6 Isomeryne or -C(=O)-NR 11 -

[0018] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III-3), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-3-1), general formula (III-3-2), or general formula (III-3-3), or a pharmaceutically acceptable salt thereof. , , Among them, X 2 X 3 R3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 1 n 2 n 3 and n 4 As defined in general formula (III-3).

[0019] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-3) or general formula (III-3-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-3-1A) or general formula (III-3-1B), or a pharmaceutically acceptable salt thereof. , , Among them, R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined in general formula (III-3).

[0020] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-3) or general formula (III-3-2), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-3-2A) or a pharmaceutically acceptable salt thereof. , Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n2 n 3 and n 4 As defined in general formula (III-3).

[0021] In some embodiments, the compound represented by formula (I), formula (II), formula (III-3), or formula (III-3-3), or a pharmaceutically acceptable salt thereof, is of formula (III-3-3A). , Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined in general formula (III-3).

[0022] In some embodiments, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-4), or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 6 It can be 0, 1, or 2.

[0023] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III-4), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-4-1), or a pharmaceutically acceptable salt thereof. Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 6 As defined in general formula (III-4).

[0024] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-4), or general formula (III-4-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-4-1A), or a pharmaceutically acceptable salt thereof. Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined in general formula (III-4).

[0025] In some embodiments, the compound represented by general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-5) or a pharmaceutically acceptable salt thereof. in, It can be a single bond or a double bond; Ring D is a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group, and more preferably a pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrroleyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 1 and R 2 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Deuterated alkoxy, C 1-6 aminoalkyl, C 1-6 Alkylamino, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 and ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 13 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; Each R 14 Independently selected from hydrogen, deuterium, and carbon atoms. 1-6 alkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 7 It can be 0, 1, or 2.

[0026] In some embodiments, the compound represented by general formula (I), general formula (II), or general formula (III-5), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-5-1), or a pharmaceutically acceptable salt thereof. in, X 7 and X 8 Each is independently selected from O, S, N, NR. 11 CR 12 and CR a R b ; n 8 It can be 0, 1, or 2; X 1 X 2 R 1 -R 7 R 9 R 11 R 12 R 13 R 15 R 16 R a R b n 1 n 3 n 4 and n 7 As defined in general formula (III-5).

[0027] In some embodiments, the compound represented by general formula (I), general formula (II), general formula (III-5), or general formula (III-5-1), or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (III-5-1A), or a pharmaceutically acceptable salt thereof. Among them, R 1 -R 7 R 9 R 11 R 13 R 15 R 16 n 3 n 4 and n 7 As defined in general formula (III-5).

[0028] In some embodiments, L is present in the compound represented by general formula (I), general formula (II), or general formula (III-3) or a pharmaceutically acceptable salt thereof. 2 Selected from =NC(=O)-, -NH-C(=O)-, -C(=O)-NH-, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 aryl, 5-10 quinone heteroaryl, C 2-6 imide and C 2-6 Idemyne ​​group, the C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene, 5-10 methyl arylene and C 2-6 Each alkenyl group is independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the deuterated alkoxy group are used for substitution.

[0029] In some embodiments, L is present in the compound represented by general formula (I), general formula (II), or general formula (III-3) or a pharmaceutically acceptable salt thereof. 2 Selected from =NC(=O)-, -NH-C(=O)-, -C(=O)-NH-, C 3-6 Cycloalkylene, 3-6 membered heterocyclic alkylene, phenyl, 5-6 membered heteroarylalkylene, C 2-6 imide and C 2-6 Alynyl group.

[0030] In some embodiments, L is present in the compound represented by general formula (I), general formula (II), or general formula (III-3) or a pharmaceutically acceptable salt thereof. 2 Selected from =NC(=O)-, -C(=O)-NH-, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrroleyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyridazinyl, and ethynyl.

[0031] In some embodiments, in compounds of general formula (I), general formula (II), general formula (III-3) or general formula (III-5), or pharmaceutically acceptable salts thereof, X 1 Selected from N, NR 11 CR 12 and CR a Rb ; R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and amino groups.

[0032] In some embodiments, in compounds of general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4) or general formula (III-5), or pharmaceutically acceptable salts thereof, X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 4 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and amino groups.

[0033] In some embodiments, in the compounds represented by the various general formulas or their pharmaceutically acceptable salts... R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, amino, hydroxyl, nitro, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-6-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 Hydroxyalkyl; The 3-6 membered heterocyclic or heterocyclic groups are selected from azirrobutyl, oxoheterobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

[0034] In some embodiments, in the compounds represented by the various general formulas or their pharmaceutically acceptable salts... R 9 Selected from hydrogen atoms, C 1-6 Alkoxy, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-6-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , and , where # represents the connection point with the connecting subunit; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms.1-6 Alkyl and C 1-6 Hydroxyalkyl; The 3-6 membered heterocyclic or heterocyclic groups are selected from azirrobutyl, oxoheterobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

[0035] In some embodiments, in the compounds represented by the various general formulas or their pharmaceutically acceptable salts... R 9 Selected from hydrogen atoms, , , methoxy and ;or R 9 Selected from , and .

[0036] In some embodiments, in compounds of general formulas (II), (III-1), (III-1-1), (III-1-1A), (III-1-1B), (III-2), (III-2-1), (III-2-1A), (III-2-1B), (III-3), (III-3-1), (III-3-1A), (III-3-1B), (III-3-2), (III-3-2A), (III-3-3), (III-3-3A), (III-4), (III-4-1), (III-4-1A), (III-5), (III-5-1), and (III-5-1A), or pharmaceutically acceptable salts thereof, R 3 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 3 Selected from hydrogen atoms and C 1-6 alkyl.

[0037] In some embodiments, in compounds of general formulas (III-1-1), (III-1-1A), (III-1-1B), (III-2-1), (III-2-1A), (III-2-1B), (III-3-1), (III-3-1A), (III-3-1B), (III-3-2), (III-3-2A), (III-3-3A), (III-4-1), (III-4-1A), (III-5-1), and (III-5-1A), or pharmaceutically acceptable salts thereof, R 4 Selected from hydrogen atoms, deuterium atoms, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 4 Selected from hydrogen atoms and C 1-6 alkyl.

[0038] In some embodiments, in the compounds represented by the various general formulas or their pharmaceutically acceptable salts... R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 5 and R 6 Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl.

[0039] In some embodiments, in the compounds represented by the various general formulas or their pharmaceutically acceptable salts... R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-6cycloalkyl and 3-6 membered heterocyclic groups; Preferably, R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl.

[0040] In some embodiments, in compounds of general formulas (III-1), (III-1-1), (III-1-1A), (III-1-1B), (III-2-1), (III-2-1A), (III-2-1B), (III-3-1), (III-3-1A), (III-3-1B), (III-3-2A), (III-3-3A), (III-4), (III-4-1), (III-4-1A), and (III-5-1A), or pharmaceutically acceptable salts thereof, Each R 11 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; Preferably, R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl.

[0041] Typical compounds disclosed herein include, but are not limited to: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0042] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, L has -L a -L b -L c -L d - structure, where L a Connected to the ligand unit, L d Connected to unit D, where: L a For coupling units; L b It either does not exist or is a connected segment; L c It is a polypeptide fragment; L d It can be either non-existent or any unit.

[0043] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, L a Selected from , , , and Where ** represents the connection point with Ab, and * represents the connection point with L. b The connection point; L b Selected from -(CH2)mC(=O)-, -C(=O)-(CH2)mC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, -(CH2)mOC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, -NH-(CH2)m-(CH2CH2O)pC(=O)-, -(CH2)m-(CH2CH2O)pC(=O)- and -(CH2)mC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, or L b Selected from , , , , , , , , and ; Where: m is an integer from 0 to 10, preferably m is 0, 2, 3 or 5; p is an integer from 4 to 32, preferably p is an integer from 10 to 14; c* represents the relationship with L a The connection point, d* represents the connection with L. c The connection point; L c It is a polypeptide fragment composed of 1 to 7 amino acids, or a bond; wherein the amino acid is selected from valine (V), citrulline (Cit), lysine (K), glycine (G), phenylalanine (F), alanine (A), proline (P), isoleucine (I), serine (S), glutamic acid (E), asparagine (N) and aspartic acid (D); L d It does not exist, or it is selected from the following structures: , , , , , , and ; Among them, a * Indicates with L c The connection point, b * This indicates the connection point with unit D.

[0044] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, L a Selected from , and Where ** represents the connection point with Ab, and * represents the connection point with L. b The connection point; L b Selected from -C(=O)- , , , and Where p is an integer between 10 and 14; c* represents the expression with respect to L. a The connection point, d* represents the connection with L. c The connection point; L c The amino acids derived from valine-citrulline (VC), glycine-glycine-phenylalanine-glycine (GGFG), alanine-alanine-alanine-glycine (AAAG), glycine-glycine-glycine-glycine (GGGG), valine-alanine-glycine (VAG), valine-citrulline-glycine (VCG), alanine-alanine-glycine (AAG), alanine-alanine-alanine (AAA), valine-alanine (VA), alanine-alanine (AA), glutamic acid-alanine-glycine-glycine (EAGG), and glycine- A polypeptide fragment composed of glutamic acid-alanine-glycine (GEAG), glycine-glutamic acid-glycine-glycine (GEGG), glutamic acid-glycine-glycine (EGG), glutamic acid-alanine-glycine (EAG), valine-lysine-glycine (VKG), glycine-glutamic acid-glycine (GEG), glutamic acid-alanine (EA), glutamic acid-glycine (EG), and glycine-glutamic acid (GE). L d Selected from , , and ; where a * Indicates with L c The connection point, b * This indicates the connection point with unit D.

[0045] In some embodiments, L is selected from the ligand-drug conjugate of general formula (I') or its pharmaceutically acceptable salt, wherein L is selected from: and Where, ** represents the connection point with Ab, b * This indicates the connection point with unit D.

[0046] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, Ab is an antibody; in some embodiments, Ab specifically binds to antigens selected from the following: TROP2, AXL, BAFFR, BCMA, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD163, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, Cluster of Differentiation 40 (CD40), CD44, CD45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2. CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1 / 2, CXCR4, C XCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HHLA2, type II HLA (HLA class II), HVEM, ICOSLG, IFNAR, type I interferon receptor subunit (IFNAR1), IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, integrin (Integri) ns), LAG3, LIFR, MAG / Siglec-4 (sialic acid-binding immunoglobulin-like lectin-4), MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, OX40 (CD134), PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1 (sialic acid-binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, tumor necrosis factor α (TNFα), TROY, TSLPR, TYRO, VLDLR, VSIG4, IL2R-γ, and VTCN1.

[0047] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, Ab is an anti-TROP2 antibody.

[0048] In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region includes HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3, and the light chain variable region includes LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6.

[0049] In some embodiments, the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 7, or includes a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 7. The amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8, or contains a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 8.

[0050] In some embodiments, the ligand-drug conjugate represented by general formula (I') or a pharmaceutically acceptable salt thereof, The anti-TROP2 antibody comprises a heavy chain constant region and a light chain constant region; Preferably, the heavy chain constant region is of the IgG1 type; More preferably, the heavy chain constant region contains L234A, L235A and / or P329G mutations; Most preferably, the heavy chain amino acid sequence of the anti-TROP2 antibody is as shown in SEQ ID NO: 11 or SEQ ID NO: 12, or contains a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 11 or SEQ ID NO: 12. The amino acid sequence of the light chain is as shown in SEQ ID NO: 13, or contains a sequence that has at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 13.

[0051] Typical ligand-drug conjugates disclosed herein include, but are not limited to: , and , Ab is defined as above.

[0052] This disclosure also provides a pharmaceutical composition comprising a compound of each of the general formulas or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate of general formula (I') or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0053] This disclosure provides the use of compounds represented by various general formulas or pharmaceutically acceptable salts thereof, or ligand-drug conjugates represented by general formula (I') or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of medicaments for treating and / or preventing diseases.

[0054] This disclosure provides a method for treating and / or preventing a disease, the method comprising administering to a subject a therapeutically or preventively effective amount of a compound of a particular general formula or a pharmaceutically acceptable salt thereof, or a ligand-drug conjugate of general formula (I') or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0055] The compounds represented by the various general formulas of this disclosure or their pharmaceutically acceptable salts, or the ligand-drug conjugates represented by general formula (I') or their pharmaceutically acceptable salts, or the aforementioned pharmaceutical compositions, may be used as drugs; in some embodiments, as drugs for treating or preventing disease.

[0056] In some implementations, the disease is selected from cancer, inflammation, infectious diseases, and immune-related diseases.

[0057] In some implementations, the cancer is selected from lung cancer, stomach cancer, breast cancer, pancreatic cancer, colon cancer, colorectal cancer, bladder cancer, endometrial cancer, urothelial carcinoma, cervical cancer, esophageal cancer, ovarian cancer, head and neck cancer, kidney cancer, melanoma, prostate cancer, non-small cell lung cancer, leukemia, lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin lymphoma.

[0058] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic malignancy.

[0059] In some implementations, the disease is a STING-mediated disease.

[0060] The active compounds or conjugates can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds or conjugates of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds or conjugates of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0061] As a general guideline, the active compound or conjugate is administered in some embodiments in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or conjugate or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0062] In addition to the active compound or conjugate, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound or conjugate.

[0063] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0064] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound or conjugate or its pharmaceutically acceptable salt, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound or conjugate or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or conjugate or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or conjugate or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or conjugate or its pharmaceutically acceptable salt.

[0065] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0066] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0067] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0068] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0069] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0070] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0071] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound or conjugate. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0072] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0073] The disclosed compounds or conjugates can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0074] The compounds or conjugates disclosed herein can be prepared by adding water to form water-soluble dispersible powders and particles. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0075] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound or conjugate used, the patient's age, weight, health status, behavior, diet, timing of administration, route of administration, rate of excretion, combination of drugs, and severity of disease; in addition, the optimal treatment modality, such as the treatment pattern, daily dosage of the compound or conjugate, or type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0076] Terminology Explanation Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0077] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl), in some embodiments of which are alkyl groups having 1 to 6 carbon atoms (i.e., C164 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc.

[0078] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene is an alkylene having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylene), in some embodiments of which are alkylenes having 1 to 6 carbon atoms (i.e., C16-C62 ... 1-6 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0079] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). In some embodiments, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C10). 2-6Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.

[0080] The term "alkenyl" refers to a divalent alkenyl group, where the alkenyl group is as defined above.

[0081] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group is, in some embodiments, an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 Alkyne group). Non-limiting examples include: ethynyl, propynyl, butynyl, penynyl, hexynyl, etc.

[0082] The term "alynyl" refers to a divalent ynyl group, where the ynyl group is as defined above.

[0083] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. In some embodiments, the substituent is selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0084] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl is a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl), in some embodiments it is a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), in some embodiments it is a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl), or a cycloalkyl having 5 or 6 ring atoms (i.e., 5 or 6 membered cycloalkyl), or a cycloalkyl having 5 ring atoms (i.e., 5 membered cycloalkyl).

[0085] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0086] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0087] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include: Its connection point can be anywhere; wait.

[0088] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a ternary / quaternary, ternary / pentary, ternary / hexaternary, quaternary / quaternary, quaternary / pentary, quaternary / hexaternary, pentary / pentary, pentary / pentary, pentary / pentary, pentary / hexatern ... or pentary / hexaternary bicyclic fused cyclic alkyl group. Non-limiting examples include: Its connection point can be anywhere; wait.

[0089] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0090] The term "cycloalkylene" refers to a divalent functional group derived from cycloalkyl, wherein the cycloalkyl group is as defined above.

[0091] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). The heterocyclic group is, in some embodiments, a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); in some embodiments, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group) or a heterocyclic group having 4 to 7 ring atoms (i.e., a 4 to 7-membered heterocyclic group); and in some embodiments, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group) or a heterocyclic group having 5 ring atoms (i.e., a 5-membered heterocyclic group).

[0092] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, dihydropyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0093] The polycyclic heterocyclic groups include spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. The term "spirocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one monocyclic heterocyclic group with a connecting point on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocyclic groups). The spiroheterocyclic group is, in some embodiments, a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group); in some embodiments, a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group); in some embodiments, a spiroheterocyclic group having 7 to 9 ring atoms (i.e., a 7 to 9-membered spiroheterocyclic group); and in some embodiments, a spiroheterocyclic group having 7 or 8 ring atoms (i.e., a 7 or 8-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and multispirocyclic groups (such as bispirocyclic groups). In some embodiments, it is a monospirocyclic or bispirocyclic group. In other embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic group. Non-limiting examples include: wait.

[0094] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is, in some embodiments, a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group); in some embodiments, a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group); in some embodiments, a fused heterocyclic group having 7 to 9 ring atoms (i.e., a 7 to 9-membered fused heterocyclic group); and in some embodiments, a fused heterocyclic group having 8 or 9 ring atoms (i.e., an 8 or 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments is a bicyclic or tricyclic fused heterocyclic group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include: wait.

[0095] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group is a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it is a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include: wait.

[0096] The term "subheterocyclic group" refers to a divalent functional group derived from a heterocyclic group, where the heterocyclic group is as defined above.

[0097] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) with a conjugated π-electron system, having 6 to 22 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22) ring atoms (i.e., 6 to 22-membered aryl). The aryl group is, in some embodiments, an aryl group having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl) or an aryl group having 10 to 15 ring atoms (i.e., 10 to 15-membered aryl); in some embodiments, an aryl group having 11 to 14 ring atoms (i.e., 11 to 14-membered aryl); in some embodiments, an aryl group having 8 to 14 ring atoms (i.e., 8 to 14-membered aryl); in some embodiments, an aryl group having 11 or 12 ring atoms (i.e., 11 or 12-membered aryl); and in some embodiments, an aryl group having 11 ring atoms (i.e., 11-membered aryl). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthraceneyl, phenanthryl, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system (in some embodiments, a bicyclic or tricyclic aryl group), non-limiting examples including: wait.

[0098] The term "alpharyl" refers to a divalent functional group derived from aryl, where aryl is as defined above.

[0099] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 22 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22) ring atoms (i.e., 5 to 22 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group); in some embodiments, it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group); in some embodiments, it is a heteroaryl group having 9 to 14 ring atoms (i.e., a 9 to 14-membered heteroaryl group); in some embodiments, it is a heteroaryl group having 8 to 14 ring atoms (i.e., an 8 to 14-membered heteroaryl group); in some embodiments, the heteroaryl group is a heteroaryl group having 11 or 12 ring atoms (i.e., an 11 or 12-membered heteroaryl group); in some embodiments, the heteroaryl group is a heteroaryl group having 10 ring atoms (i.e., a 10-membered heteroaryl group); in some embodiments, it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group); and in some embodiments, it is a heteroaryl group having 5 ring atoms (i.e., a 5-membered heteroaryl group).

[0100] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazoleyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0101] The polycyclic heteroaryl group (in some embodiments, a 9- to 14-membered heteroaryl group; in some embodiments, an 8- to 14-membered heteroaryl group) includes, non-limiting examples, indole, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more aryl groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system (in some embodiments, a bicyclic or tricyclic heteroaryl group). Non-limiting examples include: wait.

[0102] The term "hybrid aryl" refers to a divalent functional group derived from a heteroaryl group, where the heteroaryl group is as defined above.

[0103] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0104] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0105] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0106] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0107] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the alkyl and cycloalkyl groups are as defined above.

[0108] The term "heterocyclic alkyl" refers to an alkyl group that is substituted with one or more heterocyclic groups, wherein the alkyl group and the heterocyclic group are as defined above.

[0109] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, where the alkyl and aryl groups are as defined above; for example, -CH2Ph.

[0110] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups are as defined above.

[0111] The term "alkylcycloalkyl" refers to a cycloalkyl group being replaced by one or more alkyl groups, wherein the alkyl and cycloalkyl groups are as defined above.

[0112] The term "alkyl heterocyclic group" refers to a heterocyclic group that is substituted by one or more alkyl groups, wherein the alkyl and heterocyclic groups are as defined above.

[0113] The term "alkylaryl" refers to an aryl group that is replaced by one or more alkyl groups, where the alkyl and aryl groups are as defined above; for example, tolyl.

[0114] The term "alkyl heteroaryl" refers to a heteroaryl group that is substituted by one or more alkyl groups, wherein the alkyl and heteroaryl groups are as defined above.

[0115] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0116] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above; for example, -OCF3.

[0117] The term "heterocyclic alkoxy" refers to an alkoxy group that is substituted by one or more heterocyclic groups, wherein the alkoxy group and the heterocyclic group are as defined above.

[0118] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above; for example, -CH2OH.

[0119] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; for example, -CH2OCH3.

[0120] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above; for example, -CH2NH2.

[0121] The term "aminoalkoxy" refers to an alkoxy group that is substituted with one or more amino groups, wherein the alkoxy group is as defined above; for example, -OCH2NH2.

[0122] The term "cyanoalkyl" refers to an alkyl group that is substituted with one or more cyano groups, wherein the alkyl group is as defined above; for example, -CH2CN.

[0123] The term "methyl-xyl" refers to =CH2.

[0124] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0125] The term "hydroxyl group" refers to -OH.

[0126] The term "thiol" refers to -SH.

[0127] The term "amino" refers to -NH2.

[0128] The term "cyano" refers to -CN.

[0129] The term "nitro" refers to -NO2.

[0130] The term "oxo" or "oxo group" refers to "=O".

[0131] The term "carbonyl" refers to C=O.

[0132] The term "carboxyl group" refers to -C(O)OH.

[0133] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0134] The compounds or conjugates disclosed herein may exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or...) Z and E () isomers, (-)- and (+)- isomers, ( R )-and( S - Enantiomers, diastereomers, (D )-and( L (-)- isomers, tautomers, blocked trans isomers, conformational isomers, and mixtures thereof (e.g., racemic mixtures, mixtures of diastereomers). Substituents in the compounds or couplings disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. R )-and( S - Enantiomers and (D )-and( LThis disclosure discloses an isomer of a compound or conjugate, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, and then resolving the diastereomer by conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0135] In the chemical structure of the compounds or conjugates described in this disclosure, the bond " "or" "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " " or" "can be " "or" , or both contain " "and" "Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, Z Type and E All types are included.

[0136] The compounds or conjugates disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc.

[0137] For example, a compound or coupling should be understood to include any one or a mixture of two tautomers of the following two structures: .

[0138] All tautomer forms are within the scope of this disclosure, and the nomenclature of compounds or conjugates does not exclude any tautomers.

[0139] The compounds or conjugates disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound or conjugate in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds or conjugates of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 I In some implementation schemes, it is deuterium.

[0140] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations in the compounds or conjugates disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0141] In the compounds or conjugates disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to indicate that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the deuterium abundance of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0142] "Optionally" or "optionally" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally (optionally) alkyl group substituted with halogen or cyano" includes cases where the alkyl group is substituted with halogen or cyano and cases where the alkyl group is not substituted with halogen or cyano.

[0143] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0144] "Pharmaceutical composition" means a mixture containing one or more of the compounds or conjugates described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0145] "Pharmacologically acceptable salts" refer to salts of the compounds or conjugates disclosed herein, which may be selected from inorganic or organic salts. These salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound or conjugate, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0146] As used herein, the term "pharmaceutically acceptable" means that these compounds or conjugates, materials, compositions and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0147] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0148] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and in some embodiments within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are typically given for illustrative purposes only and not as limitations.

[0149] Ligands refer to any large molecule (peptide, protein, peptide, typically antibody) commonly used in drug conjugation techniques, or small molecules (such as folic acid or aptamers) that can be covalently conjugated to a linker or drug-linker using bioconjugation techniques (Greg T. Hermanson, Bioconjugate Techniques, 3). rdEdition, 2013, Academic Press). Ligands are traditionally selected compounds based on their targeting ability. A non-exhaustive list of ligands includes: proteins, polypeptides, peptides, antibodies, full-length antibodies and their antigen-binding fragments, interferons, lymphokines, hormones, growth factors, vitamins, transferrin, or any other cell-binding molecules or substances. The main class of ligands used to prepare conjugates is antibodies.

[0150] The term "antibody" is used in the broadest sense and encompasses a wide variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. For example, a natural IgG antibody is a heterotetraglycoprotein of approximately 150,000 Daltons, consisting of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable region, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N to C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light domain (light chain constant region, CL). Light chains are classified as κ or λ. Heavy chains are classified as γ, μ, α, δ, or ε, and antibody isotypes are defined as IgG, IgM, IgA, IgD, and IgE, respectively. In both the light and heavy chains, the variable and constant regions are linked by “J” regions of about 12 or more amino acids, while the heavy chain also includes “D” regions of about 10 or more amino acids. (For general reference, see Basic Immunology, Paul, W., ed., 2nd ed. Raven Press, NY, 1989, Ch. 7, which is incorporated herein by reference in its entirety for various purposes.)

[0151] The term "antibody fragment" refers to a molecule that is distinct from the intact antibody but contains a portion of the intact antibody that retains the antigen-binding ability of the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, single-domain antibodies, single-chain Fab (scFab), biantibodies, linear antibodies, and single-chain antibody molecules (e.g., scFv). Specifically: (i) Fab fragments having VL, CL, VH, and CH1 domains and a disulfide bond between the heavy and light chains; (ii) Fab' fragments having one or more cysteine ​​residues at the C-terminus of the CH1 domain; (iii) Fd fragments having VH and CH1 domains; (iv) Fd' fragments having VH and CH1 domains and one or more cysteine ​​residues at the C-terminus of the CH1 domain; (v) Fv fragments having VL and VH domains of one arm of the antibody; (vi) dAb fragments consisting of a VH domain; (vii) hingeless antibodies. (viii) A fragment containing at least VL, VH, CL, and CH1 domains and lacking a hinge region; (ix) A single-chain antibody molecule (e.g., single-chain Fv; scFv); (x) A “diabodies” having two antigen-binding sites, including a heavy chain variable domain (VH) and a light chain variable domain (VL) linked together in the same polypeptide chain; (xi) A “linear antibody” containing a pair of tandem Fd fragments (VH-CH1-VH-CH1) that together with a complementary light chain polypeptide form a pair of antigen-binding regions; (xii) dsFv refers to a fragment formed by replacing one amino acid residue in each of VH and VL with a cysteine ​​residue and then linking the polypeptides together via an SS bond between the cysteine ​​residues.

[0152] The term "variable region" or "variable domain" refers to the domain in an antigen-binding molecule that binds to the antigen. Both VH and VL contain four conserved frame regions (FRs) and three complementarity-determining regions (CDRs). The term "complementarity-determining region" or "CDR" refers to the region within the variable domain that primarily facilitates antigen binding; "frame" or "FR" refers to the variable domain residues excluding the CDR residues. VH contains three CDR regions: HCDR1, HCDR2, and HCDR3; VL contains three CDR regions: LCDR1, LCDR2, and LCDR3. The sequence from N-terminus to C-terminus for each VH and VL is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. A single VH or VL may be sufficient to confer antigen-binding specificity.

[0153] The amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat" numbering system (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering system, the "ABM" numbering system, the "contact" numbering system (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains[J]. 2001), and the ImMunoGenTics (IMGT) numbering system (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); FrontImmunol. 2018 Oct 16;9:2278), etc.; the correspondence between various numbering systems is well known to those skilled in the art.

[0154] The term "Fc region" or "fragment crystallizable region" is used to define the C-terminal region of an antibody heavy chain, including native and modified Fc regions. In some embodiments, the Fc region comprises two identical or different subunits. In some embodiments, the Fc region of a human IgG heavy chain is defined as an amino acid residue extending from the Cys226 position or from Pro230 to its carboxyl terminus. Suitable native sequence Fc regions for the antibodies described herein include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. Unless otherwise stated, the Fc region is numbered using the EU index. The C-terminus of the Fc region can be a full C-terminus ending with the amino acid residue PGK; or it can be a truncated C-terminus, for example, in which one or two C-terminal amino acid residues have been removed. In a preferred aspect, the C-terminus of the heavy chain is a shortened C-terminus ending with PG. Thus, in some embodiments, the composition of a complete antibody may comprise an antibody population with all K447 residues and / or G446+K447 residues removed. In some embodiments, the composition of intact antibodies may include an antibody population without the removal of K447 residues and / or G446+K447 residues. In some embodiments, the composition of intact antibodies has an antibody population consisting of a mixture of antibodies with and without K447 residues and / or G446+K447 residues.

[0155] The term antibody-drug conjugate (ADC) refers to a monoclonal antibody or antibody fragment linked to a biologically active drug via a linker unit. The drug described in this disclosure can be conjugated to an antibody or antibody fragment in any manner. For example, the antibody or antibody fragment can be attached to the drug chemically or recombinantly. Chemical methods for preparing fusions or conjugates are known in the art. Methods for conjugating antibodies or antibody fragments to drugs must be able to link the antibody to the drug without interfering with the ability of the antibody or antibody fragment to bind to the target molecule.

[0156] The term "sequence identity" refers to the degree (percentage) to which two sequences share the same amino acids / nucleic acids at equivalent positions when optimally aligned. During alignment, gaps may be introduced where necessary to achieve the maximum percentage of sequence identity, but any conserved substitutions are not considered part of the sequence identity. To determine the percentage of sequence identity, alignment can be performed using techniques known in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine the parameters suitable for measuring alignment, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.

[0157] The term "linker unit," "connector fragment," or "connector cell" refers to a chemical structural fragment or bond that is linked at one end to an antibody or its antigen-binding fragment and at the other end to a drug. It may also be linked to other linkers before being attached to a drug. Linkers can be degradable or non-degradable. Degradable linkers are typically readily degraded in intracellular environments, such as at the target site, thereby releasing the drug from the antibody. Suitable degradable linkers include, for example, enzyme-degradable linkers, including peptide-containing linkers that can be degraded by intracellular proteases (e.g., lysosomal proteases or endosomal proteases), or sugar linkers, such as glucuronidase-containing linkers. Peptide linkers can include, for example, dipeptides, such as valine-citrulline, phenylalanine-lysine, or valine-alanine; or tripeptides, such as glycine-phenylalanine-glycine; or tetrapeptides, such as glycine-glycine-phenylalanine-glycine. Other suitable degradable linkers include, for example, pH-sensitive linkers (e.g., linkers that hydrolyze at pH less than 5.5, such as hydrazone linkers) and linkers that degrade under reducing conditions (e.g., disulfide linkers). Non-degradable linkers typically release drugs under conditions where antibodies are hydrolyzed by proteases.

[0158] Prior to attachment to the antibody, the linker has a reactive group capable of reacting with certain amino acid residues, and the attachment is achieved through the reactive group. Thiol-specific reactive groups are preferred and include, for example, maleimide compounds, haloamides (e.g., iodinated, brominated, or chlorinated); haloesters (e.g., iodinated, brominated, or chlorinated); halomethyl ketones (e.g., iodinated, brominated, or chlorinated); benzyl halides (e.g., iodinated, brominated, or chlorinated); vinyl sulfones; pyridyl disulfides; mercury derivatives such as 3,6-di-(mercurymethyl)dioxane, with the counter ion being acetate, chloride, or nitrate; and polymethylene dimethyl sulfide thiosulfonate. The linker may include, for example, a maleimide attached to the antibody via a thiosuccinimide.

[0159] In this disclosure, drug-connector compounds can be used to form an ADC in a simple step. In other embodiments, bifunctional linker compounds can be used to form an ADC in a two- or multi-step process. For example, cysteine ​​residues react with the reactive portion of the linker in a first step, and in a subsequent step, the functional groups on the linker react with the drug to form an ADC.

[0160] Typically, functional groups on the linker are selected to facilitate specific reaction with suitable reactive groups on the drug moiety. As a non-limiting example, azide-based moieties can be used to specifically react with reactive alkynyl groups on the drug moiety. The drug is covalently bound to the linker via a 1,3-dipolar cycloaddition between the azide and alkynyl groups. Other useful functional groups include, for example, ketones and aldehydes (suitable for reaction with hydrazides and alkoxyamines), phosphine (suitable for reaction with azides); isocyanates and isothiocyanates (suitable for reaction with amines and alcohols); and activated esters, such as N-hydroxysuccinimide esters (suitable for reaction with amines and alcohols). These and other linking strategies, such as those described in Bioconjugation Techniques, Second Edition (Elsevier), are well known to those skilled in the art. Those skilled in the art will understand that for selective reaction between the drug moiety and the linker, when a complementary pair of reactive functional groups is selected, each member of that complementary pair can be used for either the linker or the drug.

[0161] Drug loading, also known as drug-to-antibody ratio (DAR), is the average number of drugs conjugated to each antibody in an ADC. It can range from about 1 to about 10 drugs per antibody, and in some embodiments, from about 1 to about 8 drugs per antibody, preferably from the ranges of 2-8, 2-7, 2-6, 2-5, 2-4, 3-4, 3-5, 5-6, 5-7, 5-8, and 6-8. Exemplarily, the drug loading can be an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The general formula of the ADC disclosed herein includes a set of antibody-drug conjugates within the aforementioned range. In embodiments of the present disclosure, the drug loading can be expressed as n, which can be a decimal or an integer. The drug loading can be determined using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays, and HPLC.

[0162] In one embodiment of this disclosure, the drug is coupled to the antibody via a linker unit.

[0163] The loading of ligand-drug conjugates can be controlled using the following non-limiting methods, including: (1) Control the molar ratio of drug linker fragments to monoclonal antibodies, (2) Control the reaction time and temperature. (3) Choose different reaction reagents. Attached Figure Description

[0164] Figure 1 The cytotoxicity curves of STING agonists on human PBMCs are shown. Figures 2A to 2D The killing curves of the antibody-drug conjugates against various tumor cell lines are shown. Figure 2A Showing the kill curve against HCC1954; Figure 2B Showing the kill curve against BxPC3; Figure 2C The kill curve for HCC1806 is shown; Figure 2D Showing the kill curve against Colo205; Figures 3A to 3D This study demonstrates the effect of STING agonists on cytokine levels, among which... Figure 3A This study demonstrates the effect of STING agonists on TNFα levels in immune cells. Figure 3B This study demonstrates the effect of STING agonists on IFN-β levels in immune cells. Figure 3C This study demonstrates the effect of STING agonists on IL-1β levels in immune cells. Figure 3D This study demonstrates the effect of STING agonists on IFNα levels in immune cells. Detailed Implementation

[0165] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0166] Example The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using an AVANCE NEO 300 MHz, AVANCE NEO 400 MHz, AVANCE III 300 MHz, or AVANCE III HD 400 MHz NMR spectrometer. The solvent used was deuterated dimethyl sulfoxide (DMSO). d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0167] MS was determined using a Shimadzu LCMS-2020 MS liquid chromatography-mass spectrometry system (manufacturer: Shimadzu, MS model: LCMS-2020). Chiral HPLC analysis was performed using a Shimadzu SPD-M20A high-performance liquid chromatograph.

[0168] High-performance liquid chromatography (HPLC) was performed using a Waters 2767 / SQD2 preparative chromatograph.

[0169] Chiral preparation was performed using a Gilson GX-281 preparative chromatograph.

[0170] The CombiFlash rapid preparation instrument uses the Isolera Prime low-pressure preparative chromatograph.

[0171] The silica gel plates used for thin-layer chromatography are from Yantai Xinnuo New Material Technology Co., Ltd. The silica gel plates used for thin-layer chromatography (TLC) are 0.2 mm to 0.25 mm in size, while the size used for thin-layer chromatography separation and purification of products is 1 mm.

[0172] Silica gel column chromatography generally uses 100-200 mesh silica gel from Rushan Shangbang New Materials Co., Ltd. as the carrier.

[0173] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Bid Pharmaceutical Technology Co., Ltd., Shaoyuan Technology (Shanghai) Co., Ltd., Gu'an County Jingqiu Chemical Co., Ltd., and Suzhou Haofan Biotechnology Co., Ltd.

[0174] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1L.

[0175] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0176] The microwave reaction was performed using a Biotage Initiator Robot 60 microwave reactor.

[0177] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0178] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 ℃ to 30 ℃.

[0179] In this example, the reaction process was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as ammonia and acetic acid could also be added for adjustment.

[0180] Commonly used chemical reagent abbreviations and full names: DMF: N, N dimethylformamide DMSO: Dimethyl sulfoxide Ph3P: Triphenylphosphine EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-Hydroxybenzotriazole NMP: N -Methylpyrrolidone DIAD: Diisopropyl azodicarbonate DIEA: N, N- Diisopropylethylamine HATU: N, N, N′, N ′-Tetramethyl- O -(7-azabenzotriazol-1-yl)hexafluorophosphate TCFH: N, N, N', N' -Tetramethylchloromethylammonium hexafluorophosphate NMI: N -Methylimidazole DMP: Dys-Martin Oxidant DMAc: N , N -Dimethylacetamide AcONH4: Ammonium acetate AcONa: Sodium acetate NaOH: Sodium hydroxide HNO3: nitric acid HCl: hydrochloric acid PMB2NH: Bis[(4-methoxyphenyl)methyl]amine Py-BOP: Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate DBU: 1,8-diazacyclic[5,4,0]undecene-7 BBr3: Boron tribromide TFA: Trifluoroacetic acid TfOH: Trifluoromethanesulfonic acid B2(OH)2: Tetrahydroxydiboron Pd(PPh3)2Cl2: Palladium dichloride of bis(triphenylphosphine) Pd(dppf)Cl2: 1,1-bis(diphenylphosphine)diferropalladium dichloride Na2S2O4: Sodium dithionite K3PO4: Potassium phosphate TEA: Triethylamine 4,4-bipyridine: 4,4'-bipyridine.

[0181] DCI: N,N'-Diisopropylcarbodiimide.

[0182] Preparation of compounds Example 1. Synthesis of Compound 5 (±) E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-7-methoxy-2,3-dihydro-1 H -benzimidazole-5-formamide 5 The synthesis route is as follows: Step 1: Preparation of (±) 1-chloro-4-(methanesulfonylimino)-2-nitrobenzene 5a 1-Chloro-4-(methylthio)-2-nitrobenzene (1 g, 4.9 mmol, 1 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., Product No.: SY302584) was dissolved in methanol (20 mL) at room temperature and under nitrogen atmosphere. Then, diacetoxyiodobenzene (3.3 g, 10.3 mmol, 2.1 equivalent, Shanghai Bid Pharmaceutical Technology Co., Ltd., Product No.: BD0081) and ammonium carbonate (708 mg, 7.3 mmol, 1.5 equivalent, Shanghai Haohong Biomedical Technology Co., Ltd., Product No.: 1715132) were added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with a dichloromethane / methanol system (12:1) to give the title compound 5a (1 g, yield: 87%) as a yellow solid.

[0183] MS m / z (ESI): 234.95 [M + 1] + .

[0184] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 2.0 Hz, 1H), 8.19 (dd, J =8.4, 2.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 4.66 (s, 1H), 3.18 (d, J = 1.2Hz, 3H).

[0185] Step 2: (±) E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-1-(( E )-4-(4-(methanesulfonylimino)-2-nitrophenylamino)but-2-enyl)-2,3-dihydro-1 H Preparation of -benzimidazole-5-carboxamide 5c Compound 5a (900 mg, 3.8 mmol, 1 equivalent) and ( ) were subjected to nitrogen atmosphere at room temperature and under nitrogen atmosphere. E )-1-(( E )-4-aminobut-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydro-1 H-benzimidazole-5-carboxamide 5b (1.74 g, 4.2 mmol, 1.1 equivalents, prepared by the method disclosed in Example 8 on page 82 of patent application "WO2020010451A1") was dissolved in n-butanol (20 mL), and DIEA (2.0 g, 15.3 mmol, 4 equivalents) was added. The reaction system was heated to 120 °C and stirred under these conditions for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (12:1) to give the title compound 5c (1.9 g, yield: 81%) as a yellow solid.

[0186] MS m / z (ESI): 610.25 [M + 1] + .

[0187] 1 H NMR (300 MHz, DMSO- d 6) δ 12.85 (s, 1H), 8.68 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 7.99 (s, 1H), 7.78 (dd, J = 9.3, 2.1 Hz, 1H), 7.66- 7.65 (m, 1H), 7.36 - 7.35 (m, 2H), 7.05 (d, J = 9.3 Hz, 1H), 6.58 (s, 1H),5.95 - 5.86 (m, 1H), 5.68 - 5.59 (m, 1H), 4.95 - 4.94 (m, 2H), 4.60 - 4.53(m, 2H), 4.15 (s, 1H), 4.09 - 4.06 (m, 2H), 3.87 (s, 3H), 3.01 (s, 3H), 2.16(s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0188] Step 3: (±) E )-1-(( E )-4-(2-amino-4-(methanesulfonylimino)phenylamino)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydro-1 H Preparation of Benzimazole-5-carboxamide 5d Compound 5c (400 mg, 0.7 mmol, 1 equivalent) and ammonia (3 mL, 28% aqueous solution) were dissolved in methanol (4 mL) and tetrahydrofuran (4 mL) under ice bath and nitrogen atmosphere, followed by the addition of an aqueous solution of sodium dithionite (1.4 g dissolved in 8 mL of water, 7.8 mmol, 12 equivalent). The reaction system was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and water (200 mL) was added to dilute the mixture, resulting in the precipitation of a white solid. The solid was filtered. The filter cake was washed with water (3 × 10 mL) and dried to give the title compound 5d (racemic mixture, 300 mg, yield: 79%, purity: 91%) as a white solid.

[0189] MS m / z (ESI): 580.25 [M + 1] + .

[0190] 1 H NMR (400 MHz, DMSO- d 6) δ 12.85 (s, 1H), 8.01 (s, 1H), 7.65 (s, 1H),7.37 - 7.35 (m, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.97 - 6.95 (m, 1H), 6.61 (s,1H), 6.40 (d, J = 8.4 Hz, 1H), 5.86 - 5.80 (m, 1H), 5.69 - 5.64 (m, 1H), 5.45- 5.43(m, 1H), 4.95 - 4.87 (m, 4H), 4.60 - 4.53 (m, 2H), 3.89 (s, 3H), 3.79 -3.76 (m, 2H), 2.89 (s, 3H), 2.17 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0191] Step 4: (±) E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-methanesulfonylimino-2,3-dihydrobenzo[ d[Imidazol-1-yl)but-2-enyl)-7-methoxy-2,3-dihydro-1 H Preparation of -benzimidazole-5-formamide 5 Compound 5d (70 mg, 121 μmol, 1 equivalent), 2-ethyl-5-methylpyrazole-3-carboxymethyl isothiocyanate 1b (26 mg, 133 μmol, 1.1 equivalent), and (3-[[(ethylimino)methylene]amino]propyl)dimethylamine hydrochloride (58 mg, 0.3 mmol, 2.5 equivalent) were dissolved in nitrogen at room temperature. N, N Triethylamine (37 mg, 0.4 mmol, 3 equivalents) was added to dimethylformamide (2.5 mL). The reaction mixture was heated to 30 °C and stirred for 3 hours. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C 18 Silica gel; mobile phase: acetonitrile and water; gradient: acetonitrile in water 5% to 80%, 30 min; detector: UV 254 nm, yielding title compound 5 (crude). The crude product was purified by high performance liquid chromatography (HPLC) under the following conditions: column: Xselect CSH F-Phenyl OBD column 30 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 50% acetonitrile over 12 min; wavelength: 254 / 220 nm; retention time: 9.88 min, yielding title compound 5 (16.1 mg, yield: 18%, purity: 98%) as a grayish-white solid.

[0192] MS m / z (ESI): 741.35 [M + 1] + .

[0193] 1 H NMR (400 MHz, DMSO- d 6) δ 12.99 (s, 1H), 12.84 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.74 (dd, J = 8.4, 2.0 Hz, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.36 - 7.32 (m, 2H), 6.61 (s, 1H), 6.54 (s, 1H), 6.01 - 5.95 (m,1H), 5.76 - 5.70 (m, 1H), 4.93 - 4.85 (m, 4H), 4.56 - 4.51 (m, 4H), 3.77 (s, 3H), 3.24 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 1.31 - 1.26 (m, 6H).

[0194] Example 2. Synthesis of Compound 6 (±) E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d Imidazol-1-yl)but-2-enyl)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzimidazole-5-carboxamide formate 6 The synthesis route is as follows: Step 1: (±) E Preparation of tert-butyl 4-(4-(methanesulfonylimino)-2-nitrophenylamino)butyl-2-enylcarbamate 6a Compound 5a (2 g, 8.5 mmol, 1 equivalent) and ( ) were subjected to nitrogen atmosphere at room temperature and under nitrogen atmosphere. E 4-Aminobut-2-enylcarbamate tert-butyl ester (2.4 g, 12.8 mmol, 1.5 equivalents) was dissolved in n-butanol (20 mL), and then DIEA (4.4 g, 34.1 mmol, 4 equivalents) was added. The reaction system was heated to 120 °C and stirred under this condition for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 6a (3 g, yield: 92%, purity: 96%) as a yellow solid.

[0195] MS m / z (ESI): 385.10 [M + 1]+ .

[0196] 1 H NMR (400 MHz, DMSO- d 6) δ 8.70 (t, J = 6.0 Hz, 1H), 8.55 (d, J = 2.4Hz, 1H), 7.91 - 7.88 (m, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.97 (t, J = 6.0 Hz,1H), 5.63 - 5.56 (m, 2H), 4.20 (s, 1H), 4.09 - 4.06 (m, 2H), 3.55 - 3.52 (m,2H), 3.05 (s, 3H), 1.36 (s, 9H).

[0197] Step 2: (±) E )- N 1 Preparation of 6b-(4-(methanesulfonylimino)-2-nitrophenyl)but-2-ene-1,4-diamine hydrochloride Compound 6a (1.2 g, 3.1 mmol, 1 equivalent) was dissolved in ethyl acetate (10 mL) under nitrogen atmosphere at room temperature, and 10 mL of 4.0 M hydrogen chloride in ethyl acetate was added dropwise. The mixture was stirred for 2 hours at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 6b (1.1 g, crude product) as a yellow solid. The product did not require further purification and was used directly in the next step.

[0198] MS m / z (ESI): 285.10 [M + 1] + .

[0199] 1 H NMR (400 MHz, DMSO- d 6) δ 9.01 (t, J = 6.0 Hz, 1H), 8.67 (d, J = 2.4Hz, 1H), 8.30 - 8.15 (m, 2H), 8.02 (dd, J = 9.2, 2.4 Hz, 1H), 7.26 (d, J=9.2 Hz, 1H), 5.95 - 5.89 (m, 1H), 5.78 - 5.71 (m, 1H), 4.21 - 4.18 (m, 2H), 3.75 (s, 3H), 3.45 - 3.42 (m, 2H).

[0200] Step 3: (±) E Preparation of 6c of 4-(3-(5-carbamoyl-2-(4-(4-(methanesulfonylimino)-2-nitrophenylamino)but-2-enylamino)-3-nitrophenoxy)propyl)piperazine-1-carboxylic acid tert-butyl ester In a nitrogen atmosphere at room temperature, crude compound 6b (1.1 g, 3.8 mmol, 1 equivalent) and DIEA (3 g, 23.2 mmol, 6 equivalent) were dissolved in n-butanol (20 mL), followed by the addition of compound 2a (1.7 g, 3.8 mmol, 1 equivalent). The reaction mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 6c (1 g, yield: 37%, purity: 95%) as a yellow solid.

[0201] MS m / z (ESI): 691.30 [M + 1] + .

[0202] Step 4: (±) E Preparation of tert-butyl piperazine-1-carboxylic acid 6d Compound 6c (600 mg, 0.9 mmol, 1 equivalent) and ammonia (28% aqueous solution, 3 mL) were dissolved in methanol (10 mL) at 0°C under nitrogen atmosphere. Then, an aqueous solution of sodium dithionite (1.1 g dissolved in 5 mL of water, 6.1 mmol, 7 equivalent) was added at 0°C. After the addition was complete, the reaction mixture was removed from the ice bath and allowed to warm to room temperature naturally, under which conditions was stirred for 2 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was purified by reversed-phase rapid chromatography under the following conditions: column: C 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water 10% to 90%; detector, UV 254 nm. The title compound 6d (racemic mixture, 300 mg, yield: 55%) was obtained as a grayish-white solid.

[0203] MS m / z (ESI): 631.30 [M + 1] + .

[0204] Step 5: (±)4-(3-( E )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-3-((( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H Preparation of 6e-benzimidazole-4-yloxy)propyl)piperazine-1-carboxylic acid tert-butyl ester Compound 6d (300 mg, 0.5 mmol, 1 equivalent), compound 1b (204 mg, 1.1 mmol, 2.1 equivalent), and EDCI (369 mg, 2.4 mmol, 5 equivalent) were dissolved in DMF (10 mL) at room temperature and under nitrogen atmosphere. Triethylamine (289 mg, 2.8 mmol, 6 equivalent) was then added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by reversed-phase rapid chromatography under the following conditions: column: C10 ... 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in aqueous phase 5% to 90%; detector, UV 254 nm, yielded title compound 6e (racemic, 100 mg, yield: 22%, purity: 76%) as a grayish-white solid.

[0205] MS m / z (ESI): 953.50 [M + 1] + .

[0206] Step 6: (±) E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d Imidazol-1-yl)but-2-enyl)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H Preparation of 6-benzimidazole-5-carboxamide formate Compound 6e (100 mg, 0.1 mmol, 1 equivalent) was dissolved in ethyl acetate (5 mL) under nitrogen atmosphere at room temperature, followed by the addition of 4.0 M hydrogen chloride in ethyl acetate solution (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC): column: Xselect CSH Prep column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: methanol; flow rate: 25 mL / min; gradient: methanol in aqueous phase 35% to 65%; wavelength: 254 / 220 nm; retention time: 7.25 min. The title compound 6 (racemic mixture, 28.1 mg, yield: 31%, purity: 99%) was obtained as a white solid.

[0207] MS m / z (ESI): 853.35 [M + 1] + .

[0208] 1 H NMR (400 MHz, DMSO- d 6) δ 8.02 (s, 1H), 7.97 (s, 1H), 7.67 - 7.64(m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 6.57 (s, 2H), 6.03 - 5.98 (m, 1H), 5.75 - 5.71 (m, 1H), 4.95 - 4.94 (m, 2H), 4.85 - 4.83(m, 2H), 4.58 - 4.51 (m, 4H), 3.99 - 3.96 (m, 2H), 3.03 (s, 3H), 2.79 - 2.76(m, 4H), 2.31 - 2.27 (m, 6H), 2.14 (s, 3H), 2.13 (s, 3H), 1.74 - 1.67 (m, 2H), 1.32–1.27 (m, 6H).

[0209] Synthesis of compounds 6-1 and 6-2 ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(R (-methanesulfonylimide)-2,3-dihydrobenzo[ d Imidazol-1-yl)but-2-enyl)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzimidazole-5-carboxamide 6-1 and ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-( S (-methanesulfonylimide)-2,3-dihydrobenzo[ d Imidazol-1-yl)but-2-enyl)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzimidazole-5-formamide 6-2 Compound 6 was chirally resolved and its structure identified to yield the title compound.

[0210] Example 3. Synthesis of Compound 7 (±) E )-7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H -benzimidazole-5-carboxamide formate 7 The synthesis route is as follows: Step 1: Preparation of tert-butyl 2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethylcarbamate 7a 4-Chloro-3-hydroxy-5-nitrobenzamide (2 g, 9.2 mmol, 1 equivalent) was dissolved in tetrahydrofuran (150 mL) at room temperature and under nitrogen atmosphere. At 0 °C, tert-butyl 2-hydroxyethylcarbamate (1.8 g, 11.0 mmol, 1.2 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd.) and triphenylphosphine (4.1 g, 15.6 mmol, 1.7 equivalent) were added. Then, DIAD (3.2 g, 15.6 mmol, 1.7 equivalent) was slowly added dropwise to the system. After the addition was complete, the reaction system was removed from the ice bath, and the reaction solution was allowed to naturally warm to room temperature and reacted under these conditions for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (15:1) to obtain the crude product. The crude product was slurried with dichloromethane / diethyl ether (1:4) and filtered. The filter cake was washed with dichloromethane / diethyl ether (1:4, 3 × 30 mL). The filter cake was then dried under vacuum to give the title compound 7a (1.9 g, yield: 57%, purity: 95%) as a white solid.

[0211] MS m / z (ESI): 382.05 [M + 23] + .

[0212] 1 H NMR (400 MHz, DMSO- d 6) δ 8.28 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.04 (t, J = 5.6 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 3.40 - 3.35 (m, 2H), 1.37 (s, 9H).

[0213] Step 2: (±) E Preparation of tert-butyl 2-(5-carbamoyl-2-(4-(4-(methanesulfonylimino)-2-nitrophenylamino)but-2-enylamino)-3-nitrophenoxy)ethylcarbamate 7b Compound 6b (700 mg, 2.5 mmol, 1 equivalent) was dissolved in n-butanol (10 mL) at room temperature and under a nitrogen atmosphere, followed by the sequential addition of DIEA (1.6 g, 12.3 mmol, 5 equivalent) and compound 7a (886 mg, 2.5 mmol, 1 equivalent). The reaction mixture was heated to 120 °C and stirred for 16 hours under these conditions. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: C 18 Silica gel; mobile phase, acetonitrile and water, gradient: acetonitrile in water 5% to 95%; detector: UV 254 nm, to obtain crude product. The crude product was further purified by silica gel column chromatography, eluting with dichloromethane / methanol (12:1) to give title compound 7b (600 mg, yield 40%, purity: 97%) as an orange solid.

[0214] MS m / z (ESI): 608.20 [M + 1] + .

[0215] 1 H NMR (400 MHz, DMSO- d 6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 2.0Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.98 - 7.92 (m, 1H), 7.59(t, J = 6.0 Hz, 1H), 7.49 - 7.48 (m, 1H), 7.33 (s, 1H), 7.13 (t, J = 6.0 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 5.71 - 5.59 (m, 2H), 4.15 (s, 1H), 4.11 - 3.98(m, 6H), 3.34 - 3.33 (m, 2H), 3.04 (s, 3H), 1.36 (s, 9H).

[0216] Step 3: (±) E Preparation of tert-butyl 2-(3-amino-2-(4-(2-amino-4-(methanesulfonylimino)phenylamino)but-2-enylamino)-5-carbamoylphenoxy)ethylcarbamate 7c Compound 7b (600 mg, 1.0 mmol, 1 equivalent) and ammonia were dissolved in methanol (6 mL) and tetrahydrofuran (6 mL) under nitrogen atmosphere at 0 °C. Then, an aqueous solution of sodium dithionite (2.4 g dissolved in 10 mL of water, 13.8 mmol, 14 equivalents) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column: C 18 Silica gel; mobile phase, acetonitrile and water, gradient: acetonitrile in water 2% to 98%; detector, UV 254 nm. Title compound 7c (240 mg, yield: 44%) was obtained as a yellow solid.

[0217] MS m / z (ESI): 548.30 [M + 1] + .

[0218] 1 H NMR (400 MHz, DMSO- d 6) δ 7.60 (s, 1H), 7.13 (t, J = 6.0 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 7.02 - 7.00 (m, 1H), 6.96 (s, 1H), 6.86 - 6.85 (m,1H), 6.73- 6.72 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.79 - 5.65 (m, 2H), 5.37(t, J = 5.6 Hz, 1H), 4.90 (s, 2H), 4.63 (s, 2H), 4.15 (t, J = 7.2 Hz, 1H), 3.86 (t, J = 5.6 Hz, 2H), 3.73 - 3.72 (m, 2H), 3.57 - 3.54 (m, 3H), 3.33 -3.28 (m, 2H), 2.89 (s, 3H), 1.38 (s, 9H).

[0219] Step 4: (±)2-(( E )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-3-(( E )-4-(( E)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzimidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H Preparation of 7d benzimidazole-4-yloxy)ethyl carbamate Compound 7c (230 mg, 0.4 mmol, 1 equivalent), compound 1b (180 mg, 0.9 mmol, 2.2 equivalent), and ({[3-(dimethylamino)propyl]imino}methylene)(ethyl)amine (326 mg, 2.1 mmol, 5 equivalent)) were dissolved in DMF (5 mL) at room temperature and under nitrogen atmosphere. Triethylamine (255 mg, 2.5 mmol, 6 equivalent) was then slowly added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column: C 18 Silica gel; mobile phase, mobile phase, acetonitrile and water (0.5% formic acid), gradient: acetonitrile in water 2% to 98%, UV 254 nm to give target compound 7d (racemic, 150 mg, yield: 41%, purity: 87%) as a grayish-white solid.

[0220] MS m / z (ESI): 870.35 [M + 1] + .

[0221] Step 5: (±) E )-7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-(methanesulfonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H Preparation of 7-benzimidazole-5-carboxamide formate Compound 7d (70 mg, 80 μmol, 1 equivalent) was dissolved in ethyl acetate (3 mL) at room temperature, followed by the dropwise addition of 3 mL of 4.0 M hydrogen chloride in ethyl acetate. After the addition was complete, the reaction system was allowed to continue reacting at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) under the following conditions: column: Xselect CSH Prep column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: acetonitrile in water from 5% to 35% over 12 minutes; wavelength: 254 / 220 nm; retention time: 7.24 minutes. The title compound 7 (racemic mixture, 41 mg, yield: 66%, purity: 98%) was obtained as a white solid.

[0222] MS m / z (ESI): 770.35 [M + 1] + .

[0223] 1 H NMR (400 MHz, DMSO- d 6) δ 13.28 - 12.45 (m, 2H), 8.07 - 8.02 (m,5H), 7.78 - 7.77 (m, 1H), 7.70 - 7.69 (m, 1H), 7.63 - 7.61 (m, 1H), 7.41 (s,1H), 7.34 (s, 1H), 6.61 (s, 1H), 6.55 (s, 1H), 6.04 - 5.97 (m, 1H), 5.73-5.66 (m, 1H), 5.02 (d, J = 5.6 Hz, 2H), 4.86 (d, J = 5.6 Hz, 2H), 4.57 - 4.50(m, 4H), 4.24 - 4.22 (m, 2H), 3.50 - 3.48 (m, 3H), 3.15 - 3.10 (m, 2H), 2.13(s, 3H), 2.12 (s, 3H), 1.31 - 1.26 (m, 6H).

[0224] Synthesis of compounds 7-1 and 7-2 ( E )-7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-( R (-methanesulfonylimide)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H -benzimidazole-5-formamide 7-1 and ( E )-7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-5-( S (-methanesulfonylimide)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2,3-dihydro-1 H -benzimidazole-5-formamide 7-2 Compound 7 was chirally resolved and its structure identified to yield the title compound.

[0225] Example 4. Synthesis of Compounds 8 and 9 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide 8 ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H-Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide 9 The synthesis route is as follows: Step 1: 8,9-Dihydropyrido[4',3':4,5]imidazo[1,2- a Pyrimidine-7 (6 H Preparation of tert-butyl carboxylate 8a 3-Bromo-4-oxopiperidin-1-carboxylic acid tert-butyl ester (5 g, 17.9 mmol, 1 equivalent, Aqicon Pharmaceutical Technology (Shanghai) Co., Ltd.) was dissolved in ethanol (18 mL) at room temperature and under argon atmosphere. 2-Aminopyrimidine (3.6 g, 37.7 mmol, 2.1 equivalent, Shanghai Bid Pharmaceutical Technology Co., Ltd., product number: BD17164) was added in three portions. The reaction system was heated to 80 °C and reacted under these conditions for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 8a (1 g, yield: 13%) as a yellow solid.

[0226] MS m / z (ESI): 275.10 [M + 1] + .

[0227] Step 2: 2-Amino-6,7-dihydro-1 H- Imidazo[4,5-] c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 8b Compound 8a (1 g, 3.6 mmol, 1 equivalent) was dissolved in ethanol (10 mL) at room temperature. Hydrazine hydrate (2.0 g, 40.1 mmol, 11 equivalents) was added to the reaction solution. The reaction mixture was transferred to a microwave reactor, and the reaction temperature was set to 125 °C for 30 minutes. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the reaction solution was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40-60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 100 mL / min; gradient: acetonitrile in water from 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 19 min. The title compound 8b (372 mg, yield: 43%) was obtained as a yellow solid.

[0228] MS m / z (ESI): 239.15 [M + 1] + .

[0229] Step 3: ( Z )-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H- Imidazo[4,5-] c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 8c Compound 8b (347 mg, 1.5 mmol, 1 equivalent) and 2-ethyl-5-methylpyrazole-3-carboxylic acid (336.7 mg, 2.2 mmol, 1.5 equivalent) were dissolved in DMF (6 mL) at room temperature and under argon atmosphere. Then, HATU (831 mg, 2.2 mmol, 1.5 equivalent) and DIEA (565 mg, 4.4 mmol, 3 equivalent) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with saturated brine (2 × 300 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the crude product. The crude product was then purified by thin-layer chromatography (dichloromethane / methanol 10:1) to obtain the title compound 8c (400 mg, yield: 73%) as a yellow oil.

[0230] MS m / z (ESI): 375.25 [M + 1] + .

[0231] Step 4: ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-hydroxybut-2-enyl)-2,3-dihydro-1 H Preparation of Benzimazole-5-carboxamide 8d Compound 1a (8 g, 20.9 mmol, 1 equivalent) and potassium bromide (5 g, 41.9 mmol, 2 equivalents) were dissolved in water (40 mL) at room temperature. Sodium nitrite (2.9 g, 41.9 mmol, 2 equivalents) was then added to the reaction mixture in portions. After the addition was complete, the reaction mixture was heated to 70°C and stirred for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (6:1) to give the title compound 8d (3.5 g, yield: 44%) as a yellow solid.

[0232] MS m / z (ESI): 383.25 [M + 1] + .

[0233] Step 5: ( E )-1-(( E )-4-bromobut-2-enyl)-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydro-1 H Preparation of -benzimidazole-5-carboxamide 8e Compound 8d (3.5 g, 5.5 mmol, 1 equivalent, purity: 60%) was dissolved in tetrahydrofuran (40 mL) under ice bath and argon atmosphere. Phosphorus tribromide (3 g, 11.0 mmol, 2.0 equivalent) was then added. The reaction mixture was removed from the ice bath, and the reaction temperature was allowed to rise naturally to room temperature, where it was continued for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methane (10:1) to give the title compound 8e (3 g, yield: 98%) as a white solid.

[0234] MS m / z (ESI): 445.35 [M + 1] + .

[0235] Step 6: ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1H-imidazo[4,5- c ]Pyridine-5 (4 H )-Carboxylic acid esters 8f and ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of a mixture of 9a-carboxylic acid esters Compound 8e (353 mg, 0.8 mmol, 1.5 equivalents) and ( ) were subjected to argon atmosphere at room temperature. Z )-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H- Imidazo[4,5-] c ]Pyridine-5 (4 H 8c of tert-butyl carboxylate (37 mg, 0.12 mmol, 0.9 equivalents) was dissolved in DMF. Cesium carbonate (379 mg, 1.2 mmol, 2.2 equivalents) was then added. The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (column: AQ-C). 18 Column: 90 g, 60 Å, 40–60 μm; Mobile phase A: water, Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: acetonitrile in water 0% to 100% over 30 min; Detector: UV 254 / 210 nm; Retention time: 18 min, yielding a mixture (60 mg) of title compounds 8f and 9a as a grayish-white solid.

[0236] MS m / z (ESI): 739.45 [M + 1] + .

[0237] Step 7: ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydroimidazole[4,5- c]pyridin-1-yl)but-2-enyl)-2,3-dihydro-1 H -benzimidazole-5-carboxamide hydrochloride 8g and ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1-(( E )-4-(( Z )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-1,2,4,5,6,7-hexahydroimidazole[4,5- c ]pyridin-3-yl)but-2-enyl)-2,3-dihydro-1 H Preparation of 9b benzimidazole-5-carboxamide hydrochloride At room temperature, 1,4-dioxane (4 M, 0.6 mL) of hydrogen chloride (gas) was added dropwise to a mixture (60 mg) of compounds 8f and 9a. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was azeotropically distilled with toluene under reduced pressure three times to give a mixture (75 mg) of title compounds 8g and 9b as a yellow solid.

[0238] MS m / z (ESI): 639.45 [M + 1] + .

[0239] Step 8: ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 8-formamide ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H(-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 9-formamide A mixture of compound 8 g and compound 9b (75 mg) was dissolved in isopropanol (2 mL) at room temperature and under an argon atmosphere. Then, DIEA (10 mg, 75 μmol, 3 equivalents) and trimethylsilane isocyanate (5 mg, 45 μmol, 1.8 equivalents) were added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue (40 mg) was purified by high-performance liquid chromatography (HPLC) (column: Xbridge Prep Phenyl OBD column 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: acetonitrile in water 15% to 45B over 10 minutes; wavelength: 254 nm / 220 nm; retention time: 9.25 minutes), yielding a mixture of 8 and 9 (1:3, 22 mg).

[0240] The mixture (22 mg) was separated by preparative chiral high-performance liquid chromatography under the following conditions: column: CHIRALPAKIF 2 × 25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.5% trifluoroacetic acid), mobile phase B: methanol: dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 50%; wavelength: 220 / 254 nm; sample solvent: ethanol; injection volume: 1.0 mL; number of runs: 4), at retention times (1): 7.043 min; retention times (2): 14.281 min, respectively, yielding title compound 8 (4 mg, yield: 24%, gray solid) and title compound 9 (15 mg, yield: 29%, gray solid).

[0241] Compound 8: MS m / z (ESI): 682.30 [M + 1] + .

[0242] 1 H NMR (300 MHz, MeOH- d 4) δ 7.94 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.39 (d, J= 8.4 Hz, 1H), 6.65 (s, 1H), 6.55 (s, 1H), 5.90 - 5.86 (m, 2H), 4.98 - 4.88 (m 2H), 4.71 - 4.62 (m, 4H), 4.46 - 4.39 (m, 4H), 3.67 - 3.63 (m,2H), 2.67 - 2.62 (m, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.31 (t, J = 6.9 Hz, 3H).

[0243] Compound 9: MS m / z (ESI): 682.30 [M + 1] + .

[0244] 1 H NMR (300 MHz, MeOH- d 4) δ 7.94 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.07 - 6.01 (m, 1H), 5.79 - 5.74 (m, 1H), 4.94 - 4.92 (m, 2H), 4.76 (d, J = 5.7 Hz, 2H), 4.69 -4.62 (m, 2H), 4.47 - 4.38 (m, 4H), 3.56 - 3.52 (m, 2H), 2.68 - 2.64 (m, 2H),2.23 (s, 3H), 2.19 (s, 3H), 1.40(t, J = 6.9 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0245] Example 5. Synthesis of Compound 10 and Compound 11 ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H(-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide 10 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide 11 The synthesis route is as follows: Step 1: ( Z )-2-(3-methyl-1-propyl-1 H- Pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H- Imidazo[4,5-] c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 10a In a room temperature and argon atmosphere, 2-amino-6,7-dihydro-1 ... H- Imidazo[4,5-] c ]Pyridine-5 (4 H8b tert-butyl carboxylate (902 mg, 3.8 mmol, 1 equivalent) and 5-methyl-2-propylpyrazole-3-carboxylic acid (955.01 mg, 5.7 mmol, 1.5 equivalent, Changsha Luxing Biotechnology Co., Ltd.) were dissolved in DMF (15 mL). Then, HATU (2.2 g, 5.7 mmol, 1.5 equivalent) and DIEA (1.5 g, 11.4 mmol, 3 equivalent) were added sequentially. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residual product was purified by reversed-phase rapid chromatography: column: AQ-C 18 The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 100 mL / min; gradient: acetonitrile in water 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time = 26 min) to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / methanol (15:1) to give title compound 10a (880 mg, yield: 60%) as a yellow solid.

[0246] MS m / z (ESI): 389.20 [M + 1] + .

[0247] Step 2: ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H- Pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Carboxylic acid ester 10c and ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c]Pyridine-5 (4 H A mixture of 11a-carboxylic acid esters Compound 10b (980 mg, 2.1 mmol, 1.5 equivalents, prepared by the method disclosed in Example 4 on page 68 of patent application “US2019359608A1”) and compound 10a (534 mg, 1.4 mmol, 1.00 equivalents) were dissolved in DMF (11 mL) under an argon atmosphere. Cesium carbonate (985 mg, 3.0 mmol, 2.2 equivalents) was then added. The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was then purified directly by reversed-phase rapid chromatography under the following conditions: column: AQ-C 18 The chromatographic column was 120 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 65 mL / min; gradient: acetonitrile in water 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 22 min. 600 mg of crude product was obtained. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1), to give a mixture of title compounds 10c and 11a (157 mg, yield: 15%, purity: 92%) as a pale yellow solid.

[0248] MS m / z (ESI): 783.25 [M + 1]+.

[0249] Step 3 ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-1-(( E )-4-(( Z )-2-(3-methyl-1-propyl-1 H -pyrazole-5-carbonylimino)-1,2,4,5,6,7-hexahydroimidazole[4,5- c ]pyridin-3-yl)but-2-enyl)-2,3-dihydro-1 H -benzimidazole-5-carboxamide hydrochloride 10d and ( E )-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-1-(( E )-4-(( E )-2-(3-methyl-1-propyl-1 H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydroimidazole[4,5- c]pyridin-1-yl)but-2-enyl)-2,3-dihydro-1 H Preparation of 11b benzimidazole-5-carboxamide At room temperature, a mixture of compounds 10c and 11a (136 mg) was dissolved in 1,4-dioxane (3 mL). A solution of 1,4-dioxane with hydrogen chloride (4.0 M, 1 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was azeotropically distilled three times under reduced pressure with toluene to give a mixture of title compounds 10d and 11b (73 mg) as a pale yellow solid. The crude product mixture was used directly in the next step without further purification.

[0250] MS m / z (ESI): 683.35 [M + 1] + .

[0251] Step 4: ( Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 10-formamide ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1 H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 11-formamide A mixture of compounds 10d and 11b was dissolved in isopropanol (2 mL) at room temperature and under an argon atmosphere. Then, 3-benzodiazepine-5-carboxamide (16 mg, 23 μmol, 0.32 equivalents) and DIEA (29 mg, 219 μmol, 3 equivalents) were added. The mixture was stirred for 2 hours at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to give a mixture of 10 and 11 (10:11 = 1:2, 70 mg).

[0252] The crude product was prepared and separated by chiral high-performance liquid chromatography under the following conditions: column: CHIRALPAK IA 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol: dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 40%; wavelength: 220 / 254 nm; sample solvent: ethanol; injection volume: 0.7 mL; number of runs: 8). Title compound 10 (19 mg, yield: 36%, grayish-white solid) and title compound 11 (24 mg, yield: 45%, grayish-white solid) were obtained at retention times of 10.914 min and 20.366 min, respectively.

[0253] Compound 10: MS m / z (ESI): 726.20 [M + 1] + .

[0254] 1 H NMR (300 MHz, MeOH-) d 4)) δ 7.58 (s, 1H), 7.36 (s, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 5.93 - 5.88 (m, 1H), 5.70 - 5.65 (m, 1H), 5.06 (d, J = 5.4 Hz,2H), 4.67 - 4.60 (m, 2H), 4.54 - 4.53 (m, 2H), 4.40 - 4.38 (m, 2H), 4.30 (s,2H), 3.93 (s, 3H), 3.48 - 3.47 (m, 2H), 2.55 (s, 2H), 2.25 - 2.10 (m, 6H), 1.75 - 1.66 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H).

[0255] Compound 11: MS m / z (ESI): 726.25 [M + 1] + .

[0256] 1 H NMR (300 MHz, MeOH-) d 4) δ 7.59 (s, 1H), 7.36 (s, 1H), 6.63 (s, 1H), 6.50 (s, 1H), 5.84 - 5.76 (m, 2H), 5.04 - 5.02 (m, 2H), 4.68 - 4.61 (m, 2H), 4.52 (s, 2H), 4.38 - 4.32 (m, 4H), 3.91 (s, 3H), 3.63 - 3.54 (m, 2H), 2.51(s, 2H), 2.20 (d, J = 9.0 Hz, 6H), 1.73 - 1.66 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.6 Hz, 3H).

[0257] Example 6. Synthesis of Compound 14 and Compound 33 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1] H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide hydrochloride 14 ( Z -3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d[Imidazol-1-yl)but-2-en-1-yl)-2-(((3-methyl-1-propyl-1-yl)] H -pyrazine-5-carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c ]Pyridine-5-carboxamide hydrochloride 33 The synthesis route is as follows: Step 1: ( Z )-3-methyl-1-propyl- N -(4,5,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-2 (3 H )-subunit)-1 H Preparation of pyrazole-5-carboxamide 14a Compound 10a (640 mg, 1.6 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL) at room temperature, followed by the addition of 1,4-dioxane (4.0 M, 5 mL) of hydrogen chloride. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was azeotropically distilled three times with toluene to give crude 14a (470 mg, yield: 99%) as a yellow solid. The product did not require further purification and was used directly in the next step.

[0258] MS m / z (ESI): 289.10 [M + 1] + .

[0259] Step 2: (Z)-2-(3-methyl-1-propyl-1) H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 14b-formamide Compound 14a (520 mg, 1.8 mmol, 1 equivalent) and trimethylsilane isocyanate (374 mg, 3.2 mmol, 1.8 equivalent) were dissolved in isopropanol (10.4 mL) at room temperature and under an argon atmosphere. DIEA (699 mg, 5.4 mmol, 3 equivalent) was then added. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with dichloromethane / methanol (0.01% ammonia) = (8:1) to give title compound 14b (492 mg, yield: 82%, purity: 95%) as a yellow solid.

[0260] MS m / z (ESI): 332.15 [M + 1] + .

[0261] Step 3: ( E Preparation of tert-butyl piperazine-1-carboxylic acid ester 14d Compound 2a (3 g, 6.8 mmol, 1 equivalent) and ( ) were subjected to an argon atmosphere at room temperature. E 14c-4-(tert-butyldimethylsiloxy)but-2-en-1-amine (1.9 g, 9.5 mmol, 1.4 equivalents, prepared by the method disclosed in Example S49 on page 230 of patent application “US11596692B1”) was dissolved in n-butanol (45 mL), and then DIEA (3.5 g, 27.1 mmol, 4 equivalents) was added. The reaction mixture was then heated to 120 °C and stirred overnight under these conditions. After the reaction was completed, the reaction system was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 90 mL / min; gradient: acetonitrile in water from 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 25 min. The title compound 14d (3.2 g, yield: 78%, purity: 95%) was obtained as a red solid.

[0262] MS m / z (ESI): 608.30 [M + 1] + .

[0263] Step 4: ( EPreparation of tert-butyl piperazine-1-carboxylic acid ester 14e Compound 14d (3.1 g, 5.1 mmol, 1 equivalent) was dissolved in methanol (60 mL) and water (20 mL) under argon atmosphere at 0 °C. Anhydrous sodium carbonate (2.2 g, 20.4 mmol, 4 equivalent) and sodium dithionite (6.2 g, 35.7 mmol, 7 equivalent) were then added sequentially. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the temperature was allowed to rise naturally to room temperature, and the mixture was concentrated under reduced pressure. The residual product was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40-60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 90 mL / min; gradient: acetonitrile in water 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 23 min. The title compound 12e (1.6 g, yield: 55%, purity: 86%) was obtained as a yellow solid.

[0264] MS m / z (ESI): 578.35 [M + 1] + .

[0265] Step 5: 4-(3-(( E )-3-(( E )-4-(tert-butyldimethylsiloxy)but-2-enyl)-6-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-4-yloxy)propyl)piperazine-1-carboxylic acid tert-butyl ester 14f Compound 14e (1.6 g, 2.7 mmol, 1 equivalent) and compound 1b (1.11 g, 5.7 mmol, 2.1 equivalent) were dissolved in DMF (30 mL) at room temperature and under argon atmosphere. Triethylamine (1.9 g, 19.0 mmol, 7 equivalent) and EDCI (2.6 g, 13.6 mmol, 5 equivalent) were added sequentially. After addition, the reaction was stirred overnight at room temperature. After the reaction was complete, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine (2 × 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reversed-phase rapid chromatography (column: AQ-C). 18The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 90 mL / min; gradient: acetonitrile in water from 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 30 min. The title compound 12f (1.8 g, yield: 88%, purity: 73%) was obtained as a yellow solid.

[0266] MS m / z (ESI): 739.50 [M + 1] + .

[0267] Step 6: 4-(3-(( E )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-3-(( E )-4-hydroxybut-2-ene)-2,3-dihydro-1 H -benzo[ d Preparation of 14g of imidazole-4-yloxy)propyl)piperazine-1-carboxylic acid tert-butyl ester Compound 14f (1.7 g, 2.3 mmol, 1 equivalent) was dissolved in tetrahydrofuran (15 mL) under an argon atmosphere at room temperature. Tetrabutylammonium fluoride (3.9 mL, 3.9 mmol, 1.7 equivalent) was then added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residual product was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 100 mL / min; gradient: acetonitrile in water from 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 20 min. 14 g (1.4 g, yield: 97%, purity: 90%) of the title compound was obtained as a yellow solid.

[0268] MS m / z (ESI): 625.35 [M + 1] + .

[0269] Step 7: 4-(3-(( E )-3-(( E )-4-bromobut-2-enyl)-6-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydro-1 H Preparation of tert-butyl benzimazole-4-yloxy)propyl)piperazine-1-carboxylic acid ester for 14 hours Under a mild argon atmosphere, 14 g (1.4 g, 2.2 mmol, 1 equivalent) of the compound was dissolved in tetrahydrofuran (40 mL), followed by the addition of phosphorus tribromide (1.2 g, 4.5 mmol, 2.0 equivalent). The reaction mixture was then heated to 35 °C and reacted under these conditions for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 90 mL / min; gradient: acetonitrile in water from 0% to 100% over 35 min; detector: UV 254 / 210 znm; retention time: 26 min. The title compound was given as a grayish-white solid at 14 h (89 mg, yield: 6%, purity: 98%).

[0270] MS m / z (ESI): 687.20 689.20 [M + 1] + .

[0271] Step 8: 4-(3-(( E )-6-carbamoyl-3-( E )-4-(( E )-5-carbamoyl-2-(3-methyl-1-propyl-1 H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydroimidazole[4,5- c ]pyridin-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydro-1 H Preparation of 14i of 1-benzimidazole-4-yloxy)propyl)piperazine-1-carboxylate 4-(3-(( E )-6-carbamoyl-3-( E )-4-(( Z )-5-carbamoyl-2-((3-methyl-1-propyl-1) H -pyrazole-5-carbonyl)imino)-1,2,4,5,6,7-hexahydro-3 H -Imidazolidine[4,5- c ]pyridin-3-yl)but-2-en-1-yl)-2-((1-ethyl-3-methyl-1-yl) H -pyrazine-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-4-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester 33a Compound 14b (106 mg, 0.3 mmol, 1 equivalent) was dissolved in DMF (2 mL) under an argon atmosphere at room temperature, followed by the addition of cesium carbonate (229 mg, 0.7 mmol, 2.2 equivalents). The resulting mixture was stirred at room temperature for 30 minutes. Then, a DMF solution of compound 14h (220 mg, 0.3 mmol, 1.00 equivalent) was added dropwise to the reaction mixture (0.5 mL). After the addition was complete, the reaction system was heated to 50°C and stirred under these conditions for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residual product was purified by reversed-phase rapid chromatography (column: C10). 18 The crude product (30 mg) was obtained by chiral high-performance liquid chromatography (HPLC) under the following conditions: column: 48 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 45 mL / min; gradient: acetonitrile in water 0%–100% over 30 min; detector: UV 254 / 210 nm; retention time: 20 min. The crude product was then separated by chiral HPLC under the following conditions: column: CHIRALPAK IF 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5%, 2 M ammonia in methanol), mobile phase B: ethanol: dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 60%; wavelength: 220 / 254 nm; retention time: 15.735 min; sample solvent: ethanol; injection volume: 1.0 mL; number of runs: 3. Title compound 33a (14 mg, yield: 5%, purity: 98%) was obtained as a pale yellow solid at retention times of 7.995 min and 15.735 min, respectively, and title compound 14i (6 mg, yield: 2%, purity: 98%) was obtained as a pale yellow solid.

[0272] Compound 14c: MS m / z (ESI): 938.50 [M + 1] + .

[0273] Compound 33a: MS m / z (ESI): 938.50 [M + 1] + .

[0274] Step 9: ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydrobenzo[ d[Imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1] H (-pyrazole-5-carbonylimino)-2,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 14-formamide hydrochloride ( Z -3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((3-methyl-1-propyl-1-yl)] H -pyrazine-5-carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide hydrochloride 33 Compound 14i (6 mg, 6 μmol, 1 equivalent) was dissolved in 1,4-dioxane (0.5 mL) under argon atmosphere at room temperature, followed by the addition of 1,4-dioxane hydrogen chloride (4.0 M, 0.5 mL, 41 μmol, 0.4 equivalent). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 14 (5.5 mg, yield: 98%, purity: 92%) as a yellow solid.

[0275] Compound 33a (14 mg, 0.014 mmol, 1 equivalent) was dissolved in 1,4-dioxane (0.5 mL) under argon atmosphere at room temperature, followed by the addition of 1,4-dioxane hydrogen chloride (4.0 M, 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 33 (11.8 mg, yield: 90%, purity: 95%) as a yellow solid.

[0276] Compound 14: MS m / z (ESI): 838.50 [M + 1] + .

[0277] 1 H NMR (400 MHz, MeOH- d4) δ 7.70 (s, 1H), 7.50 - 7.46 (m, 1H), 6.95(s, 1H), 6.76 (s, 1H), 6.21- 6.15 (m, 1H), 5.87 - 5.76 (m, 1H), 5.24 - 5.22(m, 2H), 4.82 - 7.75 (m, 2H), 4.56- 4.37 (m, 2H), 4.34 - 4.31 (m, 4H), 3.95-3.80 (m, 2H), 3.75- 3.65 (m, 7H), 3.60 - 3.55 (m, 3H), 2.80 - 2.76 (m, 2H),2.48 - 2.35 (m, 4H), 2.18 (s, 3H), 1.76 - 1.71 (m, 2H), 1.52 - 1.49 (m, 3H),1.32 - 1.28 (m, 3H), 0.83 (t, J = 7.2 Hz, 3H).

[0278] Compound 33: MS m / z (ESI): 838.50 [M + 1] + .

[0279] 1 H NMR (400 MHz, Methanol- d 4) δ 7.70 (s, 1H), 7.50 - 7.46 (m, 1H),6.93 (s, 1H), 6.82 (s, 1H), 6.33- 6.29 (m, 1H), 5.78 - 5.72 (m, 1H), 5.32 -5.25 (m, 2H), 4.98 - 4.88 (m, 2H), 4.82 - 4.76 (m, 2H), 4.59 - 4.53 (m, 2H),4.33 - 4.31 (m, 4H), 4.01- 3.91 (m, 2H), 3.81- 3.65 (m, 7H), 3.60 - 3.55 (m,3H), 2.72- 2.69 (m, 2H), 2.46 - 2.40 (m, 2H), 2.19 (s, 3H), 1.75 - 1.70 (m,2H), 1.52 - 1.48 (m, 3H), 1.32 - 1.28 (m, 3H), 0.81 (t, J = 7.2 Hz, 3H).

[0280] Example 7. Synthesis of Compound 15 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1-yl) H- Pyrazole-5-yl)ethynyl)-1 H- Benzimidazole-5-carboxamide 15 The synthesis route is as follows: Step 1: 5-Bromo-1-ethyl-3-methyl-1 H- Preparation of pyrazole 15a (by the method disclosed in intermediate 153 on page 31 of patent application "WO2022204235A1") 3-Bromo-5-methyl-2- H- Pyrazole (6 g, 37.3 mmol, 1 equivalent, Jiangsu Aikon Biopharmaceutical R&D Co., Ltd., Product No.: AK00EIND) was dissolved in DMF (150 mL), followed by the addition of potassium carbonate (18.0 g, 130.4 mmol, 3.5 equivalent) and iodoethane (17.4 g, 111.8 mmol, 3 equivalent, Shanghai Titan Technology Co., Ltd.). The reaction mixture was then heated to 35°C and stirred for 1.5 hours. After the reaction was complete, the mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine (2 × 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with diethyl ether / ethyl acetate (1:1) to give the title compound 15a (5.9 g, yield: 84%) as a yellow oil.

[0281] MS m / z (ESI): 189.00 [M + 1] + .

[0282] Step 2: 5-(3-(tert-butyldimethylsiloxy)prop-1-ynyl)-1-ethyl-3-methyl-1 H- Preparation of pyrazole 15b Compound 15a (1 g, 5.3 mmol, 1 equivalent) and triphenylphosphine (21 mg, 79 μmol, 0.015 equivalent) were dissolved in tetrahydrofuran (1.5 mL) under an argon atmosphere at room temperature. Triethylamine (1.07 g, 10.6 mmol, 2 equivalent) and tert-butyldimethyl(propane-2-alkynoxy)silane 15e (991 mg, 5.8 mmol, 1.1 equivalent, Shanghai Bied Pharmaceutical Technology Co., Ltd., product number: BD29591) were then added. The reaction mixture was stirred at room temperature for 20 minutes. Cuprous iodide (30 mg, 159 μmol, 0.03 equivalent) was then added. After the addition was complete, the reaction mixture was heated to 50 °C and stirred under these conditions for 16 hours. After the reaction was complete, water (200 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined and washed with saturated brine (2 × 400 mL), then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 330 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 100 mL / min; gradient: acetonitrile in water 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 29 min. The title compound 15b (74 mg, yield: 5%) was obtained as a brown oil.

[0283] MS m / z (ESI): 279.10 [M + 1] + .

[0284] 1 H NMR (400 MHz, MeOH- d 4) δ 6.21 (s, 1H), 4.59 (s, 2H), 4.20 - 4.15 (m, 2H), 2.20 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.16 (s, 6H).

[0285] Step 3: 3-(1-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-3-ethyl ... H- Preparation of pyrazol-5-yl)prop-2-yn-1-ol 15c Compound 15b (75 mg, 269 μmol, 1 equivalent) was dissolved in tetrahydrofuran (0.5 mL) under an argon atmosphere at room temperature, followed by the addition of tetrabutylammonium fluoride (540 μL, 1 M tetrahydrofuran, 538 μmol, 2 equivalents). The resulting mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (dichloromethane / ethyl acetate 2:1) to give title compound 15c (29 mg, yield: 66%) as a yellow solid.

[0286] MS m / z (ESI): 165.10 [M + 1] + .

[0287] Step 4: 3-(1-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-3-ethyl ... H- Preparation of pyrazol-5-yl)propanol 15d Compound 15c (29 mg, 177 μmol, 1 equivalent) was dissolved in dichloromethane (1.5 mL) under argon atmosphere at room temperature, followed by the addition of DMP (149.81 mg, 354 μmol, 2 equivalents). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium thiosulfate aqueous solution (10 mL) at room temperature. The mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (dichloromethane / ethyl acetate = 3:1) to give the title compound 15d (20 mg, yield: 70%) as a yellow solid.

[0288] MS m / z (ESI): 163.05 [M + 1] + .

[0289] Step 5: 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1-yl) H- Pyrazole-5-yl)ethynyl)-1 H- Preparation of benzimidazole-5-carboxamide 15 At room temperature and under an argon atmosphere, (2) E )-1-[(2) E )-4-[(2-amino-4-carbamoylphenyl)amino]but-2-en-1-yl]-2-(2-ethyl-5-methylpyrazole-3-carbonylimino)-3 H- 1,3-Benzimazole-5-carboxamide 18b (20 mg, 39 μmol, 1 equivalent) and compound 15d (19 mg, 117 μmol, 3 equivalent) were dissolved in DMF. Potassium peroxymonosulfonate (6.5 mg, 39 μmol, 1 equivalent) was then added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC). Column: XSelect CSH Prep C 18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile in water from 15% to 42% over 12 min; wavelength: 254 nm / 220 nm; retention time: 8.9 min. Title compound 15 (5.5 mg, yield: 21%) was obtained as a white solid.

[0290] MS m / z (ESI): 658.25 [M + 1] + .

[0291] 1 H NMR (400 MHz, DMSO- d 6) δ 12.76 (s, 1H), 8.25 (s, 1H), 8.04 - 7.88 (m, 4H), 7.69 (t, J = 9.2 Hz, 2H), 7.42 - 7.34 (m, 3H), 6.53 (s, 1H), 6.38(s, 1H), 6.03 - 5.96 (m, 1H), 5.83 - 5.78 (m, 1H), 5.05 (d, J = 5.6 Hz, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.55 - 4.50 (m, 2H), 4.10 - 4.04 (m, 2H), 2.14 (d, J = 12.4 Hz, 6H), 1.29 - 1.22 (m, 6H).

[0292] Example 8. Synthesis of Compound 16 7-(2-Aminoethoxy)-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1-yl) H- Pyrazole-5-yl)ethynyl)-1 H- Benzimidazole-5-carboxamide formate 16 The synthesis route is as follows: Step 1: Preparation of 3-(2-(tert-butyldimethylsiloxy)ethoxy)-4-chloro-5-nitrobenzamide 16a Under an argon atmosphere at room temperature, 4-chloro-3-hydroxy-5-nitrobenzamide (1 g, 4.6 mmol, 1 equivalent) and (2-bromoethoxy)(tert-butyl)dimethylsilane 16e (1.33 g, 5.5 mmol, 1.2 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd.) were dissolved in DMF (15 mL), followed by the addition of potassium carbonate (2.55 g, 18.5 mmol, 4 equivalent). The reaction mixture was then heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic phases were washed with saturated brine (3 × 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane / ethyl acetate (1:1) to give the title compound 16a (1.4 g, yield: 81%) as a yellow solid.

[0293] MS m / z (ESI): 375.15 [M + 1] + .

[0294] Step 2: ( E )-1-(( E )-4-(2-(2-(tert-butyldimethylsiloxy)ethoxy)-4-carbamoyl-6-nitrophenylamino)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydro-1 H- Preparation of benzimidazole-5-carboxamide 16b Compound 16a (500 mg, 1.3 mmol, 1 equivalent) and compound 10b (768.3 mg, 1.9 mmol, 1.4 equivalent) were dissolved in n-butanol (7 mL) at room temperature and under an argon atmosphere. DIEA (689.5 mg, 5.3 mmol, 4 equivalent) was then added, and the reaction mixture was heated to 120 °C and stirred overnight under these conditions. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (5:1) to give the title compound 16b (430 mg, yield: 35%) as a red solid.

[0295] MS m / z (ESI): 750.35 [M + 1] + .

[0296] Step 3: ( E )-1-(( E )-4-(2-amino-6-(2-(tert-butyldimethylsiloxy)ethoxy)-4-carbamoylphenylamino)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydro-1 H- Preparation of benzimidazole-5-carboxamide 16c Compound 16b (450 mg, 0.6 mmol, 1 equivalent) and sodium carbonate (254 mg, 2.4 mmol, 4 equivalent) were dissolved in methanol (4 mL) under a nitrogen atmosphere at room temperature, followed by the addition of sodium dithionite (731 mg, 4.2 mmol, 7 equivalent). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (5:1) to give the title compound 16c (380 mg, 88%) as a yellow solid.

[0297] MS m / z (ESI): 720.45 [M + 1] + .

[0298] Step 4: 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1-yl) H- Pyrazol-5-yl)ethynyl)-7-(2-hydroxyethoxy)-1 H- Preparation of benzimidazole-5-carboxamide 16d Compound 16c (194 mg, 269 μmol, 1 equivalent) and compound 15d (109.3 mg, 673 μmol, 2.5 equivalent) were dissolved in DMF (4 mL) at room temperature and under nitrogen atmosphere. Potassium peroxide monosulfonate (45.31 mg, 269 μmol, 1 equivalent) was then added to the system. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residual product was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The chromatographic column was 90 g, 60 Å, 40–60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 0%B to 100%B over 30 min; detector: UV 254 / 210 nm; retention time: 21 min. The title compound 16d (73 mg, yield: 36%) was obtained as a yellow solid.

[0299] MS m / z (ESI): 748.35 [M + 1] + .

[0300] Step 5: 7-(2-Aminoethoxy)-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1-yl) H- Pyrazole-5-yl)ethynyl)-1 H- Preparation of benzimidazole-5-carboxamide formate 16 Compound 16d (50 mg, 67 μmol, 1 equivalent) and triethylamine (33.8 mg, 355 μmol, 5 equivalent) were dissolved in tetrahydrofuran (8 mL) and pyridine (2 mL) under a nitrogen atmosphere at room temperature. Then, methanesulfonyl chloride (76.6 mg, 670 μmol, 10 equivalent) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then cooled to 0°C, and a methanol solution of ammonia (7 M, 1.5 mL) was added. After the addition was complete, the reaction temperature was raised to 60°C and stirred under these conditions for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue (50 mg) was purified by high performance liquid chromatography (HPLC) (column: XSelect CSHPrep C18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile in water from 8% to 38% B over 12 minutes; wavelength: 220 nm; retention time: 7.23 minutes) to obtain the crude product. The crude product (1.5 mg) was purified twice by high performance liquid chromatography (column: Xselect CSH Prep Fluoro-Phenyl Column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: methanol; flow rate: 25 mL / min; gradient: methanol to water 30% to 60% over 10 min; wavelength: 254 nm / 220 nm; retention time: 8.31 min) to give title compound 16 (0.9 mg, yield: 2%) as a pale yellow solid.

[0301] MS m / z (ESI): 747.10 [M + 1] + .

[0302] 1 H NMR (300 MHz, MeOH- d 4) δ 7.86 (s, 2H), 7.56 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 6.53 (s, 1H), 6.26 (s, 1H), 5.95 - 5.86 (m, 1H), 5.74 - 5.68(m, 1H), 5.27 - 5.22 (m, 2H), 5.03 - 4.98 (m, 2H), 4.61 - 4.54 (m, 2H), 4.24- 4.11 (m, 4H), 3.70 (s, 3H), 3.18 - 3.12 (m, 2H), 2.20 - 2.16 (m, 6H), 1.36- 1.28 (m, 6H).

[0303] Example 9. Synthesis of Compound 17 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H- Pyrazol-5-yl)ethynyl)-7-(3-(piperazin-1-yl)propoxy)-1 H- Benzo[ d Imidazole-5-carboxamide formate 17 The synthesis route is as follows: Step 1: 4-(3-(5-carbamoyl-2-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Preparation of 17a pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enylamino)-3-nitrophenoxy)propyl)piperazine-1-carboxylic acid tert-butyl ester Compound 1e (900 mg, 2.4 mmol, 1.2 equivalents) and compound 2a (871 mg, 2.0 mmol, 1 equivalent) were dissolved in n-butanol under nitrogen atmosphere at room temperature, followed by the addition of DIEA (1.0 g, 7.9 mmol, 4 equivalents). The reaction mixture was then heated to 120 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (60 mL), and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine (3 × 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol (0.1% ammonia) = 5:1 to give title compound 17a (700 mg, yield: 45%, purity: 97%) as an orange solid.

[0304] MS m / z (ESI): 788.40 [M + 1] + .

[0305] Step 2: 4-(3-(3-amino-5-carbamoyl-2-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Preparation of 17b of pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enylamino)phenoxy)propyl)piperazine-1-carboxylic acid tert-butyl ester Compound 17a (200 mg, 254 μmol, 1 equivalent) and ammonia (28% aqueous solution, 1.5 mL) were dissolved in tetrahydrofuran (4 mL) and methanol (4 mL) under a nitrogen atmosphere at room temperature. An aqueous solution of sodium dithionite (354 mg dissolved in 8 mL, 2.0 mmol, 8 equivalents) was then added. The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C10 ... 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water from 5% to 80% over 25 min; detector, UV 254 nm. Title compound 17b (110 mg, yield: 57%) was obtained as a grayish-white solid.

[0306] MS m / z (ESI): 758.35 [M + 1] + .

[0307] 1 H NMR (400 MHz, DMSO-d 6) δ 12.78 (s, 1H), 7.99 - 7.88 (m, 1H), 7.95 -7.92 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.32 - 7.26 (m, 2H), 6.99 (s, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.61 (s,1H), 5.79 - 5.70 (m, 2H), 4.78 - 4.77 (m, 2H), 4.65 - 4.58 (m, 4H), 3.92 -3.82 (m, 3H), 3.59 - 3.56 (m, 2H), 3.27 - 3.24 (m, 4H), 2.31 (t, J = 7.2 Hz,2H), 2.24 - 2.22 (m, 4H), 2.17 (s, 3H), 1.74 - 1.70 (m, 2H), 1.38 - 1.32 (m,12H).

[0308] Step 3: 4-(3-(6-carbamoyl-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H- Pyrazole-5-yl)ethynyl)-3 H- Preparation of benzimidazole-4-yloxy)propyl)piperazine-1-carboxylic acid tert-butyl ester 17c Compound 17b (100 mg, 132 μmol, 1 equivalent), compound 15d (42.8 mg, 264 μmol, 2 equivalents), and potassium peroxymonosulfonate (81 mg, 132 μmol, 1 equivalent) were dissolved in DMF (2.5 mL) at room temperature and under an argon atmosphere. The reaction solution was heated to 30 °C and stirred for 3 hours under these conditions. After the reaction was completed, the reaction solution was purified by reversed-phase rapid chromatography under the following conditions: column, C 18Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water from 5% to 80% over 30 min; detector, UV 254 nm. Title compound 17c (40 mg, yield: 34%) was obtained as a yellow solid.

[0309] MS m / z (ESI): 900.50 [M + 1] + .

[0310] Step 4: 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H- Pyrazol-5-yl)ethynyl)-7-(3-(piperazin-1-yl)propoxy)-1 H- Benzo[ d Preparation of imidazole-5-carboxamide formate 17 Compound 17c (40 mg, 44 μmol, 1 equivalent) was dissolved in ethyl acetate (3 mL) under a nitrogen atmosphere at room temperature, followed by the addition of a 4.0 M, 3 mL solution of hydrogen chloride in ethyl acetate. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography: column: Xselect CSH Prep column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid); mobile phase B: methanol; flow rate: 25 mL / min; gradient: acetonitrile in water 47% to 67% over 10 minutes; wavelength: 254 / 220 nm; retention time: 9.15 minutes. The title compound 17 (6 mg, yield: 17%, purity: 95%) was obtained as a grayish-white solid.

[0311] MS m / z (ESI): 800.40 [M + 1] + .

[0312] 1 H NMR (400 MHz, DMSO- d6) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.9 - 796 (m, 2H), 7.86 (s, 1H), 7.71 - 7.68 (m, 1H), 7.39 - 7.34 (m, 4H), 6.51 (s, 1H), 6.40 (s, 1H), 6.09 - 6.02 (m, 1H), 5.68 - 5.61 (m, 1H), 5.14 - 5.13 (m, 2H), 4.81 - 4.80 (m, 2H), 4.52 (d, J = 7.2 Hz, 2H), 4.12 - 4.04 (m, 4H), 3.50 -3.51 (m, 2H), 2.77 - 2.74 (m, 3H), 2.34 - 2.27 (m, 6H), 2.16 (s, 3H), 2.12(s, 3H), 1.79 - 1.73 (m, 2H), 1.28 - 1.24 (m, 6H).

[0313] Example 10. Synthesis of Compounds 18 and 19 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(2-ethylnicotinamide)-2,3-dihydro-1 H -benzimidazole-5-formamide 18 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(2-ethylnicotinamide)-3-methyl-2,3-dihydro-1 H -benzimidazole-5-formamide 19 The synthesis route is as follows: Step 1: ( E )-1-(( E)-4-(4-carbamoyl-2-nitrophenylamino)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Preparation of benzimidazole-5-carboxamide 18a Compound 1e (200 mg, 524 μmol, 1 equivalent) was dissolved in DMF (6 mL) at room temperature and under a nitrogen atmosphere, followed by the sequential addition of 4-fluoro-3-nitrobenzamide (96 mg, 524 μmol, 1 equivalent) and potassium carbonate (217 mg, 1.6 mmol, 3 equivalent). After the addition was complete, the reaction system was heated to 70 °C and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, diluted with water (30 mL), filtered, and the filter cake was washed with water (3 × 10 mL) to give the title compound 18a (150 mg, yield: 52%) as a yellow solid.

[0314] MS m / z (ESI): 546.25 [M + 1] + .

[0315] 1 H NMR (300 MHz, DMSO- d 6) δ 12.84 (s, 1H), 8.64 (s, 1H), 8.55 - 8.51 (m, 1H), 8.00 - 7.91 (m, 4H), 7.77 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz,1H), 7.34 (s, 1H), 7.29 (s, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.59 (s, 1H), 5.85(s, 2H), 4.85 (s, 2H), 4.61 - 4.54 (m, 2H), 4.07 (m, 2H), 2.15 (s, 3H), 1.31(t, J = 7.2 Hz, 3H).

[0316] Step 2 ( E )-1-(( E )-4-(2-amino-4-carbamoylphenylamino)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1H- Preparation of benzimidazole-5-carboxamide 18b Compound 18a (150 mg, 275 μmol, 1 equivalent) was dissolved in DMF (3 mL) under nitrogen atmosphere at room temperature, followed by the addition of ammonia (1 mL, 25.7 mmol, 93.40 equivalent) and an aqueous solution of sodium dithionite (383 mg dissolved in 3 mL of water, 2.2 mmol, 8 equivalent). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the residue was purified by reversed-phase rapid chromatography by distillation under reduced pressure to give title compound 18b (100 mg, yield: 71%) as a white solid.

[0317] MS m / z (ESI): 516.25 [M + 1] + .

[0318] Step 3: 2-Amino-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-1 H- Benzimidazole-5-carboxamide 18c and 1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-imino-3-methyl-2,3-dihydro-1 H- Preparation of a mixture of benzimidazole-5-carboxamide 19a Compound 18b (100 mg, 0.2 mmol, 1 equivalent) was dissolved in methanol (4 mL) under an argon atmosphere at room temperature, followed by the addition of a solution of cyanogen bromide (31 mg, 0.3 mmol, 1.5 equivalent) in acetonitrile (0.2 mL). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions: column: SunFire C10 ... 18 OBD Prep column 19 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 8% to 20%; wavelength: 254 / 210 nm; retention time: 6 min. A mixture (30 mg) of title compounds 18c and 19a was obtained as a white solid.

[0319] MS m / z (ESI): 541.30 [M + 1] + .

[0320] Step 4: ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(2-ethylnicotinamide)-2,3-dihydro-1 H Preparation of Benzimazole-5-formamide 18 ( E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(2-ethylnicotinamide)-3-methyl-2,3-dihydro-1 H Preparation of Benzimazole-5-formamide 19 A mixture of compounds 18c and 19a (30 mg) and 2-ethylpyridine-3-carboxylic acid (17 mg, 110 μmol, 2 equivalents, Shanghai Haohong Biomedical Technology Co., Ltd., product number: 1066029) were dissolved in DMF (3 mL) at room temperature and under nitrogen atmosphere. Then, HATU (42 mg, 110 μmol, 2 equivalents) and DIEA (15 mg, 110 μmol, 2 equivalents) were added sequentially. The resulting reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reactants were purified by high-performance liquid chromatography (HPLC) under the following conditions: column: SunFire C10 ... 18 OBD Prep column 19 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: acetonitrile in water 15% to 25% over 6 minutes; wavelength: 254 / 210 nm; title compound 18 (10 mg, yield: 6%, white solid) and title compound 19 (5 mg, yield: 13%, white solid) were obtained at retention times (1): 5.78 min and retention times (2): 6.88 min, respectively.

[0321] Compound 18: MS m / z (ESI): 674.25 [M + 1] + .

[0322] 1 1H NMR (400 MHz, DMSO- d 6) δ 12.91 (s, 1H), 12.83 (s, 1H), 8.51 - 8.49(m, 1H), 8.13 - 8.10 (m, 1H), 8.01 - 7.96 (m, 4H), 7.75 - 7.72 (m, 2H), 7.46(t, J J = 8.0 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.19 - 7.16 (m, 1H), 6.54 (s, 1H),5.99 - 5.88 (m, 2H), 4.84 (m, 4H), 4.55 - 450 (m, 2H), 3.13 - 3.08 (m, 2H),2.12 (s, 3H), 1.26 (t, J J = 6.8 Hz, 3H), 1.18 (t, J J = 7.2 Hz, 3H).

[0323] Compound 19: MS m / z (ESI): 688.30 [M + 1] + .

[0324] 1 1H NMR (400 MHz, DMSO- d 6) δ 12.81 (s, 1H), 8.47 - 8.45 (m, 1H), 8.09 -8.05 (m, 1H), 8.02 - 7.95 (m, 4H), 7.82 - 7.80 (m, 1H), 7.72 - 7.70 (m, 1H),7.54 -7.34 (m, 4H), 7.16 - 7.13 (m, 1H), 6.54 (s, 1H), 5.89 (t, J J = 3.2 Hz,2H), 4.81 (m, 4H), 4.53- 4.51 (m, 2H), 3.58 (s, 3H), 3.08 - 3.03 (m, 2H),2.12 (s, 3H), 1.26 (t, J J = 7.2 Hz, 3H), 1.15 (t, J J = 7.6 Hz, 3H).

[0325] Example 11. Synthesis of Compounds 23 and 24 (±) E )-1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzimidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 23 (±) E )-1-(( E )-4-( Z )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 24 The synthesis route is as follows: Step 1: (±)6,7,8,9-Tetrahydrobenzo[4,5]imidazo[1,2- a Preparation of 23a pyrimidine-7-carboxylic acid ethyl ester 3-Bromo-5-hydroxy-4-oxopiperidin-1-carboxylic acid tert-butyl ester (1 g, 4.0 mmol, 1 equivalent) was dissolved in ethanol (5 mL) under an argon atmosphere, and 2-aminopyrimidine (764 mg, 8.0 mmol, 2 equivalents) was added. The resulting mixture was heated to 80 °C under an argon atmosphere and stirred overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1), to give title compound 23a (racemic mixture, 900 mg, yield: 86%, purity: 85%) as a dark green solid.

[0326] Step 2: (±)2-amino-4,5,6,7-tetrahydro-1 H- Preparation of benzimidazole-5-carboxylic acid ethyl ester 23b Compound 23a (864 mg, 3.5 mmol, 1 equivalent) was dissolved in ethanol (10 mL) under air atmosphere, and hydrazine hydrate (2.3 g, 45.8 mmol, 13 equivalents) was added at room temperature. The mixture was heated to 80 °C and stirred under these conditions for 7 hours. The residual product was purified by reversed-phase rapid chromatography (column: AQ-C). 18 220 g, 60 Å, 40 – 60 µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 80 mL / min; gradient: 30 min 0% to 100%; detector: UV 254 / 210 nm; retention time: 19 min), yielded title compound 23b (racemic mixture, 190 mg, yield: 26%) as a yellow solid.

[0327] MS m / z (ESI): 210.25 [M + 1] + .

[0328] Step 3: (±) Z )-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H- Preparation of benzimidazole-5-carboxylic acid ethyl ester 23c Compound 23b (159 mg, 0.8 mmol, 1 equivalent) and 2-ethyl-5-methylpyrazol-3-carboxylic acid (176 mg, 1.1 mmol, 1.5 equivalent) were dissolved in DMF (4 mL) at room temperature and under an argon atmosphere, followed by the addition of TCFH (426 mg, 1.5 mmol, 2 equivalent) and NMI (206 mg, 2.5 mmol, 3.3 equivalent). The reaction mixture was heated to 50 °C under an argon atmosphere and stirred for 2 hours. After the reaction was completed, water (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with saturated brine (2 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was prepared by thin-layer chromatography (dichloromethane / methanol, 10:1). The crude product was purified by reversed-phase rapid chromatography (column: AQ-C). 18 The column was 120 g, 60 Å, 40-60 µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile in water from 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 20 min), yielding the title compound 23c (racemic mixture, 130 mg, yield: 50%) as a pale yellow solid.

[0329] MS m / z (ESI): 346.20 [M + 1] + .

[0330] Step 4: (±) E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H- Benzimidazole-5-carboxylate 23d and (±) Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- (pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H- A mixture of benzimidazole-5-carboxylic acid ester 24a Compound 8e (122 mg, 0.35 mmol, 1 equivalent) and compound 23c (315 mg, 0.71 mmol, 2 equivalents) were dissolved in argon atmosphere. N, N Cesium carbonate (288 mg, 0.88 mmol, 2 equivalents) was added to dimethylformamide (3 mL) at room temperature. The mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the reaction system was purified by reversed-phase rapid chromatography under the following conditions (column: AQ-C). 18 90 g, 60 Å, 40–60 µm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile in water 0% to 100% over 30 min; detector: UV 254 / 210 nm; retention time: 22 min), to obtain the crude product. The crude product was prepared by thin-layer chromatography (purification with dichloromethane / methanol (0.1% ammonia 10:1) to give a mixture of compounds 23d and 24a (title 1:2) (59 mg, purity 97%) as a grayish-white solid.

[0331] MS m / z (ESI): 710.35 [M + 1] + .

[0332] Step 5: (±) E )-1-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H- Benzimidazole-5-carboxylic acid 23 and (±) Z )-3-(( E )-4-(( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzimidazole-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H- Preparation of a mixture of benzimidazole-5-carboxylic acid 24 A mixture of compounds 23d and 24a (1:2, 59 mg) was dissolved in tetrahydrofuran (4 mL) at room temperature, followed by the addition of an aqueous lithium hydroxide solution (1 M, 0.23 mL, 3 equivalents). The reaction mixture was then heated to 40 °C and stirred under these conditions for 16 hours. After the reaction was complete, the mixture was purified by reversed-phase rapid chromatography (column: AQ-C). 18 Column, 40 g, 60 Å, 40-60 μm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 40 mL / min; gradient: acetonitrile in water 0% to 100% for 30 min; detector: UV 254 / 210 nm; retention time: 16 min) yielded a mixture of title compounds 23 and 24 (23:24 = 1:2, 45 mg) as a grayish-white solid.

[0333] MS m / z (ESI): 682.40 [M + 1] + .

[0334] Synthesis of compounds 23-1, 23-2, 24-1 and 24-2 ( E )-1-(( E )-4-(( S, E )-5-carbamoyl-2-(1-ethyl-3-methyl-1H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzimidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 23-1, ( E )-1-(( E )-4-(( R, E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 23-2, ( E )-1-(( E )-4-(( S, Z )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 24-1 and ( E )-1-(( E )-4-(( R, Z )-6-carbamoyl-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydrobenzimidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 24-2 A mixture of compounds 23 and 24 (45 mg) was dissolved in DMF (2 mL) at room temperature, followed by the addition of ammonium chloride (71 mg, 1.3 mmol, 60.3 equivalents), HATU (100.5 mg, 0.26 mmol, 12 equivalents), and DIEA (51 mg, 0.40 mmol, 18 equivalents). The reaction mixture was stirred overnight under these conditions, then concentrated under reduced pressure. The residue was prepared by thin-layer chromatography (dichloromethane / methanol (0.01% ammonia) 4:1) to obtain the crude product. The crude product (30 mg) was purified by preparative chiral high-performance liquid chromatography under the following conditions (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: chromatographic methyl tert-butyl ether (0.1% formic acid), mobile phase B: methanol: dichloromethane = 1:1; gradient: 70%; wavelength: 220 / 254 nm). Compounds 23 (10 mg), 24-1 (7.2 mg, yield: 48%, purity: 96%), and 24-2 (6.3 mg, yield: 42%, purity: 96%) were obtained at retention times (1) 5.952 min, (2) 7.048 min, and (3) 8.045 min, respectively.

[0335] Compound 23 (10 mg) was further purified by preparative chiral high-performance liquid chromatography (HPLC). The conditions were as follows: column: CHIRALPAK IK 2 × 25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.1% formic acid); mobile phase B: ethanol:dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 50%; wavelength: 220 / 254 nm; sample solvent: ethanol; injection volume: 1.0 mL; runs: 3). Compounds 23-1 (3 mg, 20% yield, 99% purity, light gray solid) and 23-2 (2.9 mg, 19% yield, 99% purity, light gray solid) were obtained at retention times of 12.599 min and 18.626 min, respectively.

[0336] Compound 23-1: MS m / z (ESI): 681.30 [M + 1] + .

[0337] 1 H NMR (400 MHz, DMSO- d 6) δ 12.09 (s, 1H), 7.98 - 7.95 (m, 2H), 7.74(d, J = δδ8.4 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.37 - 7.34 (m, 2H), 6.93(s, 1H), 6.60 (s, 1H), 6.37 (s, 1H), 5.86 - 5.72 (m, 2H), 4.84 - 4.83 (m,2H), 4.60 - 4.48 (m, 6H), 2.40 - 2.33 (m, 1H), 2.14 (s, 3H), 2.08 (s, 3H), 1.96 - 1.93 (m, 1H), 1.65 - 1.63 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.24 -1.15 (m, 5H).

[0338] Compound 23-2: MS m / z (ESI): 681.35 [M + 1] + .

[0339] 1 H NMR (400 MHz, DMSO- d 6) δ 12.84 (s, 1H), 12.09 (s, 1H), 7.98 - 7.95 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.37 - 7.34 (m,2H), 6.93 (s, 1H), 6.60 (s, 1H), 6.36 (s, 1H), 5.86 - 5.73 (m, 2H), 4.84 -4.83 (m, 2H), 4.61 - 4.48 (m, 6H), 2.40 - 2.30 (m, 1H), 2.14 (s, 3H), 2.08(s, 3H), 1.96 - 1.93 (m, 1H), 1.66 - 1.63 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H),1.23 - 1.16 (m, 5H).

[0340] Compound 24-1: MS m / z (ESI): 681.25 [M + 1] + .

[0341] 1 H NMR (400 MHz, MeOH- d4) δ 7.95 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.54 (s, 1H), 5.84 - 5.79 (m, 2H), 4.68 - 4.63 (m, 4H), 4.46 - 4.39 (m, 2H), 2.74 - 2.70 (m, 2H), 2.65 - 2.61(m, 2H), 2.53 - 2.47 (m, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.06 - 2.02 (m,1H), 1.86 - 1.81 (m, 1H), 1.40 (t, J = 6.8 Hz, 3H), 1.31 - 1.28 (m, 5H).

[0342] Compound 24-2: MS m / z (ESI): 681.45 [M + 1] + .

[0343] 1 H NMR (400 MHz, MeOH- d 4) δ 7.95 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.53 (s, 1H), 5.84 - 5.82 (m, 2H), 4.68 - 4.63 (m, 4H), 4.47 - 4.41 (m, 2H), 2.73 - 2.70 (m, 2H), 2.64 - 2.61(m, 2H), 2.51 - 2.48 (m, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.05 - 2.02 (m,1H), 1.85 - 1.81 (m, 1H), 1.40 (t, J = 6.8 Hz, 3H), 1.31 - 1.28 (m, 5H).

[0344] Example 12. Synthesis of Compound 25 ( E )-1-(( E)-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- pyrrolo-1-yl)pent-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Benzimidazole-5-carboxamide 25 The synthesis route is as follows: Step 1: 5-(2-chloropyrimidin-5-yl)-1 H- Preparation of methyl pyrrole-3-carboxylate 25a 5-Bromo-1 H- Methyl pyrrole-3-carboxylate (3 g, 14.7 mmol, 1 equivalent, Beijing Feilongrui Trading Co., Ltd.), 2-chloropyrimidin-5-ylboronic acid (2.8 g, 17.6 mmol, 1.2 equivalent, Shanghai Bid Pharmaceutical Technology Co., Ltd., Product No.: BD8050), potassium phosphate (6.2 g, 29.4 mmol, 2 equivalent, Shanghai Haohong Biomedical Technology Co., Ltd., Product No.: 1043059), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (1.1 g, 1.5 mmol, 0.1 equivalent, Nanjing Cynthia Biotechnology Co., Ltd.) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). The reaction system was then heated to 80 °C and stirred under these conditions for 16 hours. After the reaction was completed, the reaction system was cooled to room temperature. It was diluted with water (300 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (9:1) to obtain the crude product. The crude product was purified by reversed-phase rapid chromatography: column, C10 ... 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water 5% to 70% over 25 min; detector, UV 210 / 254 nm, yielded title compound 25a (1.2 g, 34%) as a yellow solid.

[0345] MS m / z (ESI): 238.00 [M + 1] + .

[0346] 1 H NMR (400 MHz, DMSO- d6)δ 12.33 (s, 1H), 9.11 (s, 2H), 7.73 (d, J =1.5 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 3.75 (s, 3H).

[0347] Step 2; 5-(2-(1-ethyl-3-methyl-1-ethyl ... H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- Preparation of methyl pyrrole-3-carboxylate 25b Compound 25a (1 g, 4.2 mmol, 1 equivalent), 1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (994 mg, 4.2 mmol, 1 equivalent, Shanghai Shixian Chemical Technology Co., Ltd.), potassium phosphate (1.8 g, 8.4 mmol, 2 equivalent), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (307.9 mg, 421 μmol, 0.1 equivalent) were dissolved in 1,4-dioxane (30 mL) and water (6 mL) under an argon atmosphere at room temperature. The reaction system was then heated to 80 °C and stirred for 16 hours. After the reaction was complete, the reaction system was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (50%–100%) to give the title compound 25b (400 mg, yield: 30%) as an orange solid.

[0348] MS m / z (ESI): 312.35 [M + 1] + .

[0349] 1 H NMR (300 MHz, DMSO- d 6)δ 12.30 (s, 1H), 9.21 (s, 2H), 7.72 - 7.71 (m, 1H), 7.25 - 7.23 (m, 1H), 6.77 (s, 1H), 4.70 - 4.63 (m, 2H), 3.76 (s, 3H), 2.21 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0350] Step 3: 5-(2-(1-ethyl-3-methyl-1-ethyl ... H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- Preparation of pyrrole-3-carboxylic acid 25c Compound 25b (200 mg, 0.6 mmol, 1 equivalent) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL) under a nitrogen atmosphere, followed by the addition of an aqueous solution of lithium hydroxide (2 M, 154 mg, 6.4 mmol, 10 equivalents). The reaction mixture was then heated to 75 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the resulting solution was neutralized with hydrochloric acid (1 M) to a pH of 4. The neutralized mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water 5% to 45% over 20 min; yielded title compound 25c (150 mg, yield: 79%) as a white solid.

[0351] MS m / z (ESI): 298.15 [M + 1] + .

[0352] Step 4: 5-(2-(1-ethyl-3-methyl-1-ethyl ... H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- Preparation of pyrrole-3-carboxamide 25d Under a nitrogen atmosphere, compound 25c (150 mg, 505 μmol, 1 equivalent) and HATU (230 mg, 606 μmol, 1.2 equivalent) were dissolved in DMF (4 mL), followed by the addition of DIEA (196 mg, 1.5 mmol, 3 equivalent) and ammonium bicarbonate (60 mg, 758 μmol, 1.5 equivalent). The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction system was purified by reversed-phase rapid chromatography under the following conditions: column, C60 ... 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water from 5% to 65% over 25 min, yielding the title compound 25d (110 mg, yield: 74%) as a grayish-white solid.

[0353] MS m / z (ESI): 297.30 [M + H] + .

[0354] 1 H NMR (400 MHz, DMSO- d6) δ 12.04 (s, 1H), 9.12 (s, 2H), 7.60 (s, 1H), 7.40 (s, 1H), 7.17 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 4.69 - 4.63 (m, 2H),2.21 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0355] Step 5: 1-(but-3-enyl)-5-(2-(1-ethyl-3-methyl-1-ethyl-3 ... H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- Preparation of pyrrole-3-carboxamide 25e Compound 25d (100 mg, 337 μmol, 1 equivalent) and potassium carbonate (93 mg, 674 μmol, 2 equivalents) were dissolved in DMF (4 mL) at room temperature and under a nitrogen atmosphere, followed by the addition of 4-bromobut-1-ene (683 mg, 5.1 mmol, 15 equivalents, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY001374). The resulting reaction solution was heated to 80 °C and stirred under these conditions for 16 hours. After the reaction was completed, the reaction system was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water at a gradient of 5% to 80% over 30 minutes, yielding title compound 25e (35 mg, yield: 30%) as a grayish-white solid.

[0356] MS m / z (ESI): 351.15 [M + 1] + .

[0357] Step 6: ( E )-1-(( E )-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H- Pyrazol-5-yl)pyrimidin-5-yl)-1 H- pyrrolo-1-yl)pent-2-enyl)-2-(1-ethyl-3-methyl-1 H- Pyrazole-5-carbonylimino)-2,3-dihydro-1 H- Preparation of benzimidazole-5-carboxamide 25 At room temperature, compounds 25e (30 mg, 86 μmol, 1 equivalent) and (2 E)-2-(2-ethyl-5-methylpyrazole-3-carbonylimino)-1-(prop-2-en-1-yl)-3 H- 1,3-Benzimidazolium-5-carboxamide 25f (60 mg, 172 μmol, 2 equivalents, prepared by the method disclosed in Example 2 on page 215 of patent application "WO2019069269A1") and 4-methylbenzene-1-sulfonic acid hydrate (19 mg, 258 μmol, 3 equivalents) were dissolved in dichloromethane (2.5 mL) and methanol (2.5 mL). The resulting mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure. Dichloromethane (2.5 mL) was added to the residue and stirred at room temperature for 20 minutes. Subsequently, under an argon atmosphere, the above mixture was added to [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-yl]dichloro{[2-(propyl-2-yloxy)phenyl]methylene}ruthenium (48 mg, 77 μmol, 0.90 equivalents). The resulting mixture was then heated to 80 °C and stirred under these conditions for 16 hours. After the reaction was complete, the reaction was neutralized to pH 7 with a solution of bis(trimethylsilylamino)lithium (1 M tetrahydrofuran solution, Panjin Yanfeng Technology Co., Ltd.). The resulting mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane / methanol 9:1) to obtain the crude product. The crude product was further purified by high-performance liquid chromatography under the following conditions: column: Xbridge Prep Phenyl OBD column, 19 × 250 nm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: acetonitrile in water 22% to 39% over 12 minutes; wavelength: 254 / 220 nm; retention time: 11.23 minutes, yielding the title compound 25 (2 mg, yield: 3%) as a grayish-white solid.

[0358] MS m / z (ESI): 675.15 [M + H] + .

[0359] 1 H NMR (400 MHz, DMSO- d6) δ 8.94 - 8.90 (m, 2H), 8.40 (s, 2H), 7.98 -7.71 (m, 2H), 7.61 - 7.58 (m, 1H), 7.40 - 7.34 (m, 2H), 6.87 - 6.77 (m, 4H), 6.57 - 6.54 (m, 1H), 5.62 - 5.57 (m, 2H), 4.74 - 4.59 (m, 5H), 4.07 - 4.03(m, 2H), 2.40 - 2.35 (m, 2H), 2.22 -2.15 (m, 6H), 1.34 - 1.31 (m, 6H).

[0360] Example 13. Preparation of compounds 34 and 35 ( E )-1-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-(2-hydroxyethyl)-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c ]Pyridine-5-carboxamide formate 34 ( Z -3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-(2-hydroxyethyl)-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c ]Pyridine-5-carboxamide formate 35 The synthesis route is as follows: Step 1: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H Preparation of pyrazole-5-carboxylic acid ethyl ester 34a 3-methyl-1 H Ethyl pyrazole-5-carboxylate (1.8 g, 11.5 mmol, 1 equivalent, Shanghai Titan Technology Co., Ltd., Product No.: 013357945), 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol (3.1 g, 17.3 mmol, 1.5 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., Product No.: SY041907), and triphenylphosphine (5.2 g, 19.6 mmol, 1.7 equivalent) were dissolved in tetrahydrofuran (100 mL), and DIAD (4.0 g, 19.6 mmol, 1.7 equivalent) was added dropwise. After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1) to give title compound 34a (3 g, yield: 83%, purity: 95%) as a colorless oil.

[0361] MS m / z (ESI): 313.05 [M + 1] + .

[0362] 1 H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H), 4.65 (t, J = 5.6 Hz, 2H), 4.30(q, J = 7.2 Hz, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.27 (s, 3H), 1.35 (t, J = 7.2Hz, 3H), 0.80 (s, 9H), -0.09 (s, 6H).

[0363] Step 2: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H Preparation of pyrazole-5-carboxylic acid 34b Compound 34a (3 g, 9.6 mmol, 1 equivalent) was dissolved in methanol (30 mL) under a nitrogen atmosphere at 0°C, followed by the addition of lithium hydroxide (690 mg, 28.8 mmol, 3 equivalents) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 3 by adding an aqueous citric acid solution. The resulting mixture was extracted with ethyl acetate (2 × 150 mL). The combined organic phases were washed with saturated brine (2 × 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give title compound 34b (2 g, yield: 73.2%, purity: 93%) as a white solid.

[0364] MS m / z (ESI): 285.05 [M + 1] + .

[0365] 1 H NMR (400 MHz, DMSO- d 6) δ 13.25 (s, 1H), 6.68 (s, 1H), 4.63 (t, J =5.6 Hz, 2H), 3.96 (t, J = 5.6 Hz, 2H), 2.27 (s, 3H), 0.88 (s, 9H), 0.00 (s, 6H).

[0366] Step 3: ( Z )-2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of tert-butyl pyridine-5-carboxylic acid 34c Compound 8b (300 mg, 1.3 mmol, 1 equivalent), compound 34b (358 mg, 1.3 mmol, 1 equivalent), and NMI (207 mg, 2.6 mmol, 2 equivalent) were dissolved in DMF (6 mL) under a nitrogen atmosphere at room temperature, followed by the addition of TCFH (424 mg, 1.5 mmol, 1.2 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C10 ... 18Silica gel; mobile phase, acetonitrile and water; gradient: acetonitrile in water from 5% to 95% over 30 minutes; detector, UV 254 nm, yielded title compound 34c as a yellow solid (330 mg, yield 52%, purity: 93%).

[0367] MS m / z (ESI): 505.40 [M + 1] + .

[0368] 1 H NMR (400 MHz, DMSO- d 6) δ 11.61 (s, 2H), 6.86 (s, 1H), 4.60 (t, J =5.6 Hz, 2H), 4.27 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.60 (t, J = 5.6 Hz,2H), 2.53 - 2.50 (m, 2H), 2.16 (s, 3H), 1.42 (s, 9H), 0.77 (s, 9H), -0.12 (s,6H).

[0369] Step 4: ( Z ) - N -(1, 3, 4, 5, 6, 7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-yl)-1-(2-hydroxyethyl)-3-methyl-1 H Preparation of pyrazole-5-carboxamide 34d Compound 34c (330 mg, 0.7 mmol, 1 equivalent) was dissolved in 1,4-dioxane (5 mL) under a nitrogen atmosphere at room temperature, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (2 M, 5 mL, 10 mmol, 14 equivalents, Shanghai Weiji Environmental Protection Technology Co., Ltd.). The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile and water; gradient: acetonitrile in water 5% to 50% over 15 min; detector, UV 254 nm, yielded 2 title compounds 34d (180 mg, yield: 95%, purity: 95%) as a yellow solid.

[0370] MS: m / z = 291.15 [M + H] + .

[0371] Step 5: ( Z ) -1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- N -(1, 3, 4, 5, 6, 7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-ylyl)-3-methyl-1 H Preparation of pyrazole-5-carboxamide 34e Compound 34d (220 mg, 0.76 mmol, 1 equivalent) and imidazole (309.5 mg, 4.55 mmol, 6 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY006685) were dissolved in DMF (4 mL) at room temperature and under a nitrogen atmosphere, followed by the addition of tert-butyldimethylchlorosilane (171.3 mg, 1.1 mmol, 1.5 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY001514). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile and water; gradient: acetonitrile in water from 2% to 98% over 30 minutes; detector, UV 254 nm, yielded title compound 34e (140 mg, yield: 45%, purity: 89%) as a yellow solid.

[0372] MS m / z (ESI): 405.20 [M + 1] + .

[0373] 1 H NMR (400 MHz, DMSO- d 6) δ 11.89 (s, 1H), 11.53 (s, 1H), 8.97 (s, 1H), 6.95 (s, 1H), 4.61 (t, J = 5.6 Hz, 2H), 4.06 (s, 2H), 3.88 (t, J = 5.6Hz, 2H), 3.40 - 3.37 (m, 2H), 2.82 - 2.70 (m, 2H), 2.18 (s, 3H), 0.76 (s,9H), -0.13 (s, 6H).

[0374] Step 6: ( Z ) -2-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H-pyrazole-5-carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide 34f Compound 34e (100 mg, 0.25 mmol, 1 equivalent) was dissolved in isopropanol (4 mL) under a nitrogen atmosphere at room temperature, followed by the addition of DIEA (96 mg, 0.7 mmol, 3 equivalents) and trimethylsilane isocyanate (51.25 mg, 0.45 mmol, 1.8 equivalents). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C10 ... 18 Silica gel; mobile phase: acetonitrile and water; gradient: acetonitrile in water from 2% to 98% over 25 minutes; detector: UV 254 nm, yielded title compound 34f (85 mg, yield 77%, purity: 90%) as a yellow solid.

[0375] MS m / z (ESI): 448.20 [M + 1] + .

[0376] Step 7: tert-butyl 4-(3-(( E )-3-( E )-4-( E )-2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-5-carbamoyl-2,3,4,5,6,7-hexahydro-1 H -Imidazolidine[4,5- c ]pyridin-1-yl)but-2-en-1-yl)-6-carbamoyl-2-((1-ethyl-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-2,3-dihydro-1 H -benzo[ d Preparation of 34g of imidazole-4-yl)oxy)propyl)piperazine-1-carboxylate 4-(3-((()) E )-3-(( E )-4-(( Z )-2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-5-carbamoyl-1,2,4,5,6,7-hexahydro-3 H -imidazo[4,5-c ]pyridin-3-yl)but-2-en-1-yl)-6-carbamoyl-2-((1-ethyl-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-4-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester 35a Compound 34f (30 mg, 0.06 mmol, 1 equivalent) was dissolved in DMF (0.3 mL) under an argon atmosphere at room temperature, followed by the addition of cesium carbonate (48 mg, 0.15 mmol, 2.2 equivalents). The reaction mixture was stirred at room temperature for 10 minutes. Then, a solution of compound 12h (50.70 mg, 0.07 mmol, 1.1 equivalents) in DMF (0.3 mL) was added dropwise at room temperature. The reaction mixture was heated to 50°C and stirred for 2 hours. After the reaction was complete, the resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, AQ-C. 18 Column, 48 g, 60 Å, 40–60 µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 45 mL / min; 0% B to 100% B over 30 min; detector: UV 254 / 210 nm; retention time 25 min, yielding a mixture of crude product 34 g and 35 a (55 mg). The crude product was further separated by chiral preparation using HPLC (55 mg) under the following conditions: column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 M NH3-MeOH), mobile phase B: ethanol: dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 70%; wavelength: 220 / 254 nm; at retention times of 5.787 min and 12.652 min, the title compound 34 g (20 mg, yield: 17%, purity: 79.5%) and title compound 35a (10 mg, yield: 8%, purity: 84%) were obtained as white solids, respectively.

[0377] Compound 34g: MS m / z (ESI): 527.85 [M + 1] + .

[0378] Compound 35a: MS m / z (ESI): 527.95 [M + 1] + .

[0379] Step 8: ( E ) -1-((E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-(2-hydroxyethyl)-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide formate 34 Compound 34 g (9 mg, 0.009 mmol, 1 equivalent) was dissolved in DCM (1 mL) under an argon atmosphere at room temperature, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions (column: Xselect CSH preparative column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 15%B to 45%B over 12 min; wavelength: 254 / 220 nm; retention time (min): 9.15) to give title compound 34 (1.3 mg, yield 5.95%, purity 98%) as a white solid.

[0380] 34g of compound MS m / z (ESI): 840.55 [M + 1] + .

[0381] 1 H NMR (400 MHz, DMSO- d6) δ 7.99 (s, 1H), 7.64 (s, 1H), 7.35 - 7.31 (m, 2H), 6.60 (s, 1H), 6.46 (s, 1H), 5.84 - 5.79 (m, 2H), 5.71 - 5.66 (m,2H), 4.95 (s, 1H), 4.60 - 4.47 (m, 8H), 4.21 (s, 2H), 4.10 (s, 2H), 3.35 (s,2H), 2.76 (s, 4H), 2.49 - 2.37 (m, 8H), 2.35 (s, 3H), 2.33 (s, 3H), 1.81 (m, 2H), 1.32 (m, 3H).

[0382] Step 9: ( Z -3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H- Pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-(2-hydroxyethyl)-3-methyl-1-yl) H -1 H -pyrazole-5 carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide formate 35 Compound 35a (20 mg, 0.019 mmol, 1 equivalent) was dissolved in DCM (1 mL) under an argon atmosphere at room temperature, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (HPLC) under the following conditions (column: Xselect CSH preparative column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 15%B to 45%B over 12 minutes; wavelength: 254 / 220 nm; retention time (min): 9.20), yielding title compound 35 (4 mg, yield: 24%, purity: 95%) as a white solid.

[0383] Compound 35: MS m / z (ESI): 840.35 [M + 1] + .

[0384] 1 H NMR (400 MHz, DMSO- d 6) δ 7.98 (s, 1H), 7.64 (s, 1H), 7.32 (s, 2H), 6.57 (s, 1H), 6.45 - 6.41 (m, 1H), 6.10 (s, 1H), 5.93 - 5.89 (m, 1H), 5.63 -5.59 (m, 1H), 5.03 (s, 2H), 4.58 - 4.39 (m, 6H), 4.21 - 4.01 (m, 5H), 3.66 (s, 4H), 2.96 (s, 4H), 2.49 - 2.33 (m, 8H), 2.23 - 2.10 (m, 6H), 1.84 (s,2H), 1.31 (m, 3H).

[0385] Example 14. Preparation of compounds 36 and 37 3-(5-(( E )-5-carbamoyl-1-( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d Imidazol-1-yl)but-2-en-1-yl)-1,3,4,5,6,7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-yl)carbamoyl)-3-methyl-1 H 36-pyrazole-1-yl)propionic formate 36 3-(5-(( Z )-5-carbamoyl-3-( E )-4-(( E )-5-aminocarbonyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ dImidazol-1-yl)but-2-en-1-yl)-1,3,4,5,6,7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-yl)carbamoyl)-3-methyl-1 H 37-pyrazole-1-yl)propionate The synthesis route is as follows: Step 1: 1-(3-(tert-butoxy)-3-oxopropyl)-3-methyl-1 H Preparation of pyrazole-5-carboxylic acid ethyl ester 36a 3-methyl-1 H Ethyl pyrazole-5-carboxylate (6.3 g, 41.0 mmol, 1.2 equivalents), tert-butyl 3-hydroxypropionate (5 g, 34.2 mmol, 1.00 equivalents, Changzhou Xiya Biotechnology Co., Ltd.), and triphenylphosphine (14.4 g, 54.7 mmol, 1.6 equivalents) were dissolved in tetrahydrofuran (100 mL), and DIAD (4.0 g, 19.6 mmol, 1.7 equivalents) was added dropwise. After the addition was complete, the reaction system was moved to room temperature and stirred for 16 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1) to give the title compound 36a (859 mg, yield: 9%, purity: 93%) as a yellow oil.

[0386] MS m / z (ESI): 283.10 [M + 1] + .

[0387] Step 2: 1-(3-(tert-butoxy)-3-oxopropyl)-3-methyl-1 H Preparation of pyrazole-5-carboxylic acid 36b Compound 36a (1.1 g, 4.1 mmol, 1 equivalent) was dissolved in THF (18 mL) at 0°C, followed by the addition of lithium hydroxide (1 M, 8.2 mL, 8.2 mmol, 2 equivalents, Shanghai Huaran Industrial Co., Ltd.). The reaction system was stirred at room temperature for 3 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure, and the pH of the reaction solution was adjusted to 6 with HCl (1 M). The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column: AQ-C 18The column was 330 g, 60 Å, 40–60 µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 90 mL / min; gradient: 0%B to 100%B over 30 min; detector: UV 254 / 210 nm; retention time: 20 min), yielding title compound 36b (473 mg, yield: 45%, purity: 95%) as a grayish-white solid.

[0388] MS m / z (ESI): 255.05 [M + 1] + .

[0389] Step 3: ( Z )-2-((1-(3-(tert-butoxy)-3-oxopropyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of tert-butyl pyridine-5-carboxylic acid ester 36c Compound 8b (450 mg, 1.9 mmol, 1 equivalent), compound 36b (528 mg, 2.1 mmol, 1.1 equivalent), and NMI (310 mg, 3.8 mmol, 2 equivalent) were dissolved in DMF (6 mL) under a nitrogen atmosphere at room temperature, followed by the addition of TCFH (636 mg, 2.3 mmol, 1.2 equivalent). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (10:1) elution to obtain crude product 36c. The crude product was purified by reversed-phase flash evaporation under the following conditions: column: AQ-C 18 The column was 120 g, 60 Å, 40–60 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 0%B to 100%B over 30 min; detector: UV254 / 210 nm; retention time: 20 min), yielding the title compound 36c (360 mg, yield: 40%, purity: 78%) as a yellow solid.

[0390] MS m / z (ESI): 475.20 [M + 1] + .

[0391] Step 4: ( Z )-3-(5-((1, 3, 4, 5, 6, 7-hexahydro-2- H -Imidazolidine[4,5- c]pyridine-2-yl)carbamoyl)-3-methyl-1 H Preparation of tert-butyl pyrazole-1-yl)propionate 36d Compound 36c (390 mg, 0.8 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL) at -78 °C, followed by the addition of trifluoroacetic acid (3 mL). The reaction mixture was heated to 0 °C and stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5 with a 7M ammonia-methanol solution. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, AQ-C. 18 The column was 220 g, 60 Å, 40–60 µm; mobile phase A: water, mobile phase B: MeCN; flow rate: 75 mL / min; 0% B to 100% B over 30 min; detector: UV 254 / 210 nm; retention time: 20 min), yielding the title compound 36d (162 mg, yield: 52%, purity: 95%) as a yellow solid.

[0392] MS m / z (ESI): 375.15 [M + 1] + .

[0393] Step 5: ( Z )-3-(5-((5-carbamoyl-1,3,4,5,6,7-hexahydro-2- H -Imidazolidine[4,5- c ]pyridine-2-yl)carbamoyl)-3-methyl-1 H Preparation of tert-butyl pyrazole-1-yl)propionate 36e Compound 36d (162 mg, 0.4 mmol, 1 equivalent) and trimethylsilane isocyanate (89.7 mg, 0.8 mmol, 1.8 equivalent) were dissolved in isopropanol (0.5 mL) at room temperature and under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by chromatography using DCM / MeOH (10:1) as an elution to give the title compound 36e (174 mg, yield: 96%, purity: 95%) as a grayish-white solid.

[0394] MS m / z (ESI): 418.15 [M + 1] + .

[0395] Step 6: tert-butyl 4-(3-(( E )-3-( E )-4-( E)-2-(1-(3-(tert-butoxy)-3-oxopropyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-5-carbamoyl-2,3,4,5,6,7-hexahydro-1 H -Imidazolidine[4,5- c ]pyridin-1-yl)but-2-en-1-yl)-6-carbamoyl-2-((1-ethyl-3-methyl-1-yl) H -1 H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-4-yl)oxy)propyl)piperazine-1-carboxylate 36f 4-(3-((()) E )-3-(( E )-4-(( Z )-2-(1-(3-(tert-butoxy)-3-oxopropyl)-3-methyl-1 H -pyrazole-5-carbonyl)imino)-5-carbamoyl-1,2,4,5,6,7-hexahydro-3H-imidazo[4,5- c ]pyridin-3-yl)but-2-en-1-yl)-6-carbamoyl-2-((1-ethyl-3-methyl-1-yl) H -1 H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-4-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester 37a Compound 36e was dissolved in DMF (0.5 mL) under an argon atmosphere at room temperature, followed by the addition of cesium carbonate (103 mg, 0.3 mmol, 2.2 equivalents). The reaction mixture was stirred at room temperature for 10 minutes. Then, a solution of compound 12h (99 mg, 0.14 mmol, 1 equivalent) in DMF (0.3 mL) was added dropwise at room temperature. The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, AQ-C. 18Column, 48 g, 60 Å, 40–60 µm; mobile phase A: water, mobile phase B: acetonitrile; flow rate: 45 mL / min; 0% B to 100% B over 30 min; detector: UV 254 / 210 nm; retention time 20 min, yielding a mixture of crude products 36f and 37a (67 mg) as a pale yellow solid. The crude product was separated by preparative chiral high-performance liquid chromatography (HPLC) under the following conditions: column: CHIRALPAK ID, 2 × 25 cm, 5 μm; mobile phase A: n-hexane (0.5% 2 M NH3-MeOH), mobile phase B: ethanol: dichloromethane = 1:1; flow rate: 20 mL / min; gradient: 70%; wavelength: 220 / 254 nm; at retention times of 11.669 min and 21.153 min, title compound 36f (30 mg, yield: 20%, purity: 98%) was obtained as a grayish-white solid, and title compound 37a (10 mg, yield: 7%, purity: 89%) was obtained as a white solid.

[0396] Compound 36f: MS m / z (ESI): 1046.55 [M + Na] + .

[0397] Compound 37a: MS m / z (ESI): 1046.50 [M + Na] + .

[0398] Step 7: 3-(5-(( E )-5-carbamoyl-1-( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ d Imidazol-1-yl)but-2-en-1-yl)-1,3,4,5,6,7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-yl)carbamoyl)-3-methyl-1 H Preparation of pyrazole-1-yl)propionic formate 36 Compound 36f (10 mg, 0.01 mmol, 1 equivalent) was dissolved in DCM (1 mL) under an argon atmosphere at room temperature, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified directly by preparative high-performance liquid chromatography (HPLC) under the following conditions (column: Xselect CSH preparative column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 5%B to 30%B over 12 minutes; wavelength: 254 / 220 nm; retention time: 9.15 minutes) to obtain the title compound 36 (2.5 mg, yield: 28%, purity: 99%) as a grayish-white solid.

[0399] MS m / z (ESI): 868.35 [M + 1] + .

[0400] 1 H NMR (400 MHz, DMSO- d 6) 8.01 (s, 1H), 7.65 (s, 1H), 7.36 - 7.33 (m, 2H), 6.50 - 6.46 (d, J = 8.8 Hz, 2H), 6.06 (s, 2H), 6.10 (s, 1H), 5.84 - 5.77(m, 2H), 4.96 (s, 3H), 4.67 - 4.53 (m, 7H), 4.14 (s, 4H), 2.89 (s, 4H), 2.57(s, 2H), 2.44 (s, 6H), 2.30 (s, 2H), 2.13 - 2.10 (d, J = 7.4 Hz, 6H), 1.89(s, 2H), 1.31 - 1.27 (m, 3H).

[0401] Step 8: 3-(5-(( Z )-5-carbamoyl-3-( E )-4-(( E )-5-aminocarbonyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-7-(3-(piperazin-1-yl)propoxy)-2,3-dihydro-1 H -benzo[ dImidazol-1-yl)but-2-en-1-yl)-1,3,4,5,6,7-hexahydro-2 H -Imidazolidine[4,5- c ]pyridine-2-yl)carbamoyl)-3-methyl-1 H Preparation of pyrazole-1-yl)propionate 37 Compound 37a (30 mg, 0.03 mmol, 1 equivalent) was dissolved in DCM (1 mL) at room temperature and under an argon atmosphere, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and lyophilized to give the title compound 37 (8.5 mg, yield: 32%, purity: 96%) as a grayish-white solid.

[0402] MS m / z (ESI): 868.50 [M + 1] + .

[0403] 1 H NMR (400 MHz, DMSO- d 6) 9.78 (s, 2H), 8.02 (s, 1H), 7.66 (s, 1H),7.39 (s, 2H), 6.89 (s, 1H), 6.54 (s, 1H), 6.27 - 6.21 (m, 1H), 5.58 - 5.53(m, 1H), 5.04 - 4.98 (m, 2H), 4.86 - 4.78 (m, 2H), 4.54 - 4.48 (m, 4H), 4.46- 4.41 (m, 2H), 4.26 - 4.20(m, 2H), 4.00 - 3.98 (m, 4H), 3.38 - 3.35 (m, 5H), 2.72 - 2.68 (m, 2H), 2.52 - 2.48 (m, 2H), 2.27- 2.26 (m, 2H), 2.13 (s, 6H), 1.33 - 1.28 (m, 3H).

[0404] Example 15. Synthesis of Compound 44 1-(( E )-4-(( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-N 2-(1-Ethyl-3-methyl-1- H -pyrazole-5-yl)-1 H -benzo[ d Imidazole-2,5-dicarboxamide 44 The synthesis route is as follows: Step 1: ( E Preparation of 4-(4-carbamoyl-2-nitrophenylamino)but-2-phenylcarbamate tert-butyl ester 44a Under a nitrogen atmosphere at room temperature, 4-chloro-3-nitrobenzamide (2 g, 10 mmol, 1 equivalent, Shanghai Bid Pharmaceutical Technology Co., Ltd., product number: BD4374) and potassium carbonate (2.8 g, 10 mmol, 2 equivalents) were dissolved in DMSO (30 mL), and then (… E 4-Aminobut-2-enylcarbamate tert-butyl ester (2.2 g, 12 mmol, 1.2 equivalents). After addition, the resulting mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the reaction system was cooled to room temperature. Water (200 mL) was added to the mixture, and a pale yellow solid precipitated. The resulting mixture was filtered and washed with water (3 × 20 mL), and the filter cake was collected to give the title compound 44a (1.9 g, yield: 54%) as a yellow solid.

[0405] MS m / z (ESI): 701.35 [M + 1] + .

[0406] 1 H NMR (300 MHz, DMSO- d 6) δ 8.66 (d, J = 2.1 Hz, 1H), 8.54 - 8.50 (m,1H), 8.02 - 7.94 (m, 2H), 7.28 (s, 1H), 7.12 - 6.95 (m, 2H), 5.70 - 5.55 (m,2H), 4.07 - 4.02 (m, 2H), 3.55 - 3.52 (m, 2H), 1.36 (s, 9H).

[0407] Step 2: ( E Preparation of 4-(2-amino-4-carbamoylphenylamino)but-2-phenylcarbamate tert-butyl ester 44b Compound 44a (1.5 g, 4.3 mmol, 1 equivalent) and ammonia (8 mL, 205.4 mmol, 48 equivalent) were dissolved in methanol (30 mL) under a nitrogen atmosphere at 0°C, followed by the addition of sodium dithionite (8.9 g, 51.4 mmol, 12 equivalent) and water (15 mL). After the addition was complete, the reaction mixture was removed from the ice bath and allowed to rise naturally to room temperature, where it was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (2 × 200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 44b (1.1 g, yield: 80%) as a yellow solid.

[0408] MS m / z (ESI): 692.2 [M + 1] + .

[0409] 1 H NMR (400 MHz, DMSO- d 6) δ 7.43 (s, 1H), 7.09 - 7.06 (m, 2H), 6.97(t, J = 5.6 Hz, 1H), 6.74 (s, 1H), 6.36 - 6.33 (m, 1H), 5.65 - 5.55 (m, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.59 (s, 2H), 3.73 - 3.72 (m, 2H), 3.55 - 3.52 (m, 2H), 1.37 (s, 9H).

[0410] Step 3: ( E )-1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-1 H -benzo[ d Preparation of ethyl imidazole-2-carboxylate 44c Compound 44b (3 g, 9.4 mmol, 1 equivalent) was dissolved in DMF (30 mL) under a nitrogen atmosphere at room temperature, followed by the addition of ethyl 2-oxoacetate (2.9 g, 28.1 mmol, 3 equivalents). The resulting mixture was stirred at 80°C for 2 hours. Sodium metabisulfite (3.6 g, 18.7 mmol, 2 equivalents) was then added to the reaction mixture, and the mixture was stirred at 120°C for 16 hours. After the reaction was complete, water (300 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (400 mL). The organic phase was then washed with saturated brine (2 × 200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (9:1) to give the title compound 44c (3 g, yield: 80%) as a yellow solid.

[0411] MS m / z (ESI): 403.05 [M + 1] + .

[0412] 1 H NMR (300 MHz, DMSO- d 6) δ 8.35 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.39 (s, 1H), 6.95 - 6.91(m, 1H), 5.73 - 5.56 (m, 2H), 5.23 (d, J = 5.7 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.51 - 3.45 (s, 2H), 1.40 - 1.33 (m, 12H).

[0413] Step 4: ( E ) -1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-1 H -benzo[ d Preparation of imidazole-2-carboxylic acid 44d Compound 44c (2 g, 5 mmol, 1 equivalent) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) at room temperature, followed by the addition of an aqueous solution of lithium hydroxide (1 M, 10 mL, 10 mmol, 2 equivalents). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude title compound 44d (2 g). The product did not require further purification and was used directly in the next step.

[0414] MS m / z (ESI): 375.15 [M + 1] + .

[0415] Step 5: ( E )-(4-(5-carbamoyl-2-((1-ethyl-3-methyl-1) H -pyrazole-5-yl)carbamoyl)-1 H -benzo[ d Preparation of imidazole-1-yl)but-2-en-1-yl)tert-butyl carbamate 44e Under a nitrogen atmosphere at room temperature, 44d (3 g, 8 mmol, 1 equivalent) and 2-ethyl-5-methylpyrazole-3-amine (1.5 g, 12 mmol, 1.5 equivalent, Shanghai Bied Pharmaceutical Technology Co., Ltd., product number: BD58241) were dissolved in DMF (20 mL), followed by the addition of HATU (3.7 g, 9.6 mmol, 1.2 equivalent) and DIEA (2.1 g, 16 mmol, 2 equivalent). After the addition was complete, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated brine (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with saturated brine (2 × 200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and eluted with dichloromethane / methanol (9:1) to give the title compound 44e (1.2 g, yield: 31%) as a white solid.

[0416] MS m / z (ESI): 482.25 [M + 1] + .

[0417] 1 H NMR (300 MHz, DMSO- d 6) δ 10.91 (s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.09 (s, 1H), 7.98 (dd, J= 8.7, 1.5 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.42(s, 1H), 6.95 - 6.92 (m, 1H), 6.05 (s, 1H), 5.77 - 5.61 (m, 2H), 5.30 (d, J =5.4 Hz, 2H), 3.97 (q, J = 7.2 Hz, 2H), 3.51 - 3.47 (m, 2H), 2.15 (s, 3H), 1.33 - 1.27 (m, 12H).

[0418] Step 6: ( E ) -1-(4-aminobut-2-en-1-yl)-5-(aminomethyl)- N -(1-ethyl-3-methyl-1 H -pyrazole-5-yl)-1 H -benzo[ d Preparation of imidazole-2-carboxamide 44f Compound 44e (1.3 g, 2.7 mmol, 1 equivalent) was dissolved in ethyl acetate (10 mL) at room temperature, followed by the addition of an ethyl acetate solution of hydrogen chloride (4 M, 10 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product, title compound 44f (1 g), as a white solid. The product did not require further purification and was used directly in the next step.

[0419] MS m / z (ESI): 382.05 [M + 1] + .

[0420] Step 7: ( E ) -1-(4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)- N 2-(1-Ethyl-3-methyl-1- H -pyrazole-5-yl)-1 H -benzo[ d Preparation of 44g of imidazole-2,5-dicarboxamide Compound 44f (600 mg, 1.6 mmol, 1 equivalent) and 4-chloro-3-nitrobenzamide (290 mg, 1.6 mmol, 1 equivalent) were dissolved in DMF (10 mL) at room temperature and under a nitrogen atmosphere, followed by the addition of potassium carbonate (652.2 mg, 4.7 mmol, 3 equivalent). After the addition was complete, the reaction system was heated to 70 °C and stirred for 16 hours. After the reaction was completed, water (60 mL) was added to quench the reaction, resulting in the precipitation of a solid. The mixture was filtered and washed with water (3 × 10 mL). The filter cake was collected, dried, and the crude title compound 44f (500 mg) was obtained as a yellow solid.

[0421] MS m / z (ESI): 546.55 [M + 1] + .

[0422] 1 H NMR (400 MHz, DMSO- d 6) δ 10.90 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.09 (s, 1H), 7.98 - 7.95(m, 2H), 7.91 (dd, J = 9.2, 2.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.43 (s,1H), 7.29 (s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.97 (s, 1H), 5.96 - 5.89 (m,1H), 5.76 - 5.70 (m, 1H), 5.33 (d, J = 6.0 Hz, 2H), 4.06 - 4.02 (m, 2H), 3.92(q, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0423] Step 8: ( E ) -1-(4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)- N 2-(1-Ethyl-3-methyl-1-H -pyrazole-5-yl)-1 H -benzo[ d Preparation of imidazole-2,5-dicarboxamide 44h Under a nitrogen atmosphere at room temperature, 44 g of compound 44 was dissolved in tetrahydrofuran (6 mL) and methanol (3 mL). Ammonia (36%, 3 mL, 77 mmol, 84 equivalents) and sodium dithionite (3.2 g dissolved in 15 mL of water, 18.3 mmol, 20 equivalents) were then added to the reaction mixture. After the addition was complete, the resulting mixture was heated to 40°C and stirred at this temperature for 24 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and water (250 mL) was added to the resulting mixture. The mixture was then filtered to give the title compound 44h (400 mg, yield: 85%) as a white solid.

[0424] MS m / z (ESI): 516.25 [M + 1] + .

[0425] 1 H NMR (300 MHz, DMSO- d 6) δ 10.91 (s, 1H), 8.36 - 8.35 (m, 1H), 8.09 (s, 1H), 7.98 (dd, J = 8.7, 1.5 Hz, 1H), 7.81 - 7.78 (m, 1H), 7.47 - 7.40 (m,2H), 7.15 - 7.10 (m, 2H), 6.78 (br s, 1H), 6.35 - 6.32 (m, 1H), 6.06 - 6.03(m, 1H), 5.93 - 5.76 (m, 2H), 5.34 - 5.21 (m, 3H), 3.95 (q, J = 7.2 Hz, 2H),3.74 - 3.67 (m, 2H), 2.15 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0426] Step 9: ( E ) -1-(4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)- N 2-(1-Ethyl-3-methyl-1- H -pyrazole-5-yl)-1 H -benzo[ d Preparation of imidazole-2,5-dicarboxamide 44h Compound 44h (50 mg, 0.1 mmol, 1 equivalent) and 2-ethyl-5-methylazole-3-carbonyl isothiocyanate 1b (28 mg, 0.15 mmol, 1.5 equivalent) were dissolved in DMF (3 mL) at room temperature and under a nitrogen atmosphere, followed by the addition of EDCI (46.5 mg, 0.2 mmol, 2.5 equivalent) and triethylamine (29 mg, 0.3 mmol, 3 equivalent). The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was purified by high-performance liquid chromatography (HPLC) under the following conditions: column: Xselect CSH C 18 OBD column 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: methanol; flow rate: 60 mL / min; gradient: acetonitrile in water from 40% B to 70% B over 8 minutes; wavelength: 254 nm; retention time (min): 7, yielding title compound 44 (10.6 mg, yield: 16%) as a white solid.

[0427] MS m / z (ESI): 677.40 [M + 1] + .

[0428] 1 H NMR (400 MHz, DMSO- d 6) δ 12.77 (s, 1H), 10.87 (s, 1H), 8.34 (s,1H), 8.07 (s, 1H), 7.98 - 7.92 (m, 3H), 7.77 - 7.71 (m, 2H), 7.41 - 7.33 (m,3H), 6.53 (s, 1H), 6.06 - 5.99 (m, 1H), 5.91 (s, 1H), 5.84 - 5.77 (m, 1H),5.32 (d, J = 5.6 Hz, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 3.86 (q, J = 7.2 Hz, 2H), 2.13 (s, 6H), 1.27 - 1.20 (m, 6H).

[0429] Example 16. Synthesis of Compounds 45 and 46 ( E ) - N -(2-aminoethyl)-1-(( E )-4-(E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-methyl-3-methyl-1-yl)] H -1 H -pyrazole-5 carbonyl)imine)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c ]Pyridine-5-carboxamide hydrochloride 45 ( E ) - N -(2-aminoethyl)-3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-methyl-3-methyl-1-yl)] H -1 H -pyrazole-5 carbonyl)imine)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c ]Pyridine-5-carboxamide formate 46 The synthesis route is as follows: Step 1: 2-(( E )-1-( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-methyl-3-methyl-1] H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H -Imidazolidine[4,5- c Preparation of 45a pyridine-5-carbamate (tert-butyl ethyl carbamate) 2-(( E )-3-(E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-methyl-3-methyl-1] H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H -Imidazolidine[4,5- c Preparation of 46a of pyridine-5-carboxamido(tert-butyl)ethylcarbamate Under an argon atmosphere and at room temperature, tert-butyl (2-aminoethyl)carbamate (25.1 mg, 0.16 mmol, 1.00 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY002861) was dissolved in DCM (0.5 mL), followed by the addition of triethylamine (47.5 mg, 0.5 mmol, 3 equivalents). After the addition was complete, the resulting mixture was stirred at room temperature for 10 minutes. Then, the reaction mixture was added... N, N '-Carbonyldiimidazole (31.7 mg, 0.2 mmol, 1.3 equivalents, Shanghai Haohong Biomedical Technology Co., Ltd., Product No.: 1034792) was used, and the resulting mixture was stirred at room temperature for 1 hour. A mixture of compounds 8 g and 9b (100 mg, 0.16 mmol, 1 equivalent) was dissolved in tetrahydrofuran (0.5 mL), and triethylamine (47.5 mg, 0.5 mmol, 3 equivalents) was added as mixture B. Then, mixture B was added to the above reaction system, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography, eluting with dichloromethane / methanol (0.01% ammonia) 7:1, to give a crude mixture of title compounds 45a and 46a (106 mg). The crude product was prepared and separated by chiral high-performance liquid chromatography (HPLC) under the following conditions: column: CHIRALPAK IG 2 × 25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.1% formic acid), mobile phase B: (methanol: dichloromethane = 1:1); flow rate: 20 mL / min; gradient: 0–80%; wavelength: 220 / 254 nm; sample solvent: ethanol; injection volume: 2.0 mL. At retention times of 8.29 min and 16.083 min, title compound 46a (47 mg, yield: 36%, purity: 70%) was obtained as a pale yellow solid, and title compound 45a (33 mg, yield: 25%, purity: 75%) was obtained as a grayish-white solid.

[0430] Compound 45a: MS m / z (ESI): 847.35 [M + 1] + .

[0431] Compound 46a: MS m / z (ESI): 847.40 [M + 1] + .

[0432] Step 2: ( E ) - N -(2-aminoethyl)-1-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-methyl-3-methyl-1-yl)] H -1 H -pyrazole-5 carbonyl)imine)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide hydrochloride 45 Compound 45a (33 mg, 0.04 mmol, 1 equivalent) was dissolved in 1,4-dioxane (1.5 mL) at room temperature, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give title compound 45 (24.9 mg, yield: 86%, purity: 95%) as a pale yellow solid.

[0433] MS m / z (ESI): 725.50 [M + 1] + .

[0434] 1 H NMR (300 MHz, Methanol- d 4) δ 8.07 (d, J = 1.5 Hz, 1H), 7.89 - 7.86(m, 1H), 7.57 (d, J= 8.7 Hz, 1H), 6.98 (s, 1H), 6.72 (s, 1H), 6.02 (s, 2H), 5.07 (s, 2H), 4.90 (s, 2H), 4.79 - 4.72 (m, 2H), 4.54 (s, 2H), 4.44 - 4.36(m, 2H), 3.76 (s, 2H), 3.48 (t, J = 5.7 Hz, 2H), 3.09 (t, J = 5.7 Hz, 2H),2.75 (s, 2H), 2.39 (s, 3H), 2.20 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0435] Step 3: ( E ) - N -(2-aminoethyl)-3-(( E )-4-( E )-5-carbamoyl-2-((1-ethyl-3-methyl-1-) H -pyrazole-5-carbonyl)imino)-2,3-dihydro-1 H -benzo[ d [Imidazol-1-yl)but-2-en-1-yl)-2-(((1-methyl-3-methyl-1-yl)] H -1 H -pyrazole-5 carbonyl)imine)-1,2,3,4,6,7-hexahydro-5 H -Imidazolidine[4,5- c Preparation of pyridine-5-carboxamide formate 46 Compound 46a (47 mg, 0.06 mmol, 1 equivalent) was dissolved in 1,4-dioxane (1.5 mL) at room temperature, followed by the addition of 1,4-dioxane hydrogen chloride (4.0 M, 1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting mixture was separated by high-performance liquid chromatography (HPLC) under the following conditions: (Column: XbridgeShield RP) 18OBD column 19 × 250 cm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: methanol; flow rate: 25 mL / min; gradient: 5% B to 35% B over 10 min; wavelength: 254 nm / 220 nm; retention time (min): 7.24), yielded title compound 46 (15.5 mg, yield: 35%, purity: 97%) as a white solid.

[0436] MS m / z (ESI): 725.55 [M + 1] + .

[0437] 1 H NMR (400 MHz, Methanol- d 4) δ 7.96 (d, J = 1.6 Hz, 1H), 7.79 - 7.76(m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 5.84 - 5.77(m, 2H), 4.90 (s, 2H), 4.67 - 4.61 (m, 2H), 4.56 - 4.55 (m, 2H), 4.52 - 4.46(m, 2H), 4.31 (s, 2H), 3.51 (t, J = 5.6 Hz, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.04 (t, J = 5.6 Hz, 2H), 2.57 - 2.54 (m, 2H), 2.23 - 2.18 (m, 6H), 1.38 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0438] Example 17. Synthesis of Compound 47 ( E ) - N -(3-aminopropyl)-1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1] H -1H -pyrazole-5-carbonylimino)-1,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide hydrochloride 47 The synthesis route is as follows: Step 1: 3-(( E )-1-( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-methyl-3-methyl-1] H -pyrazole-5-carbonylimino)-2,3,4,5,6,7-hexahydro-1 H -Imidazolidine[4,5- c Preparation of 47a pyridine-5-carbamate (tert-butyl propyl carbamate) 3-Aminopropylcarbamate tert-butyl ester (41 mg, 0.2 mmol, 1 equivalent) was dissolved in DCM (1 mL) at room temperature and under an argon atmosphere, followed by the addition of triethylamine (71.4 mg, 0.7 mmol, 3 equivalents). After the addition was complete, the resulting mixture was stirred at room temperature for 10 minutes. Then, the reaction mixture was added... N, N'-Carbonyldiimidazole (47.7 mg, 0.3 mmol, 1.25 equivalents) was added and stirred at room temperature for 1 hour. 8 g (50 mg, 0.078 mmol, 0.3 equivalents) of the compound was dissolved in tetrahydrofuran (0.5 mL), and triethylamine (71.4 mg, 0.7 mmol, 3 equivalents) was added as mixture B. Mixture B was then added to the above reaction system, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was separated by thin-layer chromatography, eluting with dichloromethane / methanol (0.01% ammonia) = 7:1, to give the crude title compound 47a. The crude product was further purified by chiral high-performance liquid chromatography under the following conditions: column: CHIRALPAK IG 2 × 25 cm, 5 μm; mobile phase A: methyl tert-butyl ether (0.1% formic acid), mobile phase B: (methanol: dichloromethane = 1:1); flow rate: 20 mL / min; gradient: 0-80%; wavelength: 220 / 254 nm; retention time (min): 15.958; sample solvent: ethanol; injection volume: 2.0 mL, yielding the title compound 47a (46 mg, yield: 23%, purity: 95%) as a grayish-white solid.

[0439] MS m / z (ESI): 839.40 [M + 1] + .

[0440] Step 2: ( E ) - N -(3-aminopropyl)-1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1] H -1 H -pyrazole-5-carbonylimino)-1,3,6,7-tetrahydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 47-formamide hydrochloride Compound 47a (46 mg, 0.06 mmol, 1 equivalent) was dissolved in 1,4-dioxane (1.5 mL) at room temperature and in an air atmosphere, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4 M, 1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to give compound 47 (30.3 mg, yield: 75%, purity: 97%) as a pale yellow solid.

[0441] MS m / z (ESI): 739.60 [M + 1] + .

[0442] 1 H NMR (300 MHz, Methanol- d 4) 8.10 (d, J = 1.5 Hz, 1H), 7.91 - 7.88(m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 6.76 (s, 1H), 6.10 - 5.95(m, 2H), 5.17 - 5.10 (m, 2H), 4.95 - 4.85 (m, 2H), 4.81 - 4.74 (m, 2H), 4.54(s, 2H), 4.44 - 4.37 (m, 2H), 3.80 - 3.70 (m, 2H), 3.35 - 3.34 (m, 2H), 3.01- 2.96 (m, 2H), 2.74 (s, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 1.92 - 1.84 (m, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0443] Example 18. Synthesis of Compound 49 1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((4-ethyl-2-methylthiazolyl-5-yl)ethynyl)-1 H -benzo[ d Imidazole-5-formamide 49 The synthesis route is as follows: Step 1: Preparation of 4-ethyl-2-methylthiazole 49a Ethylthioamide (1 g, 13.3 mmol, 1 equivalent, Shanghai Haohong Biomedical Technology Co., Ltd., Product No.: 1038178) was dissolved in toluene (10 mL) at room temperature and under an argon atmosphere, followed by the addition of 1-chlorobut-2-one (1.4 g, 13.3 mmol, 1 equivalent, Shanghai Bide Pharmaceutical Technology Co., Ltd., Product No.: BD57897). After the addition was complete, the resulting mixture was heated to 110 °C and stirred overnight at this temperature. After the reaction was complete, the mixture was allowed to cool to room temperature. Then, triethylamine (1.5 g, 14.6 mmol, 1.1 equivalent) was added to the above reaction solution. The resulting mixture was then filtered and the filter cake was washed with water (2 × 8 mL). The filtrate was concentrated under reduced pressure to give the title compound 49a (200 mg, yield: 12%) as a brown oil.

[0444] MS m / z (ESI): 128.15 [M + 1] + .

[0445] Step 2: Preparation of 4-ethyl-2-methylthiazole 5-bromo-4-ethyl-2-methylthiazole 49b Compound 49a (400 mg, 3.1 mmol, 1 equivalent) was dissolved in DCM (10 mL) at room temperature and under an argon atmosphere, and then... N - Bromosuccinimide (839.5 mg, 4.7 mmol, 1.5 equivalents). The resulting mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:3) to give title compound 49b (333 mg, yield: 51%) as a yellow solid.

[0446] MS m / z (ESI): 205.90, 207.90 [M + 1] + .

[0447] Step 3: Preparation of 5-(3-(tert-butyldimethylsiloxy)prop-1-ynyl)-4-ethyl-2-methylthiazole 49c Compound 49b (200 mg, 1 mmol, 1 equivalent) was dissolved in 1,4-dioxane (5 mL) at room temperature and under an argon atmosphere, followed by the sequential addition of tert-butyldimethyl(propane-2-alkynoxy)silane (330.6 mg, 2 mmol, 2 equivalents), triethylamine (982 mg, 9.7 mmol, 10 equivalents), cuprous iodide (55.4 mg, 0.3 mmol, 0.3 equivalents), and palladium dichloride bis(triphenylphosphine) (136.2 mg, 0.2 mmol, 0.2 equivalents). After the addition was complete, the reaction mixture was heated to 70°C and stirred at this temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:3) to give 49c (55 mg, yield: 19%) as a yellow solid.

[0448] MS m / z (ESI): 296.10 [M + 1] + .

[0449] Step 4: Preparation of 3-(4-ethyl-2-methylthiazolyl-5-yl)prop-2-yn-1-ol 49d Compound 49c (40 mg, 0.14 mmol, 1 equivalent) was dissolved in tetrahydrofuran (0.5 mL) under an argon atmosphere at room temperature, followed by the addition of triethylamine trifluoride (109.1 mg, 0.7 mmol, 5 equivalents). After the addition was complete, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were then washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 49d (18 mg, yield: 73%) as a yellow oil.

[0450] MS m / z (ESI): 182.10 [M + 1] + .

[0451] Step 5: Preparation of 3-(4-ethyl-2-methylthiazolyl-5-yl)propionaldehyde 49e Compound 49d (18 mg, 0.1 mmol, 1 equivalent) was dissolved in DCM (0.5 mL) at 0°C under an argon atmosphere, followed by the addition of Dys-Martin oxidant (63.2 mg, 0.15 mmol, 1.5 equivalent, Shanghai Bid Pharmaceutical Technology Co., Ltd., product number: BD35199). The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then washed with saturated brine (3 × 15 mL), dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 49e (15 mg, yield: 84%) as a yellow solid.

[0452] MS m / z (ESI): 180.10 [M + 1] + .

[0453] Step 6: 1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H- pyrazole-5-carbonylimino)-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((4-ethyl-2-methylthiazolyl-5-yl)ethynyl)-1 H -benzo[ d Preparation of imidazole-5-formamide 49 Compound 49e (15 mg, 0.1 mmol, 1 equivalent) was dissolved in DMF (0.3 mL) at room temperature and under an argon atmosphere, followed by the addition of compound 18b (47.5 mg, 0.11 mmol, 1.1 equivalent) and potassium peroxymonosulfonate (14.1 mg, 0.1 mmol, 1 equivalent). After the addition was complete, the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions: column: Xselect CSH preparative column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 25%B to 40%B over 10 minutes; wavelength: 254 nm / 220 nm; R retention time: 8.67 minutes, yielding title compound 49 (7.8 mg, yield: 13%) as a grayish-white solid.

[0454] MS m / z (ESI): 675.30 [M + 1] + .

[0455] 1 H NMR (400 MHz, DMSO- d 6) δ 8.23 ​​(s, 1H), 8.04 - 7.87 (m, 4H), 7.70 -7.67 (m, 2H), 7.42 - 7.35 (m, 3H), 6.52 (s, 1H), 6.03 - 5.97 (m, 1H), 5.82 -5.77 (m, 1H), 5.03 (d, J = 4.4 Hz, 2H), 4.82 (d, J = 5.2 Hz, 2H), 4.55 - 4.50(m, 2H), 2.69 - 2.59 (m, 6H), 2.12 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.18 -1.10 (m, 3H).

[0456] Example 19. Synthesis of Compound 50 E ) -7-(3-aminopropoxy)-1-(( E )-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H -pyrazol-5-yl)pyrimidin-5-yl)-1 H -pyrrolo-1-yl)pent-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrrole-5-carbonylimino)-2,3-dihydro-1 H -benzo[ d Imidazole-5-formamide 50 The synthesis route is as follows: Step 1: ( E Preparation of 6-ethoxy-6-oxohex-3-enoic acid 50a At room temperature and under a nitrogen atmosphere, ( EHexanoic acid (10 g, 69.4 mmol, 1 equivalent, produced by TCI (Shanghai) Chemical Industry Development Co., Ltd., product number: H0477) was dissolved in ethanol (200 mL), and concentrated hydrochloric acid (2 mL, 65.8 mmol, 0.95 equivalent) was added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography, eluting with dichloromethane / methanol (2% formic acid) = (19:1) to give the title compound 50a (7 g, yield: 59%) as a colorless oil.

[0457] MS m / z (ESI): 173.10 [M + 1] + .

[0458] 1 H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 5.78 - 5.64 (m, 2H), 4.17 -4.11 (m, 2H), 3.16 - 3.10 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H).

[0459] Step 2: ( E Preparation of ethyl 50b of 5-(tert-butoxycarbonylamino)pent-3-enoate Compound 50a (1.1 g, 6.4 mmol, 1 equivalent) was dissolved in tert-butanol (20 mL) under a nitrogen atmosphere at room temperature, followed by the addition of diphenyl azidophosphate (1.9 g, 7.0 mmol, 1.1 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY001035) and triethylamine (0.7 g, 7.0 mmol, 1.1 equivalent). After the addition was complete, the reaction mixture was heated to 85°C and stirred at this temperature for 20 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1) to give a colorless oil of title compound 50b (400 mg, yield: 26%).

[0460] MS m / z (ESI): 244.25 [M + 1] + .

[0461] 1H NMR (400 MHz, CDCl3) δ 5.76 - 5.68 (m, 1H), 5.63 - 5.57 (m, 1H), 4.58 (s, 1H), 4.17 - 4.11 (m 2H), 3.74 - 3.73 (m, 2H), 3.07 - 3.05 (m, 2H),1.45 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H).

[0462] Step 3: ( E Preparation of 5-hydroxypent-2-enylcarbamate tert-butyl 50c Compound 50b (440 mg, 1.8 mmol, 1 equivalent) was dissolved in tetrahydrofuran (5 mL) under a nitrogen atmosphere at room temperature, followed by the addition of lithium borohydride (118.2 mg, 5.4 mmol, 3 equivalent, Cangzhou Lingang Xingchen Chemical Co., Ltd.). After the addition was complete, the resulting mixture was heated to 50°C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction system was cooled to 0°C, and then water (20 mL) was slowly added to quench the reaction. The resulting turbid liquid was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (1:1) to give the title compound 50c (300 mg, yield: 82%) as a colorless oil.

[0463] MS m / z (ESI): 224.10 [M + 23] + .

[0464] 1 H NMR (400 MHz, CDCl3) δ 5.64 - 5.53 (m, 2H), 4.59 (s, 1H), 3.71 -3.65 (m, 4H), 2.32 - 2.28 (m, 2H), 1.45 (s, 9H).

[0465] Step 4: ( E Preparation of 50d of 5-bromopentane-2-phenylcarbamate tert-butyl ester Compound 50c (2.2 g, 10.9 mmol, 1 equivalent) and triphenylphosphine (3.4 g, 13.1 mmol, 1.2 equivalent) were dissolved in dichloromethane (20 mL) at 0°C under a nitrogen atmosphere, and carbon tetrabromide (4.4 g, 13.1 mmol, 1.2 equivalent) was added. After the addition was complete, the reaction mixture was removed from the ice bath and allowed to rise naturally to room temperature, where it was stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3:1) to give the title compound 50d (2.5 g, yield: 86%, purity: 95%) as a colorless oil.

[0466] MS m / z (ESI): 208.00 and 210.00 [M +1 - 56] + .

[0467] 1 H NMR (400 MHz, CDCl3) δ 5.64 - 5.54 (m, 2H), 4.55 (s, 1H), 3.71 (s,2H), 3.39 (t, J = 7.2 Hz, 2H), 2.62 - 2.57 (m, 2H), 1.45 (s, 9H).

[0468] Step 5: ( E )-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H -pyrazol-5-yl)pyrimidin-5-yl)-1 H Preparation of tert-butyl pyrrolo-1-yl)pentyl-2-phenylcarbamate 50e Compound 25d (800 mg, 2.7 mmol, 1 equivalent) was dissolved in a nitrogen atmosphere at room temperature. N , N Compound 50d (2.9 g, 10.8 mmol, 4 equivalents) and potassium carbonate (746.2 mg, 5.4 mmol, 2 equivalents) were added to 10 mL of dimethylacetamide. After the addition was complete, the reaction mixture was heated to 110 °C and stirred at this temperature for 16 hours. After the reaction was complete, the resulting mixture was allowed to cool naturally to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C10 ... 18 Silica gel; mobile phase, acetonitrile and water, gradient: acetonitrile in water from 5% to 80% over 25 minutes; detector, UV 254 nm, yielded title compound 50e (450 mg, yield: 35%, purity: 97%) as a grayish-white solid.

[0469] MS m / z (ESI): 480.20 [M +1] + .

[0470] Step 6: ( E )-1-(5-amino-3-enyl)-5-(2-(1-ethyl-3-methyl-1) H -pyrazol-5-yl)pyrimidin-5-yl)-1 H Preparation of pyrrole-3-carboxamide 50f Compound 50e (450 mg, 0.9 mmol, 1 equivalent) was dissolved in ethyl acetate (10 mL) at room temperature and under a nitrogen atmosphere, followed by the addition of an ethyl acetate solution of hydrogen chloride (4.0 M, 5 mL). After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give crude title compound 50f (350 mg) as a yellow solid. This product did not require further purification and was used directly in the next step.

[0471] MS m / z (ESI): 380.25 [M +1] + .

[0472] 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 2H), 8.12 (s, 2H), 7.71 (d, J =2.0 Hz, 1H), 6.83 - 6.81 (m, 2H), 5.73 - 5.65 (m, 1H), 5.53 - 5.46 (m, 1H), 4.73 - 4.71 (m, 2H), 4.09 (t, J = 7.2 Hz, 2H), 3.33 - 3.27 (m, 2H), 2.45 -2.41 (m, 2H), 2.23 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).

[0473] Step 7: Preparation of 50g of 3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propylcarbamate tert-butyl ester Under a nitrogen atmosphere at 0°C, 4-chloro-3-hydroxy-5-nitrobenzamide (4 g, 18.5 mmol, 1 equivalent), triphenylphosphine (8.2 g, 31.4 mmol, 1.7 equivalent), and tert-butyl 3-hydroxypropylcarbamate (3.9 g, 22.2 mmol, 1.2 equivalent, Shaoyuan Technology (Shanghai) Co., Ltd., product number: SY032553) were dissolved in tetrahydrofuran (300 mL), and DIAD (6.4 g, 32 mmol, 17 equivalent) was added dropwise to the mixture. After the addition was complete, the reaction system was removed from the ice bath, and the reaction temperature was allowed to rise naturally to room temperature and stirred at that temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10:1), to give 50 g of the crude title compound. The crude product was slurried with dichloromethane / diethyl ether (1:4) and filtered. The filter cake was washed with dichloromethane / ethyl ether (3 × 100 mL) and dried under vacuum to give 50 g (4.6 g, yield: 67%, purity: 98%) of the title compound as a grayish-white solid.

[0474] MS m / z (ESI): 396.15 [M + 23] + .

[0475] 1 H NMR (400 MHz, DMSO- d 6) δ 8.29 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.79 (s, 1H), 6.94 (t, J = 5.6 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.16 - 3.11 (m, 2H), 1.94 - 1.87 (m, 2H), 1.36 (s, 9H).

[0476] Step 8: ( E 3-(5-carbamoyl-2-(5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1-ethyl-1-ethyl-2-ethyl-3-methyl-1-ethyl-2-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-3-ethyl ... H -pyrazol-5-yl)pyrimidin-5-yl)-1 H Preparation of tert-butyl pyrrolo-1-yl)pent-2-enylamino)-3-nitrophenoxy)propylcarbamate 50h Under a nitrogen atmosphere, 50 g (420 mg, 1.1 mmol, 1 equivalent) of compound 50 and diisopropylethylamine (572.2 mg, 4.4 mmol, 4 equivalents) were dissolved in n-butanol (12 mL), and compound 50f (413.7 mg, 1.1 mmol, 1 equivalent) was added. After the addition was complete, the reaction mixture was heated to 120 °C and stirred at this temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10:1) to give the title compound 50h (450 mg, yield: 57%, purity: 84%) as a red solid.

[0477] MS m / z (ESI): 717.35 [M + 1] + .

[0478] Step 9: ( E 3-(3-amino-5-carbamoyl-2-(5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1-ethyl-1-ethyl-2-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-3 ... H -pyrazol-5-yl)pyrimidin-5-yl)-1 H Preparation of 50i of 1-pyrrolo-1-yl)pent-2-enylamino)phenoxy)propylcarbamate tert-butyl ester Compound 50h (450 mg, 0.6 mmol, 1 equivalent) was dissolved in methanol (10 mL) at 0°C under a nitrogen atmosphere, followed by the addition of ammonia (28%, 3 mL) and sodium dithionite (765 mg dissolved in 5 mL water, 4.4 mmol, 7 equivalent). After the addition was complete, the reaction mixture was removed from the ice bath and allowed to warm naturally to room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water from 5% to 80% over 25 minutes; detector, UV 254 nm, yielded title compound 50i (240 mg, yield: 56%, purity: 97%) as a grayish-white solid.

[0479] MS m / z (ESI): 687.40 [M + 1] + .

[0480] 1 H NMR (400 MHz, DMSO- d6) δ 8.94 (s, 2H), 7.61 - 7.56 (m, 2H), 7.38(s, 1H), 6.97 (s, 1H), 6.89 - 6.82 (m, 4H), 6.77 - 6.74 (m, 2H), 5.56 - 5.51(m, 1H), 5.45 - 5.39 (m, 1H), 4.71 - 4.61 (m, 4H), 4.06 - 4.02 (m, 2H), 3.91(t, J = 6.4 Hz, 2H), 3.76 - 3.72 (m, 1H), 3.43 (t, J = 6.4 Hz, 2H), 3.3.08 -3.05 (m, 2H), 2.36 - 2.30 (m, 2H), 2.22 (s, 3H), 1.82 - 1.76 (m, 2H), 1.36 -1.33 (m, 12H).

[0481] Step 10: 3-(( E )-6-carbamoyl-3-( E )-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H -pyrazol-5-yl)pyrimidin-5-yl)-1 H -pyrrolo-1-yl)pent-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrrole-5-carbonylimino)-2,3-dihydro-1 H -benzo[ d Preparation of tert-butyl imidazole-4-yloxypropylcarbamate 50j Compounds 50i (240 mg, 0.3 mmol, 1 equivalent), 1b (2-ethyl-5-methylazole-3-carbonyl isothiocyanate, 102.3 mg, 0.5 mmol, 1.5 equivalent, prepared according to the method disclosed in Intermediate 5 on page 202 of the specification in WO2019069269A1), and EDCI (135.6 mg, 0.8 mmol, 2.5 equivalent) were dissolved in DMF (6 mL), and triethylamine (106.1 mg, 1 mmol, 3 equivalent) was added. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: 25% to 80% in water over 25 minutes; detector, UV 254 nm, yielded title compound 50j (200 mg, yield: 67%, purity: 80%) as a grayish-white solid.

[0482] MS m / z (ESI): 848.45 [M + 1] + .

[0483] Step 11: ( E ) -7-(3-aminopropoxy)-1-(( E )-5-(4-carbamoyl-2-(2-(1-ethyl-3-methyl-1) H -pyrazol-5-yl)pyrimidin-5-yl)-1 H -pyrrolo-1-yl)pent-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrrole-5-carbonylimino)-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-5-formamide 50 Compound 50j (50 mg, 0.06 mmol, 1 equivalent) was dissolved in ethyl acetate (3 mL) under a nitrogen atmosphere at room temperature, and then added to an ethyl acetate solution of hydrogen chloride (4.0 M, 3 mL, Shanghai Weiji Environmental Protection Technology Co., Ltd.). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography under the following conditions: column: Xselect CSH Prep fluorophenyl column, 19 × 250 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 5%B to 35%B over 10 minutes; wavelength: 254 / 220 nm; retention time: 8.31 minutes, yielding title compound 50 (22.3 mg, yield: 51%, purity: 99%) as a white solid.

[0484] MS m / z (ESI): 748.35 [M + 1] + .

[0485] 1 H NMR (400 MHz, DMSO- d6) δ 8.85 (s, 2H), 8.00 (s, 1H), 7.66 - 7.63(m, 2H), 7.45 (s, 1H), 7.38 (s, 2H), 6.92 (s, 1H), 6.78 - 6.75 (m, 2H), 6.56(s, 1H), 5.73 - 5.66 (m, 1H), 5.51-5.43 (m, 1H), 4.86 - 4.84 (m, 2H), 4.63 -4.61(m, 2H), 4.58 - 4.53 (m, 2H), 4.23 (t, J = 6.4 Hz, 2H), 4.04 (t, J = 7.2Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.45 - 2.39 (m, 2H), 2.22 (s, 3H), 2.14 (s, 3H), 2.10 - 2.04 (m, 2H), 1.33 - 1.28 (m, 6H).

[0486] Example 20. Synthesis of Compounds 51 and 52 1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H )-Formamide 51 3-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-3 H -Imidazolidine[4,5- c ]Pyridine-5 (4H )-Formamide 52 The synthesis route is as follows: Step 1: 1-Ethyl-3-methyl-5-((trimethylsilyl)ethynyl)-1 H Preparation of pyrazole 51a Compound 15a (2 g, 10.6 mmol, 1 equivalent) was dissolved in 1,4-dioxane (40 mL) at room temperature and under an argon atmosphere. Ethynyltrimethylsilane (2.1 g, 21.1 mmol, 2 equivalent), Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol, 0.2 equivalent), triethylamine (10.7 g, 105.8 mmol, 10 equivalent), and cuprous iodide (604.4 mg, 3.2 mmol, 0.3 equivalent) were added. After the addition was complete, the reaction mixture was heated to 70°C and stirred at this temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (2:1). The title compound 51a (1 g, yield: 46%, purity: 85%) was given as a yellow solid.

[0487] MS m / z (ESI): 207.10 [M + 1] + .

[0488] Step 2: 1-Ethyl-5-ethynyl-3-methyl-1 H Preparation of pyrazole 51b 1-Ethyl-3-methyl-5-[2-(trimethylsilyl)ethynyl]pyrazole (1 g, 4.8 mmol, 1 equivalent) was dissolved in methanol (20 mL) under an argon atmosphere, and potassium carbonate (2.0 g, 14.5 mmol, 3 equivalents) was added. After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1:1). The title compound 51b (400 mg, yield: 61%, purity: 85%) was given as a yellow oil.

[0489] MS m / z (ESI): 135.20 [M + 1] + .

[0490] Step 3: 2-Iodine-6,7-Dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 51c Under room temperature and an argon atmosphere, 6,7-dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H 2 g of tert-butyl carboxylate (9 mmol, 1 equivalent) was dissolved in tetrahydrofuran (40 mL) and added... N - Iodosuccinimide (3 g, 13 mmol, 1.5 equivalents). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (2:1) to give the title compound 51c (2 g, yield: 64%, purity: 85%) as a yellow solid.

[0491] MS m / z (ESI): 350.05 [M + 1] + .

[0492] Step 4: 2-((1-ethyl-3-methyl-1-ethyl-3-methyl-1-ethyl-3-methyl-3-ethyl ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 51d Compound 51c (350 mg, 1 mmol, 1 equivalent) was dissolved in 1,4-dioxane (10 mL) at room temperature and under an argon atmosphere. Compound 51b (134.5 mg, 1 mmol, 1 equivalent), Pd(PPh3)2Cl2 (140.7 mg, 0.2 mmol, 0.2 equivalent), triethylamine (1 g, 10 mmol, 10 equivalent), and cuprous iodide (57.3 mg, 0.3 mmol, 0.3 equivalent) were then added. After the addition was complete, the reaction mixture was heated to 70°C and stirred at this temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (4:1) to give the title compound 51d (200 mg, yield: 56%, purity: 85%) as a yellow solid.

[0493] MS m / z (ESI): 356.25 [M + 1] + .

[0494] Step 5: 1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 51e 3-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-3 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 52a Compounds 10b (200 mg, 0.4 mmol, 1 equivalent) and 52d (299.1 mg, 0.842 mmol, 2 equivalents) were dissolved in DMF (5 mL) at room temperature and under an argon atmosphere, followed by the addition of cesium carbonate (301.6 mg, 1 mmol, 2.2 equivalents). After the addition was complete, the reaction mixture was heated to 50°C and stirred at this temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by reversed-phase rapid chromatography under the following conditions: column, C20 ... 18 Silica gel; mobile phase, acetonitrile and water (0.1% formic acid), gradient: acetonitrile in water from 5% to 100% over 25 minutes; detector, UV 254 nm, yielded a mixture of title compounds 51e and 52a (100 mg, yield: 30%) as a pale yellow solid.

[0495] MS m / z (ESI): 750.40 [M + 1] + .

[0496] Step 6: 3-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-3 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of tert-butyl carboxylate 51f ( E ) -1-(( E )-4-(2-((1-ethyl-3-methyl-1 H -pyrazol-5-yl)ethynyl)-4,5,6,7-tetrahydroimidazo[4,5-] c ]pyridin-3-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1 H (-pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydro-1 H -benzo[ d Preparation of imidazole-5-carboxamide 52b At room temperature, a mixture of compounds 51e and 52a (100 mg, 0.15 mmol, 1 equivalent) was dissolved in 1,4-dioxane (1 mL), followed by the addition of a 1,4-dioxane solution of hydrogen chloride (4.0 M, 1 mL). The reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give a crude mixture of title compounds 51f and 52b (53 mg, yield: 60%) as a pale yellow solid. The crude product mixture was used directly for the next step without further purification.

[0497] MS m / z (ESI): 650.45 [M + 1] + .

[0498] Step 7: 1-(( E )-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-5-yl)ethynyl)-6,7-dihydro-1 H -Imidazolidine[4,5- c ]Pyridine-5 (4 H Preparation of 51-formamide 3-(( E)-4-( E )-5-carbamoyl-2-(1-ethyl-3-methyl-1 H -pyrazole-5-carbonylimino)-7-methoxy-2,3-dihydrobenzo[ d [Imidazol-1-yl)but-2-enyl)-2-((1-ethyl-3-methyl-1- ... H -pyrazol-...

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, ， in: It can be a single bond or a double bond; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; R 1 and R 2 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 Replace; or, R 1 and R 2 Together with the carbon atom attached thereto, it forms a cycloalkyl, heterocyclic, or phenyl group, which may optionally be influenced by one or more R groups. 10 replace; X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; L 1 Selected from alkylene, alkylene-O-alkylene, alkenyl, and ynylene, wherein the alkylene and alkenyl groups are each independently and optionally influenced by one or more R groups. 13 replace, L 2 Selected from =NC(=O)-、-NR 11 -C(=O)-、-C(=O)-NR 11 - Cycloalkylene, heterocyclic, aryl, heteroaryl, alkenyl, and alkyneyl groups, each of which is independently optionally influenced by one or more R groups. 13 replace; Each R B and R 7 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 and -NR 17 S(=O)2R 14 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; R 5 and R 6 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 and -NR 17 S(=O)2R 14 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; Each R 11 Independently selected from hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, -alkylene-C(=O)OH, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl and heterocyclic alkyl; R 8 selected from -C(=O)R 14 、-C(=O)OR 14 、-C(=O)NR 15 R 16 、-OC(=O)NR 15 R 16 、-OC(=O)R 14 、-OC(=O)OR 14 、-NR 17 C(=O)R 14 and -NR 17 C(=O)OR 14 ; R 9 Selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 replace; Each R 14 R 15 R 16 and R 17 Each of the following is independently selected from hydrogen atoms, deuterium atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, and alkylheteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected by one or more R atoms. 13 replace; Each R 10 and R 13 Each is independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, -NR 15 R 16 -N(alkyl)-NR 15 R 16 -C(=O)O alkyl, -C(=O)OH, -C(=O)NR 15 R 16 -C(=O)N(alkyl)-NR 15 R 16 -C(=O)NH-alkylene-NR 15 R 16 -C(=O)N(alkyl)-alkylene-NR 15 R 16 -C(=O)NH-alkylene-OH, -C(=O)N(alkyl)-alkylene-OH, -C(=O)halogen, -C(=O)alkyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, -O-alkylene-NR 15 R 16 alkoxyalkyl, oxo, =S, =CR a R b , , , cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, heterocyclic alkoxy, aryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroaryloxy and heteroarylalkoxy; R 12 R a and R b Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, hydroxyl, cyano, amino, cycloalkyl and cycloalkylalkyl; or R a and R b Together with the carbon atom attached to it, it forms a cycloalkyl group or C=O; R c and R d Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, hydroxyl, cyano, amino, cycloalkyl and cycloalkylalkyl; or R c and R d Together with the carbon atom attached to it, it forms a cycloalkyl group or C=O; n B It can be 1, 2, or 3; The condition is that when R 1 and R 2 For a phenyl group to form with the carbon atom it is attached to, one of the following conditions must be met: (i) R on the phenyl group 10 for ; (ii) Ring B is a 6-7 membered heteroaryl group; (iii) L 2 It is an acetylinyl group or -C(=O)-NR 11 -; The condition is that the compound represented by the general formula (I) is not one of the following compounds: and .

2. A ligand-drug conjugate of general formula (I') or a pharmaceutically acceptable salt thereof, (I’) in, Ab is a ligand unit; L represents the connecting subunit; n is a decimal or integer between 1 and 10; D is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. ， in, R 1 and R 2 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, deuterylyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, deuterylalkoxy, aminoalkyl, alkylamino, cyano, amino, hydroxyl, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, oxo, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 -OC(=O)OR 14 -NR 17 C(=O)R 14 -NR 17 C(=O)OR 14 -SR 14 -S(=O)R 14 -S(=O)2R 14 -S(=O)2NR 15 R 16 -NR 17 S(=O)2R 14 and The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally composed of one or more R groups. 13 Replace; or, R 1 and R 2 Together with the carbon atom attached thereto, it forms a cycloalkyl, heterocyclic, or phenyl group, which may optionally be influenced by one or more R groups. 10 replace; The condition is that one of the following conditions must be met: (i)R 8 for , where # represents the connection point with the connecting subunit; and R 9 and R 10 As defined in claim 1; (ii)R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; and R 8 and R 10 As defined in claim 1; (iii) R 10 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; and R 8 and R 9 As defined in claim 1; Ring B, X 1 L 1 L 2 R 5 R 6 R 7 R 13 R 14 R 15 R 16 R 17 R a R b R c R d R B and n B As defined in claim 1.

3. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound or a pharmaceutically acceptable salt thereof represented by general formula (I) is the compound or a pharmaceutically acceptable salt thereof represented by general formula (II). ， in, X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 3 and R 4 Each is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuteralkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteralkyl, cyano, amino, hydroxy, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl; n 1 It can be 0, 1, or 2; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; X 1 L 2 R 1 R 2 R 5 R 6 R 7 R 11 R 12 R a and R b As defined in claim 1; R 9 and R 10 As defined in claim 1 or 2; R 15 and R 16 As defined in claim 1, or, for , where # represents the connection point with the connecting subunit.

4. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, R 1 and R 2 Together with the carbon atom attached thereto, they form a 3-8 membered heterocyclic group, preferably... , where X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 n 5 0, 1, or 2, preferably , , , , , or ;or R 1 and R 2 It forms together with the carbon atoms attached to it. ;or R 1 and R 2 It forms together with the carbon atoms attached to it. n 6 It can be 0, 1, or 2; or R 1 and R 2 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Deuterated alkoxy, C 1-6 aminoalkyl, C 1-6 Alkylamino, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 and ; in, Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl group, cyano group, nitro group, -NR 15 R 16 -N(C 1-6 alkyl)-NR 15 R 16 -C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NR 15 R 16 -C(=O)N(C 1-6 alkyl)-NR 15 R 16 -C(=O)NH-C 1-6 Alkylene-NR 15 R 16 -C(=O)N(C 1-6 alkyl)-C 1-6 Alkylene-NR 15 R 16 -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)N(C 1-6 alkyl)-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NR 15 R 16 C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 alkyl; n 2 It can be 1, 2, or 3; In particular, R 1 and R 2 It forms together with the carbon atoms attached to it. , , , , , , , , , , , or ;or R 1 and R 2 Each is independently selected from hydrogen atoms and -C(=O)NH2.

5. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof. ， in, It can be a single bond or a double bond; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 5 It can be 0, 1, or 2; The condition is that the compound represented by the general formula (III-1) is not one of the following compounds: and ; Preferably, it is a compound of general formula (III-1-1) or a pharmaceutically acceptable salt thereof. ， Among them, X 4 X 5 X 6 R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 5 As defined above; The condition is that the compound represented by the general formula (III-1-1) is not one of the following compounds: and ; More preferably, it is a compound of general formula (III-1-1A) or general formula (III-1-1B) or a pharmaceutically acceptable salt thereof. 、 ， Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined above; The condition is that the compound represented by the general formula (III-1-1A) or general formula (III-1-1B) is not one of the following compounds: and .

6. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (III-2) or a pharmaceutically acceptable salt thereof. ， in, It can be a single bond or a double bond; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; X 4 X 5 and X 6 Each is independently selected from O, S, and NR. 11 and CR a R b And one of them is selected from O, S and NR. 11 ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 5 It can be 0, 1, or 2; Preferably, it is a compound of general formula (III-2-1) or a pharmaceutically acceptable salt thereof. ， Among them, X 4 X 5 X 6 R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 5 As defined above; More preferably, it is a compound of general formula (III-2-1A) or general formula (III-2-1B) or a pharmaceutically acceptable salt thereof. 、 ， Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined above.

7. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (III-3) or a pharmaceutically acceptable salt thereof. ， in, It can be a single bond or a double bond; X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; L 2 Selected from =NC(=O)-、-NR 11 -C(=O)-、-C(=O)-NR 11 -and C 2-6 Ethyne group; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; The condition is that one of the following conditions must be met: (i) R on the phenyl group 10 for ; (ii) Ring B is a 6-7 membered heteroaryl group, preferably pyrimidinyl, pyridinyl or pyrazinyl; (iii) L 2 C 2-6 Ethyne or -C(=O)-NR 11 -; Preferably, it is a compound of general formula (III-3-1), general formula (III-3-2), or general formula (III-3-3), or a pharmaceutically acceptable salt thereof. 、 、 ， Among them, X 2 X 3 R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 1 n 2 n 3 and n 4 As defined above; More preferably, it is a compound of general formula (III-3-1A), general formula (III-3-1B), general formula (III-3-2A) or general formula (III-3-3A), or a pharmaceutically acceptable salt thereof. 、 、 、 ， Among them, R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined above.

8. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (III-4) or a pharmaceutically acceptable salt thereof. ， in, It can be a single bond or a double bond; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 10 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)NH-C 1-6 Alkylene -NH2, -C(=O)NH-C 1-6 Alkylene -OH, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; or Each R 10 Selected independently , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 2 It can be 1, 2, or 3; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 6 It can be 0, 1, or 2; Preferably, it is a compound of general formula (III-4-1) or a pharmaceutically acceptable salt thereof. ， Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 n 4 and n 6 As defined above; More preferably, it is a compound of general formula (III-4-1A) or a pharmaceutically acceptable salt thereof. ， Among them, R 3 R 4 R 5 R 6 R 7 R 9 R 10 R 11 R 15 R 16 n 2 n 3 and n 4 As defined above.

9. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by formula (III-5) or a pharmaceutically acceptable salt thereof. ， in, It can be a single bond or a double bond; Ring D is a 5-10 membered heteroaryl group, preferably a 5-6 membered heteroaryl group, and more preferably a pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrroleyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. X 1 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 1 and R 2 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Deuterated alkoxy, C 1-6 aminoalkyl, C 1-6 Alkylamino, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)R 14 -C(=O)OR 14 -C(=O)NR 15 R 16 -OC(=O)NR 15 R 16 -OC(=O)R 14 and ; R 3 and R 4 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-8-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , , , , , and , where # represents the connection point with the connecting subunit; Each R 11 Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 cycloalkyl C 1-6 Alkyl and 3-8 membered heterocyclic C 1-6 alkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; Each R 13 Independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, nitro, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(=O)OC 1-6 Alkyl, -C(=O)OH, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2、-C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 deuterated alkoxy group, -OC 1-6 Alkylene-NH2, C 1-6 Alkoxy C 1-6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -OC 1-6 alkylene-3-8-membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups; Each R 14 Independently selected from hydrogen, deuterium, and carbon atoms. 1-6 alkyl; Each R 15 and R 16 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl C 1-6 Alkyl, 3-8 membered heterocyclic C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl and 5-10 heteroaryl C 1-6 Alkyl; or, for , where # represents the connection point with the connecting subunit; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; n 1 It can be 0, 1, or 2; n 3 It can be 1, 2, or 3; n 4 It can be 1, 2, or 3; n 7 It can be 0, 1, or 2; Preferably, it is a compound of general formula (III-5-1) or a pharmaceutically acceptable salt thereof. ， in, X 7 and X 8 Each is independently selected from O, S, N, NR. 11 CR 12 and CR a R b ; n 8 It can be 0, 1, or 2; X 1 X 2 R 1 -R 7 R 9 R 11 R 12 R 13 R 15 R 16 R a R b n 1 n 3 n 4 and n 7 As defined above, More preferably, it is a compound represented by general formula (III-5-1A) or a pharmaceutically acceptable salt thereof. ， Among them, R 1 -R 7 R 9 R 11 R 13 R 15 R 16 n 3 n 4 and n 7 As defined above.

10. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 and 7, wherein: L 2 Selected from =NC(=O)-, -NH-C(=O)-, -C(=O)-NH-, C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 aryl, 5-10 quinone heteroaryl, C 2-6 imide and C 2-6 Idemyne ​​group, the C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 6-10 arylene, 5-10 methyl arylene and C 2-6 Each alkenyl group is independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 One or more substituents of the deuterated alkoxy group are used for substitution; Preferably, L 2 Selected from =NC(=O)-, -NH-C(=O)-, -C(=O)-NH-, C 3-6 Cycloalkylene, 3-6 membered heterocyclic alkylene, phenyl, 5-6 membered heteroarylalkylene, C 2-6 imide and C 2-6 Ethyne group; Preferably, L 2 Selected from =NC(=O)-, -C(=O)-NH-, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrroleyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyridazinyl, and ethynyl.

11. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, 7, 9 and 10, wherein: X 1 Selected from N, NR 11 CR 12 and CR a R b ; R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and amino groups.

12. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3-11, wherein: X 2 Selected from O, S, N, NR 11 CR 12 and CR a R b ; X 3 Selected from O, S, N, NR 11 CR 4 and CR a R b ; R 4 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, cyano, amino, hydroxyl, nitro, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups; R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl; R 12 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, hydroxy, cyano, amino and C 3-8 cycloalkyl; R a and R b Each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and amino groups.

13. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein: R 9 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, amino, hydroxyl, nitro, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-6-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2, -OC 1-6 Alkylene-N(C) 1-6 alkyl)-NHalkyl, -OC 1-6 Alkylene-C(=O)N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , , , , , and , where # represents the connection point with the connecting subunit; Preferably, R 9 Selected from hydrogen atoms, C 1-6 Alkoxy, -OC 1-6 Alkylene -NH2, -OC 1-6 Alkyl-3-6-membered heterocyclic groups, -OC 1-6 Alkylene-N(C) 1-6 Alkyl)-NH2 and -OC 1-6 Alkylene-C(=O)N(C) 1-6 alkyl)-NHC 1-6 Alkyl; or R 9 Selected from , , , and , where # represents the connection point with the connecting subunit; Each R 14 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 aminoalkyl; Each R 15 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl and C 1-6 Hydroxyalkyl; The 3-6 membered heterocyclic or heterocyclic group is selected from azirrobutyl, oxoheterobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl; More preferably, R 9 Selected from hydrogen atoms, , , methoxy and ;or R 9 Selected from , and .

14. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 3-13, wherein: R 3 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 3 Selected from hydrogen atoms and C 1-6 alkyl.

15. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 4-14, wherein: R 4 Selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 4 Selected from hydrogen atoms and C 1-6 alkyl.

16. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein: R 5 and R 6 Each is independently selected from hydrogen atoms, deuterium atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, cyano, amino, hydroxy, nitro, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; preferably, R 5 and R 6 Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl.

17. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein: R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; Preferably, R 7 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl.

18. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 4-17, wherein: Each R 11 Independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; Preferably, R 11 Selected from hydrogen atom, deuterium atom, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -C 1-6 Alkylene-C(=O)OH, C 1-6 aminoalkyl and C 1-6 Cyanoalkyl.

19. The compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, wherein, The compounds represented by general formula (I) are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

20. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 2, wherein, L has -L a -L b -L c -L d - structure, where L a Connected to the ligand unit, L d Connected to unit D, where: L a For coupling units; L b It either does not exist or is a connected segment; L c It is a polypeptide fragment; L d It can be either non-existent or any unit; Preferably, wherein: L a Selected from , , , and Where ** represents the connection point with Ab, and * represents the connection point with L. b The connection point; L b Selected from -(CH2)mC(=O)-, -C(=O)-(CH2)mC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, -(CH2)mOC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, -NH-(CH2)m-(CH2CH2O)pC(=O)-, -(CH2)m-(CH2CH2O)pC(=O)- and -(CH2)mC(=O)-NH-(CH2)m-(CH2CH2O)pC(=O)-, or L b Selected from , , , , , , , , and ; Where: m is an integer from 0 to 10, preferably m is 0, 2, 3 or 5; p is an integer from 4 to 32, preferably p is an integer from 10 to 14; c* represents the relationship with L a The connection point, d* represents the connection with L. c The connection point; L c It is a polypeptide fragment composed of 1 to 7 amino acids, or a bond; wherein the amino acid is selected from valine (V), citrulline (Cit), lysine (K), glycine (G), phenylalanine (F), alanine (A), proline (P), isoleucine (I), serine (S), glutamic acid (E), asparagine (N) and aspartic acid (D); L d It does not exist, or it is selected from the following structures: , , , , , , and ; Among them, a * Indicates with L c The connection point, b * This indicates the connection point with unit D.

21. The ligand-drug conjugate of claim 20 or a pharmaceutically acceptable salt thereof, wherein: L a Selected from , and Where ** represents the connection point with Ab, and * represents the connection point with L. b The connection point; L b Selected from -C(=O)- , , , and Where p is an integer between 10 and 14; c* represents the expression with respect to L. a The connection point, d* represents the connection with L. c The connection point; L c The amino acids derived from valine-citrulline (VC), glycine-glycine-phenylalanine-glycine (GGFG), alanine-alanine-alanine-glycine (AAAG), glycine-glycine-glycine-glycine (GGGG), valine-alanine-glycine (VAG), valine-citrulline-glycine (VCG), alanine-alanine-glycine (AAG), alanine-alanine-alanine (AAA), valine-alanine (VA), alanine-alanine (AA), glutamic acid-alanine-glycine-glycine (EAGG), and glycine- A polypeptide fragment composed of glutamic acid-alanine-glycine (GEAG), glycine-glutamic acid-glycine-glycine (GEGG), glutamic acid-glycine-glycine (EGG), glutamic acid-alanine-glycine (EAG), valine-lysine-glycine (VKG), glycine-glutamic acid-glycine (GEG), glutamic acid-alanine (EA), glutamic acid-glycine (EG), and glycine-glutamic acid (GE). L d Selected from , , and ; where a * Indicates with L c The connection point, b * This indicates the connection point with unit D.

22. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 2, 20, and 21, wherein, L is selected from: and Where, ** represents the connection point with Ab, b * This indicates the connection point with unit D.

23. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 2 and 20-22, wherein, Ab is an antibody, preferably wherein Ab specifically binds to antigens selected from the following: TROP2, AXL, BAFFR, BCMA, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD163, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, Cluster of Differentiation 40 (CD40), CD44, CD45, CD46, CD47, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.

2. CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1 / 2, CXCR4, C XCR5, DDR1, DDR2, DEC-205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HHLA2, type II HLA (HLA class II), HVEM, ICOSLG, IFNAR, type I interferon receptor subunit (IFNAR1), IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, integrin (Integri) ns), LAG3, LIFR, MAG / Siglec-4 (sialic acid-binding immunoglobulin-like lectin-4), MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, OX40 (CD134), PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1 (sialic acid-binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, tumor necrosis factor α (TNFα), TROY, TSLPR, TYRO, VLDLR, VSIG4, IL2R-γ, and VTCN1.

24. The ligand-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 2 and 20-22, wherein, Ab is an anti-TROP2 antibody; Preferably, the anti-TROP2 antibody comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region includes HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3, and the light chain variable region includes LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6; More preferably, the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 7, or contains a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 7, and The amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8, or contains a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO:

8.

25. The ligand-drug conjugate of claim 24 or a pharmaceutically acceptable salt thereof, wherein the anti-TROP2 antibody comprises a heavy chain constant region and a light chain constant region; Preferably, the heavy chain constant region is of the IgG1 type; More preferably, the heavy chain constant region contains L234A, L235A and / or P329G mutations; Most preferably, the heavy chain amino acid sequence of the anti-TROP2 antibody is as shown in SEQ ID NO: 11 or SEQ ID NO: 12, or contains a sequence having at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO: 11 or SEQ ID NO:

12. The amino acid sequence of the light chain is as shown in SEQ ID NO: 13, or contains a sequence that has at least 85% sequence identity with the amino acid sequence shown in SEQ ID NO:

13.

26. The ligand-drug conjugate according to any one of claims 2 and 20-25, or a pharmaceutically acceptable salt thereof, wherein the conjugate is selected from: , and , Wherein Ab is as defined in any one of claims 23-25.

27. A pharmaceutical composition comprising a compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, and one or more pharmaceutically acceptable carriers, diluents or excipients.

28. Use of the compound or ligand drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, or the pharmaceutical composition of claim 27, in the preparation of a medicament for treating and / or preventing disease; Preferably, the disease is selected from cancer, inflammation, infectious diseases, and immune-related diseases; More preferably, the cancer is selected from lung cancer, gastric cancer, breast cancer, pancreatic cancer, colon cancer, colorectal cancer, bladder cancer, endometrial cancer, urothelial carcinoma, cervical cancer, esophageal cancer, ovarian cancer, head and neck cancer, kidney cancer, melanoma, prostate cancer, non-small cell lung cancer, leukemia, lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin lymphoma; most preferably, the disease is a STING-mediated disease.

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