Polycyclic derivative inhibitor and antibody conjugate thereof

Abstract

The invention relates to a polycyclic derivative inhibitor and an antibody conjugate thereof, and particularly provides a compound as shown in a formula I, or a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a pharmaceutically acceptable ester of the compound, and a linker-drug conjugate and an antibody-drug conjugate comprising the compound of the present invention.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a polycyclic derivative inhibitor and its antibody-drug conjugate. Background Technology

[0002] As a specific treatment method targeting cancer cells, antibody-drug conjugates (ADCs) have made significant progress since 2000. Currently, there are 19 marketed ADC drugs globally, primarily treating hematologic malignancies and solid tumors. ADCs consist of three key components: monoclonal antibodies or antibody fragments that selectively bind to tumor cell surface antigens, cleavable or non-cleavable linkers, and small molecule cytotoxic agents. They fully utilize the specificity of antibody binding to tumor cell antigens and the high efficiency of small molecule drugs. Most current small molecule toxins are microtubule inhibitors or DNA damaging agents.

[0003] N-Myristoyltransferase (NMT) is a monomeric enzyme ubiquitous in eukaryotes. NMT catalyzes the irreversible co-translational transfer of myristic acid from myristicoyl-CoA to a protein substrate containing an N-terminal glycine, forming an amide bond. Inhibition of human NMT has been proposed as a target for the treatment or prevention of various diseases or conditions, such as cancers (human colorectal cancer, gallbladder cancer, brain tumors, and B-cell lymphoma) and viral infections (such as HIV, human rhinovirus, and dengue virus). NMT activity is an important intervention point in cancer therapy, disrupting multiple protein pathways. Studies have shown that NMT inhibition leads to loss of function of mTOR agonist 1 (LAMTOR1), inducing an "amino acid starvation" response in tumor cells and inhibiting protein synthesis; this effect is particularly effective in cancers with high protein translation rates. Furthermore, NMT inhibitors may induce endoplasmic reticulum stress in sensitive cancer cells by inhibiting the function of ADP-riboglycosylation factor protein (ARF) and ARF-like protein (ARL), offering therapeutic opportunities for various cancers. NMT inhibitors can also induce the unfolded protein response (UPR) by inhibiting myristoylation of ADP-ribonucleotide 1 protein (ARF1), selectively clearing senescent cells produced by chemotherapy or oncogenic transformation.

[0004] Although the structures of many small NMT inhibitor molecules have been published, they are mostly used for antifungal, antiparasitic, and antiviral infections, with relatively few reports on NMT inhibitors for antitumor applications. Therefore, there is still a need to develop more efficient and safer NMT inhibitors and their antibody-drug conjugates to stably target and deliver them to tumor cells, making treatment safer and more effective, and better meeting clinical needs. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, the inventors of this application have conducted experimental research and provided a novel NMT inhibitor and an antibody-drug conjugate prepared from the NMT inhibitor.

[0006] Specifically, in a first aspect, the present invention provides a compound of Formula I, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable

[0007]

[0008] in:

[0009] L 1 Selected from -XL 1a - C1-C6 alkylene groups; preferably, X is connected to the B0 ring, L 1a Connected to ring C0;

[0010] X is selected from O, S, NH, -C(O)-, and direct bonds;

[0011] Preferably, X is O, NH, or -C(O)-;

[0012] L 1a The group is selected from direct bonds, C1-C6 alkylene groups, -C(O)-C1-C6 alkylene groups, -NH-S(O)2-, -S(O)2-, C2-C6 ynylene groups, C3-C8 cycloalkylene groups -C1-C6 alkylene groups, C3-C8 cycloalkylene groups, C2-C6 alkenylene groups, and C1-C6 alkylene groups -C(O)-, wherein each of the C1-C6 alkylene groups, C2-C6 alkenylene groups, C2-C6 ynylene groups, and C3-C8 cycloalkylene groups is independently and optionally replaced by 1-3 groups selected from C3-C8 cycloalkyl groups, deuterium, and C1-C6 alkyl groups; preferably, L 1a When not a direct key, L 1a The site on the left is connected to X, and the site on the right is connected to the C0 ring;

[0013] Preferably, L 1a The group is selected from direct bonds, C1-C6 alkylene groups (such as methylene or ethylene), -C(O)-C1-C6 alkylene groups, -NH-S(O)2-, C2-C6 ynylene groups, C3-C8 cycloalkylene groups -C1-C6 alkylene groups, C3-C8 cycloalkylene groups, C2-C6 alkenylene groups, and C1-C6 alkylene groups -C(O)-, wherein each of the C1-C6 alkylene groups (such as methylene or ethylene) and C2-C6 ynylene groups is independently and optionally substituted by 1-3 groups selected from cyclopropyl and deuterium; preferably, L 1a When not a direct key, L 1a The site on the left is connected to X, and the site on the right is connected to the C0 ring;

[0014] More preferably, L 1a Selected from direct keys, Preferably, L 1a When not a direct key, L 1a The upper site is connected to X, and the lower site is connected to the C0 ring;

[0015] Preferably, L 1 Selected from methylene, -O-, Preferably, L 1 When it is not methylene or -O-, the upper site is connected to the B0 ring, and the lower site is connected to the C0 ring;

[0016] A0 ring is selected from

[0017] R 0 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, halogen, and hydroxyl;

[0018] Preferably, R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl;

[0019] More preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl;

[0020] Each R 2 Independently selected from -L 2 -R 2A ;

[0021] L 2 Selected from direct bond, -O-, -C(O)-, -C(O)-C1-C6 alkylene, C1-C6 alkylene, -C(O)-C2-C6 alkenyl, C2-C6 alkenyl, -C(O)-C2-C6 alkyneyl, C2-C6 alkyneyl;

[0022] Preferably, L 2 Selected from direct bond, -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene, methylene, ethylidene

[0023] R 2A Selected from -NR 2m R 2n -N(R) 2r )NR 2s R 2t 5-6 member nitrogen-containing saturated heterocyclic groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperidinyl);

[0024] R 2m R 2n Each of the groups is independently selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperidinyl), wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6 member heteroaryl groups (preferably 6 member heteroaryl groups, more preferably pyridinyl), phenyl, naphthyl, and 5-6 member nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperazine). -NR 2p R 2q The groups are replaced;

[0025] R 2p R 2q R 2r R 2s R 2t Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl,

[0026] Preferably, R 2p R 2q Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl,

[0027] Preferably, R 2r R 2s R 2t Each is independently selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0028] m1 is selected from 1, 2, 3, 4, 5, 6, with 2 being the preferred choice;

[0029] Preferably, R 2A Selected from

[0030] Preferably, each R 2 Selected independently

[0031] L 2aSelected from direct bond, C1-C6 alkylene group, and C2-C6 ynylene group;

[0032] Preferably, L 2a Selected from direct bonds, methylene, ethylene,

[0033] L 2b Selected from direct bonds and C1-C6 alkylene groups;

[0034] Preferably, L 2b Selected from direct bonds and ethylene;

[0035] L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide;

[0036] Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene;

[0037] More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene,

[0038] R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0039] Preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0040] More preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced;

[0041] More preferably, R2a Selected from hydrogen, methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. The groups are replaced;

[0042] Most preferably, R 2a Selected from hydrogen, methyl,

[0043] Cyclopropyl,

[0044] R 2b Selected from hydrogen and C1-C6 alkyl groups;

[0045] Preferably, R 2b Selected from hydrogen and methyl;

[0046] R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, and is preferably 2;

[0047] Preferably, R 2c Selected from methyl,

[0048] R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups;

[0049] Preferably, R 2d Selected from -NHR 2e 6-membered nitrogen-containing saturated heterocyclic group;

[0050] More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) );

[0051] R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups;

[0052] Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups;

[0053] More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) );

[0054] Most preferably, R 2 Selected from

[0055] Preferably, each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen;

[0056] More preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl;

[0057] Most preferably, each R 4 Independently selected from hydrogen and methyl;

[0058] Preferably, R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen;

[0059] More preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups;

[0060] Preferably, R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0061] More preferably, R 6 Selected from hydrogen and deuterium;

[0062] Preferably, R 7 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0063] Preferably, R 8 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0064] Preferably, R 9 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0065] Preferably, R 10 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0066] Preferably, R 11 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0067] Preferably, R 12 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0068] Preferably, R 13 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0069] Preferably, the A0 ring is selected from...

[0070] B0 ring is selected from

[0071] Among them, position 1 is connected to ring A0, and position 2 is connected to L. 1 Connected;

[0072] R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups,

[0073] 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0074] Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0075] More preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, -C(O)-NR 1a5 R 1a6 ;

[0076] R 1a1 Selected from hydrogen and C1-C6 alkyl groups;

[0077] Preferably, R 1a1 It is methyl;

[0078] R 1a2 Selected from hydrogen and C1-C6 alkyl groups;

[0079] Preferably, R 1a2 It is methyl;

[0080] R 1a3 Selected from hydrogen and C1-C6 alkyl groups;

[0081] Preferably, R 1a3 It is methyl;

[0082] R 1a4 Selected from hydrogen and C1-C6 alkyl groups;

[0083] Preferably, R 1a4 It is methyl;

[0084] R 1a5 Selected from hydrogen and C1-C6 alkyl groups;

[0085] Preferably, R 1a5 It is hydrogen;

[0086] R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0087] Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups;

[0088] More preferably, R 1a6 It is cyclopropyl;

[0089] Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl,

[0090] R 1b R 1c R 1d R 1e R 1f R 1g R 1h R 1i R 1j R 1k R 1l R 1m Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogen, cyano, and nitro;

[0091] Preferably, R 1b Selected from halogen, cyano, and nitro groups;

[0092] More preferably, R 1b Selected from halogens;

[0093] Most preferably, R 1b For F;

[0094] Preferably, R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0095] More preferably, R 1c Selected from hydrogen and deuterium;

[0096] Preferably, R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0097] More preferably, R 1d Selected from hydrogen and deuterium;

[0098] Preferably, each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0099] More preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl;

[0100] Preferably, R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0101] More preferably, R 1f R 1g It is fluorine;

[0102] Preferably, R 1h The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0103] Preferably, R 1i The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0104] Preferably, R 1j The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0105] Preferably, R 1k The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0106] Preferably, R 1l The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0107] Preferably, R 1m The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0108] B0 ring is selected from Among them, position 1 is connected to ring A0, and position 2 is connected to L. 1 Connected;

[0109] C0 ring is selected from

[0110] R 3a R 3eEach is independently selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (such as methyl), C3-C8 cycloalkyl groups, deuterium, nitro groups, halogens (such as fluorine), phenyl groups, and R-terminated groups. 3a4 Substitution of C1-C6 alkyl groups, or optional substitution of C3-C8 cycloalkyl groups with C1-C6 alkyl groups;

[0111] Preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (such as methyl), C3-C8 cycloalkyl groups, deuterium, nitro groups, halogens (such as fluorine), phenyl groups, and R-terminated groups. 3a4 Substitution of C1-C6 alkyl groups, or optional substitution of C3-C8 cycloalkyl groups with C1-C6 alkyl groups;

[0112] More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-membered nitrogen-containing saturated heterocyclic group, -C(O)-4-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-membered heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-membered nitrogen-containing saturated heterocyclic group, 5-membered nitrogen-containing saturated heterocyclic group, phenyl, and 5-membered heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (e.g., methyl), C3-C8 cycloalkyl groups (e.g., cyclopropyl), deuterium, nitro, halogens (e.g., fluorine), phenyl, hydroxymethyl, cyclopropyl groups optionally substituted with methyl (e.g., The group replaced by )

[0113] More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, aziridine, -C(O)-aziridine, C1-C6 alkylene-tetrahydropyrrolyl, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-oxazolyl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, aziridine, tetrahydropyrrolyl, phenyl, and oxazolyl groups are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (e.g., methyl), C3-C8 cycloalkyl groups (e.g., cyclopropyl), deuterium, nitro, halogens (e.g., fluorine), phenyl, hydroxymethyl, cyclopropyl groups optionally substituted with methyl (e.g., The group replaced by )

[0114] R 3a1 R 3a2 Each is independently selected from hydrogen, C1-C6 alkyl, and deuterated C1-C6 alkyl, wherein the C1-C6 alkyl and deuterated C1-C6 alkyl are each optionally substituted by 1 to 3 (e.g., 1) hydroxyl groups;

[0115] Preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, C1-C6 alkyl, or deuterated C1-C6 alkyl, and the other is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, or hydroxyl-substituted deuterated C1-C6 alkyl.

[0116] More preferably, R 3a1 R 3a2In this context, one of the atoms is selected from hydrogen, methyl, or -CD3, and the other is selected from methyl, -CD3, ...

[0117]

[0118] R 3a3 Selected from C1-C6 alkyl groups;

[0119] Preferably, R 3a3 For tert-butyl;

[0120] R 3a4 Selected from cyano, carboxyl, mercapto, azide, and hydroxyl groups;

[0121] Preferably, R 3a4 It is a hydroxyl group;

[0122] Most preferably, R 3a Selected from

[0123] Preferably, R 3e Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups;

[0124] More preferably, R 3e for

[0125] R 3b R 3c R 3d R 3f R 3g R 3h R 3i Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0126] Preferably, R 3b Selected from C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0127] More preferably, R 3b Selected from methyl, cyclopropyl, vinyl, and ethynyl groups;

[0128] Preferably, R 3c Selected from C1-C6 alkyl groups;

[0129] More preferably, R 3c It is methyl;

[0130] Preferably, R 3d Selected from C1-C6 alkyl groups;

[0131] More preferably, R3d It is methyl;

[0132] Preferably, R 3f The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0133] Preferably, R 3g The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0134] Preferably, R 3h The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0135] Preferably, R 3i The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen;

[0136] Preferably, the C0 ring is selected from...

[0137] Or, R 1a and R 3c Connected to form

[0138] Or, R 0 With R 1d Connected to form

[0139] in:

[0140] When A0 ring is selected B0 ring is selected from C0 ring is selected from L 1a C1-C6 alkylene or L 1 for Furthermore, R 1a Selected from halogens or F, R 2A For -NR 2m R 2n (and R) 2m R 2n Each is independently selected from hydrogen, C1-C6 alkyl, or R 2a It is hydrogen or C1-C6 alkyl (such as methyl) or R 2 for R 3a C1-C6 alkyl groups substituted with one hydroxyl group or... When any one of the following conditions (a)-(c) is satisfied:

[0141] (a)R 0 and R5 They are not both hydrogen;

[0142] (b)R 1c and R 1d They are not both hydrogen;

[0143] (c)R 3b Not selected from C1-C6 alkyl groups (such as R 3b (Not methyl).

[0144] In some embodiments, the compound has the structural formula shown in Formula I-1.

[0145]

[0146] in:

[0147] A0 ring is selected from

[0148] R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl;

[0149] Preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl;

[0150] R 1a Selected from halogen, cyano, and nitro groups;

[0151] Preferably, R 1a Selected from halogens and nitro groups;

[0152] More preferably, R 1a Selected from F and nitro;

[0153] R 1b Selected from halogen, cyano, and nitro groups;

[0154] Preferably, R 1b Selected from halogens;

[0155] More preferably, R 1b For F;

[0156] R 1c Selected from hydrogen and C1-C6 alkyl groups;

[0157] Preferably, R 1c It is hydrogen;

[0158] R 1d Selected from hydrogen and C1-C6 alkyl groups;

[0159] Preferably, R 1d It is hydrogen;

[0160] L 1-XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring;

[0161] X is selected from O and S;

[0162] Preferably, X is 0;

[0163] L 1a Selected from C1-C6 alkylene and C3-C8 cycloalkylene, wherein each of the C1-C6 alkylene and C3-C8 cycloalkylene is optionally substituted by 1-3 (preferably 1-2) deuterium atoms;

[0164] Preferably, L 1a Selected from ethylene,

[0165] Preferably, L 1 Selected from

[0166] Each R 2 Selected independently

[0167] L 2a Selected from direct bond, C1-C6 alkylene group, and C2-C6 ynylene group;

[0168] Preferably, L 2a Selected from direct bonds, methylene, ethylene,

[0169] L 2b Selected from direct bonds and C1-C6 alkylene groups;

[0170] Preferably, L 2b Selected from direct bonds and ethylene;

[0171] L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide;

[0172] Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene;

[0173] More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene,

[0174] R 2aThe group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0175] Preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0176] More preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced;

[0177] More preferably, R 2a Selected from hydrogen, methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. The groups are replaced;

[0178] Most preferably, R 2a Selected from hydrogen, methyl,

[0179] Cyclopropyl, R 2b Selected from hydrogen and C1-C6 alkyl groups;

[0180] Preferably, R 2b Selected from hydrogen and methyl;

[0181] R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, preferably 2; more preferably, R 2c Selected from methyl, R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups;

[0182] Preferably, R 2d Selected from -NHR2e 6-membered nitrogen-containing saturated heterocyclic group;

[0183] More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) );

[0184] R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups;

[0185] Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups;

[0186] More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) );

[0187] Most preferably, R 2 Selected from

[0188] Each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen;

[0189] Preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl;

[0190] More preferably, each R 4 Independently selected from hydrogen and methyl;

[0191] R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen;

[0192] Preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups;

[0193] R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0194] Preferably, R 6 Selected from hydrogen and deuterium;

[0195] Preferably, the A0 ring is selected from...

[0196] R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2-C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl is independently and optionally replaced by 1-3 groups selected from hydroxyl, C3-C8 cycloalkyl, deuterium, C1-C6 alkyl, and C1-C6 alkyl substituted with hydroxyl;

[0197] Preferably, R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 groups selected from hydroxyl, cyclopropyl, deuterium, and hydroxymethyl;

[0198] R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0199] Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl;

[0200] More preferably, R 3a1 R 3a2 It is methyl;

[0201] More preferably, R 3a Selected from

[0202] R 3b Selected from C1-C6 alkyl and C3-C8 cycloalkyl groups;

[0203] Preferably, R 3b Selected from methyl and cyclopropyl;

[0204] R 3c Selected from C1-C6 alkyl groups;

[0205] Preferably, R 3c It is methyl;

[0206] Or, R 0 With R 1d Connected to form

[0207] Where A0 ring is selected And R 2a It is hydrogen or C1-C6 alkyl (such as methyl) or R 2 for When, the following conditions are met: R 0 and R 5 They are not both hydrogen.

[0208] In some embodiments, the compound has the structural formula shown in Formula I-1-1.

[0209]

[0210] in:

[0211] R 0 Selected from hydrogen and C1-C6 alkyl groups;

[0212] Preferably, R 0 It is hydrogen;

[0213] R 1a Selected from halogen, cyano, and nitro groups;

[0214] Preferably, R 1a Selected from halogens;

[0215] More preferably, R 1a For F;

[0216] R 1b Selected from halogen, cyano, and nitro groups;

[0217] Preferably, R 1b Selected from halogens;

[0218] More preferably, R 1b For F;

[0219] R 1c Selected from hydrogen and C1-C6 alkyl groups;

[0220] Preferably, R 1c It is hydrogen;

[0221] R 1d Selected from hydrogen and C1-C6 alkyl groups;

[0222] Preferably, R 1d It is hydrogen;

[0223] L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring;

[0224] X is selected from O and S;

[0225] Preferably, X is 0;

[0226] L 1a Selected from C1-C6 alkylene and C3-C8 cycloalkylene;

[0227] Preferably, L 1a Selected from ethylene,

[0228] Preferably, L 1 Selected from

[0229] R 2 Selected from

[0230] L 2a Selected from direct bonds and C1-C6 alkylene groups;

[0231] Preferably, L 2a Selected from direct bond, methylene;

[0232] L 2b Selected from direct bonds and C1-C6 alkylene groups;

[0233] Preferably, L 2b Selected from direct bonds and ethylene;

[0234] L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide;

[0235] Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene;

[0236] More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene,

[0237] R 2a Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0238] Preferably, R 2a The group is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced;

[0239] More preferably, R 2aSelected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced;

[0240] More preferably, R 2a Selected from methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. ) The groups are replaced;

[0241] Most preferably, R 2a Selected from methyl, Cyclopropyl,

[0242] R 2b Selected from hydrogen and C1-C6 alkyl groups;

[0243] Preferably, R 2b Selected from hydrogen and methyl;

[0244] R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, and is preferably 2;

[0245] Preferably, R 2c Selected from methyl,

[0246] R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups;

[0247] Preferably, R 2d Selected from -NHR 2e 6-membered nitrogen-containing saturated heterocyclic group;

[0248] More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) );

[0249] R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups;

[0250] Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups;

[0251] More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) );

[0252] Most preferably, R 2 Selected from

[0253] R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl is independently and optionally replaced by 1-3 groups selected from hydroxyl, C3-C8 cycloalkyl, deuterium, or hydroxyl-substituted C1-C6 alkyl groups;

[0254] Preferably, R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 groups selected from hydroxyl, cyclopropyl, deuterium, and hydroxymethyl;

[0255] R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0256] Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl;

[0257] More preferably, R 3a1 R 3a2 It is methyl;

[0258] More preferably, R 3a Selected from

[0259] R 3b Selected from C1-C6 alkyl groups;

[0260] Preferably, R 3b It is methyl;

[0261] R 3c Selected from C1-C6 alkyl groups;

[0262] Preferably, R 3c It is methyl;

[0263] Where R 2aC1-C6 alkyl (such as methyl) or R 2 for At that time, R 0 With R 1d Connected to form

[0264]

[0265] In some embodiments, the compound has the structural formula shown in Formula I-1-1.

[0266] in:

[0267] R 0 It is hydrogen;

[0268] R 1a For F;

[0269] R 1b For F;

[0270] R 1c It is hydrogen;

[0271] R 1d It is hydrogen;

[0272] L 1 for

[0273] R 2 for

[0274] L 2a It is methylene;

[0275] R 2a Selected from deuterated C1-C6 alkyl groups;

[0276] Preferably, R 2a for R 3a for

[0277] R 3b It is methyl;

[0278] R 3c It is a methyl group.

[0279] In some embodiments, the compound has the structural formula shown in Formula I-1-2.

[0280]

[0281] in:

[0282] R 1a Selected from halogen, cyano, and nitro groups;

[0283] Preferably, R1a Selected from halogens and nitro groups;

[0284] More preferably, R 1a Selected from F and nitro;

[0285] R 1b Selected from halogen, cyano, and nitro groups;

[0286] Preferably, R 1b Selected from halogens;

[0287] More preferably, R 1b For F;

[0288] R 1c Selected from hydrogen and C1-C6 alkyl groups;

[0289] Preferably, R 1c It is hydrogen;

[0290] R 1d Selected from hydrogen and C1-C6 alkyl groups;

[0291] Preferably, R 1d It is hydrogen;

[0292] L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring;

[0293] X is selected from O and S;

[0294] Preferably, X is 0;

[0295] L 1a Selected from C1-C6 alkylene groups, wherein the C1-C6 alkylene groups are optionally substituted with 1-3 (preferably 1-2) deuterium atoms;

[0296] Preferably, L 1a Selected from ethylene,

[0297] Preferably, L 1 Selected from

[0298] Ring A is selected from

[0299] Each R 2 Selected independently

[0300] L 2a Selected from C1-C6 alkylene and C2-C6 ynylene groups;

[0301] Preferably, L 2aSelected from methylene, ethylene, R 2a Selected from hydrogen and C1-C6 alkyl groups;

[0302] Preferably, R 2a Selected from hydrogen and methyl;

[0303] Preferably, each R 2 Selected independently Each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen;

[0304] Preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl;

[0305] More preferably, each R 4 Independently selected from hydrogen and methyl;

[0306] R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl;

[0307] Preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl;

[0308] R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen;

[0309] Preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups;

[0310] R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0311] Preferably, R 6 Selected from hydrogen and deuterium;

[0312] Among them, R 0 and R 5 They are not both hydrogen;

[0313] Preferably, ring A is selected from

[0314] R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups;

[0315] Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups;

[0316] More preferably, R 3afor

[0317] R 3b Selected from C1-C6 alkyl and C3-C8 cycloalkyl groups;

[0318] Preferably, R 3b Selected from methyl and cyclopropyl;

[0319] R 3c Selected from C1-C6 alkyl groups;

[0320] Preferably, R 3c It is a methyl group.

[0321] In some embodiments, the compound has the structural formula shown in Formula I-2.

[0322]

[0323] in:

[0324] B0 ring is selected from Among them, position 1 and Connected, position 2 and L 1 Connected;

[0325] R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups,

[0326] 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0327] Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0328] More preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, -C(O)-NR 1a5 R 1a6 ;

[0329] R 1a1Selected from hydrogen and C1-C6 alkyl groups;

[0330] Preferably, R 1a1 It is methyl;

[0331] R 1a2 Selected from hydrogen and C1-C6 alkyl groups;

[0332] Preferably, R 1a2 It is methyl;

[0333] R 1a3 Selected from hydrogen and C1-C6 alkyl groups;

[0334] Preferably, R 1a3 It is methyl;

[0335] R 1a4 Selected from hydrogen and C1-C6 alkyl groups;

[0336] Preferably, R 1a4 It is methyl;

[0337] R 1a5 Selected from hydrogen and C1-C6 alkyl groups;

[0338] Preferably, R 1a5 It is hydrogen;

[0339] R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0340] Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups;

[0341] More preferably, R 1a6 It is cyclopropyl;

[0342] Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl,

[0343] R 1b Selected from halogen, cyano, and nitro groups;

[0344] Preferably, R 1b Selected from halogens;

[0345] More preferably, R 1b For F;

[0346] R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0347] Preferably, R 1c Selected from hydrogen and deuterium;

[0348] R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0349] Preferably, R 1d Selected from hydrogen and deuterium;

[0350] Each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0351] Preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl;

[0352] R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0353] Preferably, R 1f R 1g It is fluorine;

[0354] B0 ring is selected from Among them, position 1 and Connected, position 2 and L 1 Connected;

[0355] L 1 Selected from -XL 1a - C1-C6 alkylene groups; preferably, X is connected to the B0 ring, L 1a Linked to the pyrazole ring;

[0356] X is selected from O and S;

[0357] Preferably, X is 0;

[0358] L 1a Selected from C1-C6 alkylene groups and C2-C6 ynylene groups, wherein the C1-C6 alkylene groups are optionally substituted by 1-3 (preferably 1) C3-C8 cycloalkyl groups;

[0359] Preferably, L 1a Selected from ethylene, The ethylene is optionally replaced by 1-3 (preferably 1) cyclopropyl groups;

[0360] More preferably, L 1a Selected from ethylene,

[0361] Preferably, L 1 Selected from Methylene

[0362] R 2 Selected from

[0363] L 2a Selected from direct bonds and C1-C6 alkylene groups;

[0364] Preferably, L 2a Selected from direct bond, methylene;

[0365] L 2b Selected from direct bonds and C1-C6 alkylene groups;

[0366] Preferably, L 2b Selected from direct bond, methylene;

[0367] More preferably, L 2b For direct keys;

[0368] R 2a Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0369] Preferably, R 2a Selected from hydrogen, methyl, and cyclopropyl;

[0370] R 2b Selected from C1-C6 alkyl groups;

[0371] Preferably, R 2b It is methyl;

[0372] R 2c Selected from C1-C6 alkyl groups;

[0373] Preferably, R 2c It is methyl;

[0374] Most preferably, R 2 Selected from

[0375] R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 The group is replaced by a C1-C6 alkyl group or a C3-C8 cycloalkyl group optionally replaced by a C1-C6 alkyl group;

[0376] Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 Cyclopropyl groups optionally substituted with methyl groups (e.g.) The group replaced by )

[0377] R 3a1 R 3a2Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0378] Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl;

[0379] More preferably, R 3a1 R 3a2 It is methyl;

[0380] More preferably, R 3a Selected from

[0381] R 3b Selected from C1-C6 alkyl groups;

[0382] Preferably, R 3b It is methyl;

[0383] R 3c Selected from C1-C6 alkyl groups;

[0384] Preferably, R 3c It is methyl;

[0385] Among them, when ring B0 is selected And R 1a When R is selected from halogens or is F, 1c and R 1d They are not both hydrogen.

[0386] In some embodiments, the compound has the structural formula shown in Formula I-2-1.

[0387]

[0388] in:

[0389] R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups,

[0390] 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0391] Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ;

[0392] More preferably, R1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, -C(O)-NR 1a5 R 1a6 ;

[0393] R 1a1 Selected from hydrogen and C1-C6 alkyl groups;

[0394] Preferably, R 1a1 It is methyl;

[0395] R 1a2 Selected from hydrogen and C1-C6 alkyl groups;

[0396] Preferably, R 1a2 It is methyl;

[0397] R 1a3 Selected from hydrogen and C1-C6 alkyl groups;

[0398] Preferably, R 1a3 It is methyl;

[0399] R 1a4 Selected from hydrogen and C1-C6 alkyl groups;

[0400] Preferably, R 1a4 It is methyl;

[0401] R 1a5 Selected from hydrogen and C1-C6 alkyl groups;

[0402] Preferably, R 1a5 It is hydrogen;

[0403] R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0404] Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups;

[0405] More preferably, R 1a6 It is cyclopropyl;

[0406] Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl, R 1b Selected from halogen, cyano, and nitro groups;

[0407] Preferably, R 1b Selected from halogens;

[0408] More preferably, R 1b For F;

[0409] R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0410] Preferably, R 1c Selected from hydrogen and deuterium;

[0411] R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups;

[0412] Preferably, R 1d Selected from hydrogen and deuterium;

[0413] Among them, R 1a When R is selected from halogens or is F, 1c and R 1d They are not both hydrogen;

[0414] Preferably, As a whole, selected from Among them, position 1 and Connected, position 2 and L 1 Connected;

[0415] L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring;

[0416] X is selected from O and S;

[0417] Preferably, X is 0;

[0418] L 1a Selected from C1-C6 alkylene groups;

[0419] Preferably, L 1a It is ethylene;

[0420] Preferably, L 1 for

[0421] R 2a Selected from C1-C6 alkyl groups;

[0422] Preferably, R 2a It is methyl;

[0423] R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups;

[0424] Preferably, R3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups;

[0425] More preferably, R 3a for

[0426] R 3b Selected from C1-C6 alkyl groups;

[0427] Preferably, R 3b It is methyl;

[0428] R 3c Selected from C1-C6 alkyl groups;

[0429] Preferably, R 3c It is a methyl group.

[0430] In some embodiments, the compound has the structural formula shown in Formula I-2-2.

[0431]

[0432] in:

[0433] Ring B is selected from Among them, position 1 and Connected, position 2 and L 1 Connected;

[0434] Each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0435] Preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl;

[0436] R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0437] Preferably, R 1f R 1g It is fluorine;

[0438] Preferably, ring B is selected from Among them, position 1 and Connected, position 2 and L 1 Connected;

[0439] L 1 Selected from -XL 1a - C1-C6 alkylene rings; preferably, X is connected to ring B, L1a Linked to the pyrazole ring;

[0440] X is selected from O and S;

[0441] Preferably, X is 0;

[0442] L 1a Selected from C1-C6 alkylene groups and C2-C6 ynylene groups, wherein the C1-C6 alkylene groups are optionally substituted by 1-3 (preferably 1) C3-C8 cycloalkyl groups;

[0443] Preferably, L 1a Selected from ethylene, The ethylene is optionally replaced by 1-3 (preferably 1) cyclopropyl groups;

[0444] More preferably, L 1a Selected from ethylene,

[0445] Preferably, L 1 Selected from Methylene

[0446] R 2 Selected from

[0447] L 2a Selected from direct bonds and C1-C6 alkylene groups;

[0448] Preferably, L 2a Selected from direct bond, methylene;

[0449] L 2b Selected from direct bonds and C1-C6 alkylene groups;

[0450] Preferably, L 2b Selected from direct bond, methylene;

[0451] More preferably, L 2b For direct keys;

[0452] R 2a Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;

[0453] Preferably, R 2a Selected from hydrogen, methyl, and cyclopropyl;

[0454] R 2b Selected from C1-C6 alkyl groups;

[0455] Preferably, R 2b It is methyl;

[0456] R 2c Selected from C1-C6 alkyl groups;

[0457] Preferably, R 2c It is methyl;

[0458] Most preferably, R 2 Selected from

[0459] R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 The group may be replaced by a C3-C8 cycloalkyl group that is optionally replaced by a C1-C6 alkyl group;

[0460] Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 Cyclopropyl groups optionally substituted with methyl groups (e.g.) The group replaced by )

[0461] R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0462] Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl;

[0463] More preferably, R 3a1 R 3a2 It is methyl;

[0464] More preferably, R 3a Selected from

[0465] R 3b Selected from C1-C6 alkyl groups;

[0466] Preferably, R 3b It is methyl;

[0467] R 3c Selected from C1-C6 alkyl groups;

[0468] Preferably, R 3c It is a methyl group.

[0469] In some embodiments, the compound has the structural formula shown in Formula I-3.

[0470]

[0471] in:

[0472] R 1a Selected from halogen, cyano, and nitro groups;

[0473] Preferably, R 1a Selected from halogens;

[0474] More preferably, R 1a For F;

[0475] R 1b Selected from halogen, cyano, and nitro groups;

[0476] Preferably, R 1b Selected from halogens;

[0477] More preferably, R 1b For F;

[0478] R 1c Selected from hydrogen and C1-C6 alkyl groups;

[0479] Preferably, R 1c It is hydrogen;

[0480] R 1d Selected from hydrogen and C1-C6 alkyl groups;

[0481] Preferably, R 1d It is hydrogen;

[0482] L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring;

[0483] X is selected from O, S, NH, and -C(O)-;

[0484] Preferably, X is selected from O, NH, and -C(O)-;

[0485] L 1a The group is selected from C1-C6 alkylene, -C(O)-C1-C6 alkylene, -NH-S(O)2-, C2-C6 ynylene, C3-C8 cycloalkylene-C1-C6 alkylene, C3-C8 cycloalkylene, C2-C6 alkenylene, and C1-C6 alkylene-C(O)-, wherein each of the C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynylene, and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 (preferably 1) groups selected from C3-C8 cycloalkyl, deuterium, and C1-C6 alkyl groups; preferably, L 1a The site on the left is connected to X, and the site on the right is connected to the pyrazole ring;

[0486] Preferably, L 1aThe group is selected from C1-C6 alkylene, -C(O)-C1-C6 alkylene, -NH-S(O)2-, C2-C6 ynynylene, C3-C8 cycloalkylene-C1-C6 alkylene, C3-C8 cycloalkylene, C2-C6 alkenylene, and C1-C6 alkylene-C(O)-, wherein each of the C1-C6 alkylene and C2-C6 ynynylene groups is optionally and independently replaced by 1-3 (preferably 1) groups selected from cyclopropyl and deuterium; preferably, L 1a The site on the left is connected to X, and the site on the right is connected to the pyrazole ring;

[0487] More preferably, L 1a Selected from Preferably, L 1a The upper site is connected to X, and the lower site is connected to the pyrazole ring;

[0488] Preferably, L 1 Selected from Preferably, L 1 The upper site is connected to the benzene ring, and the lower site is connected to the pyrazole ring;

[0489] R 2a Selected from hydrogen and C1-C6 alkyl groups;

[0490] Preferably, R 2a Selected from hydrogen and methyl;

[0491] R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups;

[0492] Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups;

[0493] More preferably, R 3a for

[0494] R 3b Selected from C1-C6 alkyl groups;

[0495] Preferably, R 3b Selected from methyl;

[0496] R 3c Selected from C1-C6 alkyl groups;

[0497] Preferably, R 3c It is methyl;

[0498] Among them, L 1aC1-C6 alkylene or L 1 for At that time, R 1a and R 3c Connected to form

[0499] In some embodiments, the compound has the structural formula shown in Formula I-4.

[0500]

[0501] in:

[0502] R 1a Selected from halogen, cyano, and nitro groups;

[0503] Preferably, R 1a Selected from halogens;

[0504] More preferably, R 1a For F;

[0505] R 1b Selected from halogen, cyano, and nitro groups;

[0506] Preferably, R 1b Selected from halogens;

[0507] More preferably, R 1b For F;

[0508] R 1c Selected from hydrogen and C1-C6 alkyl groups;

[0509] Preferably, R 1c It is hydrogen;

[0510] R 1d Selected from hydrogen and C1-C6 alkyl groups;

[0511] Preferably, R 1d It is hydrogen;

[0512] L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Connected to ring C;

[0513] X is selected from O and S;

[0514] Preferably, X is 0;

[0515] L 1a Selected from C1-C6 alkylene groups, direct bonds;

[0516] Preferably, L 1a Selected from methylene, ethylene, and direct bonds;

[0517] Preferably, L 1 Selected from -O- R 2a Selected from hydrogen and C1-C6 alkyl groups;

[0518] Preferably, R 2a Selected from hydrogen and methyl;

[0519] C ring is selected from R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each independently and optionally replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (such as methyl), deuterium, nitro, halogen (such as fluorine), and phenyl;

[0520] Preferably, R 3aSelected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-membered nitrogen-containing saturated heterocyclic group, -C(O)-4-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-membered heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-membered nitrogen-containing saturated heterocyclic group, 5-membered nitrogen-containing saturated heterocyclic group, phenyl, and 5-membered heteroaryl group are each independently and optionally replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (such as methyl), deuterium, nitro, halogen (such as fluorine), and phenyl;

[0521] More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, aziridine, -C(O)-aziridine, C1-C6 alkylene-tetrahydropyrrolyl, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-oxazolyl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 ,

[0522] -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, aziridine, tetrahydropyrrolyl, phenyl, and oxazolyl groups are each optionally and independently replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (e.g., methyl), deuterium, nitro, halogen (e.g., fluorine), and phenyl groups;

[0523] R 3a1 R 3a2 Each is independently selected from hydrogen, C1-C6 alkyl, and deuterated C1-C6 alkyl, wherein the C1-C6 alkyl and deuterated C1-C6 alkyl are each optionally substituted by 1 to 3 (e.g., 1) hydroxyl groups;

[0524] Preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, C1-C6 alkyl, or deuterated C1-C6 alkyl, and the other is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, or hydroxyl-substituted deuterated C1-C6 alkyl.

[0525] More preferably, R 3a1 R 3a2 In this context, one of the atoms is selected from hydrogen, methyl, or -CD3, and the other is selected from methyl, -CD3, ...

[0526]

[0527] R 3a3 Selected from C1-C6 alkyl groups;

[0528] Preferably, R 3a3 For tert-butyl;

[0529] Most preferably, R 3a Selected from

[0530] R 3b Selected from C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

[0531] Preferably, R 3b Selected from methyl, cyclopropyl, vinyl, and ethynyl groups;

[0532] R 3c Selected from C1-C6 alkyl groups;

[0533] Preferably, R 3c It is methyl;

[0534] R 3d Selected from C1-C6 alkyl groups;

[0535] Preferably, R 3d It is methyl;

[0536] R 3e Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups;

[0537] Preferably, R 3e for

[0538] Preferably, ring C is selected from

[0539] Where R 3a C1-C6 alkyl groups substituted with one hydroxyl group or... At that time, R 3b Not selected from C1-C6 alkyl groups (such as R 3b (Not methyl).

[0540] In some embodiments, the compound is any compound selected from the following examples.

[0541] In a second aspect, the present invention provides a linker-drug conjugate, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, comprising:

[0542] A pharmaceutical group, wherein the pharmaceutical group is a compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester formed by losing a hydrogen atom; and

[0543] A linker, wherein the linker is directly connected to the drug group.

[0544] In some embodiments, the pharmaceutical group has the structural formula shown in Formula II-1 or Formula II-2.

[0545]

[0546] in:

[0547] R 2a Selected from deuterated C1-C6 alkyl groups;

[0548] Preferably, R 2a for

[0549] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

[0550] In some implementations, the connector is

[0551] in:

[0552] M stands for connector;

[0553] L A Whether L exists or not, when L A When present, it is a spacing unit and / or a branch spacing unit;

[0554] L B Whether L exists or not, when L B When present, it is a single amino acid or its analogue or derivative, or a peptide fragment formed by two or more amino acids or their analogues or derivatives;

[0555] L C Whether L exists or not, when L C When present, it is a self-eliminating unit.

[0556] In some implementations, M is selected from:

[0557]

[0558] a and b are each independently selected from integers from 0 to 6;

[0559] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

[0560] In some implementations, when the L A When it exists, select from

[0561] in,

[0562] X LA Selected from direct bonds, O, or NH;

[0563] R LA1 Selected from direct key or

[0564] R LA3 Selected from direct keys,

[0565] R LA4 Selected from COOH, C1-C6 alkoxy or NR LA4-1 R LA4-2 ;

[0566] R LA4-1 R LA4-2 Each is independently selected from H, optionally substituted C1-C6 alkyl groups, or -C(O)-R. LA4-3 ;

[0567] R LA4-3 Selected from optionally substituted C1-C6 alkyl groups;

[0568] R LA2 Selected from direct bond, -C1-C6 alkylene-5-10 heteroaryl- or -C1-C6 alkylene-5-10 heterocyclic-; preferably direct bond or -C1-C3 alkylene-5-6 heteroaryl-;

[0569] r is an integer selected from 0 to 10;

[0570] w is selected from integers from 0 to 10;

[0571] y is selected from 0, 1, 2, 3 or 4;

[0572] z is selected from integers from 0 to 30;

[0573] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

[0574] In some implementations, when the L B When present, each of the amino acids is independently selected from (D / L) valine (Val), (D / L) citrulline (Cit), (D / L) glutamic acid (Glu), (D / L) lysine (Lys), (D / L) arginine (Arg), (D / L) phenylalanine (Phe), (D / L) tyrosine (Tyr), (D / L) leucine (Leu), glycine (Gly), (D / L) alanine (Ala), (D / L) asparagine (Asn), (D / L) glutamine (Gln), (D / L) serine (Ser), and (D / L) aspartic acid (Asp). Or its analogues or derivatives.

[0575] In some implementations, when the L C When it exists, select from Or any combination of the above structures;

[0576] R LC Each is independently selected from H, nitro, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, NR LC1 R LC2 Or, natural or non-natural monosaccharides, disaccharides, polysaccharides or their derivatives, or any combination of the above structures;

[0577] R LC1 R LC2 Each is independently selected from H, optionally substituted C1-C6 alkyl groups, or -C(O)-R. LC3 ;

[0578] R LC3 Selected from optionally substituted C1-C6 alkyl groups,

[0579] R LC Each is independently selected from optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl;

[0580] Preferably, the natural or non-natural monosaccharide, disaccharide, polysaccharide or its derivatives are selected from glucuronic acid;

[0581] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

[0582] In some embodiments, the linker-drug conjugate is selected from the following:

[0583]

[0584]

[0585]

[0586]

[0587] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

[0588] In a third aspect, the present invention provides an antibody-drug conjugate, or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate of said antibody-drug conjugate, comprising:

[0589] Antibody or its antigen-binding fragment;

[0590] Connector; and

[0591] The pharmaceutical group is a group formed by the loss of a hydrogen atom from a compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester described in any of the first aspects.

[0592] The antibody or its antigen-binding fragment is linked to the drug group via the linker.

[0593] In some implementations, the connector is

[0594] in:

[0595] M' is the connector unit;

[0596] L A As described in any of the technical solutions in the second aspect;

[0597] L B As described in any of the technical solutions in the second aspect;

[0598] L C As described in any of the technical solutions in the second aspect.

[0599] In some implementations, M' is selected from:

[0600]

[0601]

[0602] in:

[0603] Q is selected from:

[0604] Direct key

[0605] G is selected from the following structure:

[0606]

[0607] X1 can be independently -O-, -S-, -NH-, or -CH2-;

[0608] X2 can be independently -O-, -S-, -NH-, -C(O)-, or -CH2-;

[0609] a and b are each independently selected from integers between 0 and 6;

[0610] c are each independently selected from integers between 0 and 24;

[0611] d are each independently selected from integers between 0 and 10;

[0612] In the above structures, the configuration of any chiral carbon is independently either R-type or S-type;

[0613] When the M' structure includes maleimide, the maleimide can optionally be hydrolyzed to open the ring, that is, each maleimide can be independently in an open-ring or closed-ring form, specifically, each can be independently in an open-ring or closed-ring form.

[0614] In some embodiments, the antibody-drug conjugate is selected from the following:

[0615]

[0616]

[0617]

[0618]

[0619]

[0620] c is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8; q is selected from integers or decimals from 1 to 10;

[0621] In the above structures, the configuration of any chiral carbon can be either R-type or S-type independently;

[0622] When the antibody-drug conjugate structure includes maleimide, the maleimide can optionally be hydrolyzed to open the ring, i.e., each maleimide can be independently in an open-ring or closed-ring form. Specifically, each can be independently...

[0623] In some implementations, Ab is selected from:

[0624] Anti-EGFRvIII antibody, anti-PD 1 antibody, anti-PD L1 antibody, anti-DLL3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDGF1 antibody, anti-ETBR antibody, anti-MSLN antibody, anti-TIM 1 antibody, anti-LRRC15 antibody, anti-LIV 1 antibody, anti-CanAg / AFP antibody, anti-Claudin18.2 antibody, anti-Mesothelin antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-cMET antibody, anti-SLITRK6 antibody, anti-KIT / CD117 antibody, anti-STEAP1 antibody, anti-SLAMF7 / CS1 antibody, anti-NaPi2B / SLC34A2 antibody, anti-GPNMB antibody, anti-HER3 (ErbB3) antibody, anti-MUC1 / CD227 antibody, anti-AXL antibody, anti-CD166 antibody, anti-B7 H3(CD276) antibody, anti-PTK7 / CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-NOTCH3 antibody, anti-Nectin 4 antibody, anti-Trop2 antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-LYPD3 antibody, anti-FGFR2 antibody, anti-FGFR3 antibody, anti-FRα antibody, anti-CEACAMs antibody, anti-GCC antibody, anti-Integrin Av antibody, anti-CAIX antibody, anti-P cadherin antibody, anti-GD3 antibody, anti-Cadherin 6. Antibodies, including anti-LAMP1 antibody, anti-FLT3 antibody, anti-BCMA antibody, anti-CD79b antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD74 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD37 antibody, anti-CD47 antibody, anti-CD138 antibody, anti-CD352 antibody, anti-CD25 antibody, anti-CD123 antibody, anti-GPC3 antibody, anti-ROR1 antibody, anti-uPAR antibody, anti-NKG2D antibody, anti-CD94 antibody, anti-CD228 antibody, anti-HLA-G antibody, anti-VEGFR2 antibody, anti-VEGF antibody, anti-PD-1×CTLA-4 bispecific antibody, anti-EGFR×HER3 bispecific antibody, or any combination of antibodies targeting the above targets.

[0625] In a fourth aspect, the present invention provides a pharmaceutical composition comprising:

[0626] (1) The compound described in any of the technical solutions of the first aspect or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters, or the linker-drug conjugate described in the second aspect or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters, or the antibody-drug conjugate described in the third aspect or its pharmaceutically acceptable salts or pharmaceutically acceptable solvates;

[0627] (2) Pharmaceutically acceptable carriers and / or excipients;

[0628] And optional (3) one or more other active ingredients.

[0629] In a fifth aspect, the present invention provides the use of the compound or stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester described in any of the technical solutions of the first aspect, or the linker-drug conjugate or stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester described in the second aspect, or the antibody-drug conjugate or pharmaceutically acceptable salt or pharmaceutically acceptable solvate described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a medicament for treating and / or preventing diseases related to NMT.

[0630] Furthermore, the present invention also provides compounds or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters described in any of the first aspects, or linker-drug conjugates or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters described in the second aspect, or antibody-drug conjugates or pharmaceutically acceptable salts or pharmaceutically acceptable solvates described in the third aspect, or pharmaceutical compositions described in the fourth aspect, for the treatment and / or prevention of diseases related to NMT.

[0631] In addition, the present invention also provides a method for treating and / or preventing diseases related to NMT, comprising: administering to a subject in need an effective amount of a compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of any of the technical solutions of the first aspect, or a linker-drug conjugate or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate as described in the second aspect, or an antibody-drug conjugate or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate as described in the third aspect, or a pharmaceutical composition as described in the fourth aspect.

[0632] In some implementations, the disease associated with NMT is selected from diseases or conditions such as cancer, viral infections, neurological diseases, local ischemia, osteoporosis, diabetes, autoimmune diseases, inflammatory diseases, microbial infections (e.g., fungal infections), and protozoan infections.

[0633] In some implementations, the cancer is a hematologic malignancy or a solid tumor.

[0634] In some implementations, the hematologic malignancy is lymphoma, myeloma (e.g., multiple myeloma), or leukemia (e.g., chronic lymphocytic leukemia, AML, or acute B-lymphocytic leukemia).

[0635] In some implementations, the lymphoma is a B-cell lymphoma (e.g., high-grade mantle lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, or Burkitt lymphoma).

[0636] In some implementations, the solid tumor is brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer, or liver cancer, or blastoma (e.g., neuroblastoma, retinoblastoma, or glioma).

[0637] In some implementations, the viral infection is an enterovirus infection, a retrovirus infection, or a poxvirus infection.

[0638] In some implementations, the enterovirus infection is a piconemavirus (such as rhinovirus), poliovirus, foot-and-mouth disease virus, Coxsackievirus, hepatitis A virus, or enterovirus 71 infection.

[0639] In some implementations, the retroviral infection is a lentiviral infection (such as HIV infection).

[0640] In some implementations, the poxvirus infection is an orthopoxvirus, parapoxvirus, attapoxvirus, or molluscum poxvirus infection.

[0641] In some implementations, the orthopoxvirus infection is smallpox virus (smallpox) infection, vaccinia virus infection, cowpox virus infection, or monkeypox virus infection.

[0642] In some embodiments, the protozoan infection is a protozoan infection caused by species of the genera Plasmodium, Leishmania, or Trypanosoma (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Leishmania macrophylla, Trypanosoma brucei, Trypanosoma krusei).

[0643] The present invention also provides the use of the compound or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters of the compound described in any of the first aspects, or the linker-drug conjugates or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters of the linker-drug conjugates described in the second aspect for the preparation of antibody-drug conjugates;

[0644] Preferably, the antibody-drug conjugate is selected from the antibody-drug conjugates described in the third aspect or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the antibody-drug conjugates.

[0645] Beneficial effects

[0646] The compounds of the present invention, or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters of the compounds, or the antibody-drug conjugates of the present invention, have excellent NMT inhibitory activity and can effectively treat NMT-related diseases. Detailed Implementation

[0647] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. Furthermore, although any methods, apparatus, and materials similar to or equivalent to those described herein may be used to practice or test the invention, preferred methods, apparatus, and materials are described here.

[0648] In this invention, unless otherwise explicitly stated, the descriptive terms “each…independently” and “…each independently” used throughout this document are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0649] The substituents in the compounds of this invention are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0650] The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl", and most preferably "C1-C2 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, isobutyl, tert-butyl). Examples of "C1-C3 alkyl" include methyl, ethyl, and propyl (e.g., n-propyl, isopropyl). Examples of "C1-C2 alkyl" include methyl and ethyl.

[0651] The term "C1-C6 alkylene" refers to any of the above C1-C6 alkyl groups that lose one hydrogen atom to form a divalent group, such as methylene, ethylene, etc.

[0652] The term "deuterated C1-C6 alkyl" refers to a group obtained by substituting one or more (e.g., one, two, three, four, five, six or more) hydrogen atoms from any of the aforementioned C1-C6 alkyl groups with deuterium atoms, such as... wait.

[0653] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0654] The term "C3-C8 cycloalkyl" refers to a saturated monocyclic or polycyclic compound (such as a fused ring, bridged ring, or spirocyclic compound) containing 3-8 carbon atoms, preferably "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" more preferably refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0655] The term "C3-C8 cycloalkylene" refers to the divalent group obtained by losing one hydrogen atom from any of the above-mentioned C3-C8 cycloalkyl groups, such as... wait.

[0656] The term "C2-C6 alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group with 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, allyl, etc.

[0657] The term "C2-C6 alkenyl" refers to any of the above-mentioned C2-C6 alkenyl groups that lose one hydrogen atom to form a divalent group, such as vinylidene. wait.

[0658] The term "C2-C6 ynyl" refers to a straight-chain or branched unsaturated hydrocarbon group with 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl.

[0659] The term "C2-C6 ynylene" refers to any of the above-mentioned C2-C6 ynylene groups that lose one hydrogen atom to form a divalent group, such as... wait.

[0660] The term "C1-C6 alkoxy" refers to a group in which one or more methylene groups in the C1-C6 alkyl group are replaced by an O atom, or -O-(C3-C6 cycloalkyl); wherein the alkyl or cycloalkyl group is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0661] The term "direct bond" refers to a bond in which groups on both sides are directly connected, such as L. 1 -XL 1a -When, if L 1a If it is a direct key, then L 1 It will become -X-.

[0662] The term "heteroatoms" refers to N, O, or S.

[0663] The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, tricyclic, or more cyclic group comprising 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 5-6-membered, more preferably 5-membered) ring having at least one heteroatom (N, O, or S) in at least one ring, wherein the heteroatom-containing ring optionally also has one, two, or three heteroatoms selected from N, O, or S. For a heteroaryl group to be bicyclic, tricyclic, or multicyclic, each ring in the bicyclic, tricyclic, or multicyclic system must constitute an aromatic system. Non-limiting examples of the heteroaryl group include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiazolyl, pyrroleyl, phenyl-pyrroleyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzimidazolyl, inzolyl, quinolinyl, isoquinolinyl, etc.

[0664] The term "heterocyclic group" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered (preferably 3-7-, 3-6-, 5-10-, or 5-6-membered) carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur, and the group as a whole does not constitute an aromatic system. Non-limiting examples of heterocyclic groups include, for example, pyranyl, pyrrolylyl, pyrrololinyl, imidazolinyl, imidazolinyl, pyrazolealkyl, pyrazolelinyl, thiazolinyl, thiazolinyl, dihydrofuranyl, tetrahydrofuranyl, 1,3-dioxolanecycloyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc. For example, a "6-membered heterocyclic group" refers to a 6-membered saturated or partially unsaturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 6-membered heterocyclic groups include, for example, pyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. A "6-membered nitrogen-containing saturated heterocyclic group" refers to a 6-membered saturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur, and at least one nitrogen atom is present; examples include piperidinyl and piperazinyl. Similarly, a "5-membered heterocyclic group" refers to a 5-membered saturated or partially unsaturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 5-membered heterocyclic groups include, for example, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazoalkyl, pyrazolylyl, pyrazolyl, thiazolinyl, thiazoalkyl, 1,3-dioxolanecycloyl, and tetrahydropyrrolidinyl. A "5-membered nitrogen-containing saturated heterocyclic group" refers to a 5-membered saturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur, and at least one nitrogen atom is present; examples include tetrahydropyrrolidinyl. Similarly, "4-membered nitrogen-containing saturated heterocyclic group" refers to a 4-membered saturated carbon ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur, and contains at least one nitrogen atom, such as nitrogen-containing heterocyclic butyl groups.

[0665] The term "substituted" refers to the selective substitution of any or more hydrogen atoms on a specified atom or group by a specified group, provided that the substitution does not exceed the normal valence state of the specified atom. For example, the term "optionally cyano-substituted C3-C8 cycloalkyl" refers to a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl group substituted with one or more (e.g., one, two, three, four, five, six or more, preferably one) cyano groups, specifically for example... For example, the term "hydroxyl-substituted C1-C6 alkyl" refers to a C1-C6 alkyl group being substituted with one or more (e.g., one, two, three, four, five, six or more, preferably one) hydroxyl groups, such as hydroxymethyl. Other similar definitions can be understood by referring to the foregoing.

[0666] In this invention, for example, "R" 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR3a1 R 3a2 The phrase "-C(O)-C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently and optionally substituted by 1-3 groups selected from hydroxyl, cyclopropyl, deuterium, and hydroxymethyl" means that the C1-C6 alkyl and C3-C8 cycloalkyl may or may not be substituted, and when substituted, the substituents of the C1-C6 alkyl and the C3-C8 cycloalkyl may be the same or different. Furthermore, when the C1-C6 alkyl or the C3-C8 cycloalkyl is independently substituted by 2 or 3 substituents, the 2 or 3 substituents of each C1-C6 alkyl or the C3-C8 cycloalkyl may be the same or different from each other. Other similar definitions are understood by referring to the foregoing content.

[0667] In this invention, the composite group, such as "C1-C6 alkylene-C3-C8 cycloalkyl", refers to a C1-C6 alkylene group directly linked to a C3-C8 cycloalkyl group, specifically as follows: For example, "-C(O)-C1-C6 alkyl" refers to a carbonyl group -C(O)- directly bonded to a C1-C6 alkyl group, specifically as follows: For example, "-C(O)-C3-C8 cycloalkylene-C1-C6 alkyl" refers to carbonyl-C(O)-, C3-C8 cycloalkylene, and C1-C6 alkyl groups being directly linked from left to right, as shown in the example below. Please refer to the foregoing content for understanding other similar definitions.

[0668] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effects. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) preventing the occurrence of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., preventing its progression; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptom to regress.

[0669] In this invention, "subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0670] In this invention, "effective amount" refers to the amount that effectively achieves the desired therapeutic effect at the necessary dosage and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the ability of the substance / molecule to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences.

[0671] In this invention, "pharmaceuticalally acceptable carriers and / or excipients" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient, and are well known in the art (see, for example, Remington's Pharmaceutical Sciences, Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers, diluents, osmotic pressure maintaining agents, absorption delaying agents, and preservatives. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Osmotic pressure maintaining agents include, but are not limited to, sugars, NaCl, and the like. Absorption delaying agents include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, p-hydroxybenzoate, chlorobutanol, phenol, sorbic acid, etc.

[0672] The pharmaceutical composition of the present invention can be prepared in various forms according to different routes of administration. For example, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, and non-enteric administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, and intracranial injection or infusion, or via an external implantation device. Oral or intravenous administration is preferred.

[0673] As used herein, unless otherwise stated, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compounds of the present invention. Prodrugs become active compounds only under biological conditions, or they do not have or have only low activity in their unreacted forms. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0674] As used herein, the term “stereoisomer” refers to isomers of molecules in which atoms or groups of atoms are connected in the same order but have different spatial arrangements. The term “stereoisomer” as used herein encompasses (R)-isomers, (S)-isomers, meso compounds, racemic compounds, enantiomers, diastereomers, or any mixtures thereof of the compounds described herein.

[0675] As used herein, the terms "solvent" or "solvent compound" are used interchangeably and refer to a compound existing in combination with a solvent molecule. This combination may include a stoichiometric amount of a solvent, such as a monohydrate or dihydrate, or may include any amount of water; similarly, methanol or ethanol may form an "alcohol," which may be stoichiometric or non-stoichiometric. The term "solvent compound" as used herein refers to a solid form, i.e., a compound in solution of a solvent that, while solvated, is not a solvate compound as used herein.

[0676] As used herein, the term "pharmaceutically acceptable salt" means (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided by the present invention and a suitable inorganic or organic cation (base), including but not limited to, alkali metal salts such as sodium, potassium, lithium, etc.; alkaline earth metal salts such as calcium, magnesium, etc.; other metal salts such as aluminum, iron, zinc, copper, nickel, cobalt, etc.; inorganic base salts such as ammonium salts; organic base salts such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenylethylamine salts, piperazine salts, tetramethylamine salts, and tris(hydroxymethyl)aminomethane salts. (ii) The salts formed by the basic functional group (e.g., -NH2) present in the compounds provided by the present invention and suitable inorganic or organic anions (acids), including but not limited to, hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkyl sulfonates such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; aryl sulfonates such as benzenesulfonates, p-benzenesulfonates, etc.; organic acid salts such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamate salts, aspartate salts, etc.

[0677] As used herein, the term "pharmaceutically acceptable ester" refers to an ester formed by the -COOH group present in the compounds provided by the present invention and a suitable alcohol, or an ester formed by the -OH group present in the compounds provided by the present invention and a suitable acid (e.g., a carboxylic acid or an oxy-containing inorganic acid). Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate, or palmitate. Esters can undergo hydrolysis in the presence of acid or base to produce the corresponding acid or alcohol.

[0678] As used herein, the term "crystal form" refers to the crystal structure of a substance. During crystallization, various factors alter the intramolecular or intermolecular bonding patterns, resulting in different arrangements of molecules or atoms in the crystal lattice, thus forming different crystal structures. The compounds of this invention can exist in one crystal structure or multiple crystal structures, i.e., they possess "polymorphism." The compounds of this invention can exist in different crystal forms.

[0679] The present invention will be further explained and described below with reference to specific embodiments.

[0680] Example: Preparation of Compounds

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688] Example 1: Synthesis of compound D-1

[0689]

[0690] Synthesis of Compound 2

[0691] Sodium hydride (60% dispersed in mineral oil, 62.3 g, 1.56 mol, 1.2 eq.) was dispersed in dry tetrahydrofuran (1400 mL). A tetrahydrofuran solution (600 mL) of compound 1 (200 g, 1.30 mol, 1.0 eq.) and iodomethane (96.9 mL, 1.56 mol, 1.2 eq.) were slowly added at 0 °C. The mixture was allowed to rise to room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 2 (216 g, 99% yield). LC-MS m / z (ES) + ): [M+H] + :169.1.

[0692] Synthesis of Compound 3

[0693] Compound 2 (216 g, 1.28 mol, 1.0 eq.) was dissolved in acetonitrile (1500 mL), and N-bromosuccinimide (251 g, 1.41 mol, 1.1 eq.) was slowly added at 0 °C. The mixture was allowed to rise to room temperature for 20 hours, and the reaction was monitored by TLC until complete. The reaction solution was concentrated and diluted with water, extracted with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 3 (282 g, 89% yield). LC-MS m / z (ES) + ): [M+H] + :247.0.

[0694] Synthesis of Compound 4

[0695] Compound 3 (130 g, 526 mmol, 1.0 eq.) was dissolved in degassed DMF (1000 mL) under nitrogen protection, followed by the addition of tributylvinyltin (308 mL, 1.05 mmol, 2.0 eq.) and tetrakis(triphenylphosphine)palladium (30.3 g, mmol, 0.05 eq.). The reaction was then heated at 110 °C for 20 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and quenched with water, then extracted with ethyl acetate. The organic phase was washed with saturated potassium fluoride aqueous solution, and the insoluble matter was filtered off. The filtrate was dried over anhydrous sodium sulfate, filtered again, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 4 (77 g, 75% yield). LC-MS m / z (ES) + ): [M+H] + :195.1.

[0696] Synthesis of Compound 5

[0697] Compound 4 (50.0 g, 257 mmol, 1.0 eq.) was dissolved in acetonitrile (800 mL), cooled to -30 °C, and iodobenzene diacetate (91.2 g, 283 mmol, 1.1 eq.) was added, followed by slow dropwise addition of 5% sulfuric acid (80 mL). After the addition was complete, the mixture was brought to room temperature and reacted for 1 hour. The mixture was diluted with saturated sodium carbonate aqueous solution and extracted with methanol / dichloromethane (1 / 5). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 5 (44 g, 81% yield). LC-MS m / z (ES) + ): [M+H] + :211.1.

[0698] Synthesis of Compound 6

[0699] Compound 5 (40 g, 190 mmol, 1.0 eq.) was dissolved in ethanol (400 mL), and sodium borohydride (18 g, 476 mmol, 2.5 eq.) was slowly added at 0 °C. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated and diluted with saturated sodium carbonate aqueous solution, and extracted with methanol / dichloromethane (1 / 5). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 6 (21 g, 52% yield). LC-MS m / z (ES) + ): [M+H] + :213.1.

[0700]

[0701] Synthesis of Compound 8

[0702] 4-Methoxybenzylamine (12.2 g, 88.6 mmol, 1.5 eq.) was added to a methanol (120 mL) solution of compound 7 (13.3 g, 59.1 mmol, 1.0 eq.). After reacting at room temperature for 2 hours, sodium borohydride (4.5 g, 118.2 mmol, 2.0 eq.) was added at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for another 2 hours. The reaction was monitored by TLC until complete. The mixture was quenched with saturated sodium carbonate solution and extracted with dichloromethane. The combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 8 (15.6 g, 76% yield). LC-MS m / z (ES) + ): [M+H] + :346.0.

[0703] Synthesis of Compound 9

[0704] Compound 8 (15.6 g, 45.1 mmol, 1.0 eq.) was dissolved in dichloromethane (150 mL), and triethylamine (12.5 mL, 90.1 mmol, 2.0 eq.) and di-tert-butyl dicarbonate (11.8 g, 54.07 mmol, 1.2 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 9 (18.7 g, 93% yield). LC-MS m / z (ES) + ): [M+H] + :446.1.

[0705] Synthesis of Compound 11

[0706] In a 500 mL three-necked flask, compound 9 (18.7 g, 41.9 mmol, 1.0 eq.), compound 10 (8.01 g, 46.1 mmol, 1.1 eq.), tetraphenylphosphine palladium (4.84 g, 4.19 mmol, 0.1 eq.), and an aqueous solution of potassium phosphate (26.7 g, 125.7 mmol, 3.0 eq.) in 36 mL were added sequentially, followed by degassing of 1,4-dioxane (180 mL). The reaction mixture was then refluxed for 2 hours. The reaction mixture was then cooled to room temperature, filtered through a diatomaceous earth filter, concentrated under reduced pressure, diluted with a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 11 (13.9 g, 67% yield). LC-MS m / z (ES) + ): [M+H] + :496.2.

[0707] Synthesis of Compound 12

[0708] Compound 11 (15.1 g, 30.5 mmol, 1.0 eq.), compound 6 (9.7 g, 45.7 mmol, 1.5 eq.), cyanomethylenetri-n-butylphosphine (14.7 g, 61.0 mmol, 2.0 eq.), and toluene (150 mL) were added sequentially to a 500 mL three-necked flask. The reaction mixture was reacted at 110 °C for 16 hours, and TLC showed complete reaction. The reaction mixture was then diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 12 (13.9 g, yield 66%). LC-MS m / z (ES) + ): [M+H] + :690.3.

[0709] Synthesis of Compound 13

[0710] Compound 12 (13.9 g, 20.2 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (120 mL) and water (30 mL), and lithium hydroxide monohydrate (1.7 g, 40.3 mmol, 2.0 eq.) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC until complete. The reaction solution was acidified with aqueous citric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 13 (12.5 g, 94% yield). LC-MS m / z (ES) + ): [M+H] + :662.3.

[0711] Synthesis of Compound 14

[0712] Compound 13 (12.5 g, 18.9 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (120 mL), followed by the addition of N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28.3 mmol, 1.5 eq.), triethylamine (13.1 mL, 94.5 mmol, 5.0 eq.), EDCI (5.4 g, 28.3 mmol, 1.5 eq.), and 1-hydroxybenzotriazole (3.8 g, 28.3 mmol, 1.5 eq.). The reaction mixture was reacted at room temperature for 16 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 14 (6.0 g, 45% yield). LC-MS m / z (ES) + ): [M+H] + :705.3.

[0713] Synthesis of Compound 15

[0714] Compound 14 (6.0 g, 8.51 mmol, 1.0 eq.) was dissolved in dry tetrahydrofuran (60 mL), cooled to -50 °C, and tert-butyllithium (1.3 M in pentane, 13.1 mL, 17.02 mmol, 2.0 eq.) was slowly added dropwise under a nitrogen atmosphere. After the addition was complete, the reaction was continued at -50 °C for 2 hours, and the reaction was monitored by TLC until complete. The reaction was quenched by slow addition of saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 15 (2.8 g, 47% yield). LC-MS m / z (ES) + ): [M+H] + :702.3.

[0715] Synthesis of Compound 16

[0716] At 0 °C, an aqueous solution of cerium ammonium nitrate (4.23 g, 7.98 mmol, 2.0 eq.) in 30 mL of acetonitrile solution (2.8 g, 3.99 mmol, 1.0 eq.) was added. The reaction was continued at 0 °C for 1 hour, and the reaction was monitored by TLC until complete. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 16 (880 mg, yield 38%). LC-MS m / z (ES) + ): [M+H] + :582.3.

[0717] Synthesis of Compound 17

[0718] Compound 16 (880 mg, 1.51 mmol, 1.0 eq.) and 2 M diethyl chloride ether solution (9 mL) were added sequentially to a 25 mL round-bottom container. The reaction was carried out at room temperature for 2 hours, and TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 17 (692 mg, 95% yield). LC-MS m / z (ES) + ): [M+H] + :482.2.

[0719] Synthesis of compound D-1

[0720] Benzaldehyde (8.3 mg, 0.078 mmol, 1.5 eq.) was added to a methanol (1 mL) solution of compound 17 (25 mg, 0.052 mmol, 1.0 eq.). After reacting at room temperature for 2 hours, sodium borohydride (7.9 mg, 0.208 mmol, 4.0 eq.) was added at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for another 2 hours. The reaction was monitored by TLC until complete. The mixture was quenched with saturated sodium carbonate solution and extracted with dichloromethane. The combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound D-1 (19 mg, 64% yield). LC-MS m / z (ES) + ): [M+H] + :574.3. 1 HNMR(400MHz,DMSO)δ8.96(s,1H),8.19(s,1H),7.95–7.86(m,2H),7.54–7.32(m,7H),4.81(s,2H),4.32(s,2H) ,4.10(s,1H),4.05–3.94(m,2H),3.55(s,3H),2.86–2.79(m,1H),2.68–2.59(m,1H),1.97(s,3H),0.78(s,9H).

[0721] Example 2: Synthesis of compound D-2

[0722]

[0723] Synthesis of compound D-2

[0724] Following the synthetic route of compound D-1, the synthesis of compound D-2 was completed. LC-MSm / z (ES) + ): [M+H] + :624.3.

[0725] Example 3: Synthesis of compound D-3

[0726]

[0727] Synthesis of Compound 19

[0728] Compound 17 (30 mg, 0.062 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), and compound 18 (3-bromomethylpyridine hydrobromide, 23.6 mg, 0.093 mmol, 1.5 eq.) and N,N-diisopropylethylamine (0.032 mL, 0.187 mmol, 3.0 eq.) were added. The mixture was reacted at room temperature for 4 hours. The reaction solution was then diluted with water, extracted with dichloromethane, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 19 (25 mg, 70% yield). LC-MS m / z (ES) + ): [M+H] + :573.3.

[0729] Synthesis of compound D-3

[0730] Compound 19 (25 mg, 0.044 mmol, 1.0 eq.) was dissolved in methanol (1 mL), and sodium borohydride (3.3 mg, 0.087 mmol, 2.0 eq.) was slowly added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated and diluted with saturated sodium carbonate aqueous solution, and extracted with methanol / dichloromethane (1 / 5). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound D-3 (20 mg, 80% yield). LC-MS m / z (ES) + ): [M+H] + :575.3.

[0731] Example 4: Synthesis of compound D-4

[0732]

[0733] Synthesis of compound D-4

[0734] Following the synthetic route for compound D-3, compound D-4 was synthesized. LC-MSm / z (ES) + ): [M+H] + :609.3. 1 H NMR(400MHz,DMSO)δ9.17(s,2H),9.01(s,1H),8.18(s,1H),7.98–7.85(m,2H),7.47–7.36(m,2H),4.77(s,2H),4.10(s,1H),4.05 –3.94(m,2H),3.74–3.65(m,2H),3.56(s,3H),3.29–3.18(m,2H),2.88–2.78(m,1H),2.69–2.60(m,4H),1.97(s,3H),0.79(s,9H).

[0735] Example 5: Synthesis of compound D-5

[0736]

[0737] Synthesis of compound D-5

[0738] Compound D-4 (20 mg, mmol, 1.0 eq.) was dissolved in acetonitrile (1 mL), and an aqueous sodium hydroxide solution (pH 9) (1 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound D-5 (16 mg, 78% yield). LC-MS m / z (ES) + ): [M+H] + :627.3. 1 H NMR(400MHz,DMSO)δ8.97(s,1H),8.12(s,1H),7.92–7.78(m,2H),7.44–7.34(m,2H),4.75(s,2H),4.10(s,1H),4.05–3.92(m,2H),3.55(s,3H) ,3.43–3.33(m,2H),3.17–3.05(m,2H),2.88–2.76(m,1H),2.70–2.59( m,1H),2.45–2.38(m,2H),2.38–2.30(m,2H),1.96(s,3H),0.79(s,9H).

[0739] Example 6: Synthesis of compound D-6

[0740]

[0741] Synthesis of Compound 24

[0742] Following the synthetic route from compound 17 to compound D-4, compounds 17 to 24 were synthesized. LC-MSm / z (ES) + ): [M+H] + :696.4.

[0743] Synthesis of compound D-6

[0744] Compound 24 (20 mg, 1.51 mmol, 1.0 eq.) was mixed with 2 M diethyl ether hydrochloride solution (2 mL) and reacted at room temperature for 2 hours. TLC showed complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound D-6 (16 mg, 93% yield). LC-MS m / z (ES) + ): [M+H] + :596.3.

[0745] Example 7: Synthesis of compound D-7

[0746]

[0747] Synthesis of compound D-7

[0748] Following the synthetic route from compound 17 to compound D-4, the synthesis of compounds 17 to D-7 was completed. LC-MSm / z (ES) + ): [M+H] + :610.4.

[0749] Example 8: Synthesis of compound D-8

[0750]

[0751] Synthesis of compound D-8

[0752] Following the synthetic route from compound 17 to compound D-4, the synthesis of compounds 17 to D-8 was completed. LC-MSm / z (ES) + ): [M+H] + :524.3.

[0753] Example 9: Synthesis of compound D-9

[0754]

[0755] Synthesis of Compound 30

[0756] Compound 29 (5-bromo-1-benzofuran-2-carboxaldehyde, 327 mg, 1.45 mmol, 1.0 eq.) was dissolved in methanol (4 mL), and methylamine solution (0.44 mL, 4.36 mmol, 3.0 eq.) was added. The reaction was carried out at room temperature for 12 hours. Subsequently, sodium borohydride (110 mg, 2.91 mmol, 2.0 eq.) was added to the reaction solution at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, and the organic phase was washed with water and saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 30 (192 mg, 55% yield). LC-MS m / z (ES) + ): [M+H] + :240.0.

[0757] Synthesis of Compound 31

[0758] Compound 30 (192 mg, 0.800 mmol, 1.0 eq.) was dissolved in dichloromethane (3 mL). Triethylamine (0.222 mL, 1.60 mmol, 2.0 eq.) and di-tert-butyl dicarbonate (209 mg, 0.960 mmol, 1.2 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 31 (226 mg, 83% yield). LC-MS m / z (ES) + ): [M+H] + :340.0.

[0759] Synthesis of Compound 32

[0760] To a mixture of compound 31 (226 mg, 0.664 mmol, 1.0 eq.), compound 10 (127 mg, 0.731 mmol, 1.1 eq.), and tetrakis(triphenylphosphine)palladium (77 mg, 0.066 mmol, 0.1 eq.), 0.8 mL of degassed 1,4-dioxane (4 mL) and potassium phosphate (423 mg, 1.99 mmol, 3.0 eq.) aqueous solution was added sequentially, and the reaction mixture was refluxed for 2 hours. The reaction mixture was then cooled to room temperature, filtered through a diatomaceous earth filter, concentrated under reduced pressure, diluted with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 32 (150 mg, 58% yield). LC-MS m / z (ES) + ): [M+H] + :390.1.

[0761] Synthesis of Compound 33

[0762] Toluene (3 mL) was added to a mixture of compound 32 (150 mg, 0.385 mmol, 1.0 eq.), compound 6 (123 mg, 0.578 mmol, 1.5 eq.), and cyanomethylenetri-n-butylphosphine (186 mg, 0.770 mmol, 2.0 eq.). The reaction mixture was reacted at 110 °C for 16 hours, and TLC showed that the reaction was complete. The reaction mixture was then diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 33 (137 mg, yield 61%). LC-MS m / z (ES) + ): [M+H] + :584.2.

[0763] Synthesis of Compound 34

[0764] Compound 33 (137 mg, 0.235 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (19.7 mg, 0.469 mmol, 2.0 eq.) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC until complete. The reaction solution was acidified with aqueous citric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 34 (120 mg, 92% yield). LC-MS m / z (ES) + ): [M+H] + :556.2.

[0765] Synthesis of Compound 35

[0766] Compound 34 (120 mg, 0.216 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (4 mL), and N,O-dimethylhydroxylamine hydrochloride (31.6 mg, 0.324 mmol, 1.5 eq.), triethylamine (0.15 mL, 1.08 mmol, 5.0 eq.), EDCI (62.1 mg, 0.324 mmol, 1.5 eq.), and 1-hydroxybenzotriazole (43.8 mg, 0.324 mmol, 1.5 eq.) were added sequentially. The reaction mixture was reacted at room temperature for 16 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 35 (61 mg, 47% yield). LC-MS m / z (ES) + ): [M+H] + :599.3.

[0767] Synthesis of Compound 36

[0768] Compound 35 (61 mg, 0.102 mmol, 1.0 eq.) was dissolved in dry tetrahydrofuran (3 mL), cooled to -50 °C, and tert-butyllithium (1.3 M in pentane, 0.16 mL, 0.204 mmol, 2.0 eq.) was slowly added dropwise under a nitrogen atmosphere. After the addition was complete, the reaction was continued at -50 °C for 2 hours, and the reaction was monitored by TLC until complete. The reaction was quenched by slow addition of saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 36 (32 mg, yield 53%). LC-MS m / z (ES) + ): [M+H] + :596.3.

[0769] Synthesis of Compound 37

[0770] Compound 36 (32 mg, 0.054 mmol, 1.0 eq.) was dissolved in methanol (2 mL), and sodium borohydride (4.0 mg, 0.107 mmol, 2.0 eq.) was slowly added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated and diluted with saturated sodium carbonate aqueous solution, and extracted with methanol / dichloromethane (1 / 5). The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 37 (27 mg, 84% yield). LC-MS m / z (ES) + ): [M+H] + :598.3.

[0771] Synthesis of compound D-9

[0772] Compound 37 (27 mg, mmol, 1.0 eq.) was mixed with 2 M diethyl ether hydrochloride solution (2 mL) and reacted at room temperature for 2 hours. TLC showed complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound D-9 (21 mg, 93% yield). LC-MS m / z (ES) + ): [M+H] + :498.2.

[0773] Example 10: Synthesis of compound D-10

[0774]

[0775] Synthesis of compound D-10

[0776] Compound D-10 was synthesized following the synthetic route of compound D-9. LC-MSm / z (ES) + ): [M+H] + :514.2.

[0777] Example 11: Synthesis of compound D-11

[0778]

[0779] Synthesis of compound D-11

[0780] Compound D-11 was synthesized following the synthetic route of compound D-9. LC-MSm / z (ES) + ): [M+H] + :515.2.

[0781] Example 12: Synthesis of compound D-12

[0782]

[0783] Synthesis of compound D-12

[0784] Compound D-12 was synthesized following the synthetic route of compound D-9. LC-MSm / z (ES) + ): [M+H] + :515.2.

[0785] Example 13: Synthesis of compound D-13

[0786]

[0787] Synthesis of compound D-13

[0788] Compound D-13 was synthesized following the synthetic route of compound D-9. LC-MSm / z (ES) + ): [M+H] + :499.3.

[0789] Example 14: Synthesis of compound D-14

[0790]

[0791] Synthesis of Compound 39

[0792] Compound 39 was synthesized under the same conditions as compound 30. LC-MSm / z (ES) + ): [M+H] + :239.0.

[0793] Synthesis of Compound 40

[0794] Compound 39 (201 mg, 0.841 mmol, 1.0 eq.) was dissolved in dichloromethane (3 mL), and triethylamine (0.58 mL, 4.20 mmol, 5.0 eq.) and di-tert-butyl dicarbonate (459 mg, 2.10 mmol, 2.5 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 40 (281 mg, 76% yield). LC-MS m / z (ES) + ): [M+H] + :439.1.

[0795] Synthesis of Compound 41

[0796] Following the synthetic routes of compounds 31 to 37, compounds 40 to 41 were synthesized. LC-MSm / z (ES + ): [M+H] + :697.4.

[0797] Synthesis of compound D-14

[0798] Compound 41 (31 mg, 0.044 mmol, 1.0 eq.) was mixed with 2 M diethyl ether hydrochloride solution (2 mL) and reacted at room temperature for 2 hours. TLC showed complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound D-14 (19 mg, yield 86%). LC-MS m / z (ES) + ): [M+H] + :497.3.

[0799] Example 15: Synthesis of compound D-15

[0800]

[0801] Synthesis of Compound 43

[0802] Following the synthetic routes of compounds 29 to 31, compounds 7 to 43 were synthesized. LC-MS m / z (ES) + ): [M+H] + :340.1.

[0803] Synthesis of Compound 44

[0804] Compound 44 was synthesized under the same conditions as compound D-9. LC-MSm / z (ES) + ): [M+H] + :240.0.

[0805] Synthesis of Compound 46

[0806] Compound 46 was synthesized under the same conditions as compound 30. LC-MSm / z (ES) + ): [M+H] + :397.1.

[0807] Synthesis of compound D-15

[0808] Following the synthetic routes of compounds 31 to D-9, compounds 46 to D-15 were synthesized. LC-MSm / z (ES) + ): [M+H] + :555.3.

[0809] Example 16: Synthesis of compound D-16

[0810]

[0811] Synthesis of Compound 47

[0812] Compound 47 was synthesized under the same conditions as compound 30. LC-MSm / z (ES) + ): [M+H] + 369.1.

[0813] Synthesis of compound D-16

[0814] Following the synthetic routes of compounds 31 to D-9, compounds 47 to D-16 were synthesized. LC-MSm / z (ES) + ): [M+H] + :527.3.

[0815] Example 17: Synthesis of compound D-17

[0816]

[0817] Synthesis of Compound 49

[0818] A mixture of compound 48 (2-bromo-1-naphthol, 447 mg, 1.89 mmol, 1.0 eq.), bis-pinacol borate (527 mg, 2.07 mmol, 1.1 eq.), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (83 mg, 0.113 mmol, 0.06 eq.), potassium acetate (555 mg, 5.66 mmol, 3.0 eq.), and 1,4-dioxane (6 mL) was reacted at 80 °C for 14 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter, concentrated under reduced pressure, diluted with a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 49 (493 mg, 92% yield). LC-MS m / z (ES) + ): [M+H] + :285.2.

[0819] Synthesis of Compound 50

[0820] Compound 49 (493 mg, 1.73 mmol, 1.0 eq.) was dissolved in dry dichloromethane (6 mL), and boron tribromide (1 M in CH2Cl2, 3.5 mL, 3.47 mmol, 2.0 eq.) was added at 0 °C. The reaction was quenched with ice water after 30 min at 0 °C, followed by extraction with methanol / dichloromethane (1 / 5). The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product, concentrated under reduced pressure, was purified by column chromatography to give compound 50 (199 mg, 61% yield). LC-MS m / z (ES) + ): [M+H] + :189.1.

[0821] Synthesis of compound D-17

[0822] Following the synthetic routes of compounds 10 to D-9, compounds 50 to D-17 were synthesized. LC-MSm / z (ES) + ): [M+H] + :512.3.

[0823] Example 18: Synthesis of compound D-18

[0824]

[0825] Synthesis of compound D-18

[0826] Compound D-18 was synthesized following the synthetic route used for compound D-17. LC-MSm / z (ES) + ): [M+H] + :513.3.

[0827] Example 19: Synthesis of compound D-19

[0828]

[0829] Synthesis of compound D-19

[0830] Compound D-19 was synthesized following the synthetic route used for compound D-17. LC-MSm / z (ES) + ): [M+H] + :463.3.

[0831] Example 20: Synthesis of compound D-20

[0832]

[0833] Synthesis of compound D-20

[0834] Compound D-20 was synthesized following the synthetic route of compound D-17. LC-MSm / z (ES) + ): [M+H] + :481.3.

[0835] Example 21: Synthesis of compound D-21

[0836]

[0837] Synthesis of Compound 53

[0838] Compound 1 (3-hydroxyazacyclobutane hydrochloride, 1.5 g, 13.7 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL). Imidazole (4.7 g, 68.5 mmol, 5.0 eq.) and tert-butyldimethylchlorosilane (5.2 g, 34.2 mmol, 2.5 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 53 (2.4 g, 93% yield). LC-MS m / z (ES) + ): [M+H] + :188.1.

[0839] Synthesis of Compound 55

[0840] Compound 53 (2.4 g, 12.8 mmol, 1.0 eq.), compound 54 (3-bromo-1,5-dimethylpyrazole, 2.7 g, 15.4 mmol, 1.2 eq.), cesium carbonate (8.4 g, 25.6 mmol, 2.0 eq.), and DMF (20 mL) were added sequentially to a 50 mL round-bottom flask. The reaction was carried out at room temperature for 6 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 55 (2.3 g, yield 64%). LC-MS m / z (ES) + ): [M+H] + :282.2.

[0841] Synthesis of Compound 56

[0842] Following the synthetic routes of compounds 2 to 6, compounds 55 to 56 were synthesized. LC-MSm / z (ES + ): [M+H] + :326.2.

[0843] Synthesis of Compound 58

[0844] Following the synthetic route of compounds 10 to 33, compounds 10 to 58 were synthesized. LC-MSm / z (ES + ): [M+H] + :683.3.

[0845] Synthesis of compound D-21

[0846] Compound 58 (36 mg, 0.053 mmol, 1.0 eq.) was mixed with 2 M diethyl chloride ether solution (2 mL) and reacted at room temperature for 2 hours. TLC showed complete reaction. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound D-21 (21 mg, yield 83%). LC-MS m / z (ES) + ): [M+H] + :483.2.

[0847] Example 22: Synthesis of compound D-22

[0848]

[0849] Synthesis of Compound 60

[0850] Compound 1 (2.0 g, 13.0 mmol, 1.0 eq.), compound 59 (cyclopropylboronic acid, 2.2 g, 26.0 mmol, 2.0 eq.), copper acetate (2.4 g, 13.0 mmol, 1.0 eq.), 4-dimethylaminopyridine (6.3 g, 51.9 mmol, 4.0 eq.), cesium carbonate (10.6 g, 32.4 mmol, 2.5 eq.), and 1,4-dioxane (20 mL) were added sequentially to a 50 mL three-necked flask. The reaction mixture was heated at 90 °C for 36 hours, then cooled to room temperature and filtered through a diatomaceous earth filter. The filtrate was adjusted to pH 5 with 2 M HCl (aq.), and extracted with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 60 (1.9 g, 75% yield). LC-MS m / z (ES) + ): [M+H] + :195.1.

[0851] Synthesis of Compound 61

[0852] Following the synthetic routes of compounds 2 to 6, compounds 60 to 61 were synthesized. LC-MSm / z (ES) + ): [M+H] + :239.1.

[0853] Synthesis of compound D-22

[0854] Following the synthetic route for compounds 6 to D-9, compounds 61 to D-22 were synthesized. LC-MSm / z (ES) + ): [M+H] + :524.3.

[0855] Example 23: Synthesis of compound D-23

[0856]

[0857] Synthesis of Compound 63

[0858] Sodium hydride (60% dispersed in mineral oil, 934 mg, 23.4 mmol, 1.2 eq.) was dispersed in dry tetrahydrofuran (20 mL). A tetrahydrofuran solution (10 mL) of compound 1 (3.0 g, 19.5 mmol, 1.0 eq.) and 2-bromoethanol (2.9 g, 23.4 mmol, 1.2 eq.) were slowly added at 0 °C. The mixture was allowed to rise to room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 63 (2.6 g, 67% yield). LC-MS m / z (ES) + ): [M+H] + :199.1.

[0859] Synthesis of Compound 64

[0860] Compound 63 (2.6 g, 13.1 mmol, 1.0 eq.) was dissolved in dichloromethane (25 mL). Triethylamine (3.6 mL, 26.2 mmol, 2.0 eq.) and methanesulfonyl chloride (1.5 mL, 19.7 mmol, 1.5 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 64 (3.4 g, 94% yield). LC-MS m / z (ES) + ): [M+H] + :277.1.

[0861] Synthesis of Compound 65

[0862] Compound 64 (3.4 g, 12.3 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (30 mL), and DBU (3.7 mL, 24.6 mmol, 2.0 eq.) was added. The mixture was refluxed for 2 hours, then cooled to room temperature. After concentration under reduced pressure to remove most of the tetrahydrofuran, the solution was diluted with dichloromethane, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 65 (1.4 g, 63% yield). LC-MS m / z (ES) + ): [M+H] + :181.1.

[0863] Synthesis of compound D-23

[0864] Following the synthetic route from compounds 60 to D-22, compounds 65 to D-23 were synthesized. LC-MSm / z (ES) + ): [M+H] +:510.3.

[0865] Example 24: Synthesis of compound D-24

[0866]

[0867] Synthesis of Compound 67

[0868] Following the synthetic routes of compounds 2 to 6, compounds 66 to 67 were synthesized. LC-MSm / z (ES + ): [M+H] + :235.1.

[0869] Synthesis of compound D-24

[0870] Following the synthetic routes for compounds 6 to D-9, compounds 67 to D-24 were synthesized. LC-MSm / z (ES) + ): [M+H] + :520.2.

[0871] Example 25: Synthesis of compound D-25

[0872]

[0873] Synthesis of Compound 68

[0874] Compound 68 was synthesized under the same conditions as compound 12. LC-MSm / z (ES) + ): [M+H] + :584.3.

[0875] Synthesis of Compound 69

[0876] Compound 68 (112 mg, 0.192 mmol, 1.0 eq.) was dissolved in dry tetrahydrofuran (2 mL), and methyl magnesium bromide (3 M in Et₂O, 0.26 mL, 0.768 mmol, 4.0 eq.) was added at 0 °C. After reacting at room temperature for 2 hours, the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 69 (73 mg, 67% yield). LC-MS m / z (ES) + ): [M+H] + :570.3.

[0877] Synthesis of Compound 70

[0878] Compound 69 (73 mg, 0.128 mmol, 1.0 eq.) was dissolved in dry toluene (2 mL), and Lawesson's reagent (104 mg, 0.256 mmol, 2.0 eq.) was added under a nitrogen atmosphere. The mixture was heated under reflux for 30 minutes, and the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 70 (31 mg, 41% yield). LC-MS m / z (ES) + ): [M+H] + :586.3.

[0879] Synthesis of compound D-25

[0880] Following the synthetic conditions for compound D-9, compound D-25 was synthesized. LC-MSm / z (ES) + ): [M+H] + :486.2.

[0881] Example 26: Synthesis of compound D-26

[0882]

[0883] Synthesis of Compound 71

[0884] Compound 71 was synthesized under the same conditions as compound 64. LC-MSm / z (ES) + ): [M+H] + :648.3.

[0885] Synthesis of Compound 72

[0886] Compound 71 (47 mg, 0.073 mmol, 1.0 eq.) was dissolved in DMF (1 mL), and sodium azide (7.1 mg, 0.109 mmol, 1.5 eq.) was added. The reaction mixture was reacted at 60 °C for 2 h. The reaction solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 72 (31 mg, 72% yield). LC-MS m / z (ES) + ): [M+H] + :595.3.

[0887] Synthesis of compound D-26

[0888] Following the synthetic conditions for compound D-9, compound D-26 was synthesized. LC-MSm / z (ES) + ): [M+H] + :495.2.

[0889] Example 27: Synthesis of compound D-27

[0890]

[0891] Synthesis of Compound 73

[0892] Compound 71 (64 mg, 0.099 mmol, 1.0 eq.) was dissolved in DMF (1 mL), and an aqueous solution of sodium cyanide (12.1 mg, 0.247 mmol, 2.5 eq.) (0.3 mL) was added. The reaction mixture was reacted at 60 °C for 8 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 73 (30 mg, yield 52%). LC-MS m / z (ES) + ): [M+H] + :579.3.

[0893] Synthesis of compound D-27

[0894] Following the synthetic conditions for compound D-9, compound D-27 was synthesized. LC-MSm / z (ES) + ): [M+H] + :479.2.

[0895] Example 28: Synthesis of compound D-28

[0896]

[0897] Synthesis of Compound 74

[0898] Compound 74 was synthesized under the same conditions as compound 13. LC-MSm / z (ES + ): [M+H] + :556.2.

[0899] Synthesis of Compound 76

[0900] Compound 74 (33 mg, 0.059 mmol, 1.0 eq.) was dissolved in dichloromethane (1.5 mL), followed by the addition of HATU (33.9 mg, 0.089 mmol, 1.5 eq.), HOBt (12.0 mg, 0.089 mmol, 1.5 eq.), compound 75 (benzenesulfonamide, 12.1 mg, 0.077 mmol, 1.3 eq.), and N,N-diisopropylethylamine (0.021 mL, 0.119 mmol, 2.0 eq.). The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was quenched with water and extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 76 (29 mg, 70% yield). LC-MS m / z (ES) +): [M+H] + :695.2.

[0901] Synthesis of compound D-28

[0902] Following the synthetic conditions for compound D-9, compound D-28 was synthesized. LC-MSm / z (ES) + ): [M+H] + :595.2.

[0903] Example 29: Synthesis of compound D-29

[0904]

[0905] Synthesis of compound D-29

[0906] Following the synthetic route for compound D-28, compound D-29 was synthesized. LC-MSm / z (ES) + ): [M+H] + :640.2.

[0907] Example 30: Synthesis of compound D-30

[0908]

[0909] Synthesis of compound D-30

[0910] Following the synthetic route for compound D-28, compound D-30 was synthesized. LC-MSm / z (ES) + ): [M+H] + :573.2.

[0911] Example 31: Synthesis of compound D-31

[0912]

[0913] Synthesis of compound D-31

[0914] Following the synthetic route for compound D-9, compound D-31 was synthesized. LC-MSm / z (ES) + ): [M+H] + :501.3. 1H NMR (400MHz, DMSO) δ8.55(s,1H),7.57(d,J=9.6Hz,1H),7.50(s,1H),7.40–7.25(m,3H),4.68(s,1H),4.08(s,1H ),4.00(s,2H),3.99–3.81(m,2H),3.53(s,3H),2.87–2.74(m,1H),2.70–2.57(m,1H),1.83(s,3H),0.76(s,9H).

[0915] Example 32: Synthesis of compound D-32

[0916]

[0917] Synthesis of Compound 81

[0918] Compound 80 (3-bromocyclobutanone, 1.1 mL, 13.4 mmol, 1.2 eq.) was slowly added dropwise to a mixture of magnesium granules (408 mg, 16.8 mmol, 1.5 eq.), a catalytic amount of iodine granules, and tetrahydrofuran (10 mL). The reaction was carried out at room temperature for 6 hours under nitrogen protection. Then, the above solution was added to a mixture of compound 3 (2.8 g, 11.2 mmol, 1.0 eq.) and 1,3-bis(diphenylphosphine) nickel dichloride (121 mg, 0.224 mmol, 0.02 eq.) with tetrahydrofuran (10 mL). The reaction was refluxed for 16 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 81 (1.7 g, 64% yield). LC-MS m / z (ES) + ): [M+H] + :237.1.

[0919] Synthesis of Compound 82

[0920] Compound 81 (1.7 g, 7.2 mmol, 1.0 eq.) was dissolved in methanol (15 mL), and sodium borohydride (544 mg, 14.4 mmol, 2.0 eq.) was slowly added at 0 °C. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated and diluted with saturated sodium carbonate aqueous solution, and extracted with dichloromethane. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 82 (1.4 g, 82% yield). LC-MS m / z (ES) + ): [M+H] + :239.1.

[0921] Synthesis of compound D-32

[0922] Following the synthetic routes for compounds 61 to D-22, compounds 82 to D-32 were synthesized. LC-MSm / z (ES) + ): [M+H] + :524.3.

[0923] Example 33: Synthesis of compound D-33

[0924]

[0925] Synthesis of compound D-33

[0926] Following the synthetic route of compound D-32, the synthesis of compound D-33 was completed. LC-MSm / z (ES) + ): [M+H] + :538.3.

[0927] Example 34: Synthesis of compound D-34

[0928]

[0929] Synthesis of Compound 87

[0930] Under a nitrogen atmosphere, a 30 mL solution of compound 86 (2-propyn-1-ol, 3 g, 53.5 mmol, 1.0 eq.) in acetone was cooled to -78 °C. Silver nitrate (1.5 g, 5.35 mmol, 0.1 eq.) and N-bromosuccinimide (12.4 g, 69.6 mmol, 1.3 eq.) were added, and the reaction mixture was gradually brought to room temperature and reacted for 4 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 87 (6.5 g, 90% yield). LC-MS m / z (ES) + ): [M+H] + :134.9.

[0931] Synthesis of Compound 88

[0932] Compound 87 (3 g, 22.2 mmol, 1.0 eq.) was dissolved in dichloromethane (30 mL). Imidazole (3.0 g, 44.5 mmol, 2.0 eq.) and tert-butyldimethylchlorosilane (5.0 g, 33.3 mmol, 1.5 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 88 (5.1 g, 92% yield). LC-MS m / z (ES) + ): [M+H] + :249.0.

[0933] Synthesis of Compound 89

[0934] Compound 89 was synthesized under the same conditions as compound 81. LC-MSm / z (ES) + ): [M+H] + :337.2.

[0935] Synthesis of Compound 90

[0936] Compound 89 (2.8 g, 8.32 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1 min THF, 10 mL, 9.98 mmol, 1.2 eq.) was added. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC until complete. The reaction solution was diluted with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 90 (1.7 g, 92% yield). LC-MS m / z (ES) + ): [M+H] + :223.1.

[0937] Synthesis of compound D-34

[0938] Following the synthetic routes for compounds 61 to D-22, compounds 90 to D-34 were synthesized. LC-MSm / z (ES) + ): [M+H] + :508.2.

[0939] Example 35: Synthesis of compound D-35

[0940]

[0941] Synthesis of Compound 92

[0942] Compound 92 was synthesized under the same conditions as compound 88. LC-MSm / z (ES) + ): [M+H] + :205.1.

[0943] Synthesis of Compound 93

[0944] Compound 93 was synthesized under the same conditions as compound 35. LC-MSm / z (ES) + ): [M+H] + :248.2.

[0945] Synthesis of Compound 94

[0946] Under a nitrogen atmosphere, a tetrahydrofuran solution (30 mL) of compound 93 (2.9 g, 11.7 mmol, 1.0 eq.) and compound 3 (3.5 g, 14.1 mmol, 1.2 eq.) was cooled to -78 °C, and n-butyllithium (2.5 M in hexane, 11.7 mL, 29.3 mmol, 2.5 eq.) was added. After the addition, the reaction mixture was stirred at -78 °C for 1 hour, and quenched with a saturated ammonium chloride aqueous solution. The mixture was then extracted with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 94 (1.9 g, 46% yield). LC-MS m / z (ES) + ): [M+H] + :355.2.

[0947] Synthesis of Compound 95

[0948] Following the synthetic conditions for compound 90, compound 95 was synthesized. LC-MSm / z (ES) + ): [M+H] + :241.1.

[0949] Synthesis of compound D-35

[0950] Following the synthetic routes for compounds 61 to D-22, compounds 95 to D-35 were synthesized. LC-MSm / z (ES) + ): [M+H] + :526.3.

[0951] Example 36: Synthesis of compound D-36

[0952]

[0953] Synthesis of Compound 97

[0954] Compound 5 (1.9 g, 9.18 mmol, 1.0 eq.) and compound 96 (3-bromo-6-fluorobenzene-1,2-diol, 1.9 g, 9.18 mmol, 1.0 eq.) were dissolved in dichloromethane (20 mL), and p-toluenesulfonic acid monohydrate (348 mg, 1.84 mmol, 0.2 eq.) was added. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 97 (3.2 g, yield 87%). LC-MS m / z (ES) + ): [M+H] + 399.0.

[0955] Synthesis of Compound 98

[0956] Compound 98 was synthesized under the same conditions as compound 49. LC-MSm / z (ES) + ): [M+H] + :447.2.

[0957] Synthesis of Compound 99

[0958] Following the synthetic conditions for compound 51, compound 99 was synthesized. LC-MSm / z (ES) + ): [M+H] + :580.2.

[0959] Synthesis of compound D-36

[0960] Following the synthetic route from compounds 33 to D-9, compounds 99 to D-36 were synthesized. LC-MSm / z (ES) + ): [M+H] + :494.2.

[0961] Example 37: Synthesis of compound D-37

[0962]

[0963] Synthesis of Compound 101

[0964] Compound 100 (3-hydroxycyclobutylcarboxylic acid, 20 g, 172 mmol, 1.0 eq.) was dissolved in dichloromethane (200 mL). Imidazole (23.4 g, 344 mmol, 2.0 eq.) and tert-butyldimethylchlorosilane (38.9 g, 258 mmol, 1.5 eq.) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 101 (36 g, 91% yield). LC-MS m / z (ES) + ): [M+H] + :231.1.

[0965] Synthesis of Compound 102

[0966] Compound 101 (36 g, 156 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (360 mL), followed by the sequential addition of N,O-dimethylhydroxylamine hydrochloride (22.9 g, 234 mmol, 1.5 eq.), triethylamine (109 mL, 781 mmol, 5.0 eq.), EDCI (44.9 g, 234 mmol, 1.5 eq.), and 1-hydroxybenzotriazole (31.7 g, 234 mmol, 1.5 eq.). The reaction mixture was reacted at room temperature for 18 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 102 (18 g, 42% yield). LC-MS m / z (ES) + ): [M+H] + :274.2.

[0967] Synthesis of Compound 103

[0968] Under a nitrogen atmosphere, a tetrahydrofuran solution (180 mL) of compound 102 (18 g, 65.8 mmol, 1.0 eq.) and compound 54 (3-bromo-1,5-dimethylpyrazole, 13.8 g, 79.0 mmol, 1.2 eq.) was cooled to -78 °C, and n-butyllithium (2.5 M in hexane, 66 mL, 164 mmol, 2.5 eq.) was added. After the addition, the reaction mixture was stirred at -78 °C for 1 hour, and quenched with a saturated ammonium chloride aqueous solution. The mixture was then extracted with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 103 (7.7 g, 38% yield). LC-MS m / z (ES) + ): [M+H] + :309.2.

[0969] Synthesis of Compound 104

[0970] Following the synthetic routes of compounds 2 to 6, compounds 103 to 104 were synthesized. LC-MSm / z (ES + ): [M+H] + :353.2.

[0971] Synthesis of compound D-37

[0972] Following the synthetic route from compounds 56 to D-21, compounds 104 to D-37 were synthesized. LC-MSm / z (ES) + ): [M+H] + :510.2.

[0973] Example 38: Synthesis of compound D-38

[0974]

[0975] Synthesis of compound D-38

[0976] Following the synthetic route for compound D-37, compound D-38 was synthesized. LC-MSm / z (ES) + ): [M+H] + :510.2.

[0977] Example 39: Synthesis of compound D-39

[0978]

[0979] Synthesis of compound D-39

[0980] Following the synthetic route for compound D-37, compound D-39 was synthesized. LC-MSm / z (ES) + ): [M+H] + :496.2.

[0981] Example 40: Synthesis of compound D-40

[0982]

[0983] Synthesis of compound D-40

[0984] Following the synthetic route for compound D-37, compound D-40 was synthesized. LC-MSm / z (ES) + ): [M+H] + :472.2.

[0985] Example 41: Synthesis of compound D-41

[0986]

[0987] Synthesis of Compound 106

[0988] Compound 106 was synthesized under the same conditions as compound 102. LC-MSm / z (ES) + ): [M+H] + :147.1.

[0989] Synthesis of Compound 107

[0990] Compound 107 was synthesized under the same conditions as compound 103. LC-MSm / z (ES) + ): [M+H] + :182.1.

[0991] Synthesis of Compound 108

[0992] Following the synthetic routes of compounds 2 to 6, compounds 107 to 108 were synthesized. LC-MSm / z (ES + ): [M+H] + :226.1.

[0993] Synthesis of Compound 109

[0994] Compound 109 was synthesized under the same conditions as compound 33. LC-MSm / z (ES) + ): [M+H] + :597.3.

[0995] Synthesis of compound D-41

[0996] Following the synthetic conditions for compound D-9, compound D-41 was synthesized. LC-MSm / z (ES) + ): [M+H] + :497.2.

[0997] Example 42: Synthesis of compound D-42

[0998]

[0999] Synthesis of compound D-42

[1000] Compound D-41 (39 mg, 0.079 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL) and cooled to 0 °C. Lithium aluminum hydride (11.9 mg, 0.314 mmol, 4.0 eq.) was carefully added, and the reaction was refluxed for 1 hour after the addition was complete. The reaction mixture was then cooled to 0 °C and quenched dropwise with ice water. The mixture was extracted with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound D-42 (22 mg, 58% yield). LC-MS m / z (ES) + ): [M+H] + :483.3.

[1001] Example 43: Synthesis of compound D-43

[1002]

[1003] Synthesis of Compound 112

[1004] Following the synthetic routes for compounds 101 to 103, compounds 110 to 112 were synthesized. LC-MSm / z (ES+ ): [M+H] + :284.1.

[1005] Synthesis of Compound 113

[1006] Compound 112 (31 g, 109 mmol, 1.0 eq.) was weighed into a 500 mL three-necked flask, and methanol (250 mL) and hydrazine hydrate (80%, 13 g, 219 mmol, 2.0 eq.) were added. The mixture was heated at 60 °C for 4 hours. After filtering off the insoluble solids, the filtrate was concentrated, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 113 (13 g, 78% yield). LC-MS m / z (ES) + ): [M+H] + :154.1.

[1007] Synthesis of Compound 114

[1008] Compound 113 (13 g, 84.9 mmol, 1.0 eq.) and potassium carbonate (24.5 g, 170 mmol, 2.0 eq.) were weighed into a 500 mL three-necked flask. Acetone (130 mL) and deuterated iodomethane (36.9 g, 255 mmol, 3.0 eq.) were added, and the mixture was heated at 60 °C for 16 hours. The reaction solution was filtered, and most of the solvent was removed by vacuum distillation. The solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 114 (8.9 g, 56% yield). LC-MS m / z (ES) + ): [M+H] + :188.2.

[1009] Synthesis of compound D-43

[1010] Following the synthetic route from compounds 107 to D-41, compounds 114 to D-43 were synthesized. LC-MSm / z (ES + ): [M+H] + :503.3.

[1011] Example 44: Synthesis of compound D-44

[1012] Synthesis of Compound 118

[1013] Following the synthetic routes for compounds 101 to 103, compounds 116 to 118 were synthesized. LC-MSm / z (ES + ): [M+H] +:294.2.

[1014] Synthesis of Compound 119

[1015] Following the synthetic routes of compounds 2 to 6, compounds 118 to 119 were synthesized. LC-MSm / z (ES + ): [M+H] + :338.2.

[1016] Synthesis of Compound 120

[1017] Compound 120 was synthesized under the same conditions as compound 33. LC-MSm / z (ES) + ): [M+H] + :709.3.

[1018] Synthesis of Compound 121

[1019] Compound 121 was synthesized under the same conditions as compound 37. LC-MSm / z (ES) + ): [M+H] + :711.4.

[1020] Synthesis of compound D-44

[1021] Following the synthetic conditions for compound D-9, compound D-44 was synthesized. LC-MSm / z (ES) + ): [M+H] + :511.3.

[1022] Example 45: Synthesis of compound D-45

[1023]

[1024] Synthesis of compound D-45

[1025] Following the synthetic route for compound D-44, compound D-45 was synthesized. LC-MSm / z (ES) + ): [M+H] + :496.2.

[1026] Example 46: Synthesis of compound D-46

[1027]

[1028] Synthesis of compound D-46

[1029] Following the synthetic route for compound D-44, compound D-46 was synthesized. LC-MSm / z (ES) + ): [M+H]+ :524.3.

[1030] Example 47: Synthesis of compound D-47

[1031]

[1032] Synthesis of compound D-47

[1033] Following the synthetic route for compound D-44, compound D-47 was synthesized. LC-MSm / z (ES) + ): [M+H] + :684.3.

[1034] Example 48: Synthesis of compound D-48

[1035]

[1036] Synthesis of compound D-48

[1037] Following the synthetic route for compound D-44, compound D-48 was synthesized. LC-MSm / z (ES) + ): [M+H] + :537.2.

[1038] Example 49: Synthesis of compound D-49

[1039]

[1040] Synthesis of Compound 122

[1041] Following the synthetic routes of compounds 105 to 109, compounds 121 to 122 were synthesized. LC-MSm / z (ES) + ): [M+H] + :630.3.

[1042] Synthesis of Compound 123

[1043] Compound 122 (45 mg, 0.071 mmol, 1.0 eq.) was dissolved in dry tetrahydrofuran (2 mL), and methyl magnesium bromide (3 M in Et₂O, 0.036 mL, 0.107 mmol, 1.5 eq.) was added at 0 °C. After reacting at room temperature for 2 hours, the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 123 (33 mg, 72% yield). LC-MS m / z (ES) + ): [M+H] + :646.3.

[1044] Synthesis of compound D-49

[1045] Following the synthetic conditions for compound D-9, compound D-49 was synthesized. LC-MSm / z (ES) + ): [M+H] + :546.2.

[1046] Example 50: Synthesis of compound D-50

[1047]

[1048] Synthesis of Compound 125

[1049] Following the synthetic routes of compounds 105 to 109, compounds 124 to 125 were synthesized. LC-MSm / z (ES) + ): [M+H] + :695.3.

[1050] Synthesis of compound D-50

[1051] Following the synthetic conditions for compound D-14, compound D-50 was synthesized. LC-MSm / z (ES) + ): [M+H] + :495.2.

[1052] Example 51: Synthesis of compound D-51

[1053]

[1054] Synthesis of Compound 127

[1055] Compound 126 (22.9 g, 257 mmol, 1.5 eq.), compound 54 (3-bromo-1,5-dimethylpyrazole, 30 g, 171 mmol, 1.0 eq.), N,N-diisopropylethylamine (60 mL, 343 mmol, 2.0 eq.), and 1,4-dioxane (300 mL) were added sequentially to a 500 mL round-bottom flask and reacted at 80 °C for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by column chromatography to give compound 127 (16 g, 51% yield). LC-MS m / z (ES) + ): [M+H] + :184.1.

[1056] Synthesis of Compound 128

[1057] Compound 128 was synthesized under the same conditions as compound 88. LC-MSm / z (ES) + ): [M+H] + :298.2.

[1058] Synthesis of Compound 129

[1059] Compound 129 was synthesized under the same conditions as compound 9. LC-MSm / z (ES) + ): [M+H] + :398.3.

[1060] Synthesis of Compound 130

[1061] Following the synthetic routes of compounds 2 to 6, compounds 129 to 130 were synthesized. LC-MSm / z (ES + ): [M+H] + :442.3.

[1062] Synthesis of compound D-51

[1063] Following the synthetic route from compounds 56 to D-21, compounds 130 to D-51 were synthesized. LC-MSm / z (ES) + ): [M+H] + :499.3.

[1064] Example 52: Synthesis of compound D-52

[1065]

[1066] Synthesis of compound D-52

[1067] Following the synthetic conditions for compound D-42, compound D-52 was synthesized. LC-MSm / z (ES) + ): [M+H] + :489.3.

[1068] Example 53: Synthesis of compound D-53

[1069]

[1070] Synthesis of compound D-53

[1071] Compound D-53 was synthesized following the synthetic route of compound D-31. LC-MSm / z (ES) + ): [M+H] + :517.3. 1H NMR (400MHz, DMSO) δ8.59(s,1H),7.58(dd,J=9.6,1.2Hz,1H),7.54(s,1H),7.38(dd,J=9.6,2.0Hz,1H),7.35–7.30(m,2H),4.68(s,1H),4. 14(s,2H),4.09(s,1H),4.00–3.92(m,1H),3.91–3.82(m,1H),3.53(s ,3H),2.87–2.75(m,1H),2.70–2.57(m,1H),1.84(s,3H),0.77(s,9H).

[1072] Example 54: Synthesis of compound D-54

[1073]

[1074] Synthesis of compound D-54

[1075] Following the guidance of patent WO 2024052684 A, compound D-54 was synthesized. LC-MSm / z (ES) + ): [M+H] + :498.3.

[1076] Example 55: Synthesis of compound LP-1

[1077]

[1078] Synthesis of compound LP-1

[1079] Following the guidance of patent WO 2024052684 A, compound LP-1 was synthesized. LC-MSm / z (ES + ): [M+H] + :1149.5.

[1080] Example 56: Synthesis of compound LP-2

[1081]

[1082] Synthesis of compound M2

[1083] Compound M1 (synthesized according to the literature: Bioconjugate chem., 2006, 17, 831-840; 862 mg, 0.943 mmol, 1.0 eq.) was dissolved in DMF (3 mL), followed by the addition of D-31 (472 mg, 0.943 mmol, 1.0 eq.) and HOAt (13 mg, 0.094 mmol, 0.1 eq.). DIEA (39 μL, 0.225 mmol, 1.5 eq.) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound M2 (974 mg, yield 81%). LC-MS m / z (ES) + ): [M+H] + :1275.6.

[1084] Synthesis of compound M3

[1085] Compound M2 (974 mg, 0.764 mmol) was dissolved in acetonitrile / water (12 mL, 2:1), and sodium hydroxide aqueous solution (1 N, 2 mL) was added dropwise at room temperature. After reacting for 3 hours, the solution was purified by reverse-phase preparative column chromatography. The preparative solution was lyophilized to give compound M3 (516 mg, yield 74%). LC-MS m / z (ES) + ): [M+H] + :913.4.

[1086] Synthesis of compound LP-2

[1087] Compound M3 (82 mg, 0.090 mmol, 1.0 eq.) and compound M4 (maleimide-PEG2-succinimide ester, 33 mg, 0.099 mmol, 1.1 eq.) were added to a 10 mL reaction tube, dissolved in 2 mL of DMF, followed by the addition of 23 μL of DIEA (0.135 mmol, 1.5 eq.) under ice bath conditions. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound LP-2 (82 mg, 79% yield). LC-MS m / z (ES) + ): [M+H] + :1152.5.

[1088] Example 57: Synthesis of compound LP-3

[1089]

[1090] Synthesis of compound M11

[1091] Step 1: Resin Loading

[1092] 20.6 g of 2-chlorotriphenylmethyl chloride resin beads (1.3 mmol / g) were weighed into a resin reactor and swollen in DMF for 1 hour. After swelling, the solvent was filtered off, and a DMF solution (80 mL) of compound M5 (Fmoc-L-phenylalanine, 8 g, 20.6 mmol, 1.0 eq.) and DIEA (7.2 mL, 41.3 mmol, 2.0 eq.) was added to the resin. The resin reactor was shaken at room temperature for 4 hours. After filtration, the resin was blocked with MeOH / DIEA / DMF (14 mL / 7 mL / 60 mL) for 30 minutes, and then the resin was thoroughly washed with DMF (8 times) to obtain compound M6.

[1093] Step 2: Peptide chain elongation

[1094] The resin was treated twice with piperidine / DMF (20 mL / 80 mL), 20 minutes each time, and then thoroughly washed with DMF (8 times). A DMF solution (75 mL) of compound M7 (Fmoc-glycyl-glycine, 19.3 g, 54.6 mmol, 2.7 eq.), HATU (20.8 g, 54.6 mmol, 2.7 eq.), HOBt (7.4 g, 54.6 mmol, 2.7 eq.), and DIEA (16 mL, 91.0 mmol, 4.4 eq.) was added to the resin, and the resin reactor was shaken at room temperature for 2 hours. The resin was then washed with DMF (8 times) to obtain compound M8.

[1095] The resin was treated twice with piperidine / DMF (20 mL / 80 mL), 20 minutes each time, and then thoroughly washed with DMF (8 times). A DMF solution (80 mL) of compound M9 (14.5 g, 36.4 mmol, 1.8 eq., according to patent synthesis: CN113827736 A) and EEDQ (22.5 g, 91.0 mmol, 4.4 eq.) was added to the resin, and the resin reactor was shaken at room temperature for 4 hours. The resin was then washed with DMF (8 times) to obtain compound M10.

[1096] Step 3: Resin Pyrolysis

[1097] The resin was treated with HFIP / CH2Cl2 (10 mL / 90 mL) for 30 minutes, and then filtered. This process was repeated three times. The filtrates were combined, and the crude product was concentrated under reduced pressure and purified by reverse-phase preparative column chromatography. The preparative solution was lyophilized to give compound M11 (9.2 g, 68% yield). LC-MS m / z (ES) - ): [MH] - :658.2.

[1098]

[1099] Synthesis of compound M13

[1100] Compound 137 (144 mg, 0.24 mmol, 1.0 eq.), M12 (synthesized according to patent: CN111686259A, 265 mg, 0.72 mmol, 3.0 eq.), Zn(OAc)2 (132 mg, 0.72 mmol, 3.0 eq.), 4A powdered molecular sieve (150 mg), and toluene (15 mL) were added to a 50 mL single-necked flask. After purging with nitrogen, the temperature was raised to 105 °C and the reaction was carried out for 4 hours. The reaction was monitored by TLC until complete. The reaction solution was filtered, and the filter cake was washed twice with dichloromethane. The crude product after evaporation was purified by preparative TLC to obtain compound M13 (220 mg, yield 81%). LC-MS m / z (ES) + ): [M+H] + :909.3.

[1101] Synthesis of compound M15

[1102] Compound M13 (120 mg, 0.132 mmol, 1.0 eq.) was dissolved in acetonitrile (4 mL), and DBU (22 mg, 0.145 mmol, 1.1 eq.) was added dropwise under an ice-water bath. After the addition was complete, the reaction was continued under an ice-water bath for 20 minutes. The reaction of the starting material was monitored by TLC until it was complete, and this was recorded as reaction solution 1.

[1103] M11 (104 mg, 0.158 mmol, 1.2 eq.), HATU (75 mg, 0.198 mmol, 1.5 eq.), HOBt (26.7 mg, 0.198 mmol, 1.5 eq.), and DMF (1 mL) were added to a 25 mL single-necked flask. Reaction solution 1 and DIEA (25.6 mg, 0.198 mmol, 1.5 eq.) were added dropwise under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes, monitored by HPLC. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound M15 (86 mg, yield 61%). LC-MS m / z (ES) + ): [M+H] + :1328.8.

[1104] Synthesis of compound LP-3

[1105] M15 (86 mg, 0.065 mmol, 1.0 eq.), zinc bromide (437 mg, 1.94 mmol, 30.0 eq.), and nitromethane (8 mL) were added sequentially to a 10 mL reaction tube. The reaction mixture was reacted at 40 °C for 1 hour under nitrogen protection. After rotary evaporation and concentration, the crude product was purified by reverse-phase preparative column chromatography. The preparative solution was lyophilized to give compound LP-3 (62 mg, 90% yield). LC-MS m / z (ES) + ): [M+H]+ :1072.4.

[1106] Example 58: Synthesis of compound LP-4

[1107]

[1108] Synthesis of compound M17

[1109] In a 25 mL single-necked flask, compound M9 (500 mg, 1.26 mmol, 1.0 eq.) and DMF (5 mL) were added and dissolved. Then, compound M16 (propargylamine, 97 μL, 1.51 mmol, 1.2 eq.) and EEDQ (932 mg, 3.77 mmol, 3.0 eq.) were added, and the mixture was reacted overnight at room temperature. HPLC analysis showed the reaction was complete. Compound M17 (190 mg, 35% yield) was obtained by HPLC purification and lyophilization. LC-MS m / z (ES) + ): [M-Boc+H] + :336.2.

[1110] Synthesis of compound M18

[1111] Compound M17 (100 mg, 0.229 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL), and after complete dissolution, TFA (2 mL) was added. The reaction was carried out at room temperature for 3 hours. HPLC monitoring showed that the reaction was complete. After concentration, water was added and lyophilized to give compound M18 (65 mg, 100% yield). LC-MS m / z (ES) + ): [M+H] + :280.1.

[1112]

[1113] Synthesis of compound M20

[1114] HOSu (58 mg, 0.500 mmol, 1.1 eq.) and DCC (103 mg, 0.500 mmol, 1.1 eq.) were added sequentially to a tetrahydrofuran (2 mL) solution of compound 19 (azido-ethylene glycol-acetic acid, 102 mg, 0.500 mmol, 1.1 eq.). The reaction was carried out at room temperature for 3 hours. The reaction solution was filtered, and the filter cake was washed with tetrahydrofuran (1 mL). This solution was designated as reaction solution 1.

[1115] Compound M3 (415 mg, 0.455 mmol, 1.0 eq.) was dissolved in DMF (4 mL). Reaction solution 1 and DIEA (0.158 mL, 0.909 mmol, 2.0 eq.) were added under ice bath conditions. After addition, the mixture was brought to room temperature and reacted for 2 hours, monitored by HPLC. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound M20 (334 mg, yield 67%). LC-MS m / z (ES) + ): [M+H] + :1098.7.

[1116] Synthesis of compound LP-4

[1117] Compound M20 (90 mg, 0.082 mmol, 1.0 eq), compound M18 (23 mg, 0.082 mmol, 1.0 eq), copper sulfate pentahydrate (41 mg, 0.164 mmol, 2.0 eq), sodium ascorbate (32 mg, 0.164 mmol, 2.0 eq), and DMF (2 mL) were added to a 10 mL reaction tube. Water (0.4 mL) was added under ice bath conditions, and the reaction was allowed to proceed at room temperature. After 30 minutes, HPLC showed complete reaction. The reaction solution was purified using a reverse-phase preparative column, and the preparative solution was lyophilized to give compound LP-4 (103 mg, 91%). LC-MS m / z (ES) + ): [M+H] + :1377.7.

[1118] Example 59: Synthesis of compound LP-5

[1119]

[1120] Synthesis of compound M23

[1121] Compound M21 (serine benzyl ester hydrochloride, 10 g, 43.16 mmol, 1.0 eq.) was dissolved in dichloromethane (200 mL), and the system was cooled to 0 °C. Triethylamine (12.6 mL, 90.46 mmol, 2.0 eq.) was added dropwise, and the mixture was stirred for 20 minutes after the addition was complete. At the same temperature, a dichloromethane solution of compound M22 (o-nitrobenzenesulfonyl chloride, 10.04 g, 45.32 mmol, 1.05 eq.) was added dropwise. After the reaction was completed by TLC monitoring, a saturated sodium bicarbonate aqueous solution (100 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (100 mL × 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M23 (10.0 g, yield 61%). LC-MS m / z (ES) + ): [M+H] + :381.1.

[1122] Synthesis of compound M24

[1123] At room temperature, triphenylphosphine (7.2 g, 27.6 mmol, 1.05 eq.) was weighed into a three-necked flask. The system was purged under a nitrogen atmosphere, and ultra-dry tetrahydrofuran (80 mL) was added to dissolve it. The system was cooled to 0 °C, and an ultra-dry tetrahydrofuran (24 mL) solution of compound M23 (10.0 g, 26.3 mmol, 1.0 eq.) was added dropwise. After 10 minutes, the addition was completed, followed by the addition of an ultra-dry tetrahydrofuran (30 mL) solution of diethyl azodicarbonate (4.8 g, 27.6 mmol, 1.05 eq.). The reaction was carried out at this temperature for 1 hour, and the reaction was monitored by TLC to ensure complete reaction. The reaction system was quenched with saturated sodium bicarbonate aqueous solution (120 mL), extracted with ethyl acetate (120 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M24 (8.6 g, 91% yield). LC-MS m / z (ES) + ): [M+H] + 363.5.

[1124] Synthesis of compound M26

[1125] Compound M24 (7.6 g, 21.0 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (200 mL). The system was cooled to 0 °C, and compound M25 ((S)-3-amino-2-carbonylaminopropionate tert-butyl ester, 7.44 g, 25.3 mmol, 1.2 eq.) and triethylamine (5.8 mL, 42.0 mmol, 2.0 eq.) were added. The mixture was allowed to warm to room temperature naturally and reacted overnight. The reaction was monitored by TLC until complete. The reaction mixture was directly concentrated and purified by column chromatography to give compound M26 (9.8 g, 71% yield). LC-MS m / z (ES) + ): [M+H] + :657.2.

[1126] Synthesis of compound M27

[1127] Compound M26 (9.72 g, 14.8 mmol, 1.0 eq.) was dissolved in dichloromethane (330 mL), and triethylamine (6.21 mL, 44.7 mmol, 3.0 eq.) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred for 20 minutes, followed by the addition of di-tert-butyl dicarbonate (14 mL, 61.0 mmol, 4.0 eq.). The mixture was then heated to 35 °C and reacted for 5.5 hours. The reaction solution was concentrated and purified by column chromatography to give compound M27 (6.4 g, 57% yield). LC-MS m / z (ES) + ): [M+H] + :757.6.

[1128] Synthesis of compound M29

[1129] Compound M27 (6.4 g, 8.5 mmol, 1.0 eq.) was dissolved in DMF (120 mL), followed by the addition of potassium carbonate (23.4 g, 170 mmol, 20 eq.) and compound M28 (4-methoxythiophenol, 10.5 mL, 85 mmol, 10 eq.). The reaction was carried out at room temperature for 30 minutes, and TLC was used to monitor the reaction until complete. The mixture was extracted three times with water (300 mL) and ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound M29 (4.0 g, 82% yield). LC-MS m / z (ES) + ): [M+H] + :572.0.

[1130] Synthesis of compound M30

[1131] Compound M29 (3 g, 5.2 mmol, 1.0 eq.) was dissolved in methanol (50 mL), and 10% Pd / C (0.52 g) was added to replace the system with hydrogen gas. The reaction was allowed to proceed for 15 hours, and TLC was used to monitor the reaction until it was complete. Pd / C was removed by filtration, and the solution was concentrated to obtain compound M30, which could be used directly in the next step without further purification.

[1132] Synthesis of compound M31

[1133] The crude compound M30 (5.2 mmol) was dissolved in dichloromethane (55 mL), followed by the addition of glacial acetic acid (1.49 mL, 26 mmol, 5 eq.) and maleic anhydride (1.02 g, 10.4 mmol, 2.0 eq.). After reacting at room temperature for 2 hours, the reaction was monitored to be complete by HPLC. The system was then concentrated, purified by reverse-phase preparative column chromatography, and lyophilized to obtain compound M31 (2.12 g, 75% yield). LC-MS m / z (ES) - ): [MH] - :542.3.

[1134] Synthesis of compound M32

[1135] In a 25 mL single-necked flask, add M31 (680 mg, 1.26 mmol, 1.0 eq), toluene (10 mL), and DIEA (828 μL, 5.01 mmol, 4.0 eq.). Reflux at 120 °C for 1 hour, concentrate to remove solvent, and obtain crude compound M32.

[1136] Use it directly in the next step.

[1137]

[1138] Synthesis of compound M34

[1139] Compound M33 (Fmoc-O-tert-butyl-L-glutamic acid, 21.2 g, 49.8 mmol, 1.0 eq.), propargylamine (3.3 g, 60 mmol, 1.2 eq.), EDCI (14.3 g, 74.7 mmol, 1.5 eq.), HOBt (10.1 g, 74.7 mmol, 1.5 eq.), and tetrahydrofuran (100 mL) were added dropwise under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours under TLC monitoring. After the reaction was complete, the mixture was extracted with ethyl acetate, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound M34 (10.37 g, yield 45%). LC-MS m / z (ES) + ): [M+H] + :463.2.

[1140] Synthesis of compound M35

[1141] Compound M34 (398 mg, 0.861 mmol) was dissolved in acetonitrile (4 mL), and diethylamine (1 mL) was added. The mixture was reacted at room temperature for 30 minutes. The reaction was monitored by TLC until it was complete. The reaction solution was concentrated under reduced pressure to obtain crude compound M35, which was used directly in the next step.

[1142] Synthesis of compound M37

[1143] Compound M35 (crude product, 0.861 mmol, 1.0 eq.), compound M36 (N-fluorenemethoxycarbonyl-tetraethylene glycol-carboxylic acid, 420 mg, 0.861 mmol, 1.0 eq.), HATU (491 mg, 1.29 mmol, 1.5 eq.), and HOBT (174 mg, 1.29 mmol, 1.5 eq.) were weighed sequentially into a reaction flask. After dissolving in DMF (5 mL), DIEA (0.22 mL, 1.29 mmol, 1.5 eq.) was added dropwise under ice bath conditions. The mixture was then brought to room temperature and reacted for 1 hour. The reaction was monitored by HPLC until complete. The reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to obtain compound M37 (525 mg, yield 86%). LC-MS m / z (ES) + ): [M+H] + :710.5.

[1144] Synthesis of compound M38

[1145] Compound M37 (61 mg, 0.086 mmol, 1.0 eq.) was dissolved in acetonitrile (1 mL), and DBU (14 μL, 0.095 mmol, 1.1 eq.) was added dropwise under an ice-water bath. After the addition was complete, the reaction was continued under an ice-water bath for 20 minutes. The reaction of the starting material was monitored by TLC until it was complete, and this was recorded as reaction solution 1.

[1146] In a separate reaction flask, compound M32 (57 mg, 0.112 mmol, 1.3 eq.) was dissolved in DMF (2 mL). EEDQ (43 mg, 0.172 mmol, 2.0 eq.) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes. Then, reaction solution 1 was added dropwise under ice-water bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes, with the reaction monitored by HPLC. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound M38 (51 mg, yield 61%). LC-MS m / z (ES) + ): [M+H] + :977.6.

[1147] Synthesis of compound M39

[1148] Compound M38 (51 mg, 0.052 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to obtain compound M39 (17 mg, yield 43%). LC-MS m / z (ES) - ): [MH] - :763.3.

[1149] Synthesis of compound LP-5

[1150] Compound M20 (24 mg, 0.022 mmol, 1.0 eq.), compound M39 (17 mg, 0.022 mmol, 1.0 eq.), copper sulfate pentahydrate (11 mg, 0.044 mmol, 2.0 eq.), sodium ascorbate (8.7 mg, 0.044 mmol, 2.0 eq.), and DMF (2 mL) were added to a 10 mL reaction tube. Water (1 mL) was then added under ice bath conditions, and the reaction was allowed to proceed at room temperature. After 30 minutes, HPLC showed complete reaction. The reaction solution was purified using a reverse-phase preparative column, and the preparative solution was lyophilized to give compound LP-5 (36 mg, 88%). LC-MS m / z (ES) + ): [M+2H] 2+ :932.0.

[1151] Example 60: Synthesis of compound LP-6

[1152]

[1153] Synthesis of compound M41

[1154] Compound M40 (BCN-OH, 1 g, 6.66 mmol, 1.0 eq.), di(p-nitrobenzene) carbonate (3.0 g, 9.99 mmol, 1.5 eq.), and dichloromethane (70 mL) were added to a 250 mL single-necked flask. DIEA (2.3 mL, 13.3 mmol, 2.0 eq.) was added dropwise under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted overnight under TLC monitoring. After the reaction was complete, the reaction solution was washed once with water, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound M41 (1.3 g, yield 63%).

[1155] Synthesis of compound M42

[1156] Compound M37 (72 mg, 0.101 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to give compound M42 (61 mg, yield 92%). LC-MS m / z (ES) - ): [MH] - :652.3.

[1157] Synthesis of compound M43

[1158] Compound M20 (54 mg, 0.049 mmol, 1.0 eq.), compound M42 (32 mg, 0.049 mmol, 1.0 eq.), copper sulfate pentahydrate (25 mg, 0.098 mmol, 2.0 eq.), sodium ascorbate (19 mg, 0.098 mmol, 2.0 eq.), and DMF (2 mL) were added to a 10 mL reaction tube. Water (0.4 mL) was added under ice bath conditions, and the reaction was allowed to proceed at room temperature. After 30 minutes, HPLC showed complete reaction. The reaction solution was purified using a reverse-phase preparative column, and the preparative solution was lyophilized to give compound M43 (77 mg, 89%). LC-MS m / z (ES) + ): [M+2H] 2+ :876.5.

[1159] Synthesis of compound LP-6

[1160] Compound M43 (77 mg, 0.044 mmol, 1.0 eq.) was dissolved in acetonitrile (1 mL), and DBU (7.2 μL, 0.048 mmol, 1.1 eq.) was added dropwise under an ice-water bath. After the addition was complete, the reaction was continued under an ice-water bath for 20 minutes. The reaction of the starting material was monitored by TLC until it was complete, and this was recorded as reaction solution 1.

[1161] In a separate reaction flask, compound M41 (15 mg, 0.048 mmol, 1.1 eq.), HOBt (8.9 mg, 0.066 mmol, 1.5 eq.), and DMF (2 mL) were dissolved. Reaction solution 1 and DIEA (11.5 μL, 0.066 mmol, 1.5 eq.) were added under ice bath conditions. The mixture was then brought to room temperature and reacted for 1 hour. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound LP-6 (37 mg, 49% yield). LC-MS m / z (ES) + ): [M+2H] 2+ :853.4.

[1162] Example 61: Synthesis of compound LP-7

[1163]

[1164] Synthesis of compound M44

[1165] Compound M34 (377 mg, 0.815 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 2 hours under TLC monitoring. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude compound M44, which was then directly proceeded to the next step.

[1166] Synthesis of compound M46

[1167] Compound M44 crude product (0.815 mmol, 1.0 eq.), compound M45 (methyl-tetracosyl polyethylene glycol-amino, 887 mg, 0.815 mmol, 1.0 eq.), HATU (465 mg, 1.22 mmol, 1.5 eq.), and HOBT (165 mg, 1.22 mmol, 1.5 eq.) were weighed sequentially into a reaction flask. After dissolving in DMF (8 mL), DIEA (0.21 mL, 1.22 mmol, 1.5 eq.) was added dropwise under ice bath conditions. The mixture was then brought to room temperature and reacted for 1 hour. The reaction was monitored by HPLC until complete. The reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to obtain compound M46 (890 mg, yield 74%). LC-MS m / z (ES) + ): [M+H] + :1476.8.

[1168] Synthesis of compound M47

[1169] Compound M46 (890 mg, 0.603 mmol) was dissolved in acetonitrile (10 mL), and diethylamine (2.5 mL) was added. The reaction was carried out at room temperature for 30 minutes. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, purified by reverse-phase preparative column chromatography, and lyophilized to give compound M47 (703 mg, yield 93%). LC-MS m / z (ES) -): [M+H] + :1254.8.

[1170] Synthesis of compound M48

[1171] The synthesis of compound M48 was completed following the synthesis of compound M37. LC-MSm / z (ES) + ): [M+2H] 2+ :862.5.

[1172] Synthesis of compound M49

[1173] The synthesis of compound M49 was completed following the synthesis of compound M38. LC-MSm / z (ES) + ): [M+2H] 2+ :996.1.

[1174] Synthesis of compound M50

[1175] The synthesis of compound M50 was completed following the synthesis of compound M39. LC-MSm / z (ES) + ): [M+2H] 2+ :918.0.

[1176] Synthesis of compound LP-7

[1177] The synthesis of compound LP-7 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H] 3+ :978.5.

[1178] Example 62: Synthesis of compound LP-8

[1179]

[1180] Synthesis of compound M51

[1181] The synthesis of compound M51 was completed following the synthesis of compound M43. LC-MSm / z (ES) + ): [M+3H] 3+ :941.5.

[1182] Synthesis of compound LP-8

[1183] The synthesis of compound LP-8 was completed following the synthesis of compound LP-6. LC-MSm / z (ES) + ): [M+3H] 3+ :926.2.

[1184] Example 63: Synthesis of compound LP-9

[1185]

[1186] Synthesis of compound M53

[1187] Compound M9 (327 mg, 0.821 mmol, 1.0 eq.) was weighed into a reaction flask, dissolved in 3 mL of DMF, and EEDQ (460 mg, 1.64 mmol, 2.0 eq.) was added under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes. Subsequently, compound M52 (3-[2-(2-aminoethoxy)ethoxy]propionic acid, 145 mg, 0.821 mmol, 1.0 eq.) was added under ice-water bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes. The reaction was monitored by HPLC. The reaction solution was purified by reverse-phase preparative column chromatography, and the preparative solution was lyophilized to give compound M53 (348 mg, yield 76%). LC-MS m / z (ES) + ): [MH] - :556.3.

[1188] Synthesis of compound M54

[1189] Compounds M53 (92 mg, 0.165 mmol, 1.0 eq.), M47 (207 mg, 0.165 mmol, 1.0 eq.), HATU (94 mg, 0.248 mmol, 1.5 eq.), and HOBT (33 mg, 0.248 mmol, 1.5 eq.) were weighed sequentially into a reaction flask. After dissolving in DMF (3 mL), DIEA (43 μL, 0.248 mmol, 1.5 eq.) was added dropwise under ice bath conditions. The mixture was then brought to room temperature and reacted for 1 hour. The reaction was monitored by HPLC until complete. The reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to obtain compound M54 (233 mg, yield 79%). LC-MS m / z (ES) + ): [M+2H] 2+ :897.5.

[1190] Synthesis of compound M55

[1191] The synthesis of compound M55 was completed following the synthesis of compound M39. LC-MSm / z (ES) + ): [M+2H] 2+ :819.5.

[1192] Synthesis of compound LP-9

[1193] The synthesis of compound LP-9 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H] 3+ :912.8.

[1194] Example 64: Synthesis of compound LP-10

[1195] Synthesis of compound M57

[1196] The synthesis of compound M57 was completed following the synthesis of compound M34. LC-MSm / z (ES) + ): [M+H] + :506.3.

[1197] Synthesis of compound M58

[1198] Compound M57 (335 mg, 0.663 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 30 minutes under TLC monitoring. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude compound M58, which was then directly proceeded to the next step.

[1199] Synthesis of compound M60

[1200] Compound M58 crude product (0.663 mmol, 1.0 eq.), compound M45 (methyl-tetracosyl polyethylene glycol-propionic acid, 740 mg, 0.663 mmol, 1.0 eq.), HATU (378 mg, 0.994 mmol, 1.5 eq.), and HOBT (134 mg, 0.994 mmol, 1.5 eq.) were weighed sequentially into a reaction flask. After dissolving in DMF (8 mL), DIEA (0.17 mL, 0.994 mmol, 1.5 eq.) was added dropwise under ice bath conditions. The mixture was then brought to room temperature and reacted for 1 hour. The reaction was monitored by HPLC until complete. The reaction solution was purified by reverse-phase preparative column chromatography and lyophilized to obtain compound M60 (748 mg, 75% yield). LC-MS m / z (ES) + ): [M+H] + :1504.9.

[1201] Synthesis of compound M61

[1202] The synthesis of compound M61 was completed following the synthesis of compound M47. LC-MSm / z (ES) + ): [M+H] + :1282.8.

[1203] Synthesis of compound M63

[1204] The synthesis of compound M63 was completed following the synthesis of compound M53. LC-MSm / z (ES) + ): [MH] - :644.3.

[1205] Synthesis of compound M64

[1206] The synthesis of compound M64 was completed following the synthesis of compound M54. LC-MSm / z (ES) + ): [M+2H] 2+ :955.6.

[1207] Synthesis of compound M65

[1208] The synthesis of compound M65 was completed following the synthesis of compound M39. LC-MSm / z (ES) + ): [M+2H] 2+ :877.5.

[1209] Synthesis of compound LP-10

[1210] The synthesis of compound LP-10 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H] 3+ :951.5.

[1211] Example 65: Synthesis of compound LP-11

[1212]

[1213] Synthesis of compound M67

[1214] In a 250 mL single-necked flask, M66 (N-(benzyloxycarbonyl)glycylglycyl-L-phenylalanine, 5 g, 12.1 mmol), methanol (100 mL), and 5% Pd / C (250 mg, 5% w / w) were added and dissolved. Hydrogen was used to purge the gas, and the reaction was allowed to proceed overnight at room temperature. TLC analysis showed the reaction was complete. Water (100 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered through filter paper to remove palladium on carbon. The filter cake was washed with a small amount of water, concentrated, and dried to obtain a white solid compound M67 (3.3 g). The obtained product was used directly in the next reaction without purification.

[1215] Synthesis of compound M68

[1216] In a 100 mL single-necked flask, M19 (azido-ethylene glycol-acetic acid, 1.5 g, 7.38 mmol, 1.0 eq.) and acetonitrile (30 mL) were added and dissolved. HOSu (1.27 g, 11.1 mmol, 1.5 eq.) and DCC (2.28 g, 11.1 mmol, 1.5 eq.) were then added. The reaction was allowed to proceed at room temperature for 2 hours. The insoluble solids were removed by filtration. The filter cake was washed with a small amount of acetonitrile. Compound M67 (2.06 g, 7.38 mmol, 1.0 eq.) and DIEA (1.8 mL, 11.1 mmol, 1.5 eq.) were added to the filtrate. The reaction was allowed to proceed overnight at room temperature. HPLC analysis showed the reaction was complete. Compound M68 (1.7 g, 50%) was obtained by HPLC purification and lyophilization. LC-MS m / z (ES) + ): [M+H] + :465.2.

[1217]

[1218] Synthesis of compound M69

[1219] The synthesis of compound M69 was completed following the synthesis of compound M15. LC-MSm / z (ES) + ): [M+H] + :1033.5.

[1220] Synthesis of compound LP-11

[1221] The synthesis of compound LP-11 was completed following the synthesis of compound LP-4. LC-MSm / z (ES) + ): [M+H] + :1312.6.

[1222] Example 66: Synthesis of compound LP-12

[1223]

[1224] Synthesis of compound LP-12

[1225] The synthesis of compound LP-12 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+2H] 2+ :899.4.

[1226] Example 67: Synthesis of compound LP-13

[1227]

[1228] Synthesis of compound M70

[1229] The synthesis of compound M70 was completed following the synthesis of compound M43. LC-MSm / z (ES) + ): [M+2H] 2+ :843.9.

[1230] Synthesis of compound LP-13

[1231] The synthesis of compound LP-13 was completed following the synthesis of compound LP-6. LC-MSm / z (ES) + ): [M+2H] 2+ :820.9.

[1232] Example 68: Synthesis of compound LP-14

[1233]

[1234] Synthesis of compound LP-14

[1235] The synthesis of compound LP-14 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H] 3+ :956.8.

[1236] Example 69: Synthesis of compound LP-15

[1237]

[1238] Synthesis of compound M71

[1239] The synthesis of compound M71 was completed following the synthesis of compound M43. LC-MSm / z (ES) + ): [M+3H] 3+ :919.8.

[1240] Synthesis of compound LP-15

[1241] The synthesis of compound LP-15 was completed following the synthesis of compound LP-6. LC-MSm / z (ES) + ): [M+3H] 3+ :904.5.

[1242] Example 70: Synthesis of compound LP-16

[1243]

[1244] Synthesis of compound LP-16

[1245] The synthesis of compound LP-16 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H]3+ :891.1.

[1246] Example 71: Synthesis of compound LP-17

[1247]

[1248] Synthesis of compound LP-17

[1249] The synthesis of compound LP-17 was completed following the synthesis of compound LP-5. LC-MSm / z (ES) + ): [M+3H] 3+ :929.8.

[1250] A General Method for Coupling ADC Preparation

[1251] Purified antibody molecules with a monomer content greater than 95% were transferred to 20 mM NaAc pH 6.0 buffer using an ultrafiltration centrifuge tube, resulting in a concentration greater than 5 mg / ml. An appropriate amount of antibody was placed in a reaction vessel, and 25 times the molar amount of TCEP (reducing agent) was added. The reaction was carried out at 25°C for 2 hours. Then, 20-25 times the molar amount of the antibody linker-drug conjugate was added, and the reaction was carried out at 25°C for 1.5-2 hours. After the reaction, the medium was transferred to 20 mM histidine hydrochloride (pH 5.3) using an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa, and the unconjugated linker-drug conjugate was removed to obtain the ADC.

[1252] General Method B for Coupling ADC Preparation

[1253] A certain volume of antibody containing an azide group was taken and diluted with 20 mM sodium acetate buffer (5 mg / mL). Then, 20 times the amount of DMA solution (20 mg / mL) of the linker-drug conjugate was added according to the molecular ratio, and the reaction was carried out overnight at room temperature. After the reaction was completed, the sample was transferred to 20 mM sodium acetate (pH 6.5) buffer to obtain the corresponding antibody-drug conjugate (ADC) sample.

[1254] ADC fabrication

[1255] The linker-drug conjugate was conjugated with the antibody to obtain the corresponding ADC, as shown in the table below.

[1256]

[1257]

[1258]

[1259] Antibody 1 is a bispecific antibody targeting EGFR×HER3. Its sequence and preparation method are based on antibody SI-1×6.4 in Example 91 of patent WO2023083381.

[1260] Antibody 2 is an antibody that targets TROP2. Its sequence and preparation method are referenced from the hu4D3 antibody in patent WO2021259162.

[1261] ADC Evaluation

[1262] 1. Detection of DAR by reversed-phase high-performance liquid chromatography (RP-HPLC)

[1263] Sample reduction: Based on the actual amount used, reduce the protein at a ratio of 50 μg protein: 1 μl DTT. After vortexing and mixing, centrifuge at 12000 rpm for 5 minutes, and transfer the supernatant to a sample vial.

[1264] Place the sample vial containing the sample onto the sample plate, and set the corresponding position, injection volume, number of injection needles, and injection method for each sample according to the "UPLC Standard Operating Procedure". Detect the DAR value of the ADC (corresponding to the q value in the ADC example).

[1265] Chromatographic methods:

[1266]

[1267] DAR detection results of ADC

[1268] ADC number DAR ADC-1-1 7.06 ADC-1-2 7.08 ADC-2-1 7.65 ADC-2-2 6.72 ADC-3-1 7.59 ADC-3-2 7.75

[1269] The results show that the DAR values ​​of the ADCs disclosed in this invention are stable and close to the theoretical values, and the ADCs of this invention have good uniformity.

[1270] Bioactivity experiment

[1271] 1. Evaluation of the enzyme activity of N-myristyltransferase (NMT) inhibitors

[1272] Based on a fluorescence detection method, coenzyme A (CoA) was detected using the fluorescent probe CPM (7-diethylamino-3-(4-maleimidephenyl)-4-methylcoumarin) to determine the inhibitory activity of the test substance (the compound prepared in the embodiments of this invention) against NMT1 and NMT2. Specific methods are described in the articles Goncalves, V., et al., Analytical Biochemistry, 2012, 421, 342-344 and Goncalves, V., et al., J. Med. Chem, 2012, 55, 3578.

[1273] The results showed that the compounds of the present invention have a significant inhibitory effect on NMT1 and / or NMT2.

[1274] 2. Compound cell killing experiment

[1275] 1) Cell lines:

[1276]

[1277]

[1278] 2) Preparation of culture medium:

[1279] Test medium: RPMI-1640 medium + 10% FBS + 100 U / mL Penicillin / streptomycin;

[1280] Basic culture medium: purchased from source culture organisms;

[1281] FBS: Purchased from ExCell Bio.

[1282] 3) Test reagents:

[1283] Aqueous One Solution Cell Proliferation Assay (MTS): Purchased from Promega, item number G3581.

[1284] 4) Experimental methods and results:

[1285] a. An appropriate number of tumor cells were evenly seeded into 96-well cell culture plates and incubated in a CO2 incubator. After 24 hours, the cells were confirmed to be in normal condition under a microscope, and then drug treatment was initiated. The drug was diluted with the test medium, mixed well, and added to the corresponding cell wells to achieve an initial concentration of 2000 nM for each test drug, with a dilution factor of 10-fold, resulting in 8 concentration points. Each dose group was set up in triplicate, with an incubation volume of 100 μL / well. A negative control group (cells + culture medium, no drug treatment) and a blank group (cell-free, containing only culture medium for background subtraction) were also set up. The plates were incubated at 37°C for 3 days. After incubation, 20 μL of MTS assay reagent was added to each well, and the plates were incubated at 37°C for 2 hours. The absorbance was read at 490 nm using a microplate reader (Molecular Device, model: SpectraMAX ABS). Cell viability was calculated using the formula: Viability (%) = (Experimental group - Blank group) / (Negative control group - Blank group) × 100%, and then the IC50 was calculated. 50 To evaluate the killing activity of each test drug against tumor cells.

[1286]

[1287] b. A suitable number of tumor cells were evenly seeded into 96-well cell culture plates and incubated in a CO2 incubator. After 24 hours, the cells were confirmed to be in normal condition under a microscope, and then drug treatment was initiated. The drug was diluted with the test medium, mixed well, and added to the corresponding cell wells to achieve an initial concentration of 100 nM for each test drug, with a dilution factor of 10-fold, resulting in 8 concentration points. Each dose group was set up in triplicate, with an incubation volume of 100 μL / well. A negative control group (cells + culture medium, no drug treatment) and a blank group (no cells, only culture medium, used to subtract background) were also set up. The plates were incubated at 37°C for 3 days. After incubation, 20 μL of MTS test reagent was added to each well, and the plates were incubated at 37°C for 2 hours. The absorbance was read at 490 nm using a microplate reader (Molecular Device, model: SpectraMAX ABS). The cell viability was calculated using the formula: Viability (%) = (Experimental group - Blank group) / (Negative control group - Blank group) × 100%, and then the IC50 was calculated. 50 To evaluate the killing activity of each test drug against tumor cells.

[1288]

[1289] The results showed that the compound of the present invention has a significant killing effect on tumor cells.

[1290] 3. ADC cell killing experiment

[1291] 1) Cell lines:

[1292]

[1293]

[1294] 2) Preparation of culture medium:

[1295] Test medium: RPMI-1640 + 10% FBS + 100 U / mL Penicillin / streptomycin;

[1296] Basic culture medium: purchased from source culture organisms;

[1297] FBS: Purchased from ExCell Bio.

[1298] 3) Test reagents:

[1299] Aqueous One Solution Cell Proliferation Assay (MTS): Purchased from Promega, item number G3581.

[1300] Bio-Lite Luciferase Assay System: Purchased from Vazyme, DD1201-02.

[1301] 4) Experimental methods and results:

[1302] An appropriate number of tumor cells were evenly seeded into 96-well cell culture plates and incubated in a CO2 incubator. After 24 hours, the cells were confirmed to be in normal condition under a microscope, and then drug treatment was performed. The drug was diluted with the test medium, mixed well, and added to the corresponding cell wells to make the initial concentration of each antibody-drug conjugate 500 nM, with a dilution factor of 7-fold, for a total of 8 concentration points. The incubation volume was 100 μL / well, and each dose point was set up in triplicate. A negative control group (i.e., cells + culture medium, no drug treatment) and a blank group (i.e., no cells, only culture medium, used to subtract background) were also set up. The plates were incubated in a CO2 incubator at 37°C for 5 days.

[1303] For the monosomy 1 tumor cell model, the MTS assay was used to quantify viable cells and calculate cell viability. After drug incubation, 20 μL of MTS assay reagent was added to each well, and the cells were incubated at 37°C for 2 hours using a CO2 incubator. The absorbance was read at 490 nm using a microplate reader (Molecular Device, model: SpectraMAX ABS). Cell viability was calculated using the formula: Viability (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Subsequently, the IC50 was calculated. 50 To evaluate the killing effect of the tested antibody-drug conjugate on tumor cells.

[1304] For the heterogeneous tumor cell model, since negative SW620 cells stably express the luciferase reporter gene, the highly sensitive Bio-Lite Luciferase Assay System can be used to quantitatively detect Luciferase in live cells, thereby calculating the survival rate of negative SW620 cells. After drug incubation, 100 μL of Bio-Lite (Vazyme, DD1201-02) was added to each well and reacted for 10 minutes to induce cell lysis and release luciferase, which reacted fully with Luciferin in the assay reagent to emit a stable light signal. Under light-protected conditions, the chemiluminescence intensity (RLU) of each experimental group was detected using a Molecular Devices i3X multi-functional microplate reader. The survival rate of negative SW620 cells in the heterogeneous tumor model was calculated using the formula: Survival rate (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Subsequently, the IC50 was calculated. 50 To evaluate the killing effect of ADC drugs on negative tumor cells through bystander effect.

[1305]

[1306] The results showed that the ADC of the present invention has a significant killing effect on tumor cells.

[1307] 4. In vivo efficacy evaluation

[1308] This embodiment established mouse subcutaneous xenograft tumor models of different cancer types and mixed xenograft tumor models to evaluate the in vivo efficacy of compounds and ADCs. Tumor cell suspensions were subcutaneously injected into the right scapula of mice. Once the average tumor volume reached a suitable size, the mice were randomly assigned to groups and administered the test compounds or ADCs to observe their inhibitory effects on tumor growth.

[1309] The results showed that the compounds and ADCs of the present invention have significant in vivo antitumor activity and safety.

[1310] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. The compound represented by Formula I, or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters. in: L 1 Selected from -XL 1a - C1-C6 alkylene groups; preferably, X is connected to the B0 ring, L 1a Connected to ring C0; X is selected from O, S, NH, -C(O)-, and direct bonds; Preferably, X is O, NH, or -C(O)-; L 1a The group is selected from direct bonds, C1-C6 alkylene groups, -C(O)-C1-C6 alkylene groups, -NH-S(O)2-, -S(O)2-, C2-C6 ynylene groups, C3-C8 cycloalkylene groups -C1-C6 alkylene groups, C3-C8 cycloalkylene groups, C2-C6 alkenylene groups, and C1-C6 alkylene groups -C(O)-, wherein each of the C1-C6 alkylene groups, C2-C6 alkenylene groups, C2-C6 ynylene groups, and C3-C8 cycloalkylene groups is independently and optionally replaced by 1-3 groups selected from C3-C8 cycloalkyl groups, deuterium, and C1-C6 alkyl groups; preferably, L 1a When not a direct key, L 1a The site on the left is connected to X, and the site on the right is connected to the C0 ring; Preferably, L 1a The group is selected from direct bonds, C1-C6 alkylene groups (such as methylene or ethylene), -C(O)-C1-C6 alkylene groups, -NH-S(O)2-, C2-C6 ynylene groups, C3-C8 cycloalkylene groups -C1-C6 alkylene groups, C3-C8 cycloalkylene groups, C2-C6 alkenylene groups, and C1-C6 alkylene groups -C(O)-, wherein each of the C1-C6 alkylene groups (such as methylene or ethylene) and C2-C6 ynylene groups is independently and optionally substituted by 1-3 groups selected from cyclopropyl and deuterium; preferably, L 1a When not a direct key, L 1a The site on the left is connected to X, and the site on the right is connected to the C0 ring; More preferably, L 1a Selected from direct keys, Preferably, L 1a When not a direct key, L 1a The upper site is connected to X, and the lower site is connected to the C0 ring; Preferably, L 1 Selected from methylene, -O-, Preferably, L 1 When it is not methylene or -O-, the upper site is connected to the B0 ring, and the lower site is connected to the C0 ring; A0 ring is selected from R 0 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, cyano, halogen, and hydroxyl; Preferably, R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl; More preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl; Each R 2 Independently selected from -L 2 -R 2A ; L 2 Selected from direct bond, -O-, -C(O)-, -C(O)-C1-C6 alkylene, C1-C6 alkylene, -C(O)-C2-C6 alkenyl, C2-C6 alkenyl, -C(O)-C2-C6 alkyneyl, C2-C6 alkyneyl; Preferably, L 2 Selected from direct bond, -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene, methylene, ethylidene R 2A Selected from -NR 2m R 2n -N(R) 2r )NR 2s R 2t 5-6 member nitrogen-containing saturated heterocyclic groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperidinyl); R 2m R 2n Each of the groups is independently selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperidinyl), wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6 member heteroaryl groups (preferably 6 member heteroaryl groups, more preferably pyridinyl), phenyl, naphthyl, and 5-6 member nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl groups (preferably 6 member nitrogen-containing saturated heterocyclic groups, more preferably piperazine). -NR 2p R 2q The groups are replaced; R 2p R 2q R 2r R 2s R 2t Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, Preferably, R 2p R 2q Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, Preferably, R 2r R 2s R 2t Each is independently selected from hydrogen, deuterium, and C1-C6 alkyl groups; m1 is selected from 1, 2, 3, 4, 5, 6, with 2 being the preferred choice; Preferably, R 2A Selected from Preferably, each R 2 Selected independently L 2a Selected from direct bond, C1-C6 alkylene group, and C2-C6 ynylene group; Preferably, L 2a Selected from direct bonds, methylene, ethylene, L 2b Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2b Selected from direct bonds and ethylene; L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide; Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene; More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; Preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; More preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced; More preferably, R 2a Selected from hydrogen, methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. ), The groups are replaced; Most preferably, R 2a Selected from hydrogen, methyl, Cyclopropyl R 2b Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2b Selected from hydrogen and methyl; R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, and is preferably 2; Preferably, R 2c Selected from methyl, R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2d Selected from -NHR 2e 6-membered nitrogen-containing saturated heterocyclic group; More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) ); R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups; More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) ); Most preferably, R 2 Selected from Preferably, each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen; More preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl; Most preferably, each R 4 Independently selected from hydrogen and methyl; Preferably, R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen; More preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups; Preferably, R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups; More preferably, R 6 Selected from hydrogen and deuterium; Preferably, R 7 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 8 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 9 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 10 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 11 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 12 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 13 The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, the A0 ring is selected from... B0 ring is selected from Among them, position 1 is connected to ring A0, and position 2 is connected to L. 1 Connected; R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; More preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, C(O)-NR 1a5 R 1a6 ; R 1a1 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a1 It is methyl; R 1a2 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a2 It is methyl; R 1a3 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a3 It is methyl; R 1a4 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a4 It is methyl; R 1a5 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a5 It is hydrogen; R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl; Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups; More preferably, R 1a6 It is cyclopropyl; Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl, R 1b R 1c R 1d R 1e R 1f R 1g R 1h R 1i R 1j R 1k R 1l R 1m Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogen, cyano, and nitro; Preferably, R 1b Selected from halogen, cyano, and nitro groups; More preferably, R 1b Selected from halogens; Most preferably, R 1b For F; Preferably, R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups; More preferably, R 1c Selected from hydrogen and deuterium; Preferably, R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups; More preferably, R 1d Selected from hydrogen and deuterium; Preferably, each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; More preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl; Preferably, R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; More preferably, R 1f R 1g It is fluorine; Preferably, R 1h The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 1i The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 1j The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 1k The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 1l The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 1m The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; B0 ring is selected from Among them, position 1 is connected to ring A0, and position 2 is connected to L. 1 Connected; C0 ring is selected from R 3a R 3e Each is independently selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (such as methyl), C3-C8 cycloalkyl groups, deuterium, nitro groups, halogens (such as fluorine), phenyl groups, and R-terminated groups. 3a4 Substitution of C1-C6 alkyl groups, or optional substitution of C3-C8 cycloalkyl groups with C1-C6 alkyl groups; Preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (such as methyl), C3-C8 cycloalkyl groups, deuterium, nitro groups, halogens (such as fluorine), phenyl groups, and R-terminated groups. 3a4 Substitution of C1-C6 alkyl groups, or optional substitution of C3-C8 cycloalkyl groups with C1-C6 alkyl groups; More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-membered nitrogen-containing saturated heterocyclic group, -C(O)-4-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-membered heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-membered nitrogen-containing saturated heterocyclic group, 5-membered nitrogen-containing saturated heterocyclic group, phenyl, and 5-membered heteroaryl group are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (e.g., methyl), C3-C8 cycloalkyl groups (e.g., cyclopropyl), deuterium, nitro, halogens (e.g., fluorine), phenyl, hydroxymethyl, cyclopropyl groups optionally substituted with methyl (e.g., The group replaced by ) More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, aziridine, -C(O)-aziridine, C1-C6 alkylene-tetrahydropyrrolyl, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-oxazolyl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, aziridine, tetrahydropyrrolyl, phenyl, and oxazolyl groups are each optionally and independently surrounded by 1-3 groups selected from hydroxyl, -NR 3a1 R 3a2 C1-C6 alkyl groups (e.g., methyl), C3-C8 cycloalkyl groups (e.g., cyclopropyl), deuterium, nitro, halogens (e.g., fluorine), phenyl, hydroxymethyl, cyclopropyl groups optionally substituted with methyl (e.g., The group replaced by ) R 3a1 R 3a2 Each is independently selected from hydrogen, C1-C6 alkyl, and deuterated C1-C6 alkyl, wherein the C1-C6 alkyl and deuterated C1-C6 alkyl are each optionally substituted by 1 to 3 (e.g., 1) hydroxyl groups; Preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, C1-C6 alkyl, or deuterated C1-C6 alkyl, and the other is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, or hydroxyl-substituted deuterated C1-C6 alkyl. More preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, methyl, or -CD3, and the other is selected from methyl, -CD3, ... R 3a3 Selected from C1-C6 alkyl groups; Preferably, R 3a3 For tert-butyl; R 3a4 Selected from cyano, carboxyl, mercapto, azide, and hydroxyl groups; Preferably, R 3a4 It is a hydroxyl group; Most preferably, R 3a Selected from Preferably, R 3e Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups; More preferably, R 3e for R 3b R 3c R 3d R 3f R 3g R 3h R 3i Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; Preferably, R 3b Selected from C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; More preferably, R 3b Selected from methyl, cyclopropyl, vinyl, and ethynyl groups; Preferably, R 3c Selected from C1-C6 alkyl groups; More preferably, R 3c It is methyl; Preferably, R 3d Selected from C1-C6 alkyl groups; More preferably, R 3d It is methyl; Preferably, R 3f The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 3g The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 3h The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, R 3i The components are selected from hydrogen, deuterium, and C1-C6 alkyl groups, preferably from hydrogen and deuterium, and more preferably from hydrogen; Preferably, the C0 ring is selected from... Or, R 1a and R 3c Connected to form Or, R 0 With R 1d Connected to form in: When A0 ring is selected B0 ring is selected from C0 ring is selected from L 1a C1-C6 alkylene or L 1 for Furthermore, R 1a Selected from halogens or F, R 2A For -NR 2m R 2n (and R) 2m R 2n Each is independently selected from hydrogen, C1-C6 alkyl, or R 2a It is hydrogen or C1-C6 alkyl (such as methyl) or R 2 for R 3a C1-C6 alkyl groups substituted with one hydroxyl group or... When any one of the following conditions (a)-(c) is satisfied: (a)R 0 and R 5 They are not both hydrogen; (b)R 1c and R 1d They are not both hydrogen; (c)R 3b Not selected from C1-C6 alkyl groups (such as R 3b (Not methyl).

2. The compound of claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-1. in: A0 ring is selected from R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl; Preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl; R 1a Selected from halogen, cyano, and nitro groups; Preferably, R 1a Selected from halogens and nitro groups; More preferably, R 1a Selected from F and nitro; R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1c It is hydrogen; R 1d Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1d It is hydrogen; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene and C3-C8 cycloalkylene, wherein each of the C1-C6 alkylene and C3-C8 cycloalkylene is optionally substituted by 1-3 (preferably 1-2) deuterium atoms; Preferably, L 1a Selected from ethylene, Preferably, L 1 Selected from Each R 2 Selected independently L 2a Selected from direct bond, C1-C6 alkylene group, and C2-C6 ynylene group; Preferably, L 2a Selected from direct bonds, methylene, ethylene, L 2b Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2b Selected from direct bonds and ethylene; L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide; Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene; More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; Preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; More preferably, R 2a The group is selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced; More preferably, R 2a Selected from hydrogen, methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. ), The groups are replaced; Most preferably, R 2a Selected from hydrogen, methyl, Cyclopropyl R 2b Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2b Selected from hydrogen and methyl; R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, preferably 2; more preferably, R 2c Selected from methyl, R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2d Selected from -NHR 2e 6-membered nitrogen-containing saturated heterocyclic group; More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) ); R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups; More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) ); Most preferably, R 2 Selected from Each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen; Preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl; More preferably, each R 4 Independently selected from hydrogen and methyl; R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen; Preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups; R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 6 Selected from hydrogen and deuterium; Preferably, the A0 ring is selected from... R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl is independently and optionally replaced by 1-3 groups selected from hydroxyl, C3-C8 cycloalkyl, deuterium, C1-C6 alkyl, and C1-C6 alkyl substituted with hydroxyl; Preferably, R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 groups selected from hydroxyl, cyclopropyl, deuterium, and hydroxymethyl; R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl; More preferably, R 3a1 R 3a2 It is methyl; More preferably, R 3a Selected from R 3b Selected from C1-C6 alkyl and C3-C8 cycloalkyl groups; Preferably, R 3b Selected from methyl and cyclopropyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is methyl; Or, R 0 With R 1d Connected to form Where A0 ring is selected And R 2a It is hydrogen or C1-C6 alkyl (such as methyl) or R 2 for When, the condition is met: R 0 and R 5 They are not both hydrogen.

3. The compound of claim 2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-1-1. in: R 0 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 0 It is hydrogen; R 1a Selected from halogen, cyano, and nitro groups; Preferably, R 1a Selected from halogens; More preferably, R 1a For F; R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1c It is hydrogen; R 1d Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1d It is hydrogen; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene and C3-C8 cycloalkylene; Preferably, L 1a Selected from ethylene, Preferably, L 1 Selected from R 2 Selected from L 2a Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2a Selected from direct bond, methylene; L 2b Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2b Selected from direct bonds and ethylene; L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, -C(O)-C2-C6 alkenylene, C2-C6 alkenylene, -C(O)-C2-C6 alkyneide, C2-C6 alkyneide; Preferably, L 2c Selected from -O-, -C(O)-, -C(O)-C1-C6 alkylene, C2-C6 alkenylene, and C2-C6 ynylene; More preferably, L 2c Selected from -O-, -C(O)-, -C(O)-methylene, -C(O)-ethylidene, R 2a Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl is optionally replaced by 1-3 (preferably 1) groups selected from 5-6-membered heteroaryl, phenyl, naphthyl, or 5-6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; Preferably, R 2a The group is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from 6-membered heteroaryl, phenyl, naphthyl, or 6-membered nitrogen-containing saturated heterocyclic groups optionally substituted with C1-C6 alkyl. The groups are replaced; More preferably, R 2a Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C8 cycloalkyl, wherein the C1-C6 alkyl group is optionally replaced by 1-3 (preferably 1) groups selected from pyridyl, phenyl, naphthyl, piperazine group optionally substituted by a C1-C6 alkyl group. The groups are replaced; More preferably, R 2a Selected from methyl, ethyl, Cyclopropyl, wherein the methyl and ethyl groups are each optionally surrounded by 1 to 3 (preferably 1) groups selected from pyridyl groups (e.g., ...). ), phenyl, naphthyl, piperazine group optionally substituted with methyl (e.g. ), The groups are replaced; Most preferably, R 2a Selected from methyl, Cyclopropyl R 2b Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2b Selected from hydrogen and methyl; R 2c Selected from C1-C6 alkyl groups n1 is selected from 1, 2, 3, 4, 5, 6, and is preferably 2; Preferably, R 2c Selected from methyl, R 2d Selected from -NHR 2e 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2d Selected from -NHR 2e 6-membered nitrogen-containing saturated heterocyclic group; More preferably, R 2d Selected from -NHR 2e Piperidinyl (e.g.) ); R 2e Selected from hydrogen, C1-C6 alkyl, and 5-6 member nitrogen-containing saturated heterocyclic groups; Preferably, R 2e Selected from hydrogen, methyl, and 6-membered nitrogen-containing saturated heterocyclic groups; More preferably, R 2e Selected from hydrogen, methyl, piperidinyl (e.g.) ); Most preferably, R 2 Selected from R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl is independently and optionally replaced by 1-3 groups selected from hydroxyl, C3-C8 cycloalkyl, deuterium, or hydroxyl-substituted C1-C6 alkyl groups; Preferably, R 3a Selected from C1-C6 alkyl, -C(O)-C1-C6 alkyl, -OC(O)-NR 3a1 R 3a2 -C(O)-C3-C8 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 groups selected from hydroxyl, cyclopropyl, deuterium, and hydroxymethyl; R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl; More preferably, R 3a1 R 3a2 It is methyl; More preferably, R 3a Selected from R 3b Selected from C1-C6 alkyl groups; Preferably, R 3b It is methyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is methyl; Where R 2a C1-C6 alkyl (such as methyl) or R 2 for At that time, R 0 With R 1d Connected to form 4. The compound of claim 3, or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters. in: R 0 It is hydrogen; R 1a For F; R 1b For F; R 1c It is hydrogen; R 1d It is hydrogen; L 1 for R 2 for L 2a It is methylene; R 2a Selected from deuterated C1-C6 alkyl groups; Preferably, R 2a for R 3a for R 3b It is methyl; R 3c It is a methyl group.

5. The compound of claim 2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-1-2. in: R 1a Selected from halogen, cyano, and nitro groups; Preferably, R 1a Selected from halogens and nitro groups; More preferably, R 1a Selected from F and nitro; R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1c It is hydrogen; R 1d Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1d It is hydrogen; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene groups, wherein the C1-C6 alkylene groups are optionally substituted with 1-3 (preferably 1-2) deuterium atoms; Preferably, L 1a Selected from ethylene, Preferably, L 1 Selected from Ring A is selected from Each R 2 Selected independently L 2a Selected from C1-C6 alkylene and C2-C6 ynylene groups; Preferably, L 2a Selected from methylene, ethylene, R 2a Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2a Selected from hydrogen and methyl; Preferably, each R 2 Selected independently Each R 4 Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, cyano, and halogen; Preferably, each R 4 Independently selected from hydrogen, deuterium, and methyl; More preferably, each R 4 Independently selected from hydrogen and methyl; R 0 Selected from hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, and hydroxyl; Preferably, R 0 Selected from hydrogen, deuterium, cyclopropyl, and hydroxyl; R 5 Selected from hydrogen, deuterium, C1-C6 alkyl, cyano, and halogen; Preferably, R 5 Selected from hydrogen, deuterium, fluorine, and cyano groups; R 6 Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 6 Selected from hydrogen and deuterium; Among them, R 0 and R 5 They are not both hydrogen; Preferably, ring A is selected from R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups; Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups; More preferably, R 3a for R 3b Selected from C1-C6 alkyl and C3-C8 cycloalkyl groups; Preferably, R 3b Selected from methyl and cyclopropyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is a methyl group.

6. The compound of claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-2. in: B0 ring is selected from Among them, position 1 and Connected, position 2 and L 1 Connected; R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; More preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, -C(O)-NR 1a5 R 1a6 ; R 1a1 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a1 It is methyl; R 1a2 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a2 It is methyl; R 1a3 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a3 It is methyl; R 1a4 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a4 It is methyl; R 1a5 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a5 It is hydrogen; R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl; Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups; More preferably, R 1a6 It is cyclopropyl; Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl, R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 1c Selected from hydrogen and deuterium; R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 1d Selected from hydrogen and deuterium; Each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; Preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl; R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; Preferably, R 1f R 1g It is fluorine; B0 ring is selected from Among them, position 1 and Connected, position 2 and L 1 Connected; L 1 Selected from -XL 1a - C1-C6 alkylene groups; preferably, X is connected to the B0 ring, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene groups and C2-C6 ynylene groups, wherein the C1-C6 alkylene groups are optionally substituted by 1-3 (preferably 1) C3-C8 cycloalkyl groups; Preferably, L 1a Selected from ethylene, The ethylene is optionally replaced by 1-3 (preferably 1) cyclopropyl groups; More preferably, L 1a Selected from ethylene, Preferably, L 1 Selected from Methylene R 2 Selected from L 2a Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2a Selected from direct bond, methylene; L 2b Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2b Selected from direct bond, methylene; More preferably, L 2b For direct keys; R 2a Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl; Preferably, R 2a Selected from hydrogen, methyl, and cyclopropyl; R 2b Selected from C1-C6 alkyl groups; Preferably, R 2b It is methyl; R 2c Selected from C1-C6 alkyl groups; Preferably, R 2c It is methyl; Most preferably, R 2 Selected from R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 The group is replaced by a C1-C6 alkyl group or a C3-C8 cycloalkyl group optionally replaced by a C1-C6 alkyl group; Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 Cyclopropyl groups optionally substituted with methyl groups (e.g.) The group replaced by ) R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl; More preferably, R 3a1 R 3a2 It is methyl; More preferably, R 3a Selected from R 3b Selected from C1-C6 alkyl groups; Preferably, R 3b It is methyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is methyl; Wherein, when ring B0 is selected And R 1a When R is selected from halogens or is F, 1c and R 1d They are not both hydrogen.

7. The compound of claim 6, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-2-1. in: R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-6 membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; Preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, optional C3-C8 cycloalkyl groups substituted with cyano groups, nitro groups, 5-membered heteroaryl, carboxyl, -C(O)-NR 1a5 R 1a6 ; More preferably, R 1a Selected from halogens, cyano groups, -SO3H, -N3, and optional C3-C8 cycloalkyl groups substituted with cyano groups (such as cyclopropyl or...). ), nitro, Thiazole group, carboxyl group, C(O)-NR 1a5 R 1a6 ; R 1a1 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a1 It is methyl; R 1a2 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a2 It is methyl; R 1a3 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a3 It is methyl; R 1a4 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a4 It is methyl; R 1a5 Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1a5 It is hydrogen; R 1a6 Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl; Preferably, R 1a6 Selected from C3-C8 cycloalkyl groups; More preferably, R 1a6 It is cyclopropyl; Most preferably, R 1a Selected from F, cyano, -SO3H, -N3, cyclopropyl, nitro, carboxyl, R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 1c Selected from hydrogen and deuterium; R 1d Selected from hydrogen, deuterium, and C1-C6 alkyl groups; Preferably, R 1d Selected from hydrogen and deuterium; Among them, R 1a When R is selected from halogens or is F, 1c and R 1d They are not both hydrogen; Preferably, As a whole, selected from Among them, position 1 and Connected, position 2 and L 1 Connected; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene groups; Preferably, L 1a It is ethylene; Preferably, L 1 for R 2a Selected from C1-C6 alkyl groups; Preferably, R 2a It is methyl; R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups; Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups; More preferably, R 3a for R 3b Selected from C1-C6 alkyl groups; Preferably, R 3b It is methyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is a methyl group.

8. The compound of claim 6, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formula shown in Formula I-2-2. in: Ring B is selected from Among them, position 1 and Connected, position 2 and L 1 Connected; Each R 1e Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; Preferably, each R 1e Independently selected from hydrogen, fluorine, chlorine, and methyl; R 1f R 1g Independently selected from hydrogen, halogens, and C1-C6 alkyl groups; Preferably, R 1f R 1g It is fluorine; Preferably, ring B is selected from Among them, position 1 and Connected, position 2 and L 1 Connected; L 1 Selected from -XL 1a - C1-C6 alkylene groups; preferably, X is connected to ring B, L 1a Linked to the pyrazole ring; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene groups and C2-C6 ynylene groups, wherein the C1-C6 alkylene groups are optionally substituted by 1-3 (preferably 1) C3-C8 cycloalkyl groups; Preferably, L 1a Selected from ethylene, The ethylene is optionally replaced by 1-3 (preferably 1) cyclopropyl groups; More preferably, L 1a Selected from ethylene, Preferably, L 1 Selected from Methylene R 2 Selected from L 2a Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2a Selected from direct bond, methylene; L 2b Selected from direct bonds and C1-C6 alkylene groups; Preferably, L 2b Selected from direct bond, methylene; More preferably, L 2b For direct keys; R 2a Selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl; Preferably, R 2a Selected from hydrogen, methyl, and cyclopropyl; R 2b Selected from C1-C6 alkyl groups; Preferably, R 2b It is methyl; R 2c Selected from C1-C6 alkyl groups; Preferably, R 2c It is methyl; Most preferably, R 2 Selected from R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 The group may be replaced by a C3-C8 cycloalkyl group that is optionally replaced by a C1-C6 alkyl group; Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally surrounded by 1-3 (preferably 1-2) hydroxyl groups, -NR groups. 3a1 R 3a2 Cyclopropyl groups optionally substituted with methyl groups (e.g.) The group replaced by ) R 3a1 R 3a2 Each is independently selected from hydrogen and C1-C6 alkyl groups; Preferably, R 3a1 R 3a2 Each is independently selected from hydrogen and methyl; More preferably, R 3a1 R 3a2 It is methyl; More preferably, R 3a Selected from R 3b Selected from C1-C6 alkyl groups; Preferably, R 3b It is methyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is a methyl group.

9. The compound of claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formulas shown in Formulas I-3. in: R 1a Selected from halogen, cyano, and nitro groups; Preferably, R 1a Selected from halogens; More preferably, R 1a For F; R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1c It is hydrogen; R 1d Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1d It is hydrogen; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Linked to the pyrazole ring; X is selected from O, S, NH, and -C(O)-; Preferably, X is selected from O, NH, and -C(O)-; L 1a The group is selected from C1-C6 alkylene, -C(O)-C1-C6 alkylene, -NH-S(O)2-, C2-C6 ynylene, C3-C8 cycloalkylene-C1-C6 alkylene, C3-C8 cycloalkylene, C2-C6 alkenylene, and C1-C6 alkylene-C(O)-, wherein each of the C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynylene, and C3-C8 cycloalkyl groups is independently and optionally replaced by 1-3 (preferably 1) groups selected from C3-C8 cycloalkyl, deuterium, and C1-C6 alkyl groups; preferably, L 1a The site on the left is connected to X, and the site on the right is connected to the pyrazole ring; Preferably, L 1a The group is selected from C1-C6 alkylene, -C(O)-C1-C6 alkylene, -NH-S(O)2-, C2-C6 ynynylene, C3-C8 cycloalkylene-C1-C6 alkylene, C3-C8 cycloalkylene, C2-C6 alkenylene, and C1-C6 alkylene-C(O)-, wherein each of the C1-C6 alkylene and C2-C6 ynynylene groups is optionally and independently replaced by 1-3 (preferably 1) groups selected from cyclopropyl and deuterium; preferably, L 1a The site on the left is connected to X, and the site on the right is connected to the pyrazole ring; More preferably, L 1a Selected from Preferably, L 1a The upper site is connected to X, and the lower site is connected to the pyrazole ring; Preferably, L 1 Selected from Preferably, L 1 The upper site is connected to the benzene ring, and the lower site is connected to the pyrazole ring; R 2a Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2a Selected from hydrogen and methyl; R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by 1-3 (preferably 1) groups selected from hydroxyl and C1-C6 alkyl groups; Preferably, R 3a Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups; More preferably, R 3a for R 3b Selected from C1-C6 alkyl groups; Preferably, R 3b Selected from methyl; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is methyl; Among them, L 1a C1-C6 alkylene or L 1 for At that time, R 1a and R 3c Connected to form 10. The compound of claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein the compound has the structural formulas shown in Formulas I-4. in: R 1a Selected from halogen, cyano, and nitro groups; Preferably, R 1a Selected from halogens; More preferably, R 1a For F; R 1b Selected from halogen, cyano, and nitro groups; Preferably, R 1b Selected from halogens; More preferably, R 1b For F; R 1c Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1c It is hydrogen; R 1d Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 1d It is hydrogen; L 1 -XL 1a - Preferably, X is connected to a benzene ring, L 1a Connected to ring C; X is selected from O and S; Preferably, X is 0; L 1a Selected from C1-C6 alkylene groups, direct bonds; Preferably, L 1a Selected from methylene, ethylene, and direct bonds; Preferably, L 1 Selected from -O- R 2a Selected from hydrogen and C1-C6 alkyl groups; Preferably, R 2a Selected from hydrogen and methyl; C ring is selected from R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-6 member nitrogen-containing saturated heterocyclic group, -C(O)-4-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-6 member nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-6 member heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-6 nitrogen-containing saturated heterocyclic group, 5-6 nitrogen-containing saturated heterocyclic group, phenyl, and 5-6 heteroaryl group are each independently and optionally replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (such as methyl), deuterium, nitro, halogen (such as fluorine), and phenyl; Preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, 4-membered nitrogen-containing saturated heterocyclic group, -C(O)-4-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-5-membered nitrogen-containing saturated heterocyclic group, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-5-membered heteroaryl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, 4-membered nitrogen-containing saturated heterocyclic group, 5-membered nitrogen-containing saturated heterocyclic group, phenyl, and 5-membered heteroaryl group are each independently and optionally replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (such as methyl), deuterium, nitro, halogen (such as fluorine), and phenyl; More preferably, R 3a Selected from C1-C6 alkyl, C1-C6 alkylene-C3-C8 cycloalkyl, -C(O)-C1-C6 alkyl, -C(O)-C3-C8 cycloalkylene-C1-C6 alkyl, C3-C8 cycloalkyl, -C(O)-C3-C8 cycloalkyl, -C(O)-NH-S(O)2-C3-C8 cycloalkyl, aziridine, -C(O)-aziridine, C1-C6 alkylene-tetrahydropyrrolyl, C1-C6 alkylene-phenyl, -C(O)-NH-S(O)2-phenyl, C1-C6 alkylene-oxazolyl, C1-C6 alkylene-CN, C1-C6 alkylene-COOH, C1-C6 alkylene-SH, C1-C6 alkylene-N3, -NR 3a1 R 3a2 C1-C6 alkylene-NR 3a1 R 3a2 -OC(O)-NR 3a1 R 3a2 -C(O)-C1-C6 alkylene-NR 3a1 R 3a2 , -SO3H, wherein the C1-C6 alkyl, C1-C6 alkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, aziridine, tetrahydropyrrolyl, phenyl, and oxazolyl groups are each optionally and independently replaced by 1-3 groups selected from hydroxyl, C1-C6 alkyl (e.g., methyl), deuterium, nitro, halogen (e.g., fluorine), and phenyl groups; R 3a1 R 3a2 Each is independently selected from hydrogen, C1-C6 alkyl, and deuterated C1-C6 alkyl, wherein the C1-C6 alkyl and deuterated C1-C6 alkyl are each optionally substituted by 1 to 3 (e.g., 1) hydroxyl groups; Preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, C1-C6 alkyl, or deuterated C1-C6 alkyl, and the other is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, or hydroxyl-substituted deuterated C1-C6 alkyl. More preferably, R 3a1 R 3a2 In this context, one of the components is selected from hydrogen, methyl, or -CD3, and the other is selected from methyl, -CD3, ... R 3a3 Selected from C1-C6 alkyl groups; Preferably, R 3a3 For tert-butyl; Most preferably, R 3a Selected from R 3b Selected from C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; Preferably, R 3b Selected from methyl, cyclopropyl, vinyl, and ethynyl groups; R 3c Selected from C1-C6 alkyl groups; Preferably, R 3c It is methyl; R 3d Selected from C1-C6 alkyl groups; Preferably, R 3d It is methyl; R 3e Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with 1-3 (preferably 1) hydroxyl groups; Preferably, R 3e for Preferably, ring C is selected from Where R 3a C1-C6 alkyl groups substituted with one hydroxyl group or... At that time, R 3b Not selected from C1-C6 alkyl groups (such as R 3b (Not methyl).

11. The compound according to any one of claims 1-10, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound, wherein, The compound is selected from the following:

12. A linker-drug conjugate, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of said linker-drug conjugate, comprising: A pharmaceutical group, wherein the pharmaceutical group is a group formed by the loss of a hydrogen atom from a compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester according to any one of claims 1-11; and A linker, wherein the linker is directly connected to the drug group.

13. The linker-drug conjugate of claim 12, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, wherein the drug group is a group formed by losing a hydrogen atom from the compound of any one of claims 4, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the compound.

14. The linker-drug conjugate of claim 13, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, wherein the drug group has a structure shown in Formula II-1 or Formula II-2. in: R 2a Selected from deuterated C1-C6 alkyl groups; Preferably, R 2a for In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

15. The linker-drug conjugate of claim 12, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, wherein the linker is in: M stands for connector; L A Whether L exists or not, when L A When present, it is a spacing unit and / or a branch spacing unit; L B Whether L exists or not, when L B When present, it is a single amino acid or its analogue or derivative, or a peptide fragment formed by two or more amino acids or their analogues or derivatives; L C Whether L exists or not, when L C When present, it is a self-eliminating unit.

16. The linker-drug conjugate according to claim 15, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, characterized in that, The M mentioned is selected from: a and b are each independently selected from integers from 0 to 6; In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

17. The linker-drug conjugate according to claim 15, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, characterized in that, When the L A When it exists, select from in, X LA Selected from direct bonds, O, or NH; R LA1 Selected from direct key or R LA3 Selected from direct keys, R LA4 Selected from COOH, C1-C6 alkoxy or NR LA4-1 R LA4-2 ; R LA4-1 R LA4-2 Each is independently selected from H, optionally substituted C1-C6 alkyl groups, or -C(O)-R. LA4-3 ; R LA4-3 Selected from optionally substituted C1-C6 alkyl groups; R LA2 Selected from direct bond, -C1-C6 alkylene-5-10 heteroaryl- or -C1-C6 alkylene-5-10 heterocyclic-; preferably direct bond or -C1-C3 alkylene-5-6 heteroaryl-; r is an integer selected from 0 to 10; w is selected from integers from 0 to 10; y is selected from 0, 1, 2, 3 or 4; z is selected from integers from 0 to 30; In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

18. The linker-drug conjugate according to claim 15, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, characterized in that, When the L B When present, each of the amino acids is independently selected from (D / L) valine (Val), (D / L) citrulline (Cit), (D / L) glutamic acid (Glu), (D / L) lysine (Lys), (D / L) arginine (Arg), (D / L) phenylalanine (Phe), (D / L) tyrosine (Tyr), (D / L) leucine (Leu), glycine (Gly), (D / L) alanine (Ala), (D / L) asparagine (Asn), (D / L) glutamine (Gln), (D / L) serine (Ser), and (D / L) aspartic acid (Asp). Or its analogues or derivatives.

19. The linker-drug conjugate according to claim 15, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, characterized in that, When the L C When it exists, select from Or any combination of the above structures; R LC Each is independently selected from H, nitro, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, NR LC1 R LC2 Or, natural or non-natural monosaccharides, disaccharides, polysaccharides or their derivatives, or any combination of the above structures; R LC1 R LC2 Each is independently selected from H, optionally substituted C1-C6 alkyl groups, or -C(O)-R. LC3 ; R LC3 Selected from optionally substituted C1-C6 alkyl groups, R LC Each is independently selected from optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl; Preferably, the natural or non-natural monosaccharide, disaccharide, polysaccharide or its derivatives are selected from glucuronic acid; In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

20. The linker-drug conjugate according to any one of claims 12-19, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester of the linker-drug conjugate, characterized in that, The linker-drug conjugate is selected from the following: In the above structures, the configuration of any chiral carbon is independently either R-type or S-type.

21. An antibody-drug conjugate, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of said antibody-drug conjugate, comprising: Antibody or its antigen-binding fragment; Connector; and The pharmaceutical group is a group formed by the loss of a hydrogen atom from a compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable ester according to any one of claims 1-11. The antibody or its antigen-binding fragment is linked to the drug group via the linker.

22. The antibody-drug conjugate of claim 21, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate, wherein the drug group is as defined in claim 13 or 14.

23. The antibody-drug conjugate of claim 21, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate, wherein the linker is in: M' is the connector unit; L A As defined in claim 15 or 17; L B As defined in claim 15 or 18; L C As defined in claim 15 or 19.

24. The antibody-drug conjugate of claim 23, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate, characterized in that, The M' is selected from: in: Q is selected from: Direct key G is selected from the following structure: X1 can be independently -O-, -S-, -NH-, or -CH2-; X2 can be independently -O-, -S-, -NH-, -C(O)-, or -CH2-; a and b are each independently selected from integers between 0 and 6; c are each independently selected from integers between 0 and 24; d are each independently selected from integers between 0 and 10; In the above structures, the configuration of any chiral carbon is independently either R-type or S-type; When the M' structure includes maleimide, the maleimide can optionally be hydrolyzed to open the ring, that is, each maleimide can be independently in an open-ring or closed-ring form, specifically, each can be independently in an open-ring or closed-ring form.

25. The antibody-drug conjugate according to any one of claims 21-24, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate, characterized in that, The antibody-drug conjugate is selected from the following: c can be independently selected from 1, 2, 3, 4, 5, 6, 7, or 8; q is selected from integers or decimals from 1 to 10; In the above structures, the configuration of any chiral carbon can be either R-type or S-type independently; When the antibody-drug conjugate structure includes maleimide, the maleimide can optionally be hydrolyzed to open the ring, i.e., each maleimide can be independently in an open-ring or closed-ring form. Specifically, each can be independently...

26. The antibody-drug conjugate of claim 25, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate, characterized in that, The Ab is selected from: Anti-EGFRvIII antibody, anti-PD 1 antibody, anti-PD L1 antibody, anti-DLL3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDGF1 antibody, anti-ETBR antibody, anti-MSLN antibody, anti-TIM 1 antibody, anti-LRRC15 antibody, anti-LIV 1 antibody, anti-CanAg / AFP antibody, anti-Claudin 18.2 antibody, anti-Mesothelin antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-cMET antibody, anti-SLITRK6 antibody, anti-KIT / CD117 antibody, anti-STEAP1 antibody, anti-SLAMF7 / CS1 antibody, anti-NaPi2B / SLC34A2 antibody, anti-GPNMB antibody, anti-HER3 (ErbB3) antibody, anti-MUC1 / CD227 antibody, anti-AXL antibody, anti-CD166 antibody, anti-B7 H3(CD276) antibody, anti-PTK7 / CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-NOTCH3 antibody, anti-Nectin 4 antibody, anti-Trop2 antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-LYPD3 antibody, anti-FGFR2 antibody, anti-FGFR3 antibody, anti-FRα antibody, anti-CEACAMs antibody, anti-GCC antibody, anti-Integrin Av antibody, anti-CAIX antibody, anti-P cadherin antibody, anti-GD3 antibody, anti-Cadherin 6. Antibodies, including anti-LAMP1 antibody, anti-FLT3 antibody, anti-BCMA antibody, anti-CD79b antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD74 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD37 antibody, anti-CD47 antibody, anti-CD138 antibody, anti-CD352 antibody, anti-CD25 antibody, anti-CD123 antibody, anti-GPC3 antibody, anti-ROR1 antibody, anti-uPAR antibody, anti-NKG2D antibody, anti-CD94 antibody, anti-CD228 antibody, anti-HLA-G antibody, anti-VEGFR2 antibody, anti-VEGF antibody, anti-PD-1×CTLA-4 bispecific antibody, anti-EGFR×HER3 bispecific antibody, or any combination of antibodies targeting the above targets.

27. A pharmaceutical composition comprising: (1) The compound of any one of claims 1-11 or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters, or the linker-drug conjugate of any one of claims 12-20 or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters, or the antibody-drug conjugate of any one of claims 21-26 or its pharmaceutically acceptable salts or pharmaceutically acceptable solvates; (2) Pharmaceutically acceptable carriers and / or excipients; And optionally (3) one or more other active ingredients.

28. The use of the compound of any one of claims 1-11 or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters, or the linker-drug conjugate of any one of claims 12-20 or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters, or the antibody-drug conjugate of any one of claims 21-26 or its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, or the use of the pharmaceutical composition of claim 27 in the preparation of a medicament for treating and / or preventing diseases related to NMT; Preferably, the diseases associated with NMT are selected from diseases or conditions such as cancer, viral infections, neurological diseases, local ischemia, osteoporosis, diabetes, autoimmune diseases, inflammatory diseases, microbial infections (e.g., fungal infections) and protozoan infections. Preferably, the cancer is a hematologic malignancy or a solid tumor; Preferably, the hematologic malignancy is lymphoma, myeloma (e.g., multiple myeloma) or leukemia (e.g., chronic lymphocytic leukemia, AML, or acute B-lymphocytic leukemia); Preferably, the lymphoma is a B-cell lymphoma (e.g., high-grade mantle lymphoma, follicular lymphoma, plasmablastic lymphoma, diffuse large B-cell lymphoma, or Burkitt lymphoma). Preferably, the solid tumor is brain cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, colorectal cancer, gallbladder cancer, kidney cancer or liver cancer, or blastoma (e.g., neuroblastoma, retinoblastoma or glioma). Preferably, the viral infection is an enterovirus infection, a retrovirus infection, or a poxvirus infection; Preferably, the enterovirus infection is a microRNA virus (such as rhinovirus), poliovirus, foot-and-mouth disease virus, Coxsackievirus, hepatitis A virus, or enterovirus 71 infection. Preferably, the retroviral infection is a lentiviral infection (such as HIV infection); Preferably, the poxvirus infection is an orthopoxvirus, parapoxvirus, attapoxvirus, or molluscum poxvirus infection; Preferably, the vaccinia virus infection is smallpox virus infection, vaccinia virus infection, cowpox virus infection, or monkeypox virus infection; Preferably, the protozoan infection is a protozoan infection caused by species of the genera Plasmodium, Leishmania, or Trypanosoma (e.g., Plasmodium falciparum, Plasmodium vivax, Leishmania donovani, Leishmania macrophylla, Trypanosoma brucei, Trypanosoma krusei).

29. The use of the compound of any one of claims 1-11, or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters, or the linker-drug conjugate of any one of claims 12-20, or its stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable esters, in the preparation of antibody-drug conjugates; Preferably, the antibody-drug conjugate is selected from the antibody-drug conjugate of any one of claims 21-26 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the antibody-drug conjugate.

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