Camptothecin-based drug conjugate, and preparation method therefor and use thereof

Abstract

The present invention relates to a camptothecin-based drug conjugate, and a preparation method therefor and the use thereof. Specifically, the present invention relates to a compound as represented by formula I', a preparation method therefor, a pharmaceutical composition containing same, and the use thereof in the treatment and / or prevention of cancer.

Description

Camptothecin-based conjugates, their preparation methods and uses

[0001] Priority requirements

[0002] This application claims priority to Chinese Patent Application No. 202510353746.9, filed March 24, 2025, and Chinese Patent Application No. 202510576793.X, filed May 6, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0003] This invention belongs to the pharmaceutical field and relates to a camptothecin-based conjugate drug, its preparation method, and its uses. Background Technology

[0004] Chemotherapy is a primary treatment for many cancers, inhibiting or killing rapidly proliferating cancer cells with drugs. However, it also presents several problems and side effects. Traditional cytotoxic chemotherapy drugs often affect normal cells, leading to a range of side effects such as nausea, vomiting, fatigue, hair loss, digestive problems, and impaired immune system function. These side effects can impact a patient's quality of life and treatment adherence. Some tumor cells may develop resistance to chemotherapy, leading to reduced or ineffective treatment. This may necessitate changing or adjusting the drug combination, or employing alternative treatment methods. The impact of chemotherapy drugs on normal cells is a significant concern during treatment. To mitigate this impact, the medical community has adopted several strategies and technologies to improve the safety and efficacy of chemotherapy, including prodrugs and combinations with peptides or antibodies targeting specific receptors or antigens. One such strategy is enzyme-activated prodrugs, which involve designing drugs in an inactive form that is only activated under specific conditions. This can be achieved through the action of enzymes in the body, which are typically highly expressed in tumor tissue. This approach reduces the impact of drugs on normal cells because the drugs are only activated near cancer cells.

[0005] Camptothecin and its analogues are cytotoxic quinoline alkaloids that inhibit DNA topoisomerase (Topo I); paclitaxel (PTX) and its analogues are cytotoxic diterpenoid alkaloids that act on cellular tubulin. Globally marketed small molecule drugs containing camptothecin include irinotecan, topotecan, belotecone, camptothecin, and hydroxycamptothecin; globally marketed small molecule drugs containing taxanes include paclitaxel, docetaxel, and cabazitaxel. Currently, there are few reports on small molecule compounds conjugated with camptothecin or taxane fragments.

[0006] US patent 6593334B1 discloses a small molecule compound in which camptothecin and a taxane fragment are coupled via a linker containing an imine structure. US patent application 20140113875A1 discloses a biphasic amphiphilic compound containing a paclitaxel fragment and a camptothecin fragment, specifically by coupling the paclitaxel and camptothecin fragments to Sup35 via a linker comprising an arginine residue, a cysteine ​​residue, and a disulfide bond. Patent application CN105457038A discloses a conjugate containing a camptothecin fragment and a taxane fragment, wherein the linker comprises a phosphatidylcholine fragment. Patent CN106317067B also discloses a conjugate containing a camptothecin fragment and a taxane fragment, wherein the linker is a diacid fragment (such as succinic acid), and the linking site is a hydroxyl group at the 2' position of the paclitaxel fragment side chain and a hydroxyl group at the 10th position of the camptothecin fragment. The coupling compound containing camptothecin and taxane fragments disclosed in patent application CN117143049A is characterized by the connection between the camptothecin fragment and the benzamide structure of the C13 side chain of paclitaxel via a linker containing an aromatic structure, with the adjacent carbon atom on the benzene ring.

[0007] To date, achieving good efficacy and / or reducing side effects and / or enhancing enzyme selectivity and / or controlling tissue distribution and / or ensuring good pharmacokinetics and / or enzyme kinetics and / or prodrug activity and / or tolerable dose and / or cell penetration and / or efficacy against specific tumor cells and / or highly active prodrugs and / or stability in in vivo circulation and / or targeting and / or good stability in plasma and serum remain areas lacking clear guidance. Therefore, comprehensive research and development are urgently needed to create novel cytotoxic prodrugs. Summary of the Invention

[0008] One aspect of the present invention provides a compound of formula I' or a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] A is a drug payload, preferably a cytotoxic agent; more preferably, the cytotoxic agent is CPT, wherein CPT is camptothecin or camptothecin derivatives.

[0011] The B mentioned is taxane;

[0012] L is a linker, with its a-end covalently linked to a drug toxin and its b-end covalently linked to taxane. The linker enables the compound to release a drug payload in vivo.

[0013] In some embodiments, A, B, and L each independently have one or more functional groups, which are each independently a primary amine, a secondary amine, a hydroxyl group, a mercapto group, a carboxyl group, a phosphate group (-OP(=O)(OH)2), a phosphite group (-P(=O)(OH)2), a sulfonic acid group (-S(=O)2OH), a sulfinic acid group (-S(=O)OH), an aldehyde, or a ketone.

[0014] In some implementations, the covalent bond formed between the a-end of L and A is:

[0015] Wherein, the R 501 R 502 Each independently as described below in this application R 1 Defined.

[0016] In some implementations, the R 501 R 502 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Halogenated alkyl groups.

[0017] In some implementations, the covalent bond formed between the b end of L and B is as follows:

[0018] Wherein, the R 501 R 502 Each independently as described below in this invention R 1 Defined.

[0019] In some embodiments, the camptothecin derivatives include, but are not limited to, irinotecan, belootecan, topotecan, hydroxycamptothecin, gimarotecan, diantecan, SN38, cinotecan, ZD-06519, 9-Aminocamptothecin, AR-67, costacarb, CZ-112, DU-6596, letopecan, rubetcon, simminotecan, CH-0793076, DRF-1042, exatecan, GI-149893, Namitecan, and their derivatives; the structures of other exemplary camptothecin derivatives are described in US4604463A, US5004758A, CN1096297A, US5541327A, and US5734056A. , US5670500A, US5663177A, US5633260A, US5674874A, US5856333A, US5801167A, US6177439B1, U S5916897A, US5998426A, US5843954A, US6046209A, US6156897A, US6291676B1, US6306868B1, US6 The following are cited in their entirety: 403604B1, CN1176923C, CN100363366C, USRE39707E1, US20120136153A1, US9682992B2, US9266911B2, US9447126B2, CN105884789A, CN111018897A, CN110698491B, and US6407115B1.

[0020] In some embodiments, the camptothecin derivatives include irinotecan and its derivatives, belotetan and its derivatives, topotecan and its derivatives, hydroxycamptothecin and its derivatives, gemmatocan and its derivatives, dianticocan and its derivatives, SN38 and its derivatives, cinotecan and its derivatives, ZD-06519 and its derivatives, 9-Aminocamptothecin and its derivatives, AR-67 and its derivatives, cosotecan and its derivatives, CZ-112 and its derivatives, DU-6596 and its derivatives, letopotecan and its derivatives, rubeticocan and its derivatives, simenoticocan and its derivatives, CH-0793076 and its derivatives, DRF-1042 and its derivatives, ixotecan and its derivatives, GI-149893, and Namitecan and its derivatives.

[0021] In some embodiments, the taxanes include, but are not limited to, paclitaxel, docetaxel, cabazitaxel, ARC-100, ortataxel, larotaxel, BMS-184476, BMS-275183, Milataxel, Simotaxel, SK-608-20.1, testathine, BMS-188797, felotaxel, TL-310, and their derivatives; other exemplary taxane structures are described in EP0253739B1, US5248796A, EP0630428B1, US5637723A, EP0664800A1, and CA2161328. A1, EP0767786B1, US5767282A, US5824701A, US5808113A, US5767297A, US5861515A, WO1998014187A1, US5869680A, CN1590386A, EP0882732A1, CN1067682C, CN1110565C, EP0696596A1, CN1151740A, CN100339373C, CN100369908C, CN101463029B, CN101648928B, CN101648973B, CN103025739A, CN106632296A, are incorporated herein by reference in their entirety.

[0022] In some embodiments, the taxane includes paclitaxel and its derivatives, docetaxel and its derivatives, cabazitaxel and its derivatives, ARC-100 and its derivatives, ortataxel and its derivatives, larotaxel and its derivatives, BMS-184476 and its derivatives, BMS-275183 and its derivatives, Milataxel and its derivatives, Simotaxel and its derivatives, SK-608-20.1 and its derivatives, testataxel and its derivatives, BMS-188797 and its derivatives, felotaxel and its derivatives, TL-310 and its derivatives.

[0023] In some embodiments, the a-terminus of the L is covalently linked to the hydroxyl group at position 20 of the CPT.

[0024] In some embodiments, the b-terminus of L is covalently linked to a hydroxyl group at the 2', 7', or 10' position of taxane.

[0025] In some embodiments, the a-terminus of L is covalently linked to the 20-position hydroxyl group of CPT; the a-terminus of L is covalently linked to the 2'-position hydroxyl group, the 7-position hydroxyl group, or the 10-position hydroxyl group of taxane. In some embodiments, the a-terminus of L is covalently linked to the 20-position hydroxyl group of CPT; the a-terminus of L is covalently linked to the 2'-position hydroxyl group of taxane.

[0026] In some embodiments, the linker enables the compound to release drug payload A in vivo.

[0027] In some implementations, the linker enables the compound to release CPT in vivo.

[0028] In some embodiments, the linker enables the compound to release taxane (B) in vivo.

[0029] In some implementations, A is...

[0030] Among them, R 1 R 2 R 3 R 4 R 5a R 5b Each is independent as defined in this invention.

[0031] In some implementations, B is...

[0032] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this invention.

[0033] In some implementations, A is represented by the following formula:

[0034] Among them, R 1 R 2 R 3 R 4 R 5a R 5b Each is independent as defined in this application;

[0035] R 01 As stated in this application R 1 Defined.

[0036] In some implementation schemes, R 01 It is H. That is, R. 01O- represents a hydroxyl group, and the covalent bond formed between the a-terminus of L and the hydroxyl group can be...

[0037] In some implementations, B is represented by the following formula:

[0038] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0039] R 02 As stated in this application R 1 Defined.

[0040] In some implementation schemes, R 02 It is H. That is, R. 02 O- represents a hydroxyl group, and the covalent bond formed between the b-terminus of L and the hydroxyl group can be...

[0041] In some implementation schemes,

[0042] for

[0043] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0044] R 02 As stated in this application R 1 Defined.

[0045] In some implementation schemes,

[0046] for

[0047] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0048] R 02 As stated in this application R 1 Defined.

[0049] In some implementation schemes,

[0050] for

[0051] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0052] R 02 As stated in this application R 1 Defined.

[0053] In some implementation schemes,

[0054] for

[0055] Among them, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0056] R 02 As stated in this application R 1 Defined.

[0057] Another aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0058] in,

[0059] L stands for connector;

[0060] R 1 Hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R o replace;

[0061] Each R o Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R p replace;

[0062] Each R pIndependently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R q replace;

[0063] Each R q Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R r replace;

[0064] Each R r Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)OH, -S(=O)NH2, -P(=O)(OH)2, -P(=O)NH2(OH), -P(=O)(NH2)2, -PH(=O)OH, -PH(=O)NH2, -PH2(=O), -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups;

[0065] The terms heteroalkyl, heteroalkenyl, heteroynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloynyl, and heteroaromatic groups indicate that the group contains a heteroatom, wherein the heteroatom is independently selected from one, two, three, or four of O, P, S, and N; and the number of heteroatoms is independently one, two, three, or four.

[0066] R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 13 Each independently as above R 1 Defined;

[0067] Or, R 1 and R 2 Together with the atoms it is attached to, it forms a ring structure E1; the ring structure E1 is optionally bounded by one or more R... 26 Replace; each R26 Independently as above R 1 Defined;

[0068] Or, R 2 and R 3 Together with the atoms it is attached to, it forms a ring structure E2; the ring structure E2 is optionally bounded by one or more R atoms. 27 Replace; each R 27 Independently as above R 1 Defined;

[0069] Or, R 3 and R 4 Together with the atoms it is attached to, it forms a ring structure E3; the ring structure E3 is optionally bounded by one or more R atoms. 28 Replace; each R 28 Independently as above R 1 Defined.

[0070] In some implementation schemes, R 1 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a-C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0071] R 2 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0072] R 3 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0073] R 4 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NRa R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0074] Or, R 1 and R 2 Together with the atoms it is attached to, they form C 5-20 Cycloalkyl, 5-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl, wherein C 5-20 Cycloalkyl, 5-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups are each independently and optionally bound by one or more R groups. c replace;

[0075] Or, R2 and R 3 Together with the atoms it is attached to, they form C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl, wherein C 5-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups are each independently and optionally bound by one or more R groups. c replace;

[0076] Or, R 3 and R 4 Together with the atoms it is attached to, they form C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl, wherein C 5-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl or 5-20 heteroaryl groups are each independently and optionally bound by one or more R groups. c replace;

[0077] R 5a and R 5b Each is independently selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0078] R 6 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0079] R 7 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0080] R 8 Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a Rb 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0081] R 11 Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0082] R 12 Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a-C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0083] R 13 Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0084] Each Ra and R b Each is independently selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -NH(C) 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 alkylene-3-20-membered heterocyclic group, wherein C 1-20 Alkyl, C 1-20 Alkylene, C 1-20 Heteroalkyl, C 1-20 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0085] Each R c Independently selected from deuterium, halogen, nitro, cyano, =O, -OH, =O, -SH, -NH2, -NH(C 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 alkylene-3-20-membered heterocyclic group; and

[0086] m can be 0, 1, 2, 3, or 4.

[0087] In some implementation schemes, R 1 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0088] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0089] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0090] In some implementation schemes, R 1 Selected from hydrogen, Ethyl,

[0091] In some implementation schemes, R 2 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0092] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0093] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0094] In some implementation schemes, R 2 Selected from hydrogen, -NH2、

[0095] In some implementation schemes, R 1 and R 2 Together with the atoms it is attached to, they form C 5-7 cycloalkyl or 5-7 membered heterocyclic groups, wherein the C 5-7Each of the cycloalkyl or 5-7 membered heterocyclic groups is independently and optionally surrounded by one or more groups selected from deuterium, halogens, -OH, =O, -NH2, C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The group is replaced by a haloalkoxy group.

[0096] In some implementation schemes, Selected from

[0097] In some implementation schemes, R 3 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0098] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0099] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0100] In some implementation schemes, R 3 Selected from hydrogen, -OH, methyl,

[0101] In some implementation schemes, R 2 and R 3 Together with the atoms it is attached to, they form C 5-7 cycloalkyl or 5-7 membered heterocyclic groups, wherein the C 5-7 Each of the cycloalkyl or 5-7 membered heterocyclic groups is independently and optionally surrounded by one or more groups selected from deuterium, halogens, -OH, =O, -NH2, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The group is replaced by a haloalkoxy group.

[0102] In some implementation schemes, for

[0103] In some implementation schemes, R 3 Selected from hydrogen, methyl, acetyl,

[0104] In some implementation schemes, R 4 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-ORa The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0105] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0106] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0107] In some implementation schemes, R 4 It is either hydrogen or fluorine.

[0108] In some implementation schemes, R 3 and R 4 Together with the atoms it is attached to, they form C 5-7 cycloalkyl or 5-7 membered heterocyclic groups, wherein the C 5-7 Each of the cycloalkyl or 5-7 membered heterocyclic groups is independently and optionally surrounded by one or more groups selected from deuterium, halogens, -OH, =O, -NH2, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The group is replaced by a haloalkoxy group.

[0109] In some implementation schemes, Selected from

[0110] In some implementation schemes, R 5a and R 5b Each is independently selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-ORa and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0111] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0112] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0113] In some implementation schemes, R 5a and R 5b Both are hydrogen.

[0114] In some implementation schemes, R 6 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0115] Each Ra and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0116] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0117] In some implementation schemes, R 6 Selected from phenyl, 2-methylpropyl, tert-butyl, furanyl, thiophene and

[0118] In some implementation schemes, R 7Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -Si(C) 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 1-6 Alkyl, -C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0119] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0120] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0121] In some implementation schemes, R 7 Selected from phenyl, or C 1-6 Alkyl groups are preferably isopropoxy and tert-butoxy.

[0122] In some implementation schemes, R 8 Selected from hydrogen, deuterium, and -C(=O)R a -C(=O)-OR a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0123] R a Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0124] In some implementation schemes, R 8Selected from hydrogen, acetyl, methyl,

[0125] In some implementation schemes, R 11 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 3-7 Cycloalkyl, -C(=O)R a -C(=O)-OR a and C 1-6 Heteroalkyl;

[0126] R a Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0127] In some implementation schemes, R 11 Selected from H, methyl,

[0128] In some implementation schemes, R 12 Selected from hydrogen, deuterium, and -C(=O)R a -C(=O)-OR a C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl groups;

[0129] R a Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0130] In some implementation schemes, R 12 Acetyl or

[0131] In some implementation schemes, R 13 Selected from hydrogen, deuterium, and -C(=O)R a -C(=O)-OR a C 1-6 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl groups;

[0132] R a Selected from hydrogen, deuterium, and C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0133] In some implementation schemes, R 13 It is hydrogen.

[0134] In some implementation schemes, R a Selected from hydrogen, deuterium, halogens, -OH, -NH2, -NH(C) 1-6alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0135] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0136] In some implementation schemes, R b Selected from hydrogen, deuterium, halogens, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0137] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0138] In some implementation schemes, R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C)1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0139] In some implementation schemes, the aforementioned Selected from

[0140] R 121 For H or optionally by one or more R 123 Replacement C 1-6 Alkyl groups;

[0141] R 122 -C(=O)R 124 -S(=O)2R 124 or -S(=O)R 124 ;

[0142] The R 123 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 101 -NHR 101 -NR 101 R 101 -SR 101 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is independently and optionally surrounded by one or more R 102 Substitution; the aryl and heteroaryl groups are each independently and optionally replaced by one or more R 103 replace;

[0143] The R 101 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl;

[0144] The R 102 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 104 -NHR 104 -NR 104 R 104 -SR 104 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-0 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10Aryl, 5-10 heteroaryl;

[0145] The R 103 Each can be independently classified as deuterium, halogen, nitro, cyano, or -OR. 104 -NHR 104 -NR 104 R 104 -SR 104 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl;

[0146] The R 104 Each is independently hydrogen, deuterium, and C. 1-20 Alkyl, 3-20 heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl;

[0147] The R mentioned 124 For -OR 201 -NHR 201 -NR 201 R 201 -SR 201 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is independently and optionally surrounded by one or more R 202 Substitution; the aryl and heteroaryl groups are each independently and optionally replaced by one or more R 203 replace;

[0148] The R 201 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl;

[0149] The R 202 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 204 -NHR 204 -NR 204 R 204 -SR 204 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-0 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10Aryl, 5-10 heteroaryl;

[0150] The R 203 Each can be independently classified as deuterium, halogen, nitro, cyano, or -OR. 204 -NHR 204 -NR 204 R 204 -SR 204 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; the alkyl and cycloalkyl groups are each optionally and independently bound by one or more R groups. 205 Substitution; the aryl group is optionally replaced by one or more R 206 replace;

[0151] The R 204 Each is independently hydrogen, deuterium, and C. 1-20 Alkyl, 3-20 heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl;

[0152] The R 205 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or C. 1-10 Alkyl, C 3-10 cycloalkyl or C 6-10 Aryl;

[0153] The R 206 Each is independently a deuterium, halogen, nitro, cyano, or C group. 1-10 Alkyl, C 3-10 cycloalkyl or C 6-10 Aryl.

[0154] In some implementation schemes, R 121 For H, R 122 -C(=O)R 124 The R mentioned above 124 C can be optionally substituted with halogen, hydroxyl or amino groups. 1-10 Alkoxy groups, C-terminals optionally substituted with halogens, hydroxyl groups, or amino groups 1-10 Alkyl NH-, C- optionally substituted with halogen, hydroxyl or amino groups 1-10 Alkyl C 1-10 Alkyl N-, C- optionally substituted with halogen, hydroxyl or amino groups 1-10 Alkyl groups, 3-10 heteroalkyl groups optionally substituted with halogens, hydroxyl groups, or amino groups, C groups optionally substituted with halogens, hydroxyl groups, or amino groups 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups optionally substituted with halogens, hydroxyl groups, or amino groups, C groups optionally substituted with halogens, hydroxyl groups, or amino groups. 6-10 Aryl, or 5-10 heteroaryl groups optionally substituted with halogens, hydroxyl groups, or amino groups.

[0155] In some implementation schemes, R 121 For H, R 122 -C(=O)R 124 The R mentioned above 124 C can be arbitrarily replaced by halogens 1-10 Alkoxy groups, C groups optionally substituted with halogens 1-10 Alkyl NH-, C optionally substituted with halogen 1-10 Alkyl C 1-10 Alkyl N-, C- optionally substituted with halogen 1-10 Alkyl groups, 3-10 heteroalkyl groups optionally substituted with halogens, C groups optionally substituted with halogens 3-10 cycloalkyl, 3-10 membered heterocyclic groups optionally substituted with halogens, C groups optionally substituted with halogens 6-10 Aryl groups, or 5-10 heteroaryl groups optionally substituted with halogens.

[0156] In some implementation schemes,

[0157] Selected from:

[0158] Wherein, the R 3b R 121 and R 122 As defined in this application.

[0159] In some implementations, L is -W A -Q-; the W mentioned A Q is a releasable linker, and Q is a spacer group.

[0160] In some implementations, L is...

[0161] The T, Q, R mentioned 15a R 15b R 16 m is as defined in this application.

[0162] In some implementations, L is...

[0163] The Q mentioned 1 R 15a R 15b R16 R 17 m, X, Y are as defined in this invention.

[0164] In some implementations, L is...

[0165] The Q mentioned 1 R 15a R 15b R 16 R 17 m is as defined in this invention.

[0166] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is the compound represented by Formula II or a pharmaceutically acceptable salt thereof:

[0167] in,

[0168] R 1 R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this invention;

[0169] W A It is a releasable linker, capable of releasing the following chemical structure from the compound in vivo:

[0170] Q is a spacer group.

[0171] In some implementation schemes, the W A Examples include, but are not limited to:

[0172] R 15a R 15b R 16 and R 17 Each is defined independently as in this application, and m is defined as in this invention.

[0173] Examples of releasable linkers also include aromatic compounds with charge properties similar to PAB groups, such as 2-aminoimidazol-5-methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9: 2237) and ortho- or para-aminobenzyl acetals. Interval units that can cyclize upon hydrolysis of the amide bond can be used, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), suitably substituted bicyclic [2.2.1] and bicyclic [2.2.2] ring systems (Storm et al., J. Amer. Chem. Soc., 1972, 94, 5815) and 2-aminophenylpropionic acid amides (Amsberry et al., J. Org. Chem., 1990, 55, 5867); amine-containing drugs with glycine α-substitution eliminated (Kingsbury et al., J. Med. Chem., 1984, 27, 1447).

[0174] In some implementations, Q is represented by the formula -(V). q - Represents a chemical structural unit:

[0175] Each of the V values ​​can be an independent bond, amino acid residue, or -CR. L1 R L2 -, -O-, -S-, -S(=O)-, -S(=O)2-, -NR L3 -、-S(=O)2NR L3 -、-S(=O)NR L3 -、-C(=O)NR L3 -、-NR L3 C(=O)NR L4 -、-NR L3 S(=O)2NR L4 -、-C(=O)-、-CR L1 =CR L2 -、-C≡C-、-SiR L1 R L2 -、-P(=O)R L1 -、-P(=O)OR L1 -、-NR L3 C(=N-CN)NR L4 -、-NR L3 C(=N-CN)-、-NR L3 C(=C-NO2)NR L4 - Optionally assigned to 1-6 R L6 and R L7 Replacement C 3-11 Cycloalkylene, optionally with 1-6 R L6 and RL7 Replacement C 3-11 Heterocyclic alkylene, optionally with 1-6 R L6 and R L7 Replacement C 3-11 Cycloalkenyl groups, optionally surrounded by 1-6 R groups L6 and R L7 Replacement C 3-11 Heterocyclic alkenyl groups, optionally surrounded by 1-6 R groups L6 and R L7 Replacement C 3-11 Cycloethynyl group, optionally surrounded by 1-6 R groups L6 and R L7 Replacement C 3-11 Heterocyclic ynylene group, optionally surrounded by 1-6 R groups L6 and R L7 Replaced by aryl groups, optionally by 1-6 R groups L6 and R L7 The substituted heteroaryl group, optionally replaced by 1-6 R groups L6 and R L7 The subspirocyclic group is replaced, optionally with 1-6 R groups. L6 and R L7 The subbridge ring base is replaced or optionally replaced by 1-6 R L6 and R L7 Substituted fused ring groups;

[0176] in,

[0177] Optionally, the R L1 and R L2 Each group independently connects to other groups to form a cyclic structure E4, wherein the cyclic structure E4 is optionally connected by 1-4 R groups. L5 replace;

[0178] Optionally, the R L6 and R L7 Each group independently connects to other groups to form a cyclic structure E5, wherein the cyclic structure E5 is optionally bounded by 1-4 R groups. L5 replace;

[0179] The R mentioned L1 R L2 R L3 R L4 R L5 Each independently as described in the present invention R 1 Defined;

[0180] The R mentioned L5 R L6 R L7 Each independently as described in the present invention R o Defined;

[0181] The q mentioned is an integer greater than or equal to 1.

[0182] In some embodiments, q is an integer from 1 to 100. In some embodiments, q is an integer from 1 to 50. In some embodiments, q is an integer from 1 to 20. In some embodiments, q is an integer from 1 to 10. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0183] In some implementations, the R L1 R L2 R L3 R L4 Each independently represents H and C. 1-8 Alkyl, -O(C) 1-8 alkyl), -S(C 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic alkyl, -O(C) 1-8 cycloalkyl), -S(C 1-8 cycloalkyl), -NH(C 1-8 cycloalkyl), -N(C) 1-8 cycloalkyl)2, -N(C 1-8 cycloalkyl)(C 1-8 Alkyl groups, -OH, -NH2, -SH, -SO2 (C 1-8 Alkyl), -P(=O)(OC 1-8 Alkyl)(C 1-8 Alkyl), -P(=O)(OC 1-8 Alkyl)2、-C≡C-(C 1-8 Alkyl groups, -C≡CH, -CH=CH(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(=O)(C 1-8 Alkyl groups, -CO2H, halogens, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NH(C 1-8 alkyl), -SO2N(C1-8 Alkyl)2、-S(=O)NH(C 1-8 Alkyl), -S(=O)N(C 1-8 Alkyl)2、-C(=O)NH(C 1-8 Alkyl), -C(=O)N(C 1-8 Alkyl)2, -N(C 1-8 alkyl)C(=O)NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)C(=O)N(C 1-8 Alkyl)2、-NHC(=O)NH(C 1-8 Alkyl), -NHC(=O)N(C 1-8 Alkyl)2, -NHC(=O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 alkyl), -NHSO2N(C 1-8 Alkyl)2 or -NHSO2NH2.

[0184] In some implementations, the R L5 R L6 R L7 Each independently is C 1-8 Alkyl, -O(C) 1-8 alkyl), -S(C 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic alkyl, -O(C) 1-8 cycloalkyl), -S(C 1-8 cycloalkyl), -NH(C 1-8 cycloalkyl), -N(C) 1-8 cycloalkyl)2, -N(C 1-8 cycloalkyl)(C 1-8 Alkyl groups, -OH, -NH2, -SH, -SO2 (C 1-8 Alkyl), -P(=O)(OC 1-8 Alkyl)(C 1-8 Alkyl), -P(=O)(OC 1-8 Alkyl)2、-C≡C-(C 1-8 Alkyl groups, -C≡CH, -CH=CH(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH(C 1-8alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(=O)(C 1-8 Alkyl groups, -CO2H, halogens, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NH(C 1-8 alkyl), -SO2N(C 1-8 Alkyl)2、-S(=O)NH(C 1-8 Alkyl), -S(=O)N(C 1-8 Alkyl)2、-C(=O)NH(C 1-8 Alkyl), -C(=O)N(C 1-8 Alkyl)2, -N(C 1-8 alkyl)C(=O)NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)C(=O)N(C 1-8 Alkyl)2、-NHC(=O)NH(C 1-8 Alkyl), -NHC(=O)N(C 1-8 Alkyl)2, -NHC(=O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 alkyl), -NHSO2N(C 1-8 Alkyl)2 or -NHSO2NH2.

[0185] In some embodiments, the compound represented by Formula II or a pharmaceutically acceptable salt thereof is the compound represented by Formula III or a pharmaceutically acceptable salt thereof:

[0186] in,

[0187] R 1 R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 Q and Q are each defined independently as in this invention;

[0188] m can be 0, 1, 2, 3, or 4;

[0189] T is O or NR 33 ;

[0190] R 15a and R 15b Each is independently selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0191] R 16 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OR a-SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0192] R 33 Selected from hydrogen, deuterium, halogen, nitro, cyano, -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. Ra N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0193] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -NH(C) 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 alkylene-3-20-membered heterocyclic group, wherein C 1-20 Alkyl, C 1-20 Alkylene, C 1-20 Heteroalkyl, C 1-20 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0194] Each R c Independently selected from deuterium, halogen, nitro, cyano, -OH, =O, -SH, -NH2, -NH(C) 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 Alkylene-3-20-membered heterocyclic group.

[0195] In some implementations, T is O.

[0196] In some implementation schemes, R 15a and R 15b Each is independently selected from hydrogen, deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0197] In some implementation schemes, R 15a and R 15b Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0198] In some implementation schemes, R 15a and R 15b Both are hydrogen.

[0199] In some implementation schemes, R 16 Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0200] In some implementation schemes, R 16 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0201] In some implementation schemes, R 16 Selected from hydrogen, chlorine and C 1-6 Alkoxy groups are preferred over methoxy groups.

[0202] In some implementation schemes, R 33 Selected from hydrogen, C 1-6 Alkoxy groups are preferably methyl and ethyl.

[0203] In some implementations, m is 0, 1, or 2.

[0204] In some embodiments, the compound represented by Formula III or a pharmaceutically acceptable salt thereof is the compound represented by Formula IV or a pharmaceutically acceptable salt thereof:

[0205] in,

[0206] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 Each of m is independently defined as in this invention;

[0207] R 17 Hydrogen, deuterium, halogen, nitro, cyano, -OR a -SR a -NR a R b -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C1-20 Alkylene-Si(R) a 3. R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-20 Alkyl, C 1-20 Heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0208] The R mentioned a R b R c Each is independent as defined in this invention;

[0209] The X is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- or -P(=S)(OH)-;

[0210] The Y is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- or -P(=S)(OH)-;

[0211] Q 1The spacer group 1 is a chemical structural unit that covalently connects X and Y.

[0212] In some implementations, the Q... 1 For the formula -(U) r - represents a chemical structural unit;

[0213] Each of the U values ​​is independently selected from bonds, amino acid residues, and -CR. L1 R L2 -, -O-, -S-, -S(=O)-, -S(=O)2-, -NR L3 -、-S(=O)2NR L3 -、-S(=O)NR L3 -、-C(=O)NR L3 -、-NR L3 C(=O)NR L4 -、-NR L3 S(=O)2NR L4 -、-C(=O)-、-CR L1 =CR L2 -、-C≡C-、-SiR L1 R L2 -、-P(=O)R L1 -、-P(=O)OR L1 -、-NR L3 C(=N-CN)NR L4 -、-NR L3 C(=N-CN)-、-NR L3 C(=C-NO2)NR L4 - Optionally selected by 0-6 R L1 and R L2 Replacement C 3-11 Cycloalkylene, optionally with 0-6 R L1 and R L2 Replacement C 3-11 Heterocyclic alkylene, optionally with 0-6 R L1 and R L2 Replacement C 3-11 Cycloalkenyl groups, optionally surrounded by 0-6 R groups L1 and R L2 Replacement C 3-11 Heterocyclic alkenyl groups, optionally surrounded by 0-6 R groups L1 and R L2 Replacement C 3-11 Cycloethynyl group, optionally surrounded by 0-6 R groups L1 and R L2 Replacement C 3-11 Heterocyclic ynylene group, optionally surrounded by 0-6 R groups L1 and RL2 The substituted aryl group, optionally replaced by 0-6 R L1 and R L2 The substituted heteroaryl group, optionally replaced by 0-6 R L1 and R L2 The subspirocyclic group is replaced, optionally by 0-6 R groups. L1 and R L2 The subbridge ring base is replaced or optionally replaced by 0-6 R L1 and R L2 Substituted fused ring groups;

[0214] in,

[0215] Optionally, the R L1 and R L2 Each group independently connects to other groups to form a cyclic structure E4, wherein the cyclic structure E4 is optionally connected by 0-4 R groups. L5 replace;

[0216] The R mentioned L1 R L2 R L3 R L4 R L5 Each is independent as defined in this invention;

[0217] The r mentioned is an integer greater than or equal to 1.

[0218] In some embodiments, r is an integer from 1 to 100. In some embodiments, r is an integer from 1 to 50. In some embodiments, r is an integer from 1 to 20. In some embodiments, r is an integer from 1 to 10. In some embodiments, r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0219] In some implementation schemes, R 17 Selected from hydrogen, deuterium, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0220] In some implementation schemes, R 17 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0221] In some implementation schemes, R 17 Selected from hydrogen, C 1-6 Alkyl groups are preferably methyl and ethyl.

[0222] In some implementations, X is -C(=O)-.

[0223] In some implementations, Y is -C(=O)-.

[0224] In some implementation schemes,

[0225] for

[0226] in,

[0227] R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this invention.

[0228] In some implementation schemes,

[0229] for

[0230] in,

[0231] R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this invention.

[0232] In some embodiments, the compound represented by Formula IV or a pharmaceutically acceptable salt thereof is the compound represented by Formula V or a pharmaceutically acceptable salt thereof:

[0233] in,

[0234] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0235] In some implementation schemes,

[0236] Selected from

[0237] In some implementation schemes,

[0238] Selected from:

[0239] In some implementation schemes, for

[0240] in,

[0241] R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0242] In some implementation schemes, for

[0243] in,

[0244] R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0245] In some implementation schemes, for

[0246] Another aspect of the present invention provides a compound of formula VI or a pharmaceutically acceptable salt thereof:

[0247] in,

[0248] L, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this invention;

[0249] R 3a Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0250] R a R b R c Each is independent as defined in this application.

[0251] In some implementation schemes, R 3a Selected from hydrogen, deuterium, and -C(=O)R a 、-Si(C 1-6 Alkyl)3, -C 1-6 Alkylene-Si(C) 1-6 Alkyl)3, R a N=CR a -、-OC(=O)R a -OC(=O)-OR a C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-NR a R b -C 1-6 alkylene-3-7-membered heterocyclic group, -C 1-6 Alkylene-OC(=O)-C 1-6 Alkylene-C(=O)-OR a and -C 1-6 Alkylene-NR a -C(=O)-OR a The C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0252] Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace;

[0253] Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group.

[0254] In some implementation schemes, R 3a -C(=O)R 3b .

[0255] In some implementation schemes, R 3b Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -NH(C) 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 alkylene-3-20-membered heterocyclic group, wherein C 1-20 Alkyl, C 1-20 Alkylene, C 1-20 Heteroalkyl, C 1-20 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0256] Each R c Independently selected from deuterium, halogen, nitro, cyano, =O, -OH, =O, -SH, -NH2, -NH(C 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C1-20 Alkylene-3-20-membered heterocyclic group.

[0257] In some implementation schemes, R 3b Selected from C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl and 5-20 membered heteroaryl; the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace;

[0258] Each R c Independently, it can be deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)H, -C(=O)OH, -C(=O)NH2, C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 heteroalkyl, 3-20 heterocycloalkyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups.

[0259] In some implementation schemes, R 3b Selected from C that is arbitrarily substituted with halogens 1-20 Alkyl groups, C groups optionally substituted with hydroxyl groups 1-20 Alkyl groups, C groups optionally substituted with amino groups 1-20 alkyl.

[0260] In some implementation schemes, R 3b C 1-20 alkyl.

[0261] In some implementation schemes,

[0262] Selected from

[0263] In some embodiments, the compound represented by Formula VI or a pharmaceutically acceptable salt thereof is the compound represented by Formula VII or a pharmaceutically acceptable salt thereof:

[0264] in,

[0265] W A Q, R 3a R 6 R 7 R 8 R 11 R12 R 13 Each is independent as defined in this invention.

[0266] In some embodiments, the compound represented by Formula VII or a pharmaceutically acceptable salt thereof is the compound represented by Formula VIII or a pharmaceutically acceptable salt thereof:

[0267] in,

[0268] R 3a R 6 R 7 R 8 R 11 R 12 R 13 R 15a R 15b R 16 m, T, and Q are each independently defined as in this invention.

[0269] In some embodiments, the compound represented by Formula VIII or a pharmaceutically acceptable salt thereof is the compound represented by Formula IX or a pharmaceutically acceptable salt thereof:

[0270] in,

[0271] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this invention.

[0272] In some implementation schemes, for

[0273] in,

[0274] R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this invention.

[0275] In some implementation schemes, for

[0276] in,

[0277] R 15a R15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this invention.

[0278] In some embodiments, the compound represented by Formula IX or a pharmaceutically acceptable salt thereof is the compound represented by Formula XI or a pharmaceutically acceptable salt thereof:

[0279] in,

[0280] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0281] In some embodiments, the compound represented by formula XI or a pharmaceutically acceptable salt thereof is the compound represented by formula XI-1 or formula XI-2 or a pharmaceutically acceptable salt thereof:

[0282] in,

[0283] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0284] In some embodiments, the compound represented by formula XI-1 or a pharmaceutically acceptable salt thereof is a compound represented by formula XII-1, formula XII-3, or formula XII-5 or a pharmaceutically acceptable salt thereof:

[0285] in,

[0286] R 3a R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0287] In some embodiments, the compound represented by XI-2 or a pharmaceutically acceptable salt thereof is a compound represented by formula XII-2, formula XII-4 or formula XII-6 or a pharmaceutically acceptable salt thereof:

[0288] in,

[0289] R 3a R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this invention.

[0290] Another aspect of this application provides a compound of formula IA or a pharmaceutically acceptable salt thereof:

[0291] in,

[0292] R 1 R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 13 L and L are each defined independently as in this application.

[0293] In some implementation schemes,

[0294] for

[0295] Among them, R 6 R 7 R 8 R 11 R 12 R 13 L and L are each defined independently as in this application.

[0296] In some implementation schemes,

[0297] for

[0298] Among them, R 6 R 7 R 8 R 11 R 12 R 13L and L are each defined independently as in this application.

[0299] In some implementation schemes,

[0300] for

[0301] Among them, R 6 R 7 R 8 R 11 R 12 R 13 L and L are each defined independently as in this application.

[0302] In some implementation schemes,

[0303] for

[0304] Among them, R 6 R 7 R 8 R 11 R 12 R 13 L and L are each defined independently as in this application.

[0305] In some embodiments, the compound represented by formula IA or a pharmaceutically acceptable salt thereof is the compound represented by formula II-A or a pharmaceutically acceptable salt thereof:

[0306] in,

[0307] R 1 R 2 R 3 R 4 R 5a R 5b W A Q, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application.

[0308] In some embodiments, the compound represented by Formula II-A or a pharmaceutically acceptable salt thereof is the compound represented by Formula III-A or a pharmaceutically acceptable salt thereof:

[0309] in,

[0310] R 1 R 2 R3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 15a R 15b R 16 m, T, and Q are each defined independently as in this application.

[0311] In some implementation schemes,

[0312] for

[0313] in,

[0314] R 6 R 7 R 8 R 11 R 12 Each is independent as defined in this application.

[0315] In some implementation schemes,

[0316] for

[0317] in,

[0318] R 6 R 7 R 8 R 11 R 12 Each is independent as defined in this application.

[0319] In some implementation schemes,

[0320] for

[0321] in,

[0322] R 6 R 7 R 8 R 11 R 12 Each is independent as defined in this application.

[0323] In some implementation schemes,

[0324] for

[0325] in,

[0326] R 6 R 7 R 8 R 11 R 12 Each is independent as defined in this application.

[0327] In some embodiments, the compound represented by Formula III-A or a pharmaceutically acceptable salt thereof is the compound represented by Formula IV-A or a pharmaceutically acceptable salt thereof:

[0328] in,

[0329] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this application.

[0330] In some implementation schemes,

[0331] for

[0332] In some embodiments, the compound represented by formula IV-A or a pharmaceutically acceptable salt thereof is the compound represented by formula VA or a pharmaceutically acceptable salt thereof:

[0333] in,

[0334] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0335] Another aspect of this application provides a compound of formula VI-A or a pharmaceutically acceptable salt thereof:

[0336] in,

[0337] R 3a L, R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application.

[0338] In some embodiments, the compound represented by formula VI-A or a pharmaceutically acceptable salt thereof is the compound represented by formula VII-A or a pharmaceutically acceptable salt thereof:

[0339] in,

[0340] W A Q, R 3a R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application.

[0341] In some embodiments, the compound represented by formula VII-A or a pharmaceutically acceptable salt thereof is the compound represented by formula VIII-A or a pharmaceutically acceptable salt thereof:

[0342] in,

[0343] R 3a R 6 R 7 R 8 R 11 R 12 R 15a R 15b R 16 m, T, and Q are each defined independently as in this application.

[0344] In some embodiments, the compound represented by formula VIII-A or a pharmaceutically acceptable salt thereof is the compound represented by formula IX-A or a pharmaceutically acceptable salt thereof:

[0345] in,

[0346] R 3a R 7 R8 R 11 R 15a R 15b R 16 R 17 m, X, Y, Q 1 Each is independent as defined in this application.

[0347] In some embodiments, the compound represented by formula IX-A or a pharmaceutically acceptable salt thereof is the compound represented by formula XI-A or a pharmaceutically acceptable salt thereof:

[0348] in,

[0349] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0350] In some embodiments, the compound represented by formula XI-A or a pharmaceutically acceptable salt thereof is the compound represented by formula XI-A1 or formula XI-A2 or a pharmaceutically acceptable salt thereof:

[0351] in,

[0352] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0353] In some embodiments, the compound represented by formula XI-A1 or a pharmaceutically acceptable salt thereof is the compound represented by formula XII-A1, XII-A3, or XII-A5 or a pharmaceutically acceptable salt thereof:

[0354] in,

[0355] R 3a R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0356] In some embodiments, the compound represented by formula XI-A2 or a pharmaceutically acceptable salt thereof is the compound represented by formula XII-A2, XII-A4, or XII-A6 or a pharmaceutically acceptable salt thereof:

[0357] in,

[0358] R 3a R 15a R 15b R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0359] In some embodiments, the compound represented by formula XI-A or a pharmaceutically acceptable salt thereof is the compound represented by formula XVI or a pharmaceutically acceptable salt thereof:

[0360] in,

[0361] R 3a R 7 R 8 R 11 R 16 R 17 m, Q 1 Each is independent as defined in this application.

[0362] In some embodiments, the compound represented by formula XVI or a pharmaceutically acceptable salt thereof is the compound represented by formula XVII or a pharmaceutically acceptable salt thereof:

[0363] In some embodiments, the compound represented by formula XVII or a pharmaceutically acceptable salt thereof is the compound represented by formula XVIII-a or XVIII-b or a pharmaceutically acceptable salt thereof:

[0364] in,

[0365] R 3a R 7 R 8 R 11 R 160 R 161 , n, Q 1 Each is independent as defined in this application.

[0366] In some implementation schemes, R 160 For deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, C1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 heteroalkyl, 3-20 heterocycloalkyl, C 1-20 Alkoxy, C 3-20 Cycloalkoxy, 3-20 membered heteroalkoxy, 3-20 membered heterocycloalkoxy, C 1-20 Alkyl NH-, C 3-20 Cycloalkyl NH-, 3-20 heteroalkyl NH-, 3-20 heterocycloalkyl NH-, C 1-20 Alkyl (C) 1-20 Alkyl)N-,C 3-20 cycloalkyl (C 1-20 Alkyl) N-, 3-20 heteroalkyl (C 1-20 Alkyl) N- or 3-20 membered heterocyclic alkyl (C 1-20 Alkyl)N-.

[0367] In some implementation schemes, R 161 Halogen, C 1-10 Alkyl or C 1-10 Alkyl group.

[0368] In some implementation schemes, R 161 It is a halogen. In some implementations, R 161 It can be fluorine, chlorine, bromine, or iodine. In some embodiments, R 161 It is fluorine, chlorine, or bromine. In some embodiments, R 161 It is fluorine or chlorine. In some implementations, R 161 It is chlorine.

[0369] In some implementations, n is 0, 1, 2, or 3. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0370] In some embodiments, the compound represented by formula XVIII-a or a pharmaceutically acceptable salt thereof is a compound represented by formula XIX-a, XIX-b, XIX-c, XIX-d, or XIX-e or a pharmaceutically acceptable salt thereof.

[0371] in,

[0372] R 3a R 7 R 8 R 11 R 160 , n, Q 1 Each is independent as defined in this application.

[0373] In some embodiments, the compound represented by formula XVIII-b or a pharmaceutically acceptable salt thereof is a compound represented by formula XIX-f, XIX-g, XIX-h, XIX-i, or XIX-j or a pharmaceutically acceptable salt thereof.

[0374] in,

[0375] R 3a R 7 R 8 R 11 R 160 , n, Q 1 Each is independent as defined in this application.

[0376] In some embodiments, the compound represented by formula XVIII-a or a pharmaceutically acceptable salt thereof is the compound represented by formula XX-a or a pharmaceutically acceptable salt thereof:

[0377] in,

[0378] R 3b R 7 R 8 R 11 R 160 R 161 , n, Q 1 Each is independent as defined in this application.

[0379] In some embodiments, the compound represented by formula XX-a or a pharmaceutically acceptable salt thereof is a compound represented by formula XXI-a, XXI-b, XXI-c, XXI-d, or XXI-e or a pharmaceutically acceptable salt thereof.

[0380] in,

[0381] R 3b R 7 R 8 R 11 R 160 , n, Q 1 Each is independent as defined in this application.

[0382] In some embodiments, the compound represented by formula XVIII-b or a pharmaceutically acceptable salt thereof is the compound represented by formula XX-b or a pharmaceutically acceptable salt thereof:

[0383] in,

[0384] R 3b R 7R 8 R 11 R 160 R 161 , n, Q 1 Each is independent as defined in this application.

[0385] In some embodiments, the compound represented by formula XX-b or a pharmaceutically acceptable salt thereof is a compound represented by formula XXI-f, XXI-g, XXI-h, XXI-i, or XXI-j or a pharmaceutically acceptable salt thereof.

[0386] in,

[0387] R 3b R 7 R 8 R 11 R 160 , n, Q 1 Each is independent as defined in this application.

[0388] Another aspect of the present invention provides a compound of formula XXII or a pharmaceutically acceptable salt thereof:

[0389] in,

[0390] R 1 R 2 R 3 R 4 R 5a R 5b W A R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application;

[0391] W B It is a releasable linker, capable of releasing the following chemical structure from the compound in vivo:

[0392] Q 2 2 is a spacer group.

[0393] In some implementations, the Q 2 For the formula -(U) r - represents the chemical structural unit, wherein U and r are each independently defined as in this application.

[0394] In some implementation schemes, the W B Examples include, but are not limited to:

[0395] in,

[0396] R 18a R 18b Each independently as described in this application R 15a Defined; R 19 As stated in this application R 16 Defined; R 20 As stated in this application R 17 Defined;

[0397] o can be 0, 1, 2, 3 or 4.

[0398] In some implementations, o is 0. In some implementations, o is 1. In some implementations, o is 2. In some implementations, o is 3. In some implementations, o is 4.

[0399] In some embodiments, the compound represented by formula XXII or a pharmaceutically acceptable salt thereof is the compound represented by formula XXIII or a pharmaceutically acceptable salt thereof:

[0400] in,

[0401] R 1 R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 15a R 15b R 16 m, T, Q 2 Each is independent as defined in this application;

[0402] R 18a R 18b Each independently as described in this application R 15a Defined; R 19 As stated in this application R 16 Defined;

[0403] o can be 0, 1, 2, 3 or 4.

[0404] In some embodiments, the compound represented by Formula XXIII or a pharmaceutically acceptable salt thereof is the compound represented by Formula XXIV or a pharmaceutically acceptable salt thereof:

[0405] in,

[0406] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, X, Y, o, R 18a R 18b R 19 R 20 Each is independent as defined in this application;

[0407] Q 3 3 is a spacer group.

[0408] In some implementations, the Q 3 For the formula -(U) r - represents the chemical structural unit, wherein U and r are each independently defined as in this application.

[0409] In some embodiments, the compound represented by formula XXIV or a pharmaceutically acceptable salt thereof is the compound represented by formula XXV or a pharmaceutically acceptable salt thereof:

[0410] in,

[0411] R 1 R 2 R 3 R 4 R 5a R 5b R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, o, R 18a R 18b R 19 R 20 Q 3 Each is independent as defined in this application.

[0412] Another aspect of the present invention provides a compound of formula XXVII or a pharmaceutically acceptable salt thereof:

[0413] in,

[0414] R 3a W A Q 2 W B R 6 R 7 R 8 R 11 R 12 R 13 Each is independent as defined in this application.

[0415] In some embodiments, the compound represented by formula XXVII or a pharmaceutically acceptable salt thereof is the compound represented by formula XXVIII or a pharmaceutically acceptable salt thereof:

[0416] in,

[0417] R 3a R 6 R 7 R 8 R 11 R 12 R 15a R 15b R 16 m, R 18a R 18b R 19 o, T, Q 2 Each is independent as defined in this application.

[0418] In some embodiments, the compound represented by formula XXVIII or a pharmaceutically acceptable salt thereof is the compound represented by formula XXIX or a pharmaceutically acceptable salt thereof:

[0419] in,

[0420] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, X, Y, o, R 18a R 18b R 19 R 20 Q 3 Each is independent as defined in this application.

[0421] In some embodiments, the compound represented by formula XXIX or a pharmaceutically acceptable salt thereof is the compound represented by formula XXXI or a pharmaceutically acceptable salt thereof:

[0422] in,

[0423] R 3a R 7 R 8 R 11 R 15a R 15b R 16 R 17 m, o, R 18a R 18b R 19 R 20 Q 3 Each is independent as defined in this application.

[0424] This invention considers and includes all combinations and subsets of the specific groups defined above.

[0425] Another aspect of the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0426] The present invention also provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0427] This invention also relates to the use of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of medicaments for the treatment and / or prevention of cancer, preferably selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

[0428] The present invention also relates to the compounds described herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, which are used as medicines.

[0429] This invention also relates to the compounds described herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them for the treatment and / or prevention of cancer, preferably selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

[0430] The present invention also relates to a method for treating and / or preventing cancer, comprising administering to a desired patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound, wherein the cancer is preferably selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma.

[0431] The active compounds can be formulated into forms suitable for administration via any suitable route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of the present invention can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present invention can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0432] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the compounds or compositions of the present invention may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0433] In addition to the active compound, the pharmaceutical compositions of the present invention may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0434] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0435] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0436] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0437] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0438] The pharmaceutical compositions of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0439] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0440] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations can also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil can be used. Additionally, fatty acids can also be used to prepare injectable formulations.

[0441] The compounds of the present invention can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0442] The compounds of the present invention can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0443] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the pharmaceutically acceptable type of salt, can be validated based on conventional treatment protocols.

[0444] Terminology Explanation

[0445] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0446] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc.

[0447] The term "heteroalkyl" refers to an alkyl group containing one or more heteroatoms selected from N, O, or S, wherein the alkyl group is as defined above.

[0448] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-64 ... 1-6 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0449] The term "alkenyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C atoms).2-20 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 12 carbon atoms (i.e., C12). 2-12 Alkenyl), more preferably alkenyl groups having 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.

[0450] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C atoms). 2-20 The alkynyl group is preferably an alkynyl group having 2 to 12 carbon atoms (i.e., C12). 2-12 Alkyne group), more preferably alkynyl group having 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 Alynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, penynyl, hexynyl, etc.

[0451] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc.

[0452] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 3-20 Cycloalkyl groups. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., C12). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 7 ring atoms (i.e., C14-C ... 3-7 cycloalkyl groups), cycloalkyl groups having 5 to 7 ring atoms (i.e., C1646-C ... 5-7 cycloalkyl) or cycloalkyl having 3 to 6 ring atoms (i.e., C12) 3-6 (cycloalkyl).

[0453] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0454] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0455] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), preferably monospirocyclic alkyl or bispirocyclic alkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospirocyclic alkyl. Non-limiting examples include:

[0456] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl groups). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl groups), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl groups). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably ternary / quadrivalent, ternary / pentary, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentary, quadrivalent / hexavalent, pentary / pentary ... or pentary / pentary bicyclic fused cyclic alkyl groups. Non-limiting examples include:

[0457] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl is preferably a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0458] The term "cycloalkylene" refers to a divalent functional group derived from cycloalkyl, wherein the cycloalkyl group is as defined above.

[0459] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group); more preferably a heterocyclic group having 3 to 7 ring atoms (i.e., a 3 to 7-membered heterocyclic group) or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5 to 7-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group) or preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group).

[0460] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0461] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0462] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), more preferably a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes monospirocyclic and polyspirocyclic groups (such as bispirocyclic groups), preferably monospirocyclic or bispirocyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocyclic. Non-limiting examples include:

[0463] wait.

[0464] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples include:

[0465] wait.

[0466] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group with 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0467] wait.

[0468] The term "subheterocyclic group" refers to a divalent functional group derived from a heterocyclic group, where the heterocyclic group is as defined above.

[0469] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Examples of monocyclic aryl are phenyl. Non-limiting examples of polycyclic aryl include naphthyl, anthracene, phenanthrene, etc.

[0470] The term "alpharyl" refers to a divalent functional group derived from aryl, where aryl is as defined above.

[0471] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered monocyclic heteroaryl group), or preferably a heteroaryl group having 8 to 10 ring atoms (i.e., an 8 to 10-membered polycyclic heteroaryl group).

[0472] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0473] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazoleyl, pyrrolotriazinyl, etc.

[0474] The term "hybrid aryl" refers to a divalent functional group derived from a heteroaryl group, where the heteroaryl group is as defined above.

[0475] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0476] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0477] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0478] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0479] The term "hydroxyl group" refers to -OH.

[0480] The term "thiol" refers to -SH.

[0481] The term "amino" refers to -NH2.

[0482] The term "cyano" refers to -CN.

[0483] The term "nitro" refers to -NO2.

[0484] The term "oxo" or "oxo group" refers to "=O".

[0485] The term "carbonyl" refers to C=O.

[0486] The term "carboxyl group" refers to -C(O)OH.

[0487] The term "Hal" refers to halogen.

[0488] The term "drug toxin" includes any substance having biological or detectable activity, such as therapeutic agents, detectable labels, binders, etc., and prodrugs metabolized in vivo into active agents. Drug toxins can also be drug toxin derivatives, wherein the drug toxin has been functionalized to achieve coupling with the taxane of the present invention. The drug toxin has a chemically active functional group selected from primary or secondary amines, hydroxyl, thiol, carboxyl, aldehyde, or ketone.

[0489] Representative amino-containing drug toxins include mitomycin C, mitomycin A, daunorubicin, adriamycin, aminopterin, actinomycin, bleomycin, 9-aminocamptothecin, N8-acetylspermine, 1-(2-chloroethyl)-1,2-dimethylsulfonylhydrazide, tallysomycin, cytarabine and its derivatives, etc.

[0490] Representative drug toxins containing alcohol groups include podophyllotoxin, camptothecin, paclitaxel, esperamicin, 1,8-dihydroxy-bicyclo[7,3,1]tridecyl-4-9-diene-2,6-diyn-13one (US Patent, 5198, 560), podophyllotoxin, anguidine, vincristine, vinblastine, morpholino-adriamycin, n-(5,5-diacetoxypentyl)adriamycin and its derivatives.

[0491] Examples of drug toxins containing thiol groups include esperamicin and 6-mercaptopurine and its derivatives.

[0492] Representative drug toxins containing carboxyl groups include methotrexate, camptothecin (the open-ring form of lactone), butyric acid, retinoic acid and its derivatives.

[0493] Drug toxins containing aldehydes and ketones are represented by serpentin and anthracyclines and their derivatives, such as adriamycin.

[0494] The term "therapeutic agent" refers to a drug that exerts cytotoxic, cell growth inhibitory, and / or immunomodulatory effects on cancer cells or activated immune cells. Examples of therapeutic agents include cytotoxic agents, cell inhibitors, chemotherapeutic agents, and immunomodulatory agents. Cytotoxic effects refer to the deprivation, elimination, and / or killing of target cells. Cell growth inhibitory effects refer to the inhibition of cell proliferation.

[0495] Cytotoxic agents are agents that have cytotoxic and / or cell growth-inhibiting effects on cells. Cytotoxic agents include DNA-damaging agents, antimetabolites, natural products, and analogues thereof. Preferably, cytotoxic agents include, but are not limited to, enzyme inhibitors (such as dihydrofolate reductase inhibitors and thymidylate synthase inhibitors), DNA insertion factors, DNA cleavers, topoisomerase inhibitors, anthracyclines, vinca drugs, mitomycin, bleomycin, cytotoxic nucleosides, pteridines, diynenes, podophyllotoxin, differentiation inducers, and paclitaxel. Of particular use among these classes are, for example, methotrexate, methylfolate, dichloromethhotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, milfran, buprofen, lonoxin, actinomycin, daunorubicin, adriamycin, mitomycin C, mitomycin A, erythromycin, aminopterin, tamethasone, podophyllin and podophyllin derivatives such as podophyllotoxin or podophyllotoxin phosphate, vinblastine, vincristine, vincristine amide, paclitaxel, docetaxel, retinoic acid, butyric acid, N8-acetylsemine, camptothecin and their analogues.

[0496] Those skilled in the art can chemically modify the drug toxins to make them more readily participate in the reaction during the preparation of the conjugate drug of the present invention.

[0497] Cell inhibitors are agents that have an inhibitory effect on cell growth, thereby inhibiting the growth and / or reproduction of a specific subset of cells.

[0498] Chemotherapy agents are defined as chemical compounds that can be used to treat cancer.

[0499] Immunomodulators are agents that stimulate an immune response by directly or indirectly (by making another agent more effective) inhibiting or reducing the growth of a subset of cells (i.e., tumor cells) through the production of cytokines and / or antibodies and / or the regulation of T cell function.

[0500] The term "camptothecin derivatives" includes, but is not limited to, irinotecan, belotetane, topotecan, camptothecin, hydroxycamptothecin, gemmatothecin, dianticoa, SN38, cinotecan, ZD-06519, 9-Aminocamptothecin, AR-67, costanotecan, CZ-112, DU-6596, letopecan, rubetanocon, simminotecan, CH-0793076, DRF-1042, Ecinotecan, GI-149893, Namitecan, and their derivatives; the structures of other exemplary "camptothecin derivatives" can be found in US4604463A, US5004758A, CN1096297A, US5541327A, US5734056A, US5670500A, US5663177A, US5633260A, US5674874A, U S5856333A, US5801167A, US6177439B1, US5916897A, US5998426A, US5843954A, US6046209 A. US6156897A, US6291676B1, US6306868B1, US6403604B1, CN1176923C, CN100363366C, USR E39707E1, US20120136153A1, US9682992B2, US9266911B2, US9447126B2, CN105884789A, CN111018897A, CN110698491B, and US6407115B1 are incorporated herein by reference in their entirety; the camptothecin and camptothecin derivatives described herein have atoms bonded to the linker L.

[0501] In this invention, unless otherwise specified, the atomic position numbers of the chemical structure formula of CPT refer to the atomic positions of camptothecin in the reference Pan P, Chen J, Li X, et al. Structure-based drug design and identification of H2O-soluble and low toxic hexacyclic camptothecin derivatives with improved efficacy in cancer and lethal inflammation models in vivo[J]. Journal of medicinal chemistry, 2018, 61(19):8613-8624. For example, the atomic position numbers of the chemical structure formula of camptothecin are as follows:

[0502] Unless otherwise specified, the CPT described in this invention or any specific CPT (such as irinotecan) involving atom numbering shall follow the numbering rules shown in Formula A1.

[0503] The term "taxane" includes, but is not limited to, paclitaxel, docetaxel, cabazitaxel, ARC-100, ortataxel, larotaxel, BMS-184476, BMS-275183, Milataxel, Simotaxel, SK-608-20.1, testataxel, BMS-188797, felotaxel, TL-310, and their derivatives; other exemplary structures of "taxane" can be found in EP0253739B1, US5248796A, EP0630428B1, US5637723A, EP0664800A1, CA2161328A1, EP0767786B1, US5767282A, and US582. 4701A, US5808113A, US5767297A, US5861515A, WO1998014187A1, US5869680A, CN1590386A, EP0882732A1, CN1067682C, CN1110565C, EP0696596A1, CN1151740A, CN100339373C, CN100369908C, CN101463029B, CN101648928B, CN101648973B, CN103025739A, CN106632296A, are incorporated herein by reference in their entirety; the “taxane” described herein has atoms bonded to the linker L.

[0504] In this invention, unless otherwise specified, the atomic position numbers of "paclitaxel" refer to the atomic position numbers of paclitaxel and docetaxel in the reference Mastropaolo D, Camerman A, Luo Y, Brayer GD, Camerman N. Crystal and molecular structure of paclitaxel (taxol). Proc Natl Acad Sci US A. 1995 Jul 18; 92(15):6920-4. For example, the atomic position numbers of the chemical structure of paclitaxel are as follows:

[0505] For example, the atomic position numbers in the chemical structure of docetaxel are as follows:

[0506] Unless otherwise specified, the "taxane" or any specific taxane (such as paclitaxel) described in this invention, if involving atom numbering, shall follow the numbering rules shown for paclitaxel or docetaxel.

[0507] As used in this application, CPT represents camptothecin, camptothecin derivatives, such as SN-38.

[0508] The compounds disclosed herein contain their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-、 13 C- or 14 C-enriched carbon ( 11 C-、 13 C- or 14 C-carbon labeling; 11 C-、 13 C- or 14Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0509] The compounds of this invention can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds of this invention may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this invention. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a certain compound of the present invention can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, and then resolving the diastereomer using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

[0510] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0511] "Optional" or "optional" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally substituted alkyl group with halogen or cyano group" includes cases where the alkyl group is substituted with halogen or cyano group and cases where the alkyl group is not substituted with halogen or cyano group.

[0512] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0513] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or pharmaceutically acceptable salts thereof, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0514] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0515] The term “treatment” as used herein includes the treatment of disease or condition in mammals, particularly humans, and includes: (a) suppressing an infection, disease, or condition, i.e., halting or delaying the development of an infection, disease, or condition; (b) alleviating an infection, disease, or condition, i.e. causing the remission of a disease or condition; and / or (c) curing an infection, disease, or condition.

[0516] As used in this article, the term "prevention" includes preventative therapy in mammals, particularly humans, aimed at reducing the likelihood of developing an infection, disease, or condition. Patients selected for preventative therapy may be chosen based on an increased risk of infection or disease or condition compared to the general population. "Prevention" can include the management of subjects who have not yet presented with an infection or clinical condition, and the prevention of a second occurrence of the same or similar infection or clinical condition.

[0517] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0518] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0519] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0520] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0521] Method for synthesizing the compounds of the present invention

[0522] The intermediates of the present invention are prepared by the following schemes. Unless otherwise specified, the reactions involved in Schemes 1-10 can be prepared under similar reaction conditions in the prior art. For details, please refer to the relevant reaction conditions in the preparation examples or embodiments of this application.

[0523] 1. Synthesis of intermediate M1

[0524] The aforementioned REAG1 is The Hal is a halogen (e.g., F, Cl, Br, I); other substituents are each defined independently as in this invention.

[0525] In some implementations, Hal is Cl.

[0526] 2. Synthesis of intermediates M2-0 and M2-1

[0527] The aforementioned REAG2 is selected from C 1-20 Alkyl C(=O)-Hal, R 301 C(=O)-OC(=O)R 301 R 301 OC(=O)-OC(=O)OR 301 C1-20 Alkyl C(=O)OH; the R 301 Each independently is C 1-20 Alkyl; the R 3a Selected from C 1-20 Alkyl C(=O)-, C 1-20 Alkoxy C(=O)-; the Hal is a halogen (e.g., F, Cl, Br, I); the REAG1 is as defined in Scheme 1; other substituents are each independently defined as in this invention.

[0528] 3. Synthesis of intermediate M2-2

[0529] The REAG1 is as defined in Scheme 1; the other substituents are each defined independently as in this invention.

[0530] 4. Synthesis of intermediate M3-1

[0531] The R mentioned 214 For H or C 1-6 Alkyl; the R 215 It is an amino protecting group, such as Boc-; the REAG5 is... like The R mentioned 216 for like Other substituents and m are each defined independently as in this application.

[0532] 5. Synthesis of intermediate M3-2

[0533] The R mentioned 214 C 1-6 Alkyl groups, such as methyl groups; the REAG6 mentioned is selected from C10. 1-6 Alkyl-OH, such as methanol or ethanol; the R 220 C 1-6 Alkyl groups, such as methyl or ethyl; the R 215 The R is an amino protecting group, such as Boc-; 221 C 1-6 Alkyl groups, such as isopropyl; the REAG5 is... like The R mentioned 216 for like Other substituents and m are each defined independently as in this application.

[0534] 6. Synthesis of intermediates M4-0 and M4-1

[0535] The R mentioned 222 For H or C 1-6 Alkyl; the Q 101 C 1-6 Alkylene, C 1-6 alkoxide C 1-6 Alkylene; the REAG2 is as defined in Scheme 2, such as (Boc)2O; the R 203 Selected from C 1-20 Alkyl C(=O)- and C 1-20 Alkyl group C(=O)-; R as described 203 For Boc; the aforementioned REAG4 is The L mentioned 212 C 1-6 Alkylene or 3-6 heteroalkylene, such as the aforementioned REAG4. The aforementioned REAG5 is as defined in Scheme 4, and if the aforementioned REAG5 is... The R mentioned 212 For HOC (=O)C 1-6 Alkylene C(=O)-, such as The R mentioned 213 for c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene C(=O)-, with the * end connected to the nitrogen atom at the c position; as described in R 213 for

[0536] 7. Synthesis of intermediate M4-2

[0537] The aforementioned REAG7 is BocNR 223b C 1-6 Alkylene NHR 223c The R mentioned 223b and R 223c Each independently is C 1-6 Alkyl, or R 223b and R 223c Together with the nitrogen atoms they are attached to, they form 5-8 membered heterocyclic groups, such as the aforementioned REAG7. The aforementioned REAG4 is as defined in Scheme 6, and the aforementioned REAG4 is as follows: The R mentioned 223 For BocNR 223b C 1-6 Alkylene NR 223c -, the R 223band R 223c Each independently is C 1-6 Alkyl, or R 223b and R 223c Together with the nitrogen atoms to which they are attached, they form 5-8 membered heterocyclic groups, such as the R group described above. 223 for The Q mentioned 102 C 1-6 Alkylene; the aforementioned REAG5 is like The R mentioned 216 for like Other substituents and m are each defined independently as in this application.

[0538] 8. Synthesis of intermediates M5-1 and M5-2

[0539] The M4-0 is as defined in Scheme 6; the REAG7 is as defined in Scheme 7; if the REAG7 is...

[0540] The Hal is Cl, Br, or I; the Q 102 C 1-6 Alkylene; the aforementioned REAG5 is like The R mentioned 216 for like The R mentioned 222 C 1-6 Alkyl; the Q 101 C 1-6 Alkylene; the R 203 Selected from C 1-20 Alkyl C(=O)- and C 1-20 Alkyl group C(=O)-; R as described 203 For Boc; the R mentioned 222 For H or C 1-6 alkyl;

[0541] The R mentioned 223 For BocNR 223b C 1-6 Alkylene NR 223c -, the R 223b and R 223c Each independently is C 1-6 Alkyl, or R 223b and R 223c Together with the nitrogen atoms to which they are attached, they form 5-8 membered heterocyclic groups, such as the R group described above. 223 for

[0542] Other substituents and m are each defined independently as in this application.

[0543] 9. Synthesis of intermediate M6

[0544] The aforementioned REAG4 is The L mentioned 212 C 1-6 Alkylene or 3-6 heteroalkylene, such as the aforementioned REAG4. The R mentioned 212 For HOC (=O)C 1-6 Alkylene C(=O)-, as described in R 212 for The aforementioned REAG8 is an HOC 1-6 Alkylene NH2 or HOC 5-8 cyclohexene alkyl NH2; as described in the REAG8, is The R mentioned 224 For HOC 1-6 Alkylene NHC(=O)C 1-6 Alkylene C(=O)- or HOC 5-8 cycloalkyl NHC(=O)C 1-6 Alkylene C(=O)-; R as described 224 for

[0545] 10. Synthesis of intermediate M7

[0546] The aforementioned REAG5 is like The aforementioned REAG4 is The L mentioned 212 C 1-6 Alkylene or 3-6 heteroalkylene, such as the aforementioned REAG4. The R mentioned 212 For HOC (=O)C 1-6 Alkylene C(=O)- or HOC(=O)3-6 heteroalkylene C(=O), as described in R 212 for The Q mentioned 101 C 1-6 Alkylene or 3-6 heteroalkylene; other substituents and m are each independently as defined in this application.

[0547] The compounds of the present invention are prepared by the following scheme ak. Unless otherwise specified, the reactions involved in scheme ak can be prepared under similar reaction conditions in the prior art. For details, please refer to the relevant reaction conditions in the preparation examples or embodiments of this application.

[0548] (1) Some compounds were synthesized using the following scheme a:

[0549] M1 is defined as in Scheme 1, and M2-1 is defined as in Scheme 2;

[0550] 'a' indicates the position of the oxygen atom marker;

[0551] The aforementioned REAG3 is C 1-6 Alkyl NHC 1-6 Alkylene NHC 1-6 Alkyl groups, such as

[0552] The R mentioned 211 C 1-6 Alkyl NHC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, such as

[0553] The R mentioned 212 For HOC (=O)C 1-6 Alkylene C(=O)N(C) 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)- or HOC(=O)3-6 heteroalkyleneC(=O)N(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, such as

[0554] The R mentioned 213 for c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene C(=O)N(C) 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)- or *-C(=O)3-6 heteroalkyleneC(=O)N(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, with the * end connected to the nitrogen atom at the c position; as described in R 213 for

[0555] The R mentioned 3a Selected from C 1-20 Alkyl C(=O)-, C 1-20 Alkyl group C(=O)-; R as described 3a for Or acetyl;

[0556] The L mentioned is c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene C(=O)N(C) 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)- or *-C(=O)3-6 heteroalkyleneC(=O)N(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, with the * end connected to the nitrogen atom at the c position; as described above, L is

[0557] The a-end is connected to the oxygen atom at position a;

[0558] The aforementioned REAG4 is The L mentioned 212 C 1-6 Alkylenes or 3-6 heteroalkylenes, such as

[0559] The aforementioned REAG5 is like

[0560] Other substituents and m are each defined independently as in this application.

[0561] Option B:

[0562] M1 is defined as in Scheme 1; M3-1 is defined as in Scheme 4; M5-1 and M5-2 are defined as in Scheme 8; M4-1 is defined as in Scheme 6; M4-2 is defined as in Scheme 7.

[0563] 'a' indicates the position of the oxygen atom marker;

[0564] The R mentioned 3a As defined in Scheme 1; in some implementations, the R... 3a for

[0565] The R mentioned 217 for The R mentioned 217a For BocNHC 1-6 Alkylene, BocNHC 1-6 Alkylene NHC(=O)C 1-6 Alkylene or BocNH 3-6 heteroalkylene NHC(=O)C 1-6 Alkylene; as described by R 217 for

[0566] The aforementioned REAG2 is selected from C 1-20 Alkyl C(=O)-Hal, R 301 C(=O)-OC(=O)R 301 R 301 OC(=O)-OC(=O)OR 301 C 1-20 Alkyl C(=O)OH; the R 301 Each independently is C 1-20 alkyl;

[0567] The R mentioned 218 For R 301 C(=O)-; the aforementioned R 301 C 1-20 Alkyl; in some embodiments, the R 218 CH3C(=O)- or

[0568] The R mentioned 219 for The R mentioned 219a H2NC 1-6 Alkylene, H2NC 1-6 Alkylene NHC(=O)C 1-6 Alkylene or H2N3-6-membered heteroalkylene NHC(=O)C 1-6 Alkylene; as described by R 219 for

[0569] The L mentioned is d represents the carbon atom marker position, and the L... 219 -C(=O)NHC 1-6 Alkylene*, -C(=O)NHC 1-6 Alkylene NHC(=O)C 1-6 Alkylene* or -C(=O)NH3-6-membered heteroalkyleneNHC(=O)C 1-6Alkylene, * the terminal is connected to a carbon atom at the d position; as described above, L is...

[0570] The a-end is connected to the oxygen atom at position a;

[0571] Other substituents and m are each defined independently as in this application.

[0572] In some implementations, REAG2 is Ac2O or

[0573] Option C:

[0574] M1 is as defined in Scheme 1; M3-2 is as defined in Scheme 5; M5-1 is as defined in Scheme 8; a represents the oxygen atom marker position;

[0575] The R mentioned 3a for

[0576] The R mentioned 217 for The R mentioned 217a Boc-valine residue-alanine residue-, Boc-glycine residue-; as described in R 217 for

[0577] The R mentioned 219 for The R mentioned 219a The residues are H-valine residues, alanine residues, and H-glycine residues; as described in R 219 for

[0578] The L mentioned is c represents the nitrogen atom marker position, and the L 219 For -C(=O) valine residues, -alanine residues, and -C(=O) glycine residues, the * and * ends are connected to the nitrogen atom at the c position; as described above, L is...

[0579] The a-end is connected to the oxygen atom at position a;

[0580] Other substituents and m are each defined independently as in this application.

[0581] Option d:

[0582] M1 is as defined in Scheme 1; M4-1 is as defined in Scheme 6; M5-1 is as defined in Scheme 8; a represents the oxygen atom marker position;

[0583] The R mentioned 217 for The R mentioned 217a For BocN(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)C 1-6 Alkylene or BocN(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C 1-6 Alkylene; as described by R 217 for

[0584] The R mentioned 219 for The R mentioned 219a For NH(C) 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)C 1-6 Alkylene or NH(C) 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C 1-6 Alkylene; as described by R 219 for

[0585] The L mentioned is d represents the carbon atom marker position, and the L... 219 -C(=O)N(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)C 1-6 Alkylene* or -C(=O)N(C 1-6 Alkyl)C 1-6 Alkylene N(C) 1-6 Alkyl)C 1-6 Alkylene, * the terminal is connected to a carbon atom at the d position; as described above, L is...

[0586] The a-end is connected to the oxygen atom at position a;

[0587] Other substituents and m are each defined independently as in this application.

[0588] Option e:

[0589] M1 is defined as in Scheme 1; M4-1 is defined as in Scheme 6; M4-2 is defined as in Scheme 7; M5-1 and M5-2 are defined as in Scheme 8; a represents the oxygen atom marker position;

[0590] The R mentioned 3a for

[0591] The R mentioned 217 for The R mentioned 217a For BocNR 217b C 1-6 Alkylene NR 217c C(=O)C 1-6 Alkylene or BocNR 217b C 1-6 Alkylene NR 217b C 1-6 Alkylene, the R 217b and R 217c Each independently is C 1-6 Alkyl, or R 217b and R 217c Together with the nitrogen atoms to which they are attached, they form 5-8 membered heterocyclic groups, such as the R group described above. 217 for

[0592] The R mentioned 219 for The R mentioned 219a For NHR 217b C 1-6 Alkylene NR 217c C(=O)C 1-6 Alkylene or NHR 217b C 1-6 Alkylene NR 217b C 1-6 alkylene, the R 217b and R 217c Each independently is C 1-6 Alkyl, or R 217b and R 217c Together with the nitrogen atoms to which they are attached, they form 5-8 membered heterocyclic groups, such as the R group described above. 219 for

[0593] The L mentioned is d represents the carbon atom marker position, and the L... 219 -C(=O)NR 217b C 1-6 Alkylene NR217c C(=O)C 1-6 Alkylene* or -C(=O)NR 217b C 1-6 Alkylene NR 217b C 1-6 Alkylene*, the R 217b and R 217c Each independently is C 1-6 Alkyl, or R 217b and R 217c Together with the nitrogen atoms they are attached to, they form 5-8 membered heterocyclic groups, with the * end connected to the carbon atom at the d position; as described above, L is...

[0594] The a-end is connected to the oxygen atom at position a;

[0595] Other substituents and m are each defined independently as in this application.

[0596] In some embodiments, the 5-8 membered heterocyclic group contains two nitrogen heteroatoms and no other heteroatoms.

[0597] Option f:

[0598] M1 is as defined in Scheme 1; M2-0 and M2-1 are as defined in Scheme 2; M6 is as defined in Scheme 9;

[0599] 'a' indicates the position of the oxygen atom marker;

[0600] The R mentioned 225 For BnOC(=O)C 1-6 Alkylene C(=O)NHC 1-6 alkoxide C(=O)- or BnOC(=O)C 1-6 Alkylene C(=O)NHC 5-8 Cycloalkylene OC(=O)-, as described in R 225 for

[0601] The R mentioned 226 For HOC (=O)C 1-6 Alkylene C(=O)NHC 1-6 alkeneoxy C(=O)- or HOC(=O)C 1-6 Alkylene C(=O)NHC 5-8 Cycloalkylene OC (=O)-, as described in R 226 for

[0602] The R mentioned227 for c represents the nitrogen atom marker position, and the L 227 For *-C(=O)C 1-6 Alkylene C(=O)NHC 1-6 alkeneoxy C(=O)- or *-C(=O)C 1-6 Alkylene C(=O)NHC 5-8 The cycloalkylene group OC(=O)- has a *terminus connected to a nitrogen atom at the c-position; as described in R 227 for

[0603] The aforementioned REAG5 is like

[0604] The L mentioned is c represents the nitrogen atom marker position, and the L 227 For *-C(=O)C 1-6 Alkylene C(=O)NHC 1-6 alkeneoxy C(=O)- or *-C(=O)C 1-6 Alkylene C(=O)NHC 5-8 The cycloalkylene group OC(=O)- has a *terminus connected to a nitrogen atom at the c-position; as described above, L is...

[0605] The a-end is connected to the oxygen atom at position a;

[0606] Other substituents and m are each defined independently as in this application.

[0607] Option g:

[0608] 'a' indicates the position of the oxygen atom marker;

[0609] The aforementioned REAG2 is selected from C 1-20 Alkyl C(=O)-Hal, R 301 C(=O)-OC(=O)R 301 R 301 OC(=O)-OC(=O)OR 301 C 1-20 Alkyl C(=O)OH; the R 301 Each independently is C 1-20 Alkyl group; the Hal is a halogen (e.g., F, Cl, Br, I);

[0610] The R mentioned 3a For R 301 C(=O)- or R301 OC (=O)-; the R mentioned 301 C 1-20 alkyl;

[0611] The L mentioned is c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene NR 213b C 1-6 Alkylene NR 213c C(=O)-、*-C(=O)C 1-6 Alkylene C(=O)NR 213b C 1-6 Alkylene NR 213c C(=O)-、*-C(=O)C 1-6 Alkylene C(=O)NR 213b C 1-6 Alkylene NC 1-6 alkeneoxy C(=O)- or *-C(=O)3-6 heteroalkylene C(=O)NR 213b C 1-6 Alkylene NR 213c C(=O)-, the * end is connected to the nitrogen atom at position c; the R 213b and R 213c Each independently is C 1-6 Alkyl, or R 213b and R 213c Together with the nitrogen atoms they are attached to, they form 5-8 membered heterocyclic groups, such as L as described above.

[0612] The a-end is connected to the oxygen atom at position a;

[0613] Other substituents and m are each defined independently as in this application.

[0614] In some implementations, REAG2 is

[0615] Option h:

[0616] 'a' indicates the position of the oxygen atom marker;

[0617] The aforementioned REAG1 is The Hal is a halogen (e.g., F, Cl, Br, I); the REAG6 is selected from C. 1-6 Alkyl-OH, such as methanol and ethanol; in some embodiments, Hal is Cl. 3b C 1-6 Alkyl groups, such as methoxy and ethoxy groups;

[0618] The L mentioned is c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene C(=O)NR 213b C 1-6 Alkylene NR 213c C(=O)-, the * end is connected to the nitrogen atom at position c; the R 213b and R 213c Each independently is C 1-6 Alkyl, or R 213b and R 213c Together with the nitrogen atoms they are attached to, they form 5-8 membered heterocyclic groups, such as L as described above.

[0619] The a-end is connected to the oxygen atom at position a;

[0620] Other substituents and m are each defined independently as in this application.

[0621] Option i:

[0622] 'a' indicates the position of the oxygen atom marker;

[0623] The aforementioned REAG2 is C 1-20 Alkyl C(=O)-Hal, R 301 C(=O)-OC(=O)R 301 R 301 OC(=O)-OC(=O)OR 301 C 1-20 Alkyl C(=O)OH; the R 301 Each independently is C 1-20 Alkyl group; the Hal is a halogen (e.g., F, Cl, Br, I);

[0624] The R mentioned 3a R 228 R 229 Each was independently selected from C 1-20 Alkyl C(=O)-, C 1-20 alkoxy group C(=O)-; the L is c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 1-6 Alkylene C(=O)NR 213b C 1-6 Alkylene NR 213c C(=O)-, the * end is connected to the nitrogen atom at position c; the R 213b and R 213c Each independently is C1-6 Alkyl, or R 213b and R 213c Together with the nitrogen atoms they are attached to, they form 5-8 membered heterocyclic groups, such as L as described above.

[0625] The a-end is connected to the oxygen atom at position a;

[0626] Other substituents and m are each defined independently as in this application.

[0627] In some implementations, the REAG2 is

[0628] In some implementations, the R 3a for

[0629] In some implementations, the R 228 R 229 It is also an acetyl group.

[0630] Option j:

[0631] M1 is defined as in Scheme 1; M2-0 is defined as in Scheme 2; and M7 is defined as in Scheme 10.

[0632] 'a' indicates the position of the oxygen atom marker;

[0633] The R mentioned 3a Selected from C 1-20 Alkyl C(=O)-, C 1-20 Alkyl group C(=O)-;

[0634] The R mentioned 217 for The R mentioned 217a For R 217b C 1-6 alkylene C(=O)-, the R 217b for As described in R 217 for

[0635] The L mentioned is c represents the nitrogen atom marker position, and the L 219 For L 219b C 1-6 The alkylene C(=O)-, * is connected to the nitrogen atom at the c position; the L 219b for **Terminal and C 1-6 Alkylene linkage; as described above, L is...

[0636] The a-end is connected to the oxygen atom at position a;

[0637] Other substituents and m are each defined independently as in this application.

[0638] In some implementation schemes, R 3a for

[0639] Synthesis route k:

[0640] M1 is as defined in Scheme 1; M2-0 is as defined in Scheme 2;

[0641] 'a' indicates the position of the oxygen atom marker;

[0642] The aforementioned REAG3 is C 1-6 Alkyl NHC 1-6 Alkylene NHC 1-6 Alkyl, H2NC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NH2, H2NC 6-10 Aromatic C 1-6 Alkylene NH2, such as

[0643] The R mentioned 211 C 1-6 Alkyl NHC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, H2NC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, H2NC 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, such as

[0644] The aforementioned REAG4 is HO(C=O)C 6-10 arylene (C=O)OH or The L mentioned 212 C 1-6 Alkylene, 3-6 heteroalkylene, said R 212c As stated in this application R 1 As defined; as described above, REAG4 is

[0645] The R mentioned 212 For HOC (=O)C 6-10aryl (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, HOC(=O)C 1-6 Alkylene (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, HOC(=O)C 6-10 aryl (C=O)(C 1-6 Alkyl)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, HOC(=O)C 1-6 Alkylene (C=O)NHC 6-10 Aromatic C 1-6 Alkylene NHC(=O)- or HOC(=O)C 1-6 Alkylene (C=O)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, as described by R 212 for

[0646] The aforementioned REAG5 is like

[0647] The R mentioned 213 for c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 6-10 aryl (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, *-C(=O)C 1-6 Alkylene (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, *-C(=O)C 6-10 aryl (C=O)(C 1-6 Alkyl)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, *-C(=O)C 1-6 Alkylene (C=O)NHC 6-10 Aromatic C 1-6 Alkylene NHC (=O)- or *-C (=O)C1-6 Alkylene (C=O)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 The alkylene group NHC(=O)- has a * terminal bonded to a nitrogen atom at the c-position; as described in R 213 for

[0648] The L mentioned is c represents the nitrogen atom marker position, and the L 213 For *-C(=O)C 6-10 aryl (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, *-C(=O)C 1-6 Alkylene (C=O)(C 1-6 Alkyl)NC 1-6 Alkylene N(C) 1-6 Alkyl)C(=O)-, *-C(=O)C 6-10 aryl (C=O)(C 1-6 Alkyl)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 Alkylene NHC(=O)-, *-C(=O)C 1-6 Alkylene (C=O)NHC 6-10 Aromatic C 1-6 Alkylene NHC (=O)- or *-C (=O)C 1-6 Alkylene (C=O)NHC 1-6 Alkylene C 6-10 Aromatic C 1-6 The alkylene group NHC(=O)- has a * terminal bonded to a nitrogen atom at the c-position; as described above, L is...

[0649] The a-end is connected to the oxygen atom at position a;

[0650] Other substituents and m are each defined independently as in this application.

[0651] In some implementations, the R 212c Halogen, -OH, C 1-6 Alkyl, C 1-6 Alkyl group. Attached Figure Description

[0652] Figure 1 shows the weight change curve of the experimental animals after the start of treatment.

[0653] Figure 2 shows the growth curve of the NCI-N87 subcutaneous xenograft model after the start of treatment.

[0654] Figure 3 shows the weight change curve of the experimental animals after the start of treatment.

[0655] Figure 4 shows the growth curve of the NCI-N87 subcutaneous xenograft tumor model after the start of treatment.

[0656] Figure 5 shows the weight change curve of the experimental animals after the start of treatment.

[0657] Figure 6 shows the growth curve of the Capan-1 subcutaneous xenograft tumor model after the start of treatment.

[0658] Figure 7 shows the weight change curve of the experimental animals after the start of treatment.

[0659] Figure 8 shows the growth curve of the Capan-1 subcutaneous xenograft tumor model after the start of treatment.

[0660] Figure 9 shows the weight change curve of the experimental animals after the start of treatment.

[0661] Figure 10 shows the growth curve of the MDA-MB-231 subcutaneous xenograft model after the start of treatment.

[0662] Note: QW means once a week; wks means week; BIW means twice a week; Body Weight (g): body weight (grams); Tumor Volume: tumor volume; Days after Grouping: days after grouping; Compound: compound; Vehicle: solvent; Irinotean: irinotecan. Detailed Implementation

[0663] The compounds of formula (I) of this invention can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of formula (I), methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0664] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0665] Abbreviation:

[0666] Preparation Example 1: Synthesis of intermediate CBTX-PNP

[0667] Cabazitaxel (CBTX, 15 g, 17.94 mmol, 1.0 eq) was dissolved in dichloromethane (105 ml), and the system was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (0.22 g, 1.79 mmol, 0.1 eq) was added, followed by the dropwise addition of a dichloromethane solution of diisopropylethylamine (4.64 g, 35.89 mmol, 2.0 eq). After stirring for 10 minutes, a dichloromethane solution of p-nitrophenyl chloroformate (5.43 g, 26.92 mmol, 1.5 eq) (15 ml) was added dropwise. The reaction was then maintained at 10–15 °C with stirring for 1 hour. The reaction was quenched by the dropwise addition of 5% citric acid (180 ml). The organic phase was washed with 5% citric acid (180 ml), water (180 ml), and saturated sodium chloride (180 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After dissolving the residue in dichloromethane (18 ml), methyl tert-butyl ether (90 ml) was added dropwise. After the addition was complete, the mixture was stirred at 25±5℃ for 60 minutes. The mixture was then filtered, and the filter cake was washed with methyl tert-butyl ether (50 ml). The filter cake was collected and dried to obtain 16.2 g of white solid, with a yield of 90.2%.

[0668] Preparation Example 2: Synthesis of intermediate PTX-PNP

[0669] Paclitaxel (PTX, 5.0 g, 5.86 mmol, 1.0 eq) was dissolved in dichloromethane (30 ml), and the system was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (0.143 g, 1.17 mmol, 0.2 eq) was added, followed by dropwise addition of a dichloromethane solution of diisopropylethylamine (1.51 g, 11.71 mmol, 2.0 eq). After stirring for 10 minutes, a dichloromethane solution of p-nitrophenyl chloroformate (1.77 g, 8.78 mmol, 1.5 eq) (10 ml) was added dropwise. The reaction was then maintained at 0 ± 5 °C with stirring for 1 hour. The reaction was quenched by dropwise addition of 5% citric acid (40 ml). The organic phase was washed with 5% citric acid (40 ml) and saturated sodium chloride (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography [V]. PE :V EA The solution was purified at a ratio of 2:1 to obtain 4.5 g of white solid, with a yield of 75.42%.

[0670] Preparation Example 3: Synthesis of DTX-PNP

[0671] Docetaxel (DTX, 5 g, 6.19 mmol, 1.0 eq) was dissolved in dichloromethane (40 ml), and the system was cooled to -5 to 0 °C. Diisopropylethylamine (1.6 g, 12.38 mmol, 2.0 eq) was added, and the mixture was stirred for 10 minutes. Then, a dichloromethane solution (15 ml) of p-nitrophenyl chloroformate (1.31 g, 6.50 mmol, 1.05 eq) was added dropwise. After the addition was complete, the mixture was kept at 20–25 °C with stirring for 3 hours. The reaction was quenched by adding 5% citric acid (40 ml). The organic phase was washed with 5% citric acid (40 ml) and saturated sodium chloride (40 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [V]. PE :V EA Purification was performed using a ratio of 2:1 to 1:1, yielding 2.6 g of a white solid, with a yield of 43.18%.

[0672] Preparation Example 4: Synthesis of TBS-SN38

[0673] SN38 (10 g, 25.48 mmol, 1.0 eq) was dissolved in dichloromethane (200 ml) with stirring. Diisopropylethylamine (DIPEA, 11.53 g, 89.19 mmol, 3.5 eq) was added under ice bath conditions, followed by dropwise addition of tert-butyldimethylchlorosilane (9.6 g, 63.71 mmol, 2.5 eq) in dichloromethane (20 ml). After the addition was complete, the reaction was carried out at 20–25 °C for 2.5 hours. The reaction was quenched with 0.2 mol / L HCl (100 ml) solution. The organic phase was washed successively with 0.2 mol / L HCl (100 ml) solution and saturated sodium chloride (100 ml) solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was added to a mixture of EA and PE (V... EA / V PE =1 / 10 (total 110ml) was pulped for 1 hour, filtered, the filter cake was washed with petroleum ether, the solid was collected and dried to obtain 12.4g, with a yield of 96.04%.

[0674] Preparation Example 5: Synthesis of TBS-SN38-PNP

[0675] TBS-SN38 (6.7 g, 13.22 mmol, 1.0 eq) was dissolved in dichloromethane (130 ml). Under a nitrogen atmosphere, the system was cooled to -5 to 0 °C, and 4-dimethylaminopyridine solid (0.323 g, 2.64 mmol, 0.2 eq) and pyridine (6.28 g, 79.34 mmol, 6.0 eq) were added. Then, a dichloromethane solution of p-nitrophenyl chloroformate (8.0 g, 39.67 mmol, 3.0 eq) was added dropwise. The reaction mixture was then stirred at 20–25 °C for 3 hours. The reaction solution was quenched with 0.1 N HCl (50 ml) solution. The organic phase was washed successively with 0.1 N HCl (50 ml), saturated sodium bicarbonate (50 ml), and saturated sodium chloride (50 ml) solutions, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 ml) with stirring, and petroleum ether (150 ml) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours, filtered, and the filter cake was treated with a mixture of dichloromethane and petroleum ether (V). DCM / V PE =1 / 7 (total 30ml) was washed, the filtrate was concentrated, the residue was dissolved in methyl tert-butyl ether (67ml), petroleum ether (67ml) was added dropwise, and the mixture was stirred for 1 hour after the addition was completed. The mixture was then filtered, the filter cake was collected, and dried to obtain 8.4g of off-white solid, with a yield of 95.5%.

[0676] Preparation Example 6: Synthesis of Piv-SN38

[0677] SN38 (5.0 g, 12.74 mmol, 1.0 eq) was dissolved in dichloromethane (150 ml) with stirring. 4-Dimethylaminopyridine (DMAP, 1.56 g, 12.74 mmol, 1.0 eq) and diisopropylethylamine (DIPEA, 1.65 g, 12.74 mmol, 1.0 eq) were added dropwise under ice bath, followed by the dropwise addition of tervastatin (3.32 g, 17.84 mmol, 1.4 eq) in dichloromethane (10 ml). After the addition was complete, the reaction was carried out at 20–25 °C for 3 hours. The reaction was quenched with 0.1 mol / L HCl (100 ml) solution. The organic phase was washed successively with 0.1 mol / L HCl (100 ml) solution and saturated sodium chloride (100 ml) solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was added to a mixture of EA and PE (V... EA / V PE =1 / 5 (total 120ml) was pulped for 1 hour, filtered, the filter cake was washed with petroleum ether, the solid was collected and dried to obtain 5.8g, with a yield of 95.4%.

[0678] Preparation Example 7: Synthesis of Ac-SN38-PNP

[0679] Step 1) Synthesis of Ac-SN38

[0680] SN38 (1.0 g, 2.55 mmol, 1.0 eq) was dissolved in dichloromethane (20 ml) with stirring (DMF was added dropwise to aid dissolution). Under ice bath conditions, 4-dimethylaminopyridine (DMAP, 31 mg, 0.255 mmol, 0.1 eq) and pyridine (0.604 g, 7.65 mmol, 3.0 eq) were added dropwise, followed by the addition of acetic anhydride (0.26 g, 2.55 mmol, 1.0 eq) in dichloromethane (4 ml). After the addition was complete, the reaction mixture was allowed to react at 20–25 °C for 0.5 hours. The reaction solution was diluted with dichloromethane (100 ml). The organic phase was washed successively with 0.5 mol / L HCl (80 ml), saturated sodium bicarbonate (80 ml), water (80 ml), and saturated sodium chloride (80 ml) solutions. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [V]. DCM :V MeOH Purification was performed using a ratio of 70:1 to obtain 0.45 g of a foamy solid, with a yield of 40%.

[0681] Step 2) Synthesis of Ac-SN38-PNP

[0682] Ac-SN38 (0.45 g, 1.04 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL) with stirring. 4-Dimethylaminopyridine (DMAP, 25 mg, 0.207 mmol, 0.2 eq) and pyridine (0.492 g, 6.21 mmol, 6.0 eq) were added dropwise under ice bath conditions, followed by the dropwise addition of p-nitrophenyl chloroformate (0.626 g, 3.11 mmol, 3.0 eq) in dichloromethane (5 mL). After the addition was complete, the mixture was heated to 30 °C and reacted for 3 hours. After the reaction was complete, the mixture was diluted with dichloromethane (30 mL). The organic phase was washed successively with 0.1 mol / L HCl (30 mL) and saturated sodium chloride (30 mL) solution, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [V]. DCM :V MeOH Purification was performed using a ratio of 100:1 to 90:1, yielding 0.6 g of a foamy solid with a yield of 83%.

[0683] Example 1: Preparation of Compound 1

[0684] Step 1) Preparation of compound 1-M1

[0685] Compound 1-M0 (87 mg, 0.99 mmol) was dissolved in dichloromethane (5 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and CBTX-PNP (900 mg, 0.90 mmol) was added dropwise. The mixture was then stirred at 20–25 °C for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =15:1] Separation and purification yielded 650 mg, yield: 76%.

[0686] Step 2) Preparation of compound 1-M2

[0687] Compound 1-M1 (650 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL). Under a nitrogen atmosphere, the solution was cooled to 0 °C, and succinic anhydride (137 mg, 1.37 mmol) and pyridine (162 mg, 2.05 mmol) were added. The mixture was stirred at 20–25 °C for 0.5 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.6 mol / L hydrochloric acid (10 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 630 mg of a white, foamy solid (yield: 88%).

[0688] Step 3) Preparation of compound 1-M3

[0689] Compound 1-M2 (630 mg, 0.60 mmol) was dissolved in dichloromethane (10 mL) with stirring. Then, p-aminobenzyl alcohol (78 mg, 0.63 mmol) and EEDQ (297 mg, 1.20 mmol) were added sequentially, and the reaction mixture was stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =35:1] Separation and purification yielded 600 mg of white solid, yield: 87%.

[0690] Step 4) Preparation of compound 1-M4

[0691] Compound 1-M3 (550 mg, 0.48 mmol) was dissolved in dichloromethane (15 mL) with stirring. TBS-SN38-PNP (352 mg, 0.52 mmol) and 4-dimethylaminopyridine (69 mg, 0.564 mmol) were added sequentially, and the mixture was stirred at 40 °C for 3 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.6 mol / L hydrochloric acid (15 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 440 mg of solid, yield: 55%.

[0692] Step 5) Preparation of Compound 1

[0693] Under a nitrogen atmosphere, at 0–5 °C, a solution of TBAF (102 mg, 0.39 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 1-M4 (440 mg, 0.26 mmol) in dichloromethane (12 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V DCM / V MeOH =30:1] Separation and purification yielded 330 mg of solid, yield: 80%, HPLC purity: 97.95%.

[0694] 1 H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 9.99 (dd, J = 18.2, 10.5Hz, 1H), 8.09–8.01 (m, 1H), 8.01–7.81 (m ,3H),7.72(d,J=7.2Hz,1H),7.65(d,J=7.5Hz,2H),7.57(t,J=7.9Hz,2H),7.42(dd,J=7.5,5.9Hz,6H),7 .28(t,J=7.6Hz,2H),7.18(t,J=7.0Hz,1H),6.93(d,J=2.3Hz,1H),5.91–5.78(m,1H),5.50(s,2H),5.37 (d,J=6.6Hz,1H),5.30(d,J=2.3Hz,2H),5.17–4.87(m,5H),4.69(d,J=9.1Hz,1H),4.44(d,J=8.8Hz,1H), 4.02(s,2H),3.81–3.70(m,1H),3.70–3.36(m,4H),3.27(s,3H),3.19(dd,J=12.8,5.2Hz,4H),3.09(dd, J=15.0,7.4Hz,2H),3.04(s,1H),2.93(t,J=26.6Hz,3H),2.82(d,J=7.0Hz,2H),2.64(dd,J=16.5,7.4Hz, 2H),2.58–2.51(m,3H),2.25(dd,J=14.8,5.1Hz,3H),2.20–2.08(m,2H),1.92–1.72(m,4H),1.62–1.42( m, 5H), 1.35 (t, J = 12.4Hz, 9H), 1.30 (t, J = 7.6Hz, 3H), 0.97 (d, J = 9.7Hz, 6H), 0.89 (td, J = 7.3, 2.7Hz, 3H).

[0695] HRMS: 1573.6519 [M+H] + .

[0696] Example 2: Preparation of Compound 2

[0697] Step 1) Preparation of compound 2-M1

[0698] Compound TBS-SN38 (0.99 g, 1.96 mmol) was dissolved in dichloromethane (20 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.45 g, 11.9 mmol) and pyridine (0.57 g, 7.22 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.36 g, 1.2 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (15 ml) solution of compound 2-MO (0.5 g, 1.78 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.2 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA The mixture was separated and purified to obtain 0.65 g of a pale yellow solid, yield: 44.82%.

[0699] Step 2) Preparation of compound 2-M2

[0700] Under a nitrogen atmosphere at 0–5 °C, a solution of TBAF (0.25 g, 0.959 mmol) in dichloromethane (2 ml) was added to a solution of compound 2-M1 (0.65 g, 0.799 mmol) in dichloromethane (15 ml). After the addition was complete, the mixture was kept at this temperature and stirred for 10 minutes. The reaction solution was then directly concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =65:1~60:1] Separation and purification yielded 0.45g of a pale yellow solid, yield: 80.55%.

[0701] Step 3) Preparation of compound 2-M3

[0702] Compound 2-M2 (0.45 g, 0.644 mmol) was dissolved in dichloromethane (20 mL), cooled to 0–10 °C, and acetic anhydride (0.13 g, 1.29 mmol) was added dropwise under a nitrogen atmosphere, followed by pyridine (0.153 g, 1.93 mmol). The mixture was stirred at 20–25 °C for 1 hour. The reaction solution was washed with 0.2 mol / L hydrochloric acid (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified by a ratio of 60:1 to obtain 0.4 g of solid, yield: 83.84%.

[0703] Step 4) Preparation of compound 2-M4

[0704] Under a nitrogen atmosphere at 0–5°C, TFA (1.5 ml) was added dropwise to a dichloromethane (3 ml) solution of compound 2-M3, and the mixture was stirred and kept at this temperature for 30–50 minutes. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =16:1] Separation and purification yielded 0.26 g of solid, yield: 75.16%.

[0705] Step 5) Preparation of Compound 2

[0706] At 0 °C under a nitrogen atmosphere, a solution of CBTX-PNP (0.45 g, 0.446 mmol) in dichloromethane (9 ml) was added dropwise to a solution of compound 2-M4 (0.26 g, 0.406 mmol) in dichloromethane (12 ml), and the reaction was stirred at 15–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.2 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =70:1] Separation and purification yielded 0.22 g of solid, yield: 36.08%, HPLC purity: 98.255%.

[0707] 1H NMR (400MHz, DMSO) δ9.62(s,1H),8.24(d,J=9.1Hz,1H),8.04(d,J=2.1Hz,1H),7.97(d,J=7.3Hz,2 H),7.79(d,J=9.2Hz,1H),7.72(d,J=7.2Hz,1H),7.69–7.64(m,3H),7.38(d,J=7.1Hz,3H),7.33(t, J=7.6Hz,4H),7.21(dd,J=14.5,7.6Hz,2H),7.13(t,J=6.8Hz,1H),7.07(d,J=5.6Hz,1H),5.79(d, J=8.3Hz,1H),5.53(s,2H),5.36(s,2H),5.35–5.33(m,1H),5.15(s,2H),5.02(d,J=8.1Hz,1H),4.9 5(t,J=8.4Hz,2H),4.65(s,1H),4.42(s,1H),4.02(d,J=9.9Hz,2H),3.89–3.79(m,2H),3.76–3.70 (m,1H),3.55(d,J=7.1Hz,1H),3.23(d,J=6.1Hz,3H),3.20(s,2H),3.17(s,2H),2.68–2.60(m,1H), 2.37(d,J=3.7Hz,3H),2.22(s,3H),2.18(s,2H),1.76(s,3H),1.51(d,J=11.9Hz,4H),1.45(d,J=10 .7Hz,2H),1.35(s,7H),1.30(s,3H),1.28(d,J=7.7Hz,3H),0.97(s,3H),0.95(s,3H),0.93(s,3H).

[0708] HR-MS: 1502.5797 [M+H] + .

[0709] Example 3: Preparation of Compound 3

[0710] Step 1) Preparation of compound 3-M3

[0711] Compound 1-M2 (0.6 g, 0.571 mmol) was dissolved in dichloromethane (15 ml), followed by the addition of 2-aminobenzyl alcohol (77 mg, 0.628 mmol) and EEDQ (0.283 g, 1.14 mmol). The mixture was then stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH=55:1] Separation and purification yielded 0.56 g of white solid, yield: 84%.

[0712] Step 2) Preparation of Compound 3

[0713] Compounds 3-M3 (0.56 g, 0.485 mmol) and Ac-SN38-PNP (0.29 g, 0.485 mmol) were dissolved in dichloromethane (8 ml) under nitrogen atmosphere at -5 to 0 °C with stirring. Then, 4-dimethylaminopyridine (65 mg, 0.533 mmol) was added, and the reaction mixture was stirred at 25 to 30 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.1 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =60:1] Separation and purification yielded 0.14 g of solid, yield: 18%, HPLC purity: 94.331%.

[0714] 1 H NMR (400MHz, DMSO) δ (ppm) 9.59 (d, J = 7.7Hz, 1H), 8.23 ​​(dd, J = 9.1, 3.6Hz, 1H), 8.03 (s, 1H),7.97(s,2H),7.89(dd,J=24.2,9.7Hz,1H),7.76–7.60(m,4H),7.45–7.28(m,6H), 7.23(t,J=8.3Hz,1H),7.19–7.11(m,2H),7.06(s,1H),5.92–5.77(m,1H),5.52(d,J=4 .5Hz,2H),5.35(s,3H),5.20–4.87(m,5H),4.75–4.61(m,1H),4.44(d,J=9.7Hz,1H),4. 01(s,2H),3.74(d,J=8.0Hz,1H),3.63–3.32(m,4H),3.28–3.23(m,3H),3.17(dd,J=12 .6,6.0Hz,6H),2.91(d,J=10.3Hz,3H),2.81(s,1H),2.75(dd,J=12.3,8.4Hz,2H),2.6 5(d,J=13.8Hz,1H),2.53(s,3H),2.43(d,J=5.8Hz,1H),2.38(s,3H),2.30–2.13(m,5H ),1.81(d,J=7.6Hz,4H),1.50(d,J=5.7Hz,5H),1.40–1.25(m,12H),1.03–0.87(m,9H).

[0715] HR-MS: 1615.6703 [M+H] + .

[0716] Example 4: Preparation of Compound 4

[0717] Step 1) Preparation of compound 4-M1

[0718] Compound 4-M0 (1.68 g, 5.83 mmol) was dissolved in dichloromethane (15 mL) with stirring. Then, p-aminobenzyl alcohol (0.72 g, 5.83 mmol) and EEDQ (2.88 g, 11.65 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 14 hours. The reaction solution was directly filtered, and the filter cake was dried to give 0.92 g of a white solid, yield: 40%.

[0719] Step 2) Preparation of compound 4-M2

[0720] Compound TBS-SN38 (0.6 g, 1.18 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (0.868 g, 7.11 mmol) and pyridine (0.342 g, 4.32 mmol) were added and stirred for 5 minutes. Triphosgene (0.211 g, 0.711 mmol) was then added, and the dropping rate was controlled to keep the internal temperature below 0 °C. After the addition was complete, the solution was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (10 ml) solution of compound 4-M1 (0.466 g, 1.18 mmol). The reaction was then stirred at 20-25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA The mixture was separated and purified at a ratio of 1:1 to obtain 0.52 g of a yellow solid, yield: 47%.

[0721] Step 3) Preparation of compound 4-M3

[0722] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 146 mg, 0.561 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 4-M2 (0.52 g, 0.561 mmol) in dichloromethane (10 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 0.45 g of solid, yield: 98%.

[0723] Step 4) Preparation of compound 4-M4

[0724] Compound 4-M3 (0.45 g, 0.554 mmol) was dissolved in dichloromethane (5 ml) with stirring. The solution was cooled to -5 to 0 °C, and TFA (2.5 ml) was added. The mixture was then stirred at -5 to 0 °C for 0.5 hours. The reaction solution was directly concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =10:1] Separation and purification yielded 0.32 g of foamy solid, yield: 81%.

[0725] Step 5) Preparation of Compound 4

[0726] Under a nitrogen atmosphere, at -5 to 0°C, a solution of CBTX-PNP (0.45 g, 0.45 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 4-M4 (0.32 g, 0.45 mmol) in dichloromethane (10 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 20-25°C for 3 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.1 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 0.12 g of solid, yield: 17%, HPLC purity: 95.685%.

[0727] 1H NMR (400MHz, DMSO) δ10.32(s,1H),10.09(s,1H),8.29(d,J=6.8Hz,1H),8.02(dd,J=25.1,8.2Hz ,3H),7.73(t,J=7.8Hz,1H),7.69–7.54(m,5H),7.47–7.27(m,9H),7.20(d,J=6.9Hz,1H),6.95(s ,1H),5.85(t,J=8.7Hz,1H),5.51(s,2H),5.38(d,J=6.9Hz,1H),5.30(d,J=2.7Hz,2H),5.09(dt, J=24.2,5.9Hz,4H),4.96(d,J=10.2Hz,1H),4.68(s,1H),4.53(s,1H),4.48–4.41(m,1H),4.02(d ,J=1.5Hz,2H),3.91(dd,J=8.9,7.0Hz,1H),3.82–3.70(m,1H),3.59(d,J=6.7Hz,1H),3.27(s,3H ),3.20(s,3H),3.09(q,J=7.5Hz,2H),2.71–2.60(m,1H),2.26(s,3H),2.16(qd,J=14.2,7.3Hz,2 H),1.99–1.93(m,1H),1.91–1.76(m,4H),1.63(dd,J=14.7,6.7Hz,1H),1.51(s,3H),1.38(s,9H) ,1.30(t,J=7.6Hz,6H),0.99(d,J=10.5Hz,6H),0.90(dd,J=10.0,4.8Hz,3H),0.87–0.78(m,6H).

[0728] LC-MS: 1573.6505 [M+H] + .

[0729] Example 5: Preparation of Compound 5

[0730] Step 1) Preparation of compound 5-M1

[0731] Compound 5-M0 (2 g, 11.42 mmol) was dissolved in dichloromethane (20 ml) with stirring. Then, p-aminobenzyl alcohol (1.48 g, 11.99 mmol) and EEDQ (5.65 g, 22.83 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA=1:1.5] Separation and purification yielded 3g of white solid, yield: 93.74%.

[0732] Step 2) Preparation of compound 5-M2

[0733] Compound TBS-SN38 (1 g, 1.97 mmol) was dissolved in dichloromethane (10 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.45 g, 11.84 mmol) and pyridine (0.56 g, 7.11 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.35 g, 1.18 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (15 ml) solution of compound 5-M1 (0.55 g, 1.97 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA The mixture was separated and purified to obtain 1.1 g of yellow solid, yield: 68.55%.

[0734] Step 3) Preparation of compound 5-M3

[0735] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 0.53 g, 2.03 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 5-M2 (1.1 g, 1.35 mmol) in dichloromethane (10 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA =1:2] Separation and purification yielded 0.8 g of solid, yield: 84.62%.

[0736] Step 4) Preparation of compound 5-M4

[0737] Under a nitrogen atmosphere at 0–5 °C, TFA (3 ml) was added dropwise to a solution of compound 5-M3 (0.8 g, 1.14 mmol) in dichloromethane (6 ml), and the mixture was stirred and kept at this temperature for 1 hour. The reaction solution was then concentrated directly to dryness, and the residue was subjected to silica gel column chromatography [V DCM / V MeOH =8:1] Separation and purification yielded 0.5g of solid, yield: 72.95%.

[0738] Step 5) Preparation of Compound 5

[0739] Under a nitrogen atmosphere at -5 to 0 °C, a solution of CBTX-PNP (1 g, 1.0 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 5-M4 (0.5 g, 0.835 mmol) in dichloromethane (10 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 15-25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.2 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 0.3 g of solid, yield: 24.59%, HPLC purity: 93.61%.

[0740] MS(ESI): 1460.5741 [M+H] + .

[0741] 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.33 (d, J = 5.6Hz, 1H), 10.04 (s, 1H), 8.08–7.95 (m, 3H), 7.85 (d ,J=9.1Hz,1H),7.73(dd,J=6.4,3.7Hz,1H),7.66(t,J=7.6Hz,2H),7.59–7.54(m,2H),7.43(ddd ,J=12.0,5.1,3.6Hz,4H),7.40–7.23(m,5H),7.16(t,J=7.3Hz,1H),6.94(d,J=3.4Hz,1H),5.79 (t,J=9.2Hz,1H),5.51(s,2H),5.37(dd,J=12.1,7.1Hz,1H),5.32–5.26(m,2H),5.11(dd,J=12. 6,5.8Hz,1H),5.07–5.03(m,1H),4.96(dd,J=19.1,9.5Hz,2H),4.64(s,1H),4.42(s,1H),4.00( s,2H),3.88–3.75(m,2H),3.72(dd,J=10.4,6.6Hz,1H),3.56(d,J=7.0Hz,1H),3.24(s3H),3.16 (s,3H),3.09(d,J=8.0Hz,2H),2.74–2.58(m,1H),2.25(s,3H),2.15(ddd,J=14.3,10.4,7.0Hz, 3H),1.76(s,3H),1.53(s,1H),1.49(s,3H),1.39(s,9H),1.32–1.22(m,5H),1.00–0.86(m,9H).

[0742] Example 6: Preparation of Compound 6

[0743] Step 1) Preparation of compound 6-M1

[0744] Compound 6-M0 (1 g, 9.21 mmol) was dissolved in dichloromethane (20 ml) with stirring. Then, p-aminobenzyl alcohol (1.13 g, 9.21 mmol) and EEDQ (4.56 g, 18.43 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. PE / V EA =1:1] Separation and purification yielded 1.9g of solid, yield: 96%.

[0745] Step 2) Preparation of compound 6-M2

[0746] Compound 6-M1 (0.90 g, 4.21 mmol) was dissolved in 95% ethanol (20 ml), potassium iodide (1.40 g, 8.42 mmol) was added, and the mixture was stirred for 5 minutes. Then, tert-butylmethyl (2-(methylamino)ethyl)carbamate (1.98 g, 10.53 mmol) was added, and the mixture was stirred at 75 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 600 mg of oily substance, yield: 39%.

[0747] Step 3) Preparation of compound 6-M3

[0748] Compound TBS-SN38 (830 mg, 1.64 mmol) was dissolved in dichloromethane (8 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.20 g, 9.83 mmol) and pyridine (473 mg, 5.98 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (292 mg, 0.98 mmol) was added dropwise, controlling the dropping rate to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 15 minutes. The reaction solution was then slowly added to a dichloromethane (10 ml) solution of compound 6-M2 (600 mg, 1.64 mmol), and the mixture was stirred at 20–25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 800 mg of yellow solid, yield: 54%.

[0749] Step 4) Preparation of compound 6-M4

[0750] Under a nitrogen atmosphere at 0–5 °C, TFA (4 ml) was added dropwise to a dichloromethane (8 ml) solution of compound 6-M3 (0.4 g, 0.43 mmol), and the reaction was stirred at this temperature for 0.5 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =10:1] Separation and purification yielded 460 mg of solid, yield: 64%.

[0751] Step 5) Preparation of compound 6-M5

[0752] Under a nitrogen atmosphere at -5 to 0 °C, a solution of CBTX-PNP (557 mg, 0.3 mmol) in dichloromethane (5 ml) was added dropwise to a solution of compound 6-M4 (460 mg, 0.58 mmol) in dichloromethane (10 ml) (with 4 drops of DIPEA added). The reaction mixture was then stirred at 15 to 25 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 420 mg of solid, yield: 45%.

[0753] Step 6) Preparation of Compound 6

[0754] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (66 mg, 0.25 mmol) in dichloromethane (1 ml) was added dropwise to a solution of compound 6-M5 (420 mg, 0.25 mmol) in dichloromethane (5 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V DCM / V MeOH =30:1] Separation and purification yielded 280 mg of solid, yield: 71%, HPLC purity: 98.41%.

[0755] MS(ESI): 1545.6691 [M+H] + .

[0756] 1H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 9.99 (d, J = 5.0Hz, 1H), 8.05 (d, J = 9.8Hz, 1H), 7.98 (d, J = 7.4Hz, 2H) ,7.95–7.82(m,1H),7.73(t,J=7.2Hz,1H),7.65(t,J=6.0Hz,2H),7.60–7.51(m,2H),7.49–7.31(m,6H),7.29 (d,J=6.0Hz,2H),7.16(t,J=7.1Hz,1H),6.92(s,1H),5.83(q,J=9.2Hz,1H),5.50(s,2H),5.37(d,J=6.9Hz,1 H),5.30(d,J=1.9Hz,2H),5.17–5.01(m,3H),5.01–4.89(m,2H),4.69(d,J=5.1Hz,1H),4.44(s,1H),4.01(s, 2H),3.81–3.69(m,1H),3.58(d,J=5.1Hz,1H),3.53–3.35(m,1H),3.26(d,J=5.1Hz,3H),3.19(d,J=6.7Hz,3 H),3.09(q,J=7.4Hz,2H),3.01(d,J=43.7Hz,2H),2.81(s,2H),2.66(d,J=7.1Hz,3H),2.44(dd,J=14.7,7.0H z,3H),2.25(d,J=6.6Hz,3H),2.20(t,J=7.5Hz,3H),2.18–2.07(m,2H),1.80(dd,J=21.3,8.9Hz,4H),1.48(d ,J=19.3Hz,5H),1.35(t,J=9.9Hz,9H),1.30(t,J=7.6Hz,3H),0.97(d,J=10.0Hz,6H),0.90(t,J=7.4Hz,3H).

[0757] Example 7: Preparation of Compound 7

[0758] Step 1) Preparation of compound 7-M1

[0759] Compound 7-M0 (20 g, 184.9 mmol) and succinic anhydride (27.76 g, 277.4 mmol) were dissolved in tetrahydrofuran (180 ml). Under a nitrogen atmosphere, the mixture was cooled to -5 to 0 °C, and diisopropylethylamine (47.8 g, 369.9 mmol) was added. The mixture was then stirred and reacted overnight (approximately 14 hours) at 20 to 25 °C. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (200 ml). The pH of the system was adjusted to 3 to 4 with 0.6 mol / L hydrochloric acid. The organic phase was washed with saturated sodium carbonate (150 ml) with stirring. The aqueous phase was adjusted to pH 2 with 6 mol / L hydrochloric acid in an ice bath. The mixture was extracted twice more with ethyl acetate (200 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by slurrying with petroleum ether (200 ml) to give 37 g of a white solid, yield: 96.08%.

[0760] Step 2) Preparation of compound 7-M2

[0761] Compound 7-M1 (1.0 g, 4.80 mmol) was dissolved in dichloromethane (20 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, 1-hydroxybenzotriazole (HOBt, 0.72 g, 5.28 mmol) and diisopropylcarbodiimide (DIC, 0.67 g, 5.28 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 30 minutes. The reaction solution was then added to a dichloromethane (15 ml) solution of ethanolamine (0.44 g, 7.20 mmol) at 0–5 °C. After the addition was complete, the mixture was stirred at 20–25 °C for 30 minutes. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 0.5g of oily substance, yield: 41.43%.

[0762] Step 3) Preparation of compound 7-M3

[0763] Compound 7-M2 (0.2 g, 0.796 mmol) and 4-dimethylaminopyridine (0.107 g, 0.875 mmol) were dissolved in dichloromethane (10 mL) at 0–5 °C under a nitrogen atmosphere. A solution of CBTX-PNP (0.88 g, 0.875 mmol) in dichloromethane (6 mL) was added dropwise, and the mixture was stirred at 20–25 °C for 1.5 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.3 mol / L hydrochloric acid (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOHThe mixture was purified to a ratio of 55:1 to obtain 0.48 g of a white solid, yield: 90.29%.

[0764] Step 4) Preparation of compound 7-M4

[0765] Compound 7-M3 (0.36 g, 0.323 mmol) was dissolved in methanol (12 ml) with stirring. 10% Pd / C (72 mg) was added, and the mixture was purged with hydrogen three times. The reaction mixture was then stirred at 20–25 °C for 1 hour. The reaction solution was filtered directly through diatomaceous earth, and the filtrate was concentrated to dryness to give 0.28 g of a foamy white solid, yield: 84.6%.

[0766] Step 5) Preparation of compound 7-M5

[0767] Compound 7-M4 (280 mg, 0.274 mmol) was dissolved in dichloromethane (18 ml) with stirring. Then, p-aminobenzyl alcohol (37 mg, 0.301 mmol) and EEDQ (136 mg, 0.547 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 0.25 g of white solid, yield: 80.97%.

[0768] Preparation of compound 7

[0769] Referring to the synthesis of compound 1 in Example 1, 1-M3 was replaced with 7-M5 to obtain compound 7 (0.12 g solid, yield: 51.55%, HPLC purity: 94.5%).

[0770] MS (ESI): 1546.6131 [M+H] + .

[0771] 1H NMR (400MHz, DMSO) δ10.32(s,1H),9.98(s,1H),8.15(s,1H),8.05(d,J=9.2Hz,1H),7.97(t,J=9. 5Hz,3H),7.76–7.71(m,1H),7.66(t,J=7.3Hz,2H),7.56(d,J=8.4Hz,2H),7.46–7.40(m,4H),7.36 (d,J=7.3Hz,2H),7.28(d,J=8.4Hz,2H),7.18(t,J=7.1Hz,1H),6.93(s,1H),5.82(d,J=8.8Hz,1H) ,5.50(s,2H),5.40–5.28(m,3H),5.09(dd,J=13.4,10.4Hz,3H),5.04–5.00(m,1H),4.95(d,J=9.5 Hz,1H),4.70(s,1H),4.49(s,1H),4.15(d,J=4.4Hz,2H),4.03(d,J=9.6Hz,2H),3.79–3.70(m,1H) ,3.58(d,J=6.7Hz,1H),3.28(s,3H),3.21(s,3H),3.09(d,J=7.4Hz,2H),2.66(s,1H),2.54(s,2H) ,2.43(d,J=6.5Hz,2H),2.25(s,3H),2.15(dt,J=11.1,6.9Hz,2H),1.80(d,J=17.7Hz,4H),1.48(d ,J=21.4Hz,6H),1.37(s,8H),1.30(t,J=7.5Hz,4H),0.98(d,J=7.2Hz,6H),0.90(t,J=7.3Hz,3H).

[0772] Example 8: Preparation of Compound 8

[0773] Step 1) Preparation of compound 8-M1

[0774] Compound 6-M1 (1 g, 4.68 mmol) was dissolved in 95% ethanol (25 ml), potassium iodide (1.55 g, 9.36 mmol) was added, and the mixture was stirred for 5 minutes. Then, Boc-piperazine (2.18 g, 11.7 mmol) was added, and the reaction was stirred at 75 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =60:1] Separation and purification yielded 0.9g of oily substance, yield: 52%.

[0775] Step 2) Preparation of compound 8-M2

[0776] Compound TBS-SN38 (0.7 g, 1.38 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.01 g, 8.29 mmol) and pyridine (0.4 g, 5.04 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.25 g, 0.83 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (15 ml) solution of compound 8-M1 (0.502 g, 1.38 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 0.85 g of a yellow solid, yield: 68%. (50:1 ratio)

[0777] Step 3) Preparation of compound 8-M3

[0778] Under a nitrogen atmosphere at 0–5 °C, TFA (4 ml) was added dropwise to a solution of compound 8-M2 (0.85 g, 0.95 mmol) in dichloromethane (8 ml), and the reaction was stirred at this temperature for 0.5 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =15:1] Separation and purification yielded 0.45 g of solid, yield: 60%.

[0779] Step 4) Preparation of compound 8-M4

[0780] Under a nitrogen atmosphere, at -5 to 0 °C, a solution of CBTX-PNP (0.56 g, 0.56 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 8-M3 (0.45 g, 0.56 mmol) in dichloromethane (10 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 20-25 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.1 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 0.7g of solid, yield: 74%.

[0781] Step 5) Preparation of Compound 8

[0782] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 110 mg, 0.422 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 8-M4 (0.7 g, 0.422 mmol) in dichloromethane (10 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 0.34 g of solid, yield: 52%, HPLC purity: 98.046%.

[0783] 1 H NMR (400MHz, DMSO) δ (ppm) 10.33 (s, 1H), 10.01 (s, 1H), 8.05 (d, J = 9.8Hz, 1H), 7.99 (d, J = 7.3Hz, 2H ),7.92(d,J=9.8Hz,1H),7.72(t,J=7.2Hz,1H),7.65(t,J=7.5Hz,2H),7.56(d,J=8.4Hz,2H),7.45– 7.36(m,6H),7.29(d,J=8.5Hz,2H),7.18(t,J=7.1Hz,1H),6.92(s,1H),5.83(t,J=8.8Hz,1H),5.51 (s,2H),5.38(d,J=7.0Hz,1H),5.30(d,J=2.2Hz,2H),5.15–5.04(m,3H),4.95(t,J=7.1Hz,2H),4.7 0(s,1H),4.47(s,1H),4.02(s,2H),3.76(dd,J=10.1,6.9Hz,1H),3.59(d,J=7.0Hz,1H),3.52(s,2H ),3.44–3.35(m,2H),3.28(s,3H),3.21(s,3H),3.09(q,J=7.2Hz,2H),2.66(t,J=6.1Hz,3H),2.46( d,J=6.8Hz,4H),2.33(s,2H),2.27(s,3H),2.16(qd,J=14.4,7.4Hz,2H),1.88–1.78(m,4H),1.54(d ,J=21.8Hz,5H),1.37(s,9H),1.30(t,J=7.5Hz,3H),0.98(d,J=10.2Hz,6H),0.90(t,J=7.4Hz,3H).

[0784] MS(ESI): 1543.5 [M+H] + .

[0785] Example 9: Preparation of Compound 9

[0786] Step 1) Preparation of compound 9-M1

[0787] Compound 9-M0 (3 g, 16.39 mmol) and succinic anhydride (1.8 g, 18.03 mmol) were dissolved in dichloromethane (30 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and pyridine (1.56 g, 19.67 mmol) was added. The mixture was then stirred at 20–25 °C for 1 hour. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =30:1] Separation and purification yielded 3.5g, yield: 74.6%.

[0788] Step 2) Preparation of compound 9-M2

[0789] Compound 9-M1 (3.5 g, 12.22 mmol) and p-aminobenzyl alcohol (1.66 g, 13.45 mmol) were dissolved in dichloromethane (30 ml) with stirring. EEDQ (5.44 g, 22.0 mmol) was then added, and the mixture was stirred at 20–25 °C for 2 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =70:1] Separation and purification yielded 2.9 g of white solid, yield: 60.6%.

[0790] Step 3) Preparation of compound 9-M3

[0791] Compound TBS-SN38 (0.7 g, 1.38 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.13 g, 9.26 mmol) and pyridine (0.45 g, 5.6 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.28 g, 0.926 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (15 ml) solution of compound 9-M2 (0.54 g, 1.38 mmol), and the mixture was stirred at 20-25 °C for 0.5 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / VMeOH The mixture was purified by separation and purification at a ratio of 50:1 to obtain 0.7 g of a pale yellow solid, with a yield of 54.83%.

[0792] Step 4) Preparation of compound 9-M4

[0793] Compound 9-M3 (0.7 g, 0.757 mmol) was dissolved in dichloromethane (6 ml) with stirring, cooled to -5 to 0 °C, and TFA (3 ml) was added. The mixture was then stirred at -5 to 0 °C for 1 hour. The reaction solution was directly concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =10:1] Separation and purification yielded 0.58 g of foamy solid, yield: 92.92%.

[0794] Step 5) Preparation of compound 9-M5

[0795] Compound 9-M4 (580 mg, 0.704 mmol) was dissolved in dichloromethane (10 ml) with stirring. The solution was cooled to -5 to 0 °C, and then a solution of CBTX-PNP (840 mg, 0.845 mmol) in dichloromethane (8 ml) was added dropwise. The mixture was then stirred at 20–25 °C for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 0.72 g of foamy solid, yield: 62.84%.

[0796] Step 6) Preparation of Compound 9

[0797] Compound 9-M5 (720 mg, 0.427 mmol) was dissolved in dichloromethane (16 ml) with stirring. The solution was cooled to -5 to 0 °C, and then tetrabutylammonium fluoride (134 mg, 0.512 mmol) in dichloromethane (4 ml) was added dropwise. The mixture was then stirred and kept at this temperature for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =25:1] Separation and purification yielded 0.62 g of solid, yield: 92.37%, HPLC purity: 98.137%.

[0798] 1H NMR (400MHz, DMSO) δ10.33(s,1H),10.00(s,1H),8.05(d,J=9.2Hz,1H),7.98(t,J=10.4Hz,3H) ,7.73(t,J=7.3Hz,1H),7.65(t,J=7.5Hz,2H),7.57(d,J=8.4Hz,2H),7.46–7.37(m,6H),7.29( d,J=8.5Hz,2H),7.20(t,J=6.9Hz,1H),6.93(s,1H),5.86(t,J=8.8Hz,1H),5.51(s,2H),5.39( d,J=7.0Hz,1H),5.30(d,J=2.9Hz,2H),5.11(dt,J=22.0,11.6Hz,3H),4.97(d,J=10.6Hz,2H),4 .72(s,1H),4.50(s,1H),4.03(s,1H),3.77(dd,J=10.1,7.0Hz,1H),3.63–3.51(m,4H),3.29(s ,3H),3.22(s,3H),3.10(q,J=7.3Hz,2H),2.67(s,3H),2.58(s,2H),2.29(s,3H),2.16(dt,J=11 .4,6.9Hz,2H),1.99(s,3H),1.84(s,4H),1.60(dd,J=14.6,9.3Hz,1H),1.52(s,4H),1.39(s,9 H), 1.30 (t, J = 7.6Hz, 3H), 1.18 (t, J = 7.1Hz, 3H), 0.99 (d, J = 10.6Hz, 6H), 0.91 (t, J = 7.4Hz, 3H).

[0799] MS (ESI): 1571.6397 [M+H] + .

[0800] Example 10: Preparation of Compound 10

[0801] Step 1) Preparation of compound 10-M2

[0802] Compound 1-M1 (600 mg, 0.631 mmol) was dissolved in dichloromethane (12 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and glutaric anhydride (86 mg, 0.758 mmol) and pyridine (60 mg, 0.758 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 0.63 g of a white foamy solid, yield: 93.74%.

[0803] Step 2) Preparation of compound 10-M3

[0804] Compound 10-M2 (630 mg, 0.592 mmol) was dissolved in dichloromethane (20 mL) with stirring. Then, p-aminobenzyl alcohol (88 mg, 0.71 mmol) and EEDQ (293 mg, 1.18 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =25:1] Separation and purification yielded 0.6 g of white solid, yield: 86.67%.

[0805] Step 3) Preparation of compound 10-M4

[0806] Compound 10-M3 (600 mg, 0.513 mmol) and TBS-SN38-PNP (380 mg, 0.564 mmol) were dissolved in dichloromethane (20 mL) with stirring. Then, 4-dimethylaminopyridine (69 mg, 0.564 mmol) was added, and the mixture was stirred at 30–35 °C for 4 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.3 mol / L hydrochloric acid (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =35:1] Separation and purification yielded 0.3g of solid, yield: 34.35%.

[0807] Step 4) Preparation of Compound 10

[0808] Under a nitrogen atmosphere, at 0–5 °C, a solution of TBAF (56 mg, 0.211 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 10-M4 (300 mg, 0.176 mmol) in dichloromethane (12 ml), and the reaction was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V DCM / V MeOH=30:1] Separation and purification yielded 0.22 g of solid, yield: 78.61%, HPLC purity: 98.1%.

[0809] 1 H NMR (400MHz, DMSO) δ10.33(s,1H),9.90(d,J=3.8Hz,1H),8.04(d,J=9.7Hz,1H),8.01–7.85(m,3H),7.73(t,J= 6.6Hz,1H),7.64(dd,J=8.2,5.4Hz,2H),7.57(d,J=7.6Hz,2H),7.42(dd,J=10.7,2.9Hz,6H),7.28(d,J=8.5Hz, 2H),7.18(d,J=6.9Hz,1H),6.92(s,1H),5.86(dd,J=20.3,8.5Hz,1H),5.50(s,2H),5.37(s,1H),5.30(d,J=1.9 Hz,2H),5.08(td,J=12.1,2.3Hz,3H),4.94(d,J=8.4Hz,1H),4.69(d,J=3.5Hz,1H),4.45(dd,J=7.5,3.7Hz,1H) ,4.01(s,2H),3.75(s,1H),3.59(t,J=7.6Hz,1H),3.49(s,1H),3.38(s,1H),3.28–3.25(m,3H),3.19(dd,J=8. 7,4.1Hz,3H),3.09(q,J=7.3Hz,2H),2.99(s,1H),2.96(d,J=4.7Hz,1H),2.90(s,1H),2.84(s,1H),2.80(s,1H) ,2.65(s,1H),2.34(dd,J=14.7,7.5Hz,3H),2.30–2.23(m,4H),2.20–2.10(m,2H),1.87–1.74(m,6H),1.50(d,J =3.1Hz, 5H), 1.37 (dd, J = 6.6, 3.4Hz, 9H), 1.30 (t, J = 7.6Hz, 4H), 0.98 (d, J = 10.6Hz, 6H), 0.90 (t, J = 7.3Hz, 3H).

[0810] MS(ESI): 1587.6608 [M+H] + .

[0811] Example 11: Preparation of Compound 11

[0812] Step 1) Preparation of compound 11-M1

[0813] Compound 1-M1 (82 g, 0.863 mmol) and diethylene glycol anhydride (0.2 g, 1.73 mmol) were dissolved in dichloromethane (15 ml). The mixture was cooled to -5 to 0 °C under a nitrogen atmosphere, and pyridine (0.2 g, 2.59 mmol) was added. The mixture was then stirred at 20–25 °C for 0.5 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.1 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 0.6 g of white solid, yield: 65%.

[0814] Step 2) Preparation of compound 11-M2

[0815] Compound 11-M1 (0.6 g, 0.563 mmol) was dissolved in dichloromethane (15 ml), followed by the addition of p-aminobenzyl alcohol (76 mg, 0.619 mmol) and EEDQ (0.278 g, 1.13 mmol). The mixture was then stirred at 20–25 °C for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 0.5 g of white solid, yield: 76%.

[0816] Step 3) Preparation of compound 11-M3

[0817] Compounds 11-M2 (0.5 g, 0.427 mmol) and TBS-SN38-PNP (0.315 g, 0.469 mmol) were dissolved in dichloromethane (8 ml) under a nitrogen atmosphere at -5 to 0 °C with stirring. Then, 4-dimethylaminopyridine (57 mg, 0.469 mmol) was added, and the mixture was stirred at 35 to 40 °C for 5 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.1 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 0.4 g of solid, yield: 54%.

[0818] Step 4) Preparation of Compound 11

[0819] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 62 mg, 0.235 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 11-M3 (0.4 g, 0.235 mmol) in dichloromethane (10 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 0.26 g of solid, yield: 69%, HPLC purity: 96.891%.

[0820] 1 H NMR (400MHz, DMSO) δ (ppm) 10.52 (s, 1H), 10.33 (s, 1H), 8.04 (d, J = 9.8Hz, 1H), 7.98 (d, J = 7.3Hz, 2H ),7.90(d,J=6.4Hz,1H),7.73(t,J=7.3Hz,1H),7.64(dd,J=14.2,7.0Hz,4H),7.48–7.37(m,6H),7 .31(dd,J=7.9,4.7Hz,2H),7.16(d,J=6.8Hz,1H),6.93(s,1H),5.83(d,J=7.1Hz,1H),5.51(s,2H) ,5.37(d,J=6.4Hz,1H),5.30(s,2H),5.17–5.05(m,3H),5.01–4.88(m,2H),4.68(d,J=9.6Hz,1H), 4.53–4.42(m,2H),4.38(dd,J=15.1,7.3Hz,1H),4.11(d,J=14.2Hz,2H),4.01(s,2H),3.87–3.38( m,5H),3.28–3.25(m,3H),3.19(d,J=6.4Hz,3H),3.09(dd,J=14.9,7.2Hz,2H),2.95(t,J=18.0Hz, 3H),2.85(d,J=3.8Hz,3H),2.64(s,1H),2.28–2.22(m,3H),2.19–2.13(m,2H),1.81(d,J=11.5Hz, 4H), 1.50 (s, 5H), 1.37 (s, 9H), 1.30 (t, J = 7.6Hz, 3H), 0.98 (d, J = 9.7Hz, 6H), 0.90 (t, J = 7.4Hz, 3H).

[0821] MS(ESI): 1589.6322 [M+H] + .

[0822] Example 12: Preparation of Compound 12

[0823] Step 1) Preparation of compound 12-M1

[0824] Di-tert-butyl dicarbonate (2.00 g, 9.16 mmol) was dissolved in dichloromethane (6 ml). Compound 12-M0 (2.13 g, 18.3 mmol) dissolved in dichloromethane (20 ml) was added dropwise under ice bath conditions. The mixture was stirred at 20–25 °C for 1.5 hours. The mixture was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 1.90 g of yellow liquid, yield: 96%. (ratio: 100:1)

[0825] Step 2) Preparation of compound 12-M2

[0826] Compound 12-M1 (1.90 g, 8.78 mmol) and succinic anhydride (1.76 g, 17.6 mmol) were dissolved in dichloromethane (20 ml). The mixture was cooled to -5 to 0 °C under a nitrogen atmosphere, and pyridine (2.08 g, 26.3 mmol) was added. The mixture was then stirred at 20–25 °C for 0.5 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 2.2 g of a yellow oily substance, yield: 79%. (50:1 ratio)

[0827] Step 3) Preparation of compound 12-M3

[0828] Compound 12-M2 (2.2 g, 6.95 mmol) was dissolved in dichloromethane (25 ml), followed by the addition of p-aminobenzyl alcohol (856 mg, 6.95 mmol) and EEDQ (3.44 g, 13.9 mmol). The mixture was then stirred at 20–25 °C for 16 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =60:1] Separation and purification yielded 1.65 g of white solid, yield: 56%.

[0829] Step 3) Preparation of compound 12-M4

[0830] Compound TBS-SN38 (600 mg, 1.18 mmol) was dissolved in dichloromethane (6 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (868 mg, 7.11 mmol) and pyridine (342 mg, 4.32 mmol) were added, and the mixture was stirred for 5 minutes. Then, a solution of triphosgene (211 mg, 0.71 mmol) in dichloromethane (1.5 ml) was added, and the dropping rate was controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a solution of compound 12-M3 (500 mg, 1.18 mmol) in dichloromethane (15 ml). The mixture was then stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =70:1] Separation and purification yielded 830 mg of a yellow solid, yield: 73%.

[0831] Step 4) Preparation of compound 12-M5

[0832] Under a nitrogen atmosphere at 0–5 °C, TFA (2 ml) was added dropwise to a dichloromethane (4 ml) solution of compound 12-M4 (830 mg, 0.87 mmol), and the reaction was stirred at this temperature for 0.5 hours. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =15:1] Separation and purification yielded 600 mg of yellow solid, yield: 80%.

[0833] Step 5) Preparation of compound 12-M6

[0834] Under a nitrogen atmosphere, at -5 to 0°C, a solution of CBTX-PNP (703 mg, 0.70 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 12-M5 (0.25 g, 0.3 mmol) in dichloromethane (10 ml) (with 6 drops of DIPEA added). The reaction mixture was then stirred at 15 to 25°C for 3 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =60:1] Separation and purification yielded 770 mg of solid, yield: 63%.

[0835] Step 6) Preparation of Compound 12

[0836] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (118 mg, 0.45 mmol) in dichloromethane (2 ml) was added dropwise to a solution of compound 12-M6 (770 mg, 0.45 mmol) in dichloromethane (10 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 380 mg of yellow solid, yield: 53%, HPLC purity: 99.00%.

[0837] 1 H NMR (400MHz, DMSO) δ (ppm) 10.38 (s, 1H), 10.04 (d, J = 12.4Hz, 1H), 8.15–7.91 (m, 4H), 7.84–7.74 (m, 1H) ),7.70(dd,J=14.6,7.1Hz,2H),7.63(t,J=8.9Hz,2H),7.46(t,J=6.3Hz,6H),7.33(t,J=7.1Hz,2H),7. 22(s,1H),6.98(d,J=3.4Hz,1H),5.91(dt,J=16.9,8.5Hz,1H),5.54(d,J=16.8Hz,2H),5.49–5.31(m,3 H),5.25–4.95(m,5H),4.74(dd,J=12.6,4.8Hz,1H),4.52(d,J=18.2Hz,1H),4.06(d,J=5.0Hz,2H),3.8 0(d,J=7.4Hz,1H),3.70–3.59(m,1H),3.58–3.41(m,4H),3.33(d,J=3.5Hz,4H),3.29–3.23(m,4H),3.2 3–3.07(m,3H),2.65(dd,J=14.4,8.5Hz,5H),2.41–2.26(m,3H),2.20(qd,J=14.4,7.4Hz,2H),2.00–1. 78(m,4H),1.69(dd,J=14.6,6.8Hz,1H),1.63–1.46(m,5H),1.41(d,J=8.0Hz,9H),1.35(t,J=7.6Hz,3H ),1.21(t,J=6.9Hz,1H),1.14(dd,J=15.5,7.3Hz,2H),1.10–0.98(m,9H),0.95(td,J=7.3,2.4Hz,3H).

[0838] MS(ESI): 1601.6731 [M+H] + .

[0839] Example 13: Preparation of Compound 13

[0840] Referring to the preparation method of compound 7-M5 in Example 7, in order to replace 13-M4 (0.8 g white solid, yield: 74.9%) was obtained.

[0841] Following the preparation method of compound 1 in Example 1, 1-M3 was replaced with 13-M4 to obtain compound 13 (0.26 g solid, yield: 33.22%, HPLC purity: 92.076%).

[0842] 1 H NMR (400MHz, DMSO) δ10.39(s,1H),10.03(s,1H),8.10(d,J=9.5Hz,1H),8.06–7.97(m,4H),7.79( t,J=7.3Hz,1H),7.71(t,J=7.5Hz,2H),7.61(d,J=8.5Hz,2H),7.52–7.46(m,4H),7.42(d,J=7.5Hz ,2H),7.33(d,J=8.6Hz,2H),7.24(t,J=7.2Hz,1H),6.98(s,1H),5.89(t,J=8.6Hz,1H),5.56(s,2H ),5.43(d,J=7.0Hz,1H),5.36(d,J=2.1Hz,2H),5.13(dd,J=25.3,10.7Hz,4H),5.01(d,J=9.7Hz,1 H),4.76(s,1H),4.56(s,1H),4.22(t,J=6.3Hz,2H),4.07(s,1H),3.80(dd,J=10.1,6.9Hz,1H),3. 65(d,J=6.8Hz,1H),3.33(s,3H),3.26(s,3H),3.21–3.13(m,4H),2.45(t,J=7.1Hz,2H),2.31(s,3 H),2.21(dt,J=11.3,6.9Hz,2H),2.05(s,3H),1.87(s,3H),1.85–1.79(m,2H),1.56(s,4H),1.42( s, 8H), 1.35 (t, J = 7.6Hz, 4H), 1.23 (t, J = 7.1Hz, 3H), 1.03 (d, J = 8.2Hz, 6H), 0.95 (t, J = 7.4Hz, 3H).

[0843] MS(ESI): 1560.6113 [M+H] + .

[0844] Example 14: Preparation of Compound 14

[0845] Step 1) Preparation of compound 14-M2

[0846] Compound 6-M1 (1.9 g, 8.89 mmol) was dissolved in 95% ethanol (25 ml), potassium iodide (3.11 g, 18.72 mmol) was added, and the mixture was stirred for 5 minutes. Then, tert-butylethyl (2-(ethylamino)ethyl)carbamate (3.04 g, 14.04 mmol) was added, and the mixture was stirred at 75 °C for 14 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =4:1] Separation and purification yielded 1.7g of oily substance, yield: 46.15%.

[0847] Step 2) Preparation of compound 14-M3

[0848] Compound TBS-SN38 (0.8 g, 1.58 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.16 g, 9.47 mmol) and pyridine (0.45 g, 5.68 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.28 g, 0.95 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (15 ml) solution of compound 14-M2 (0.62 g, 1.58 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 0.4 g of a yellow solid, yield: 27.35%.

[0849] Step 3) Preparation of compound 14-M4

[0850] Under a nitrogen atmosphere at 0–5 °C, TFA (1 ml) was added dropwise to a 2 ml solution of compound 14-M3 (0.4 g, 0.43 mmol) in dichloromethane, and the mixture was stirred and kept at this temperature for 1 hour. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =10:1] Separation and purification yielded 0.25 g of solid, yield: 70.07%.

[0851] Step 4) Preparation of compound 14-M5

[0852] Under a nitrogen atmosphere, at -5 to 0°C, a solution of CBTX-PNP (0.3 g, 0.3 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 14-M4 (0.25 g, 0.3 mmol) in dichloromethane (10 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 15-25°C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 0.33 g of solid, yield: 64.6%.

[0853] Step 5) Preparation of Compound 14

[0854] Under a nitrogen atmosphere at 0–5 °C, a solution of tetrabutylammonium fluoride (TBAF, 52 mg, 2.03 mmol) in dichloromethane (1 ml) was added dropwise to a solution of compound 14-M5 (0.33 g, 0.195 mmol) in dichloromethane (5 ml), and the reaction was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =25:1] Separation and purification yielded 0.23 g of solid, yield: 74.76%, HPLC purity: 99.23%.

[0855] 1H NMR (400MHz, DMSO) δ (ppm) 10.35 (s, 1H), 10.07 (d, J = 25.8Hz, 1H), 8.17–7.88 (m, 4 H),7.78(t,J=7.2Hz,1H),7.74–7.58(m,4H),7.53–7.31(m,8H),7.23(t,J=6.7Hz ,1H),7.02(d,J=32.7Hz,1H),5.88(s,1H),5.49(s,2H),5.43(d,J=6.6Hz,1H),5. 33(s,2H),5.23–4.95(m,5H),4.75(s,1H),4.55(s,1H),4.07(s,2H),3.88–3.74( m,1H),3.70–3.39(m,4H),3.34(d,J=2.1Hz,3H),3.25(dd,J=16.1,4.3Hz,4H),3. 20–3.07(m,3H),3.02(d,J=5.9Hz,1H),2.86–2.66(m,4H),2.60(s,1H),2.49(d,J =6.6Hz,2H),2.40(s,1H),2.30(d,J=2.6Hz,3H),2.24–2.10(m,2H),1.85(s,4H), 1.66–1.50(m,5H),1.46–1.28(m,13H),1.14(t,J=6.9Hz,2H),1.09–0.87(m,12H).

[0856] MS(ESI): 1573.6860 [M+H] + .

[0857] Example 15: Preparation of Compound 15

[0858] Referring to the preparation of 7-M5 in Example 7, with replace replace 15-M5 (620 mg white solid, yield: 87%) was obtained.

[0859] Referring to the preparation of compound 1 in Example 1, 1-M3 was replaced with 15-M5 to obtain compound 15 (150 mg solid, yield: 42%, HPLC purity: 95.03%).

[0860] 1H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 9.90 (s, 1H), 8.04 (d, J = 9.8Hz, 1H), 7.98 (d, J = 7.4Hz, 2H),7.92(d,J=7.9Hz,1H),7.78–7.69(m,2H),7.64(t,J=7.5Hz,2H),7.56(d,J=8.5Hz,2H),7. 49–7.39(m,4H),7.36(d,J=7.5Hz,2H),7.27(d,J=8.6Hz,2H),7.19(t,J=7.2Hz,1H),6.91(s,1 H),5.83(t,J=8.7Hz,1H),5.50(s,2H),5.38(d,J=6.9Hz,1H),5.30(d,J=2.4Hz,2H),5.15–5.0 0(m,4H),4.96(d,J=9.8Hz,1H),4.70(s,1H),4.51(s,2H),4.08–3.96(m,2H),3.82–3.70(m,1H ),3.59(d,J=6.6Hz,2H),3.29(s,3H),3.21(s,3H),3.11(d,J=7.2Hz,2H),2.73–2.60(m,1H),2 .35–2.22(m,5H),2.13(ddd,J=21.9,13.0,7.2Hz,4H),1.97(dd,J=21.5,11.2Hz,2H),1.89–1. 69(m,8H),1.70–1.38(m,8H),1.42–1.25(m,13H),0.98(d,J=6.8Hz,6H),0.89(t,J=7.4Hz,3H).

[0861] ES (ESI): 1614.6663 [M+H] + .

[0862] Example 16: Preparation of Compound 16

[0863] Following the preparation method of compound 6 in Example 6, compound 16 was obtained by replacing CBTX-PNP with PTX-PNP (900 mg solid, yield: 80%, HPLC purity: 98.29%).

[0864] MS(ESI): 1563.5 [M+H] + .

[0865] 1H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 9.95 (d, J = 6.3Hz, 1H), 9.20 (dd, J = 16.8, 8.8Hz, 1H), 8.08–8.02 (m, 1 H),7.98(d,J=7.1Hz,2H),7.84(dd,J=15.8,7.2Hz,2H),7.72(d,J=7.4Hz,1H),7.66(t,J=7.4Hz,2H),7.60–7. 37(m,10H),7.28(d,J=8.3Hz,2H),7.18(s,1H),6.92(s,1H),6.29(s,1H),5.83(t,J=9.0Hz,1H),5.63–5.47( m,3H),5.41(d,J=6.6Hz,1H),5.31(s,2H),5.22(dd,J=19.3,9.0Hz,1H),5.08(dd,J=24.1,12.1Hz,2H),4.95– 4.85(m,2H),4.59(d,J=5.0Hz,1H),4.11(t,J=9.0Hz,1H),4.01(t,J=10.1Hz,2H),3.58(t,J=7.3Hz,1H),3.5 2–3.35(m,2H),3.29–3.16(m,2H),3.09(dd,J=14.6,7.1Hz,2H),2.84(d,J=18.6Hz,3H),2.67–2.59(m,1H),2. 45–2.27(m,5H),2.25(d,J=5.7Hz,3H),2.14(dd,J=11.3,7.1Hz,3H),2.11(d,J=8.7Hz,3H),2.01(s,2H),1.8 0(s,4H),1.68–1.59(m,1H),1.49(s,4H),1.30(t,J=7.6Hz,3H),1.01(d,J=8.1Hz,6H),0.89(t,J=7.4Hz,3H).

[0866] Example 17: Preparation of Compound 17

[0867] Compound 6 (220 mg, 0.14 mmol) was dissolved in dichloromethane (15 mL) with stirring. Acetic anhydride (16 mg, 0.16 mmol), DMAP (1 mg, 0.01 mmol), and pyridine (52 mg, 0.43 mmol) were added sequentially at 0–5 °C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.2 mol / L hydrochloric acid (20 mL), saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 110 mg of white solid, yield: 49%, HPLC purity: 97.97%.

[0868] 1 H NMR (400MHz, DMSO) δ (ppm) 9.63 (d, J = 184.3Hz, 1H), 8.15 (d, J = 9.1Hz, 1H), 8.01 (d, J = 7.6Hz, 2H ),7.76(d,J=2.1Hz,1H),7.54–7.47(m,2H),7.41(t,J=7.4Hz,4H),7.28(d,J=7.0Hz,2H),7.25 –7.17(m,7H),6.15(s,1H),5.60(d,J=17.2Hz,1H),5.54(d,J=7.0Hz,1H),5.33(s,1H),5.28(s ,1H),5.17(s,2H),5.06(d,J=12.0Hz,1H),4.91(dd,J=10.2,5.3Hz,2H),4.72(s,1H),4.21(d, J=8.5Hz,1H),4.07(d,J=8.3Hz,1H),3.85–3.72(m,2H),3.49–3.37(m,1H),3.19(d,J=7.1Hz,3 H),3.08(dd,J=15.2,7.5Hz,2H),2.82(d,J=9.6Hz,3H),2.76–2.35(m,9H),2.27(d,J=9.8Hz,3 H),2.22–2.14(m,2H),2.06(dd,J=14.1,7.4Hz,2H),1.93(t,J=14.1Hz,4H),1.84–1.64(m,9H) ,1.60(d,J=7.3Hz,4H),1.32(d,J=7.6Hz,3H),1.26(s,9H),1.10(s,6H),0.89(t,J=7.4Hz,3H).

[0869] MS(ESI): 1587.6 [M+H]+ .

[0870] Example 18: Preparation of Compound 18

[0871] Step 1) Preparation of compound 18-M1

[0872] Camptothecin (CPT, 1 g, 2.87 mmol) was dissolved in dichloromethane (20 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (2.1 g, 17.22 mmol) and pyridine (0.82 g, 10.33 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (BTC, 0.52 g, 1.72 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (20 ml) solution of compound 18-MO (1.05 g, 2.87 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was analyzed by silica gel column chromatography [V]. DCM / V MeOH The mixture was purified by separation and purification at a ratio of 50:1 to obtain 1.4 g of a yellow solid, yield: 65.92%.

[0873] Step 2) Preparation of compound 18-M2

[0874] Under a nitrogen atmosphere at 0–5 °C, TFA (2 ml) was added dropwise to a dichloromethane (4 ml) solution of compound 18-M1 (0.8 g, 1.08 mmol), and the reaction was stirred at this temperature for 1 hour. The reaction solution was then concentrated to dryness, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =10:1] Separation and purification yielded 0.5g of solid, yield: 72.28%.

[0875] Step 3) Preparation of Compound 18

[0876] Under a nitrogen atmosphere, at -5 to 0°C, a solution of CBTX-PNP (0.78 g, 0.78 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 18-M2 (0.5 g, 0.78 mmol) in dichloromethane (10 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 20-25°C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH=20:1] Separation and purification yielded 0.6 g of solid, yield: 51.12%, HPLC purity: 99.002%.

[0877] 1 H NMR (400MHz, DMSO) δ (ppm) 9.96 (d, J = 7.6Hz, 1H), 8.70 (s, 1H), 8.19 (d, J = 8.5Hz, 1H), 8.14 (d, J = 8.0Hz, 1H),7.98(d,J=7.4Hz,2H),7.88(ddd,J=13.3,9.7,5.8Hz,2H),7.73(t,J=7.4Hz,2H),7.65(t,J=6.1Hz ,2H),7.59–7.49(m,2H),7.47–7.33(m,4H),7.28(dd,J=8.1,4.0Hz,2H),7.16(t,J=7.0Hz,1H),7.02(s ,1H),5.83(d,J=8.4Hz,1H),5.52(s,2H),5.37(d,J=6.4Hz,1H),5.31(s,2H),5.09(dd,J=23.1,12.1Hz ,3H),5.03–4.89(m,2H),4.68(d,J=8.3Hz,1H),4.44(s,1H),4.01(s,2H),3.74(dd,J=16.9,7.4Hz,1H) ,3.58(s,1H),3.47(d,J=25.2Hz,1H),3.26(d,J=6.6Hz,4H),3.19(d,J=10.3Hz,3H),2.66(d,J=6.8Hz, 3H),2.48–2.35(m,4H),2.20(ddd,J=12.3,11.2,4.9Hz,8H),1.80(t,J=15.2Hz,4H),1.47(d,J=19.4Hz ,5H),1.36(d,J=2.6Hz,9H),1.26(dd,J=12.6,6.2Hz,3H),0.97(d,J=9.4Hz,6H),0.90(t,J=7.4Hz,3H).

[0878] MS(ESI): 1501.6 [M+H] + .

[0879] Example 19: Preparation of Compound 19

[0880] Following the preparation method of compound 17 in Example 17, compound 6 was replaced with compound 1 to obtain compound 19 (382 mg solid, yield: 74%, HPLC purity: 98.86%).

[0881] 1 H NMR (400MHz, DMSO) δ (ppm) 9.99 (dd, J = 17.8, 10.2 Hz, 1H), 8.22 ( dd, J = 9.1, 1.6 Hz, 1H), 7.95 ( ddd, J =33.7,19.9,8.5Hz,4H),7.72(t,J=7.2Hz,1H),7.70–7.60(m,3H),7.57(t,J=7.9Hz,2H),7.49–7.3 2(m,4H),7.28(t,J=7.5Hz,2H),7.18(t,J=6.8Hz,1H),7.02(d,J=1.8Hz,1H),5.91–5.77(m,1H),5. 52(s,2H),5.37(d,J=9.6Hz,3H),5.08(dd,J=21.9,12.2Hz,3H),5.03–4.85(m,2H),4.69(d,J=9.4H z,1H),4.44(d,J=8.3Hz,1H),4.01(d,J=7.0Hz,2H),3.80–3.71(m,1H),3.69–3.35(m,4H),3.26(t, J=5.3Hz,4H),3.25–3.09(m,6H),3.05–2.93(m,3H),2.92–2.73(m,3H),2.58(dd,J=24.9,5.9Hz,4H ),2.37(s,3H),2.25(dd,J=14.1,4.7Hz,3H),2.17(dt,J=10.5,7.0Hz,2H),1.84(s,4H),1.50(s,5H ), 1.37 (d, J = 4.8Hz, 9H), 1.29 (t, J = 7.6Hz, 3H), 0.97 (d, J = 9.7Hz, 6H), 0.90 (td, J = 7.3, 2.6Hz, 3H).

[0882] MS(ESI): 1615.6 [M+H] + .

[0883] Example 20: Preparation of Compound 20

[0884] Step 1) Preparation of compound 20-M1

[0885] Compound 1 (250 mg, 0.16 mmol) was dissolved in dichloromethane (12 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, DIPEA (41 mg, 0.32 mmol) was added, followed by dropwise addition of 4-nitrochlorophenyl ester (48 mg, 0.24 mmol) in dichloromethane (2 ml). The mixture was stirred at 25 °C for 1 hour. The reaction solution was then directly used for the next step.

[0886] Step 2) Preparation of Compound 20

[0887] Methanol (19 mg, 0.58 mmol) and DMAP (3 mg, 0.02 mmol) were added sequentially to the previous reaction solution. After the addition was complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.01 mol / L hydrochloric acid (15 ml × 2) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 120 mg of solid, yield: 64%, HPLC purity: 98.85%.

[0888] 1 H NMR (400MHz, DMSO) δ (ppm) 9.98 (dd, J = 17.2, 9.1Hz, 1H), 8.25 (d, J = 9.2Hz, 1H), 8.17 (d, J = 2.4Hz ,1H),7.97(d,J=7.1Hz,3H),7.81–7.70(m,2H),7.65(d,J=7.1Hz,2H),7.55(d,J=8.4Hz,2H),7. 47–7.34(m,4H),7.28(t,J=7.6Hz,2H),7.20–7.15(m,1H),7.02(s,1H),5.87–5.80(m,1H),5.52 (s,2H),5.36(s,3H),5.08(dd,J=20.6,12.0Hz,3H),4.93(dd,J=23.1,8.0Hz,2H),4.69(d,J=9. 6Hz,1H),4.44(d,J=8.1Hz,1H),4.01(s,2H),3.90(d,J=1.8Hz,3H),3.75(s,1H),3.67–3.41(m, 4H),3.25(d,J=8.4Hz,4H),3.22–3.14(m,5H),3.09–2.91(m,4H),2.89–2.77(m,3H),2.64(dd,J =16.8,9.0Hz,3H),2.29–2.20(m,3H),2.16(dd,J=16.5,9.1Hz,2H),1.83(s,4H),1.50(s,5H),1 .37(d,J=4.9Hz,9H), 1.29(t,J=7.5Hz,3H), 0.97(d,J=9.7Hz,6H), 0.90(dd,J=8.7,6.0Hz,3H).

[0889] MS(ESI): 1631.6 [M+H] + .

[0890] Example 21: Preparation of compound 21

[0891] Step 1) Preparation of compound 21-M1

[0892] Di-tert-butyl dicarbonate (6.00 g, 27.49 mmol) was dissolved in dichloromethane (15 ml), and added dropwise to a dichloromethane solution of compound 21-M0 (4.85 g, 54.98 mmol) under ice bath conditions. The mixture was stirred at 20–25 °C for 2 hours. The solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 4.90 g of yellow liquid, yield: 94%. (100:1 ratio)

[0893] Step 2) Preparation of compound 21-M2

[0894] Compound 21-M1 (1.50 g, 7.97 mmol) and succinic anhydride (1.60 g, 15.9 mmol) were dissolved in dichloromethane (20 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and pyridine (1.89 g, 2.39 mmol) was added. The mixture was then stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.3 mol / L hydrochloric acid (20 ml × 3) and saturated sodium chloride (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 1.8g of a yellow oily substance, yield: 78%.

[0895] Step 3) Preparation of compound 21-M3

[0896] Compound 21-M2 (1.8 g, 6.24 mmol) was dissolved in dichloromethane (20 ml), followed by the addition of p-aminobenzyl alcohol (846 mg, 6.87 mmol) and EEDQ (3.09 g, 12.49 mmol). The mixture was then stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =65:1] Separation and purification yielded 1.2 g of white solid, yield: 49%.

[0897] Step 3) Preparation of compound 21-M4

[0898] Compound CPT (600 mg, 1.72 mmol) was dissolved in dichloromethane (15 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.26 g, 10.33 mmol) and pyridine (497 mg, 6.29 mmol) were added, and the mixture was stirred for 5 minutes. Then, a solution of triphosgene (307 mg, 1.03 mmol) in dichloromethane (1.5 ml) was added, and the dropping rate was controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a solution of compound 21-M3 (678 mg, 1.72 mmol) in dichloromethane (15 ml). The mixture was then stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (40 ml) and saturated sodium chloride (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was separated and purified to obtain 850 mg of a yellow solid, yield: 64%.

[0899] Step 4) Preparation of compound 21-M5

[0900] Under a nitrogen atmosphere at 0–5 °C, 2 ml of TFA was added dropwise to a 4 ml solution of compound 21-M4 (850 mg, 1.11 mmol) in dichloromethane, and the mixture was stirred and kept at this temperature for 0.5 hours. Then, 20 ml of dichloromethane was added to the reaction mixture to concentrate it; the residue was used directly in the next step.

[0901] Step 5) Preparation of Compound 21

[0902] Under a nitrogen atmosphere at -5 to 0°C, a solution of CBTX-PNP (739 mg, 0.74 mmol) in dichloromethane (10 ml) was added dropwise to a solution of compound 21-M5 in dichloromethane (15 ml) from the previous step (pH adjusted to 9 with DIPEA). The mixture was stirred at 15 to 25°C for 3 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =65:1] Separation and purification yielded 385 mg of solid, yield: 23%, HPLC purity: 99.00%.

[0903] 1H NMR (400MHz, DMSO) δ (ppm) 9.95 (dd, J = 18.0, 8.0 Hz, 1H), 8.70 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.14 (d,J=8.0Hz,1H),7.96(t,J=10.4Hz,3H),7.87(t,J=7.3Hz,1H),7.72(t,J=7.2Hz,2H),7.65(t,J =7.4Hz,2H),7.55(t,J=9.8Hz,2H),7.41(q,J=8.0Hz,4H),7.27(t,J=7.3Hz,2H),7.21–7.15(m,1 H),7.03(d,J=2.0Hz,1H),5.93–5.79(m,1H),5.52(s,2H),5.43–5.27(m,3H),5.06(dt,J=13.8,9 .5Hz,3H),4.94(dt,J=12.9,11.9Hz,2H),4.68(d,J=13.2Hz,1H),4.43(d,J=16.2Hz,1H),4.02(s ,2H),3.75(s,1H),3.71–3.40(m,4H),3.25(d,J=11.2Hz,4H),3.19(dd,J=11.2,9.1Hz,4H),2.98 (dd,J=27.0,9.8Hz,4H),2.89–2.76(m,3H),2.73–2.59(m,2H),2.29–2.12(m,5H),1.87–1.74(m, 4H), 1.61–1.46 (m, 5H), 1.37 (d, J = 4.5Hz, 9H), 0.97 (d, J = 8.1Hz, 6H), 0.90 (dd, J = 8.5, 6.2Hz, 3H).

[0904] MS(ESI): 1529.6 [M+H] + .

[0905] Example 22: Preparation of compound 22

[0906] Referring to the preparation method of compound 6 in Example 6, compound 6-M2 was replaced with compound 21-M3 and CBTX-PNP was replaced with PTX-PNP to obtain compound 22 (0.27 g solid, yield: 72.35%, HPLC purity: 97.723%).

[0907] 1H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 9.97 (t, J = 13.0Hz, 1H), 9.30–9.10 (m, 1H), 8.09–7.95 (m, 3H), 7.8 4(dt,J=13.6,6.7Hz,2H),7.77–7.70(m,1H),7.65(t,J=7.0Hz,2H),7.60–7.52(m,3H),7.46(ddd,J=18.7,9 .2,5.7Hz,8H),7.27(d,J=6.4Hz,2H),7.20(d,J=6.4Hz,1H),6.93(d,J=2.1Hz,1H),6.30(d,J=3.1Hz,1H), 5.94–5.79(m,1H),5.63(ddd,J=26.7,17.2,8.7Hz,1H),5.51(s,2H),5.43(s,1H),5.30(s,2H),5.27–5.15( m,1H),5.08(dd,J=25.2,12.1Hz,2H),4.96–4.86(m,2H),4.67–4.58(m,1H),4.08(dt,J=41.3,9.5Hz,3H), 3.67–3.37(m,4H),3.31–3.00(m,4H),2.93(s,3H),2.86(d,J=5.5Hz,1H),2.81(s,1H),2.73(d,J=29.9Hz,1 H),2.66–2.53(m,2H),2.31(d,J=13.0Hz,2H),2.24(s,2H),2.15(dt,J=11.5,7.1Hz,3H),2.12–2.07(m,3H) ,1.94–1.74(m,4H),1.68–1.46(m,5H),1.30(t,J=7.5Hz,3H),1.02(d,J=9.0Hz,6H),0.90(t,J=7.3Hz,3H).

[0908] MS(ESI): 1591.5 [M+H] + .

[0909] Example 23: Preparation of compound 23

[0910] Compound 1 (250 mg, 0.16 mmol) and tervastatin (19 mg, 0.19 mmol) were dissolved in dichloromethane (10 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, 4-dimethylaminopyridine (4 mg, 0.032 mmol) and diisopropylcarbodiimide (30 mg, 0.24 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 3 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.12 mol / L hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and saturated sodium chloride (20 ml), respectively. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 230 mg of solid, yield: 67.74%, HPLC purity: 98.95%.

[0911] 1 H NMR(400MHz, DMSO)δ(ppm)9.98(dd,J=19.4,11.4Hz,1H),8.22(dd,J=9.1,3.0Hz,1H),8.03–7.83 (m,4H),7.71(d,J=7.0Hz,1H),7.69–7.61(m,3H),7.57(t,J=8.4Hz,2H),7.45–7.35(m,4H),7.28 (t,J=7.5Hz,2H),7.17(d,J=7.0Hz,1H),7.01(s,1H),5.90–5.79(m,1H),5.55(d,J=17.7Hz,2H), 5.43–5.31(m,3H),5.08(dd,J=21.6,12.2Hz,3H),5.03–4.88(m,2H),4.69(d,J=9.4Hz,1H),4.44 (d,J=7.9Hz,1H),3.76(s,1H),3.61(dt,J=42.7,10.8Hz,2H),3.52–3.39(m,2H),3.29–3.15(m,9 H),3.04(s,1H),2.97(d,J=18.4Hz,2H),2.84(d,J=11.6Hz,1H),2.81(s,1H),2.58(dd,J=25.4,6 .6Hz,4H),2.29–2.21(m,3H),2.17(dd,J=7.1,3.8Hz,2H),1.83(s,4H),1.49(d,J=12.9Hz,6H),1 .38(t,J=6.0Hz,20H),1.29(t,J=7.5Hz,4H),0.97(d,J=9.9Hz,6H),0.90(td,J=7.4,2.8Hz,3H).

[0912] MS(ESI): 1657.6 [M+H] + .

[0913] Example 24: Preparation of compound 24

[0914] Referring to the preparation method of compound 17 in Example 17, compound 6 was replaced with compound 1. Replacing acetic anhydride yielded compound 24 (0.33 g solid, yield: 77.57%, HPLC purity: 97.239%).

[0915] 1 H NMR (400MHz, DMSO) δ9.98 (dd, J=18.4, 10.9Hz, 1H), 8.23 ​​(dd, J=9.2, 2.6Hz, 1H), 8.10 (d, J=2.5Hz, 1H), 8.01 –7.83(m,3H),7.76–7.70(m,2H),7.64(t,J=7.4Hz,2H),7.55(d,J=8.2Hz,2H),7.41(q,J=8.0Hz,4H),7.28(t ,J=7.6Hz,2H),7.17(dd,J=14.1,7.2Hz,1H),7.02(d,J=2.1Hz,1H),5.90–5.79(m,1H),5.55(d,J=17.7Hz,2 H),5.41–5.32(m,3H),5.08(dd,J=21.3,12.2Hz,3H),5.03–4.88(m,2H),4.69(d,J=9.2Hz,1H),4.44(d,J=8. 3Hz,1H),4.02(s,1H),3.76(s,1H),3.67–3.37(m,4H),3.26(d,J=8.6Hz,3H),3.22–3.16(m,5H),3.04(s,1H ),2.97(d,J=18.5Hz,2H),2.84(d,J=12.5Hz,1H),2.81(s,1H),2.71–2.53(m,4H),2.25(dd,J=14.0,4.6Hz,3 H),2.17(dt,J=10.9,7.1Hz,2H),1.99(s,2H),1.80(d,J=25.7Hz,4H),1.54(s,10H),1.50(s,4H),1.37(d,J= 4.9Hz, 9H), 1.29 (t, J = 7.6Hz, 3H), 1.18 (t, J = 7.1Hz, 2H), 0.97 (d, J = 9.6Hz, 6H), 0.90 (td, J = 7.3, 2.7Hz, 3H).

[0916] MS(ESI): 1617.5 [M-tBu] - +2H + ] + .

[0917] Example 25: Preparation of Compound 25

[0918] Following the preparation method of compound 23 in Example 23, compound 25 was obtained by replacing pentovaric acid with valeric acid (200 mg solid, yield: 76%, HPLC purity: 98.25%).

[0919] 1 H NMR (400MHz, DMSO) δ (ppm) 9.99 (dd, J = 17.9, 11.0 Hz, 1H), 8.22 ( dd, J = 9.1, 2.4 Hz, 1H), 7.99 ( dd, J = 11 .0,4.8Hz,4H),7.72(t,J=7.3Hz,1H),7.65(dd,J=9.1,2.4Hz,3H),7.57(t,J=7.8Hz,2H),7.41(q,J= 8.1Hz,4H),7.28(t,J=7.5Hz,2H),7.23–7.11(m,1H),7.01(s,1H),5.84(dt,J=17.4,8.6Hz,1H),5.5 2(s,2H),5.37(d,J=9.8Hz,3H),5.19–5.05(m,3H),5.03–4.87(m,2H),4.69(d,J=9.6Hz,1H),4.44(d ,J=8.0Hz,1H),4.02(s,2H),3.80–3.72(m,1H),3.70–3.38(m,4H),3.27(s,3H),3.25–3.15(m,6H),2 .98(dd,J=26.9,10.1Hz,4H),2.90–2.74(m,3H),2.73–2.53(m,6H),2.25(dd,J=14.0,4.6Hz,3H),2. 17(dt,J=10.8,7.0Hz,2H),1.90–1.76(m,4H),1.73–1.65(m,2H),1.46(dd,J=19.4,11.9Hz,7H),1.3 8(t,J=8.4Hz,9H), 1.29(t,J=7.6Hz,3H), 0.96(dd,J=13.6,6.3Hz,9H), 0.90(td,J=7.3,2.7Hz,3H).

[0920] MS(ESI): 1657.7 [M+H]+ .

[0921] Example 26: Preparation of Compound 26

[0922] Referring to the preparation method of compound 6 in Example 6, compound 6-M2 was replaced with compound 21-M3 and CBTX-PNP was replaced with DTX-PNP to obtain compound 26 (0.85 g solid, yield: 76.07%, HPLC purity: 96.739%).

[0923] 1 H NMR (400MHz, DMSO) δ (ppm) 10.32 (s, 1H), 10.00 (dd, J = 17.8, 10.2Hz, 1H), 8.10–7.81 (m, 4 H),7.71(d,J=7.1Hz,1H),7.68–7.52(m,4H),7.41(t,J=6.9Hz,6H),7.29(t,J=9.6Hz,2H) ,7.17(d,J=6.4Hz,1H),6.93(d,J=2.4Hz,1H),5.90–5.77(m,1H),5.50(s,2H),5.41(d,J= 6.4Hz,1H),5.30(d,J=2.3Hz,2H),5.21–4.95(m,6H),4.91(s,2H),4.39(d,J=4.2Hz,1H), 4.06(dd,J=17.7,9.1Hz,3H),3.74–3.37(m,4H),3.28–3.16(m,1H),3.09(q,J=7.4Hz,2H ),2.95(dd,J=44.1,22.4Hz,4H),2.80(d,J=8.6Hz,2H),2.57(t,J=14.5Hz,3H),2.26(dd, J=14.8,4.5Hz,4H),2.20–2.08(m,2H),1.95–1.80(m,1H),1.75(s,3H),1.73–1.41(m,6H) ,1.35(t,J=11.1Hz,9H),1.30(t,J=7.6Hz,3H),0.99(d,J=2.4Hz,6H),0.92–0.86(m,3H).

[0924] MS(ESI): 1545.5 [M+H] + .

[0925] Example 27: Preparation of Compound 27

[0926] Compound 22 (220 mg, 0.138 mmol) was dissolved in dichloromethane (5 ml) with stirring. Acetic anhydride (21 mg, 0.508 mmol) and pyridine (22 mg, 10.17 mmol) were added sequentially at 0–5 °C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at 20–25 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =35:1] Separation and purification yielded 0.18 g of solid, yield: 79.7%, HPLC purity: 98.77%.

[0927] 1H NMR (400MHz, DMSO) δ9.96(t,J=12.4Hz,1H),9.27–9.14(m,1H),8.22(d,J=9.1Hz,1H),8.00(dd,J=14.1, 5.4Hz,3H),7.84(dt,J=13.4,6.5Hz,2H),7.72(s,1H),7.66(dt,J=9.8,5.0Hz,3H),7.60–7.52(m,3H),7. 51–7.40(m,6H),7.27(d,J=8.3Hz,2H),7.19(d,J=6.3Hz,1H),7.02(s,1H),6.30(d,J=3.1Hz,1H),5.92–5 .79(m,1H),5.72–5.50(m,3H),5.42(s,1H),5.37–5.29(m,2H),5.26–5.02(m,3H),4.95–4.86(m,2H),4.6 1(dd,J=13.1,6.6Hz,1H),4.12(d,J=7.4Hz,1H),4.06–3.98(m,2H),3.68–3.37(m,4H),3.28–3.21(m,1H) ,3.20–3.13(m,2H),2.92(s,2H),2.86(d,J=5.3Hz,1H),2.81(s,1H),2.73(d,J=29.4Hz,1H),2.52(s,2H) ,2.35(d,J=17.8Hz,4H),2.29(s,1H),2.24(s,2H),2.17(dt,J=10.3,7.1Hz,2H),2.09(d,J=5.5Hz,3H),1 .83(d,J=6.5Hz,3H),1.68–1.46(m,5H),1.34–1.21(m,4H),1.02(d,J=9.4Hz,6H),0.90(t,J=7.3Hz,3H).

[0928] MS(ESI): 1633.5 [M+H] + .

[0929] Example 28: Preparation of Compound 28

[0930] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 22 to obtain compound 28 (200 mg off-white solid, yield: 63%, HPLC purity: 99.46%).

[0931] 1H NMR(400MHz, DMSO)δ(ppm)9.96(t,J=13.7Hz,1H),9.31–9.11(m,1H),8.23(d,J=9.1Hz,1H),8.00(t ,J=5.7Hz,3H),7.91–7.79(m,2H),7.72(s,1H),7.69–7.60(m,3H),7.55(d,J=8.0Hz,3H),7.52–7.3 9(m,6H),7.27(d,J=6.6Hz,2H),7.20(d,J=5.9Hz,1H),7.01(s,1H),6.30(s,1H),5.86(dd,J=17.3, 9.0Hz,1H),5.73–5.48(m,3H),5.43(s,1H),5.39–5.29(m,2H),5.27–5.02(m,3H),4.91(d,J=7.7Hz, 2H),4.67–4.56(m,1H),4.12(d,J=7.5Hz,1H),4.02(s,2H),3.64–3.41(m,4H),3.20(dd,J=14.9,7. 2Hz,4H),2.92(s,3H),2.86(d,J=4.6Hz,1H),2.81(s,1H),2.73(d,J=28.7Hz,1H),2.62–2.52(m,2H) ,2.36–2.22(m,4H),2.17(dt,J=10.9,6.9Hz,2H),2.10(s,3H),1.83(d,J=6.6Hz,4H),1.72–1.56(m ,2H),1.50(s,4H),1.38(s,9H),1.29(t,J=7.5Hz,3H),1.02(d,J=9.5Hz,6H),0.90(t,J=7.2Hz,3H).

[0932] MS(ESI, e / z = 2): 838.4 [M / 2 + H] +

[0933] Example 29: Preparation of compound 29

[0934] Compound 22 (250 mg, 0.16 mmol) was dissolved in dichloromethane (10 mL) with stirring. Acetic anhydride (64 mg, 0.63 mmol), pyridine (127 mg, 1.6 mmol), and DMAP (10 mg, 0.08 mmol) were added sequentially at 0–5 °C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at 20–25 °C for 6 hours. The reaction solution was diluted with dichloromethane (20 mL), washed with 0.3 mol / L hydrochloric acid (20 mL), saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 150 mg of solid, yield: 57%, HPLC purity: 98.10%.

[0935] 1 H NMR(400MHz,DMSO)δ(ppm)9.95(d,J=14.0Hz,1H),9.34–9.14(m,1H),8.22(d,J=9.1Hz,1H),8.00 (dd,J=14.2,4.6Hz,3H),7.91–7.79(m,2H),7.74(d,J=6.0Hz,1H),7.71–7.61(m,3H),7.62–7.38( m,9H),7.32–7.23(m,2H),7.18(d,J=6.1Hz,1H),7.02(s,1H),6.06(d,J=3.3Hz,1H),5.85(dd,J=1 6.9,7.8Hz,1H),5.67–5.49(m,3H),5.43(d,J=6.7Hz,2H),5.33(d,J=14.9Hz,2H),5.26–5.02(m,3 H),4.95(d,J=9.0Hz,1H),4.73–4.65(m,1H),4.04(s,2H),3.73–3.35(m,4H),3.26–3.13(m,3H),2 .99–2.79(m,5H),2.74(d,J=31.1Hz,1H),2.63–2.52(m,2H),2.49–2.31(m,5H),2.26(d,J=16.6Hz ,3H),2.17(dt,J=10.2,7.1Hz,2H),2.10(s,3H),1.89(d,J=2.5Hz,3H),1.77(d,J=5.1Hz,4H),1.6 4(s,4H),1.62–1.37(m,2H),1.29(t,J=7.5Hz,3H),1.00(d,J=15.0Hz,6H),0.90(t,J=7.3Hz,3H).

[0936] MS(ESI,Z=2):838.5[M / 2+H] + .

[0937] Example 30: Preparation of compound 30

[0938] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 26 to obtain compound 30 (200 mg solid, yield: 54%, HPLC purity: 97.66%).

[0939] 1 H NMR (400MHz, DMSO) δ (ppm) 9.97–9.83 (m, 1H), 8.33–7.76 (m, 6H), 7.67 (dt, J = 13.2, 6.6Hz, 4H), 7.54 (t, J = 7.8Hz, 2H), 7.46 –7.33(m,4H),7.29–7.13(m,3H),5.89–5.77(m,1H),5.57–5.19(m,3H),5.22–4.80(m,8H),4.42(s,3H),4.02(s,3H),3.60( dd,J=29.1,9.9Hz,2H),3.52–3.37(m,2H),3.30–3.10(m,3H),3.03–2.84(m,4H),2.80(d,J=7.9Hz,2H),2.57(t,J=14.6Hz ,5H),2.46–1.95(m,6H),1.93–1.78(m,1H),1.74(s,3H),1.70–1.61(m,1H),1.51(s,4H),1.46–1.11(m,23H),0.98(s,6H).

[0940] MS(ESI): 1629.6 [M+H] + .

[0941] Example 31: Preparation method of compound 31

[0942] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 9 to obtain compound 31 (0.76 g solid, yield: 80.15%, HPLC purity: 99.177%).

[0943] 1H NMR (400MHz, DMSO) δ9.99(s,1H),8.23(d,J=9.1Hz,1H),7.98(dd,J=11.1,7.8H z,4H),7.72(t,J=7.3Hz,1H),7.63(dd,J=12.3,5.2Hz,3H),7.56(d,J=8.5Hz,2H ),7.47–7.35(m,4H),7.28(d,J=8.6Hz,2H),7.20(t,J=7.0Hz,1H),7.01(s,1H), 5.85(t,J=8.7Hz,1H),5.58–5.47(m,2H),5.44–5.33(m,3H),5.17–4.94(m,5H), 4.71(s,1H),4.49(s,1H),4.08–3.97(m,2H),3.76(dd,J=10.1,7.0Hz,1H),3.6 3–3.36(m,8H),3.30–3.15(m,9H),2.66(d,J=4.8Hz,3H),2.56(s,2H),2.28(s,3 H),2.16(tt,J=14.3,7.1Hz,2H),1.87(d,J=25.1Hz,4H),1.63–1.46(m,5H),1.3 9(s,18H),1.30(t,J=7.6Hz,3H),0.99(d,J=10.6Hz,6H),0.90(t,J=7.4Hz,3H).

[0944] MS(ESI): 1655.6923 [M+H] + .

[0945] Example 32: Preparation method of compound 32

[0946] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 7 to obtain compound 32 (0.2 g solid, yield: 37.94%, HPLC purity: 97.256%).

[0947] 1H NMR (400MHz, DMSO) δ9.97 (s, 1H), 8.22 (d, J = 9.1Hz, 1H), 8.15 (s, 1H), 7.97 (dd, J = 13.2, 6. 3Hz,4H),7.72(d,J=7.2Hz,1H),7.68–7.61(m,3H),7.55(d,J=8.4Hz,2H),7.44(t,J=7.5Hz ,2H),7.37(d,J=7.5Hz,2H),7.28(d,J=8.5Hz,2H),7.18(t,J=7.2Hz,1H),7.01(s,1H),5. 83(t,J=8.6Hz,1H),5.53(s,2H),5.37(d,J=7.3Hz,3H),5.14–5.00(m,4H),4.95(d,J=9.6H z,1H),4.70(s,1H),4.49(s,1H),4.20–4.10(m,2H),4.02(s,2H),3.79–3.72(m,1H),3.59 (d,J=6.7Hz,1H),3.28(s,3H),3.20(s,5H),2.66(d,J=6.7Hz,1H),2.43(d,J=6.7Hz,2H),2 .25(s,3H),2.17(dt,J=10.9,6.9Hz,2H),1.80(d,J=17.8Hz,4H),1.48(d,J=21.5Hz,7H),1 .38(d,J=8.7Hz,19H),1.30(t,J=7.5Hz,4H),0.98(d,J=7.3Hz,6H),0.90(t,J=7.4Hz,3H).

[0948] MS(ESI): 1630.6529 [M+H] + .

[0949] Example 33: Preparation method of compound 33

[0950] Compound 28 (400 mg, 0.238 mmol) and acetic anhydride (49 mg, 0.477 mmol) were dissolved in dichloromethane (12 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, 4-dimethylaminopyridine (15 mg, 0.123 mmol) and pyridine (38 mg, 0.477 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.2 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / VMeOH =45:1] Separation and purification yielded 0.38 g of solid, yield: 92.68%, HPLC purity: 98.34%.

[0951] 1 H NMR (400MHz, DMSO) δ9.99–9.87(m,1H),9.31–9.17(m,1H),8.22(dd,J=9.1,2.4Hz,1H),7.99(dd,J=7.9,5 .7Hz,3H),7.86(dd,J=16.5,7.6Hz,2H),7.74(d,J=6.0Hz,1H),7.67(t,J=7.3Hz,2H),7.62(dd,J=9.1,2. 4Hz,1H),7.52(dd,J=18.6,7.9Hz,5H),7.47(s,4H),7.27(d,J=6.5Hz,1H),7.24–7.16(m,2H),7.02(d,J= 2.5Hz,1H),6.06(d,J=3.7Hz,1H),5.85(dd,J=16.4,7.6Hz,1H),5.67–5.50(m,3H),5.40(dd,J=21.0,10.4 Hz,4H),5.32–5.01(m,4H),4.95(d,J=9.0Hz,1H),4.69(s,1H),4.43(s,1H),3.68(s,1H),3.44(d,J=6.6H z,2H),3.26–3.08(m,4H),2.95–2.80(m,6H),2.72–2.66(m,1H),2.57(s,1H),2.43(d,J=7.2Hz,1H),2.28( s,1H),2.23(d,J=6.8Hz,2H),2.17(dd,J=7.2,3.8Hz,1H),2.09(d,J=7.3Hz,3H),1.89(s,3H),1.80–1.75 (m,4H),1.64(s,4H),1.38(s,9H),1.29(t,J=7.5Hz,3H),1.02(s,3H),0.98(s,3H),0.90(t,J=7.4Hz,3H).

[0952] MS(ESI): 1717.6622 [M+H] + .

[0953] Example 34: Preparation of compound 34

[0954] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 26 to obtain compound 34-M1 (1 g solid, yield: 67.74%).

[0955] Following the preparation method of compound 33 in Example 33, compound 28 was replaced with compound 34-M1 to obtain compound 34 (0.23 g solid, yield: 43.74%, HPLC purity: 97.585%).

[0956] 1 H NMR (400MHz, DMSO) δ (ppm) 10.03–9.87 (m, 1H), 8.29–8.15 (m, 1H), 7.99 (d, J = 2.5H z,4H),7.75–7.51(m,6H),7.42(dd,J=13.7,6.5Hz,4H),7.31–7.13(m,3H),7.01( s,1H),6.06(s,1H),5.86–5.75(m,1H),5.52(s,2H),5.40(dd,J=17.3,10.1Hz,3H ),5.16–4.87(m,5H),4.67(s,1H),4.43(s,1H),4.06(d,J=8.9Hz,2H),3.75–3.39( m,4H),3.31–3.13(m,4H),2.95(dd,J=42.6,24.7Hz,4H),2.85–2.78(m,2H),2.61 (dd,J=24.9,21.3Hz,3H),2.43(dd,J=14.5,6.3Hz,2H),2.30–2.21(m,3H),2.19–2 .07(m,4H),1.86(d,J=25.0Hz,4H),1.76(s,3H),1.62(d,J=15.0Hz,5H),1.35(d, J=28.3Hz,18H),1.30(t,J=7.5Hz,3H),1.00(d,J=10.2Hz,6H),0.96–0.83(m,3H).

[0957] MS(ESI,Z=2):857.8492[M / 2+H] + .

[0958] Example 35: Preparation of compound 35

[0959] Following the preparation method of compound 23 in Example 23, isobutyric acid was used to replace pentovaric acid to obtain compound 35 (0.42 g solid, yield: 80.45%, HPLC purity: 98.839%).

[0960] 1 H NMR (400MHz, DMSO) δ10.10–9.95 (m, 1H), 8.28 (dd, J=9.1, 2.6Hz, 1H), 8.05 (dd, J= 12.7,4.8Hz,3H),8.00–7.88(m,1H),7.77(d,J=6.9Hz,1H),7.74–7.67(m,3H),7.6 6–7.57(m,2H),7.51–7.42(m,4H),7.32(dd,J=20.5,11.9Hz,2H),7.26–7.20(m,1 H),7.07(s,1H),5.97–5.84(m,1H),5.68–5.53(m,2H),5.49–5.37(m,3H),5.24–5. 02(m,4H),4.99(d,J=15.4Hz,1H),4.75(d,J=9.6Hz,1H),4.50(d,J=9.9Hz,2H),3 .81(s,1H),3.73–3.45(m,5H),3.34–3.20(m,9H),3.12–2.85(m,8H),2.66(dd,J=3 7.9,13.9Hz,5H),2.36–2.18(m,5H),2.05(s,1H),1.89(s,4H),1.56(s,6H),1.43 (d,J=4.7Hz,9H),1.37(d,J=6.9Hz,6H),1.03(d,J=9.8Hz,6H),1.00–0.91(m,3H).

[0961] MS(ESI): 1643.6891 [M+H] + .

[0962] Example 36: Preparation method of compound 36

[0963] Step 1) Preparation of compound 36-M1

[0964] Compound 36-M0 (5 g, 31.21 mmol) and succinic anhydride (6.25 g, 62.42 mmol) were dissolved in dichloromethane (100 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and pyridine (7.41 g, 93.62 mmol) was added. The mixture was then stirred at 20–25 °C for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH [15:1 to 10:1] Separation and purification yielded 8g of white solid, yield: 98.49%.

[0965] Step 2) Preparation of compound 36-M2

[0966] Compound 36-M1 (8 g, 30.73 mmol) was dissolved in dichloromethane (100 ml) and methanol (5 ml) with stirring. Then, p-aminobenzyl alcohol (4.54 g, 36.88 mmol) and EEDQ (15.2 g, 61.47 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =20:1] Separation and purification yielded 9g of white solid, yield: 80.13%.

[0967] Step 3) Preparation of compound 36-M3

[0968] Compound TBS-SN38 (2.5 g, 4.93 mmol) was dissolved in dichloromethane (30 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (3.62 g, 29.6 mmol) and pyridine (1.41 g, 17.76 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.88 g, 2.96 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (20 ml) solution of compound 36-M2 (1.8 g, 4.93 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was purified by separation and purification at a ratio of 40:1 to obtain 3.2 g of a yellow solid, yield: 72.21%.

[0969] Step 4) Preparation of compound 36-M4

[0970] Under a nitrogen atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 1.12 g, 4.28 mmol) in dichloromethane (3 ml) was added dropwise to a solution of compound 36-M3 (3.2 g, 3.56 mmol) in dichloromethane (20 ml), and the mixture was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =20:1] Separation and purification yielded 2.5g of solid, yield: 89.51%

[0971] Step 5) Preparation of compound 36-M5

[0972] Compound 36-M4 (2.5 g, 3.29 mmol) and tervastatin (0.65 g, 6.38 mmol) were dissolved in dichloromethane (30 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, 4-dimethylaminopyridine (DMAP, 78 mg, 0.638 mmol) and diisopropylcarbodiimide (DIC, 0.81 g, 6.38 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.12 mol / L hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and saturated sodium chloride (20 ml), respectively. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 2.5g of solid, yield: 90.31%.

[0973] Step 6) Preparation of compound 36-M6

[0974] Under a nitrogen atmosphere at 0–5 °C, TFA (3 ml) was added dropwise to a dichloromethane (6 ml) solution of compound 36-M5 (1.0 g, 1.15 mmol), and the mixture was stirred at this temperature for 1.5 hours. The reaction solution was concentrated directly to dryness without further purification and neutralized to alkaline (pH 8–9) with DIPEA at low temperature before being used directly in the next reaction step.

[0975] Step 7) Preparation of compound 36

[0976] Under a nitrogen atmosphere at -5 to 0 °C, a solution of CBTX-PNP (1.08 g, 1.07 mmol) in dichloromethane (6 ml) was added dropwise to a solution of compound 36-M6 (0.75 g, 0.98 mmol) in dichloromethane (6 ml) (with 2-4 drops of DIPEA added), and the reaction was stirred at 20-25 °C for 1 hour. The reaction solution was diluted with dichloromethane (20 ml), washed successively with 0.12 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =40:1] Separation and purification yielded 0.5 g of solid, yield: 31.41%, HPLC purity: 95.933%.

[0977] 1H NMR(400MHz, DMSO)δ(ppm)9.96(s,2H),9.96(s,2H),8.22(d,J=9.1Hz,1H),7.97(ddd,J=31.3,18.5,6.5Hz,8H),7.83–7.49(m,12H),7.49–7.09(m,1 3H),7.01(s,1H),5.75(s,1H),5.53(s,3H),5.44–5.24(m,6H),5.23(d,J= 6.7Hz,1H),5.15–4.88(m,7H),4.75(s,1H),4.67(d,J=10.0Hz,2H),4.51– 4.31(m,3H),4.12–3.92(m,4H),3.92–3.76(m,2H),3.76–3.40(m,5H),3.3 4–3.16(m,53H),3.15–2.79(m,4H),2.79–2.61(m,2H),2.56–2.46(m,17H) ,2.42–2.29(m,4H),2.20(dd,J=18.4,11.0Hz,9H),1.98(s,3H),1.80(s,3 H),1.58–1.36(m,27H),1.31(dd,J=16.7,9.3Hz,19H),1.06–0.81(m,15H).

[0978] MS(ESI): 1629.6755 [M+H] + .

[0979] Example 37: Preparation of compound 37

[0980] Referring to the preparation method of 21-M3 in Example 21, with replace 37-M1 (2.1 g white solid, yield: 46.63%) was prepared.

[0981] Following the preparation method of compound 6 in Example 6, compound 6-M2 was replaced with compound 37-M1 to obtain compound 37 (1.1 g solid, yield: 53.63%, HPLC purity: 98.709%).

[0982] 1H NMR (400MHz, DMSO) δ10.35(s,1H),9.62(t,J=16.8Hz,1H),8.06(d,J=8.9Hz,1H) ,8.04–7.81(m,3H),7.72(d,J=7.0Hz,1H),7.65(t,J=6.8Hz,2H),7.49–7.29(m,8 H),7.26–7.20(m,1H),7.15(s,2H),6.98(s,1H),5.87–5.77(m,1H),5.50(s,2H) ,5.40–5.26(m,3H),5.16–4.87(m,5H),4.67(d,J=9.9Hz,1H),4.44(d,J=8.9Hz,1 H),4.01(s,2H),3.74(d,J=7.7Hz,1H),3.62–3.37(m,4H),3.25(dd,J=6.2,4.1H z,4H),3.22–3.13(m,4H),3.09(dd,J=14.7,7.1Hz,2H),3.01–2.79(m,4H),2.77( d,J=9.1Hz,2H),2.64(dd,J=13.6,8.4Hz,3H),2.47–2.37(m,1H),2.30–2.11(m,5 H),1.88–1.73(m,4H),1.60–1.44(m,5H),1.40–1.24(m,12H),1.04–0.86(m,9H).

[0983] MS(ESI): 1573.6509 [M+H] + .

[0984] Example 38: Preparation of compound 38

[0985] Following the preparation method of compound 23 in Example 23, compound 1 was replaced with compound 37 to obtain compound 38 (0.55 g solid, yield: 87.02%, HPLC purity: 99.349%).

[0986] 1H NMR(400MHz,DMSO)δ(ppm)9.68(t,J=16.6Hz,1H),8.30(d,J=9.1Hz,1H),8.11– 7.89(m,4H),7.77(d,J=7.1Hz,1H),7.71(d,J=7.1Hz,3H),7.43(dt,J=16.0,7.6 Hz,6H),7.32–7.17(m,3H),7.12(s,1H),5.87(d,J=8.7Hz,1H),5.58(d,J=4.6H z,2H),5.42(s,3H),5.28–4.94(m,5H),4.73(d,J=10.1Hz,1H),4.50(d,J=9.3Hz ,1H),4.07(s,2H),3.80(d,J=7.3Hz,1H),3.70–3.41(m,4H),3.27(ddd,J=25.6 ,12.8,4.1Hz,10H),2.97(d,J=8.8Hz,2H),2.83(dd,J=22.1,13.0Hz,4H),2.69( dd,J=23.6,12.3Hz,3H),2.49(d,J=5.9Hz,1H),2.35–2.17(m,5H),1.95–1.77( m,4H),1.55(d,J=5.5Hz,5H),1.47–1.31(m,21H),0.99(dd,J=15.2,7.6Hz,9H).

[0987] MS(ESI,Z=2):829.36[M / 2+H] + .

[0988] Example 39: Preparation of compound 39

[0989] Step 1) Preparation of compound 39-M1

[0990] Compound 39-M0 (2.86 g, 27.49 mmol) was dissolved in methanol (20 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and a methanol solution of di-tert-butyl dicarbonate (4 g, 18.33 mmol) was added dropwise. The mixture was then stirred at 20–25 °C for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =70:1] Separation and purification yielded 2.6g of oily substance, yield: 69.45%.

[0991] Step 2) Preparation of compound 39-M2

[0992] Compound 39-M1 (2.6 g, 12.73 mmol) was dissolved in dichloromethane (20 mL) with stirring. Succinic anhydride (1.4 g, 14.0 mmol) and pyridine (2.0 g, 25.46 mmol) were added sequentially at 0–5 °C under a nitrogen atmosphere. After the additions were complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was washed with 0.1 mol / L hydrochloric acid (20 mL) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 3.4 g (yield: 83.9%).

[0993] Step 3) Preparation of compound 39-M3

[0994] Compound 39-M2 (3.4 g, 10.68 mmol) was dissolved in dichloromethane (25 ml) with stirring. Then, p-aminobenzyl alcohol (1.58 g, 12.82 mmol) and EEDQ (5.28 g, 21.36 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 3.0 h. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =15:1] Separation and purification yielded 2.2 g of white solid, yield: 48.64%.

[0995] Step 4) Preparation of compound 39-M4

[0996] Compound TBS-SN38 (0.7 g, 1.38 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.13 g, 9.26 mmol) and pyridine (0.45 g, 5.6 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.274 g, 0.926 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (20 ml) solution of compound 39-M3 (0.57 g, 1.38 mmol), and the mixture was stirred at 0 to 5 °C for 0.5 hours. The reaction solution was washed with 0.6 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was analyzed by silica gel column chromatography [V]. DCM / V MeOH =70:1] Separation and purification yielded 0.5 g of a pale yellow solid, yield: 38.41%.

[0997] Step 5) Preparation of compound 39-M5

[0998] Under a nitrogen atmosphere, at 0–5 °C, a solution of TBAF (166 mg, 0.637 mmol) in dichloromethane (4 mL) was added dropwise to a solution of compound 39-M4 (0.5 g, 0.531 mmol) in dichloromethane (16 mL), and the reaction was stirred at 0–5 °C for 10 minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V DCM / V MeOH =25:1] Separation and purification yielded 0.4 g of solid, yield: 91.04%.

[0999] Step 6) Preparation of compound 39-M6

[1000] Compound 39-M5 (400 mg, 0.483 mmol) and tervastatin (99 mg, 0.966 mmol) were dissolved in dichloromethane (20 ml) with stirring. Under a nitrogen atmosphere at 0–5 °C, 4-dimethylaminopyridine (DMAP, 12 mg, 0.097 mmol) and diisopropylcarbodiimide (DIC, 122 mg, 0.869 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 20–25 °C for 2 hours. The reaction solution was diluted with dichloromethane (20 ml), washed with 0.2 mol / L hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and saturated sodium chloride (20 ml), respectively. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =50:1] Separation and purification yielded 0.35 g of solid, yield: 79.43%.

[1001] Step 7) Preparation of compound 39-M7

[1002] Under a nitrogen atmosphere at 0–5 °C, 1.0 ml of TFA was added dropwise to a 2 ml solution of compound 39-M6 in dichloromethane, and the mixture was stirred and kept at this temperature for 1 hour. The reaction solution was concentrated directly to dryness without further purification and used directly in the next step, with a yield of 80%.

[1003] Step 8) Preparation of compound 39

[1004] Compound 39-M7 (250 mg, 0.308 mmol) was dissolved in dichloromethane (10 ml) with stirring. The solution was cooled to -5 to 0 °C, and diisopropylethylamine (200 mg, 1.55 mmol) was added first, followed by dropwise addition of a dichloromethane solution of CBTX-PNP (370 mg, 0.369 mmol). The reaction mixture was then stirred at 20–25 °C for 2 hours. The reaction solution was washed with 0.2 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / VMeOH =35:1] Separation and purification yielded 0.22 g of solid, yield: 42.68%, HPLC purity: 97.925%.

[1005] 1 H NMR (400MHz, DMSO) δ9.92(d,J=32.0Hz,1H),8.22(d,J=9.1Hz,1H),8.00(dt,J=8.7,6.9Hz,3H),7.9 5–7.70(m,3H),7.69–7.58(m,3H),7.53(dd,J=18.4,7.9Hz,3H),7.41(t,J=7.5Hz,2H),7.37–7.30(m ,2H),7.25(dd,J=24.4,8.5Hz,2H),7.19–7.07(m,1H),7.04(d,J=18.9Hz,1H),5.79(dd,J=24.0,15 .8Hz,1H),5.61–5.47(m,2H),5.42–5.33(m,3H),5.32–5.20(m,1H),5.14–4.97(m,3H),4.95(d,J=11 .2Hz,1H),4.69(s,1H),4.46–4.37(m,1H),3.84–3.51(m,3H),3.39(dd,J=11.6,5.7Hz,4H),3.29(d ,J=10.6Hz,3H),3.25–3.15(m,8H),2.67(dt,J=9.9,7.9Hz,1H),2.53(s,2H),2.43(d,J=6.4Hz,2H), 2.24(t,J=13.0Hz,3H),2.20–2.13(m,2H),1.99(s,2H),1.81(s,2H),1.51(d,J=10.4Hz,4H),1.42–1 .33(m,18H),1.29(t,J=7.5Hz,4H),1.18(t,J=7.1Hz,2H),1.02–0.94(m,6H),0.90(t,J=7.4Hz,3H).

[1006] MS(ESI): 1673.6983 [M+H] + .

[1007] Example 40: Preparation of Compound 40

[1008] Step 1) Preparation of compound 40-M1

[1009] Compound 40-M0 (5 g, 40.6 mmol) was dissolved in dichloromethane (40 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C, and glutaric anhydride (5.1 g, 44.66 mmol) was added. The mixture was then stirred at 20 to 25 °C for 1 hour. The reaction solution was concentrated, and the residue was slurried with ethyl acetate (80 ml) for 1 hour. The mixture was filtered, and the solid was collected and dried to give 8.6 g of a white solid. Yield: 89.25%.

[1010] Step 2) Preparation of compound 40-M2

[1011] Compound 40-M1 (8.6 g, 36.25 mmol) was dissolved in a mixture of dichloromethane (100 ml) and methanol (40 ml) with stirring. Then, p-aminobenzyl alcohol (4.91 g, 39.87 mmol) and EEDQ (13.45 g, 54.37 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 14 hours. The reaction solution was filtered, and the solid was collected. The solid was then dilute with petroleum ether and ethyl acetate (90 ml, V... PE / V EA =1:2) pulped for 1 hour, filtered, the solid was collected and dried to obtain 11.3g of white solid, yield: 91.05%.

[1012] Step 3) Preparation of compound 40-M3

[1013] Compound Piv-SN38 (1 g, 2.1 mmol) was dissolved in dichloromethane (16 ml). Under a nitrogen atmosphere, the solution was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (1.67 g, 13.64 mmol) and pyridine (0.68 g, 8.5 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (0.42 g, 1.41 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 to 15 minutes. The reaction solution was then slowly added to a dichloromethane (20 ml) solution of compound 40-M2 (1.8 g, 5.25 mmol), and the mixture was stirred at 20 to 25 °C for 0.5 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was purified by separation and purification to obtain 0.37 g of a pale yellow solid, yield: 32.15%.

[1014] Step 4) Preparation of compound 40

[1015] Compound 40-M3 (370 mg, 0.438 mmol) was dissolved in dichloromethane (8 ml) with stirring. The solution was cooled to -5 to 0 °C, and 4-dimethylaminopyridine (59 mg, 0.482 mmol) was added first, followed by dropwise addition of a dichloromethane solution of CBTX-PNP (480 mg, 0.482 mmol). The reaction mixture was then stirred at 20–25 °C for 4 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1~40:1] Separation and purification yielded 0.57g of solid, yield: 76.25%, HPLC purity: 98.756%.

[1016] 1 H NMR (400MHz, DMSO) δ10.00(s,1H),9.89(d,J=27.6Hz,1H),8.23(d,J=9.1Hz,1H),7.98(t,J=4.8Hz,3 H),7.93(d,J=9.1Hz,1H),7.73(t,J=7.3Hz,1H),7.64(dd,J=10.5,7.6Hz,5H),7.56(t,J=9.1Hz,2H), 7.43(t,J=7.6Hz,2H),7.38–7.27(m,6H),7.22–7.17(m,1H),7.01(s,1H),5.82(t,J=8.7Hz,1H),5.5 3(s,1H),5.42–5.31(m,3H),5.12(d,J=14.5Hz,3H),5.07(dd,J=10.0,4.7Hz,2H),5.05–5.00(m,1H), 4.95(d,J=9.9Hz,1H),4.70(s,1H),4.56–4.38(m,2H),3.76(dd,J=10.3,6.7Hz,1H),3.59(d,J=7.0H z,1H),3.29(s,3H),3.25–3.18(m,5H),2.67(t,J=10.4Hz,1H),2.37(dd,J=11.3,7.5Hz,4H),2.25(s, 3H),2.17(dd,J=7.3,4.0Hz,1H),1.99(s,3H),1.90(dd,J=14.0,7.0Hz,2H),1.80(s,4H),1.58–1.48 (m,5H),1.37(d,J=13.5Hz,18H),1.29(t,J=7.6Hz,3H),0.98(d,J=6.6Hz,6H),0.90(t,J=7.4Hz,3H).

[1017] MS(ESI,Z=2):862.3[(M+H + 3O) / 2] + .

[1018] Example 41: Preparation of compound 41

[1019] Following the preparation method of compound 40 in Example 40, compound 41 was obtained by replacing CBTX-PNP with DTX-PNP (0.2 g solid, yield: 16.8%, HPLC purity: 97.198%).

[1020] 1 H NMR (400MHz, DMSO) δ (ppm) 10.03 (d, J = 32.4Hz, 2H), 8.25 (d, J = 9.1Hz, 1H), 8.09–7.90 (m, 4H), 7.78–7.57 (m, 8H), 7.37 (ddd, J = 26.2, 16.4, 8.1Hz, 8H),7.19(t,J=7.2Hz,1H),7.03(s,1H),5.82(t,1H),5.55(s,2H),5.40( dd,J=16.9,4.7Hz,3H),5.25–5.00(m,8H),4.99–4.89(m,2H),4.45(s,1H) ),4.15–3.98(m,3H),3.67(d,J=6.9Hz,1H),3.23(dd,J=14.7,7.0Hz,2H) ,2.44–2.35(m,4H),2.33–2.23(m,4H),2.19(dt,J=11.1,7.0Hz,2H),1.9 7–1.81(m,3H),1.78–1.64(m,4H),1.54(t,4H),1.40(s,9H),1.36(s,6H) ,1.32(t,J=7.6Hz,3H),1.25(s,3H),1.01(s,6H),0.93(t,J=7.4Hz,3H).

[1021] Example 42: Preparation of compound 42

[1022] Step 1) Preparation of compound 42-M1

[1023] Terephthalic acid (0.64 g, 3.88 mmol) was dissolved in N',N-dimethylacetamide (DMAc, 10 ml). Diisopropylethylamine (DIPEA, 0.76 g, 5.84 mmol) was added under ice bath conditions, followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1.34 g, 3.54 mmol). The mixture was stirred at 20–25 °C for 10 minutes. Then, a solution of compound 1-M1 (3 g, 3.16 mmol) in dichloromethane (10 ml) was added to the mixture under ice bath conditions. After the addition was complete, the mixture was stirred at 20–25 °C for 1 hour. The reaction solution was diluted with dichloromethane (30 ml), washed with 0.2 mol / L HCl (20 ml), water (20 ml), and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH The mixture was purified at a ratio of 50:1 to obtain 1.8 g of a white solid, with a yield of 51.9%.

[1024] Step 2) Preparation of compound 42-M2

[1025] Compound 42-M1 (1.8 g, 1.64 mmol) was dissolved in dichloromethane (16 ml) with stirring. Then, p-aminobenzyl alcohol (0.24 g, 1.97 mmol) and EEDQ (0.81 g, 3.28 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 12 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH [45:1 to 40:1] Separation and purification yielded 1.09 g of white solid, yield: 55.77%.

[1026] Step 3) Preparation of compound 42

[1027] Compound Piv-SN38 (0.15 g, 0.315 mmol) was dissolved in dichloromethane (10 ml). Under a nitrogen atmosphere, the mixture was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (0.26 g, 2.11 mmol) and pyridine (0.1 g, 1.26 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (63 mg, 0.211 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 minutes. A dichloromethane solution of compound 42-M2 (0.32 g, 0.267 mmol) was added to the mixture, and the mixture was stirred and kept at this temperature for 0.5 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was analyzed by silica gel column chromatography [V]. DCM / V MeOH=30:1] Separation and purification yielded 0.3 g of yellow solid, yield: 55.87%, HPLC purity: 99.2526%.

[1028] 1 H NMR (400MHz, DMSO) δ10.30(d,J=9.4Hz,1H),8.23(d,J=9.1Hz,1H),8.03–7.86(m,6H),7.74(d,J=8.3Hz,3H),7.65(s,2H),7.60–7.47(m,2H),7.39 (dd,J=26.4,12.2Hz,7H),7.17(s,1H),7.02(d,J=4.0Hz,1H),5.97–5.79 (m,1H),5.54(s,2H),5.37(t,J=5.1Hz,3H),5.19–5.04(m,3H),5.00–4.77 (m,2H),4.74–4.63(m,1H),4.45(s,1H),4.01(d,J=7.0Hz,1H),3.95–3.5 2(m,4H),3.48(d,J=25.5Hz,2H),3.30–3.10(m,9H),2.98(dd,J=30.1,20. 3Hz, 4H), 2.86–2.59 (m, 3H), 2.28 (s, 3H), 2.17 (d, J = 4.4Hz, 2H), 1.92–1. 75(m,4H),1.51(d,J=17.3Hz,5H),1.42–1.25(m,21H),1.06–0.88(m,9H).

[1029] MS(ESI): 1705.6898 [M+H] + .

[1030] Example 43: Preparation of compound 43

[1031] Step 1) Preparation of compound 43-M1

[1032] Compound 1-M1 (5.0 g, 5.26 mmol) was dissolved in dichloromethane (50 ml) with stirring. Phthalic anhydride (935 mg, 6.31 mmol) and pyridine (1.25 g, 15.78 mmol) were added under ice bath conditions. The mixture was then naturally heated to 20–25 °C and stirred for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH [55:1 to 50:1] Separation and purification yielded 5.1 g of white solid, with a yield of 88.3%.

[1033] Step 2) Preparation of compound 43-M2

[1034] Compound 43-M1 (2.0 g, 1.82 mmol) was dissolved in dichloromethane (20 ml) with stirring. Then, p-aminobenzyl alcohol (0.236 g, 1.91 mmol) and EEDQ (0.9 g, 3.64 mmol) were added successively, and the reaction mixture was stirred at 20–25 °C for 4 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1~20:1] Separation and purification yielded 1.7g of white solid, yield: 77.57%.

[1035] Step 3) Preparation of compound 43

[1036] Compound Piv-SN38 (0.22 g, 0.462 mmol) was dissolved in dichloromethane (20 ml). Under a nitrogen atmosphere, the mixture was cooled to -5 to 0 °C. 4-Dimethylaminopyridine (0.378 g, 3.09 mmol) and pyridine (0.15 g, 1.87 mmol) were added, and the mixture was stirred for 5 minutes. Triphosgene (63 mg, 0.211 mmol) was then added, with the dropping rate controlled to keep the internal temperature below 0 °C. After the addition was complete, the mixture was kept at -5 to 0 °C and stirred for 10 minutes. A dichloromethane solution of compound 43-M2 (0.527 g, 0.438 mmol) was added to the mixture, and the mixture was stirred and kept at this temperature for 0.5 hours. The reaction solution was washed with 0.3 mol / L hydrochloric acid (20 ml) and saturated sodium chloride (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography [V]. DCM / V MeOH =45:1] Separation and purification yielded 0.55 g of yellow solid, yield: 69.84%, HPLC purity: 99.6038%.

[1037] 1H NMR (400MHz, DMSO) δ10.46–10.37(m,1H),8.23(dd,J=9.0,6.4Hz,1H),8.04–7.91(m ,4H),7.69(dt,J=19.3,9.2Hz,6H),7.59–7.47(m,3H),7.45–7.33(m,5H),7.33–7.22 (m,2H),7.20–7.10(m,1H),7.02(d,J=7.2Hz,1H),5.88(dd,J=39.0,8.3Hz,1H),5.54 (s,2H),5.44–5.33(m,3H),5.14(d,J=6.0Hz,3H),5.03–4.88(m,2H),4.74–4.66(m,1 H),4.48(dd,J=14.1,5.2Hz,1H),3.91–3.36(m,5H),3.30–3.16(m,9H),3.04–2.90( m,2H),2.86(d,J=12.1Hz,2H),2.69(dd,J=58.1,21.8Hz,3H),2.34–2.25(m,3H),2.1 7(tt,J=14.5,7.2Hz,2H),1.83(t,J=17.8Hz,4H),1.49(d,J=18.7Hz,5H),1.38(d,J= 2.3Hz, 15H), 1.33–1.26 (m, 6H), 1.01 (dd, J=21.9, 9.1Hz, 6H), 0.92 (t, J=7.3Hz, 3H).

[1038] MS(ESI): 1705.6807 [M+H] + .

[1039] Example 44: Preparation of compound 44

[1040] Following the preparation method of compound 42 in Example 42, terephthalic acid was replaced with isophthalic acid to obtain compound 44 (0.29 g yellow solid, yield: 40.51%, HPLC purity: 98.9104%).

[1041] 1H NMR (400MHz, DMSO) δ10.35 (s, 1H), 8.21 (d, J = 9.0Hz, 1H), 8.03–7.87 (m, 6H) ,7.74(dd,J=21.7,7.7Hz,3H),7.67–7.50(m,5H),7.44–7.32(m,6H),7.17(s ,1H),7.02(s,1H),5.88(s,1H),5.58–5.48(m,2H),5.42–5.32(m,3H),5.20– 5.07(m,3H),5.01–4.82(m,2H),4.75–4.65(m,1H),4.47(d,J=12.2Hz,1H),3 .61(dd,J=55.5,48.7Hz,6H),3.23(dd,J=24.1,16.4Hz,9H),3.03(d,J=18. 2Hz,2H),2.98–2.82(m,3H),2.64(dd,J=38.1,32.0Hz,2H),2.27(d,J=16.9H z,3H),2.23–2.13(m,2H),1.90–1.74(m,4H),1.50(s,5H),1.36(d,J=11.6Hz ,18H), 1.28(t,J=7.6Hz,3H), 0.99(d,J=14.4Hz,6H), 0.91(t,J=7.2Hz,3H).

[1042] MS(ESI): 1705.6841 [M+H] + .

[1043] Example 45: Preparation of compound 45

[1044] Referring to the preparation method of compound 43 in Example 43, succinic anhydride was used instead of phthalic anhydride. Replacing p-aminobenzyl alcohol yielded compound 45 (0.8 g pale yellow solid, yield: 56.32%, HPLC purity: 98.4639%).

[1045] 1H NMR(400MHz,DMSO)δ10.19(dd,J=17.9,11.6Hz,1H),8.21(dd,J=9.1,2.0Hz,1H),8.03–7 .86(m,5H),7.75–7.69(m,1H),7.68–7.61(m,3H),7.47–7.35(m,6H),7.16(dd,J=14.1,7. 1Hz,1H),7.03(d,J=1.9Hz,1H),5.90–5.79(m,1H),5.59–5.48(m,2H),5.41–5.32(m,3H), 5.20–5.07(m,3H),5.04–4.88(m,2H),4.73–4.66(m,1H),4.44(d,J=9.2Hz,1H),4.03(d,J =8.6Hz,2H),3.74(d,J=15.6Hz,1H),3.68–3.38(m,4H),3.23(dt,J=17.2,9.8Hz,9H),3. 05(s,1H),2.94(dd,J=28.0,25.3Hz,3H),2.82(d,J=8.5Hz,2H),2.58(dd,J=24.3,18.0Hz ,5H),2.29–2.23(m,3H),2.17(dd,J=13.3,6.1Hz,2H),1.83(d,J=3.3Hz,4H),1.50(s,5H) ,1.38(d,J=6.7Hz,18H),1.30(t,J=7.5Hz,3H),0.97(d,J=7.9Hz,6H),0.94–0.88(m,3H).

[1046] MS(ESI): 1691.6444 [M+H] + .

[1047] Example 46: Preparation of Compound 46

[1048] Referring to the preparation method of compound 43 in Example 43, succinic anhydride was used instead of phthalic anhydride. Replacing p-aminobenzyl alcohol yielded compound 46 (450 mg pale yellow solid, yield: 63%, HPLC purity: 98.90%).

[1049] 1H NMR(400MHz, DMSO)δ(ppm)9.06(dd,J=18.1,9.6Hz,1H),8.23(d,J=9.1Hz,1H),8.09–8.0 1(m,1H),8.01–7.85(m,4H),7.71(d,J=6.1Hz,1H),7.64(t,J=7.6Hz,3H),7.39(d,J=6.4H z,4H),7.17(d,J=6.7Hz,1H),7.01(d,J=10.1Hz,2H),6.87(d,J=8.3Hz,1H),5.90–5.78( m,1H),5.57–5.47(m,2H),5.36(d,J=8.9Hz,3H),5.18–5.08(m,1H),5.07–4.89(m,4H),4. 68(d,J=11.1Hz,1H),4.45(d,J=6.6Hz,1H),4.01(s,2H),3.75(s,1H),3.64(d,J=6.2Hz, 3H),3.61–3.36(m,4H),3.28–3.14(m,9H),3.01(s,1H),2.92(dd,J=33.8,22.0Hz,3H),2. 81(t,J=6.2Hz,2H),2.59(s,4H),2.29–2.12(m,5H),1.83(s,4H),1.52(d,J=20.9Hz,5H) ,1.41–1.32(m,18H),1.29(t,J=7.5Hz,3H),0.97(d,J=4.1Hz,6H),0.90(t,J=7.3Hz,3H).

[1050] MS(ESI): 1687.6818 [M+H] + .

[1051] Example 47: Preparation of Compound 47

[1052] Referring to the synthesis of compound 1-M1 in Example 1, p-phenylenediamine was used instead. 47-M1 (2.3 g, yield 48%) was obtained.

[1053] Following the preparation method of compound 43 in Example 43, compound 1-M1 was replaced with compound 47-M1 to obtain compound 47 (0.45 g of pale yellow solid, yield: 61.13%, HPLC purity: 99.0084%).

[1054] 1H NMR (400MHz, DMSO) δ (ppm) 10.38 (s, 1H), 8.89 (t, J = 5.9Hz, 1H), 8.25 (d, J = 9.1Hz, 1H), 7.99 (dd,J=12.2,9.6Hz,4H),7.83–7.75(m,1H),7.69(dt,J=15.0,9.0Hz,5H),7.57(ddd,J=10.3 ,7.5,4.5Hz,5H),7.40(t,J=7.6Hz,2H),7.32(dd,J=19.1,8.4Hz,6H),7.18(d,J=7.9Hz,2H ),7.12(t,J=7.3Hz,1H),7.04(s,1H),5.53(s,2H),5.34(dd,J=15.5,5.1Hz,3H),5.11(dt,J =16.8,10.3Hz,3H),4.97–4.89(m,2H),4.66(s,1H),4.39(d,J=7.8Hz,3H),4.17(d,J=5.8H z,1H),4.00(s,2H),3.78–3.69(m,1H),3.55(d,J=6.9Hz,1H),3.28–3.15(m,8H),2.68–2.57 (m,1H),2.25(d,J=15.2Hz,3H),2.18(dt,J=11.4,7.0Hz,2H),1.83–1.67(m,4H),1.48(s,4H ),1.40–1.33(m,18H),1.29(t,J=7.6Hz,3H),0.97(t,J=10.4Hz,6H),0.90(d,J=7.4Hz,3H).

[1055] MS(ESI): 1753.6693 [M+H] + .

[1056] Example 48: Preparation of Compound 48

[1057] Referring to the synthesis of compound 1-M1 in Example 1, 4-methylaminoaniline was used instead. 48-M1 (2.9 g, yield 98.33%) was obtained.

[1058] Referring to the preparation method of compound 43 in Example 43, compound 1-M1 was replaced with compound 48-M1, and phthalic anhydride was replaced with succinic anhydride to obtain compound 48 (0.52 g of pale yellow solid, yield: 73.23%, HPLC purity: 98.7601%).

[1059] 1H NMR (400MHz, DMSO) δ (ppm) 9.99 (d, J = 20.1Hz, 2H), 8.22 (d, J = 9.1Hz, 1H), 7.98 (dd, J = 7 .7,4.9Hz,4H),7.84–7.71(m,2H),7.70–7.61(m,3H),7.55(t,J=8.6Hz,4H),7.41(t,J= 7.5Hz,2H),7.35(t,J=10.3Hz,2H),7.28(d,J=8.4Hz,2H),7.15(dd,J=16.8,7.8Hz,3H) ,7.01(s,1H),5.80–5.73(m,1H),5.55(d,J=17.3Hz,2H),5.42–5.30(m,3H),5.09(q,J= 12.0Hz,3H),4.97(dd,J=25.3,8.2Hz,2H),4.68(s,1H),4.44(d,J=15.9Hz,1H),4.14( d,J=5.1Hz,2H),4.00(s,2H),3.79–3.70(m,1H),3.56(d,J=6.6Hz,1H),3.28(s,3H),3. 20(s,5H),2.63(s,5H),2.28–2.13(m,5H),1.85–1.68(m,4H),1.52(d,J=17.2Hz,4H),1 .41–1.32(m,18H),1.29(t,J=7.5Hz,3H),0.97(t,J=9.8Hz,6H),0.90(t,J=7.3Hz,3H).

[1060] MS(ESI): 1691.6588 [M+H] + .

[1061] Example 49: Preparation of Compound 49

[1062] Following the preparation method of compound 43 in Example 43, compound 1-M1 was replaced with compound 47-M1, and phthalic anhydride was replaced with succinic anhydride to obtain compound 49 (0.5 g pale yellow solid, yield: 69.84%, HPLC purity: 97.5358%).

[1063] 1H NMR (400MHz, DMSO) δ (ppm) 9.97 (s, 1H), 8.36 (t, J = 5.9Hz, 1H), 8.22 (d, J = 9.1Hz, 1H), 8.05– 7.93(m,4H),7.84–7.71(m,2H),7.70–7.61(m,3H),7.56(d,J=8.5Hz,2H),7.41(t,J=7.6Hz ,2H),7.36–7.27(m,4H),7.23–7.11(m,5H),7.01(s,1H),5.75(s,1H),5.52(s,2H),5.35(d ,J=6.6Hz,3H),5.14–5.04(m,3H),4.92(t,J=8.4Hz,2H),4.68(s,1H),4.43(d,J=17.1Hz,1 H),4.20(dd,J=31.0,5.8Hz,4H),4.00(s,2H),3.74(dd,J=10.3,6.7Hz,1H),3.59–3.53(m, 1H),3.28(s,3H),3.24–3.15(m,5H),2.69–2.61(m,1H),2.55(d,J=6.5Hz,2H),2.48–2.44( m,2H),2.25(d,J=12.2Hz,3H),2.17(dt,J=10.9,7.0Hz,2H),1.84–1.68(m,4H),1.49(s,4H ),1.41–1.32(m,18H),1.29(t,J=7.6Hz,3H),0.97(t,J=9.7Hz,6H),0.90(t,J=7.4Hz,3H).

[1064] MS(ESI): 1705.6740 [M+H] + .

[1065] Biological Test Example 1: Cytotoxicity of Compounds on DU145 Cells

[1066] Materials and Supplies

[1067] Human prostate cancer cell line DU145, sourced from Peking Union Medical College Cell Resource Center, catalog number PUMC000006.

[1068] RPMI-1640 culture medium, catalog number 31800-022, manufacturer: Gibco.

[1069] Fetal bovine serum, catalog number 10099-141C, manufactured by Gibco.

[1070] The product is a cyano-chain dual-antibody drug, product number SV30010, manufactured by Hyclone.

[1071] Resazurin sodium salt, product number R7017, manufactured by Sigma.

[1072] DMSO, etc.

[1073] Operating procedures

[1074] 2.1 Cell Culture

[1075] DU145 cells were cultured in RPMI-1640 complete medium (containing 10% fetal bovine serum, 100 U / mL). -1 Penicillin, 100 μg / mL -1 Streptomycin was cultured at 37°C, 5% CO2, and 95% air using conventional methods. The passage ratio was 1:2 to 1:5, and the cells were passaged at least two times before plating.

[1076] 2.2 Paving

[1077] On day 0 of the experiment (D0), cells in the logarithmic growth phase were collected, prepared into single-cell suspensions, and counted. The cell concentration was adjusted to 2 × 10^4 cells / mL, and 100 μL was added to each well of a 96-well cell culture plate. The number of cells seeded in each well was 2000.

[1078] 2.3 Drug preparation method

[1079] Blank solvent: DMSO.

[1080] Preparation of test sample: Add an appropriate volume of DMSO and vortex to completely dissolve the drug. After dispensing, store in a refrigerator at -90℃ to -60℃.

[1081] 2.4 Drug treatment

[1082] On the day following plating (D1), add 100 μL of complete culture medium containing 2× series concentrations of the test compound or positive control compound, or complete culture medium of the control, to each well (two replicates for each concentration), and continue incubation for 72 h. The treatment concentrations of each compound were diluted 4-fold.

[1083] 2.5 Detection and Data Analysis

[1084] At day 4, the fluorescence intensity of each well was detected using the Alamar blue method, and the IC was calculated. 50 .

[1085] IC 50 Calculated using the following formula:

[1086] Min, Max, and Slope represent the minimum value, maximum value, and slope, respectively.

[1087] Experimental results:

[1088] cytotoxicity of the compound to DU145 cells (IC50) 50 :nM) NT: Not tested.

[1089] Biological Test Example 2: Inhibition of MDA-MB-231 Cell Proliferation by Compound

[1090] Materials and Supplies

[1091] Human breast cancer MDA-MB-231, sourced from the Chinese Academy of Sciences Cell Bank, catalog number SCSP-5043.

[1092] L-15 powder, product number 41300-039, manufacturer: Gibco.

[1093] Fetal bovine serum, catalog number 10099-141C, manufactured by Gibco.

[1094] The product is a cyano-chain dual-antibody drug, product number SV30010, manufactured by Hyclone.

[1095] Resazurin sodium salt, product number HY-111391, manufacturer is MCE.

[1096] Trypsin, catalog number SH30042.01 / SH30042.02, manufacturer: Hyclone.

[1097] 96-well plate, part number 3340 or 167008, manufacturer is Corning or Thermo.

[1098] Trypan Blue, product number T10282, is manufactured by Invitrogen.

[1099] PBS, catalog number B040100-0005, is manufactured by companies such as Sangon Biotech.

[1100] Operating procedures

[1101] 2.1 Cell Culture

[1102] MDA-MB-231 cells were cultured in L-15 complete medium (containing 10% fetal bovine serum, 100 U / mL). -1 Penicillin, 100 μg / mL -1 Streptomycin was cultured at 37°C in 100% air using conventional methods, with a passage ratio of 1:2 to 1:5, and passaged at least 2 times before plating.

[1103] 2.2 Paving

[1104] On day 0 of the experiment (D0), cells in the logarithmic growth phase were collected, prepared into single-cell suspensions, and counted. The cell concentration was adjusted to 2 × 10^4 cells / mL, and 100 μL was added to each well of a 96-well cell culture plate. The number of cells seeded per well was 2000.

[1105] 2.3 Drug preparation method

[1106] Blank solvent: DMSO.

[1107] Preparation of test sample: Add an appropriate volume of DMSO and vortex to completely dissolve the drug. After dispensing, store in a refrigerator at -90℃ to -60℃.

[1108] 2.4 Drug treatment

[1109] On the day following plating (D1), add 100 μL of complete culture medium containing 2× series concentrations of the test compound or positive control compound, or complete culture medium of the control, to each well (two replicates for each concentration), and continue incubation for 72 h. The treatment concentrations of each compound were diluted 4-fold.

[1110] 2.5 Detection and Data Analysis

[1111] At day 4, the fluorescence intensity of each well was detected using the Alamar blue method, and the IC was calculated. 50 .

[1112] IC 50 Calculated using the following formula:

[1113] Min, Max, and Slope represent the minimum value, maximum value, and slope, respectively.

[1114] Experimental results:

[1115] cytotoxicity (IC50) of the compound to MDA-MB-231 cells 50 :nM)

[1116] Biological Test Example 3: Inhibition of NCI-N87 Cell Proliferation by Compound

[1117] Materials and Supplies

[1118] Human gastric cancer cells NCI-N87, sourced from the Chinese Academy of Sciences Cell Bank (CAS), catalog number SCSP-534.

[1119] RPMI-1640 powder, part number 31800-022, manufactured by Gibco.

[1120] Fetal bovine serum, catalog number 10099-141C, manufactured by Gibco.

[1121] The product is a cyano-chain dual-antibody drug, product number SV30010, manufactured by Hyclone.

[1122] Resazurin sodium salt, product number HY-111391, manufacturer is MCE.

[1123] Trypsin, catalog number SH30042.01 / SH30042.02, manufacturer: Hyclone.

[1124] 96-well plate, part number 3340 or 167008, manufacturer is Corning or Thermo.

[1125] Trypan Blue, product number T10282, is manufactured by Invitrogen.

[1126] PBS, catalog number B040100-0005, is manufactured by companies such as Sangon Biotech.

[1127] Operating procedures

[1128] 2.1 Cell Culture

[1129] NCI-N87 cells were cultured in RPMI-1640 complete medium (containing 10% fetal bovine serum, 100 U / mL). -1 Penicillin, 100 μg / mL -1 Streptomycin was cultured at 37°C, 5% CO2, and 95% air using conventional methods. The passage ratio was 1:2 to 1:5, and the cells were passaged at least two times before plating.

[1130] 2.2 Paving

[1131] On day 0 of the experiment (D0), cells in the logarithmic growth phase were collected, prepared into single-cell suspensions, and counted. The cell concentration was adjusted to 6 × 10^4 cells / mL, and 100 μL was added to each well of a 96-well cell culture plate. The number of cells seeded per well was 6000.

[1132] 2.3 Drug preparation method

[1133] Blank solvent: DMSO.

[1134] Preparation of test sample: Add an appropriate volume of DMSO and vortex to completely dissolve the drug. After dispensing, store in a refrigerator at -90℃ to -60℃.

[1135] 2.4 Drug treatment

[1136] On the day following plating (D1), add 100 μL of complete culture medium containing 2× series concentrations of the test compound or positive control compound, or complete culture medium of the control, to each well (two replicates for each concentration), and continue incubation for 72 h. The treatment concentrations of each compound were diluted 4-fold.

[1137] 2.5 Detection and Data Analysis

[1138] At day 4, the fluorescence intensity of each well was detected using the Alamar blue method, and the IC was calculated. 50 .

[1139] IC 50 Calculated using the following formula:

[1140] Min, Max, and Slope represent the minimum value, maximum value, and slope, respectively.

[1141] Experimental results:

[1142] cytotoxicity of the compound to NCI-N87 cells (IC50) 50 :nM)

[1143] Biological Test Example 4: Pharmacokinetic Test

[1144] 4.1 Mouse drug metabolism kinetics test

[1145] Based on the plasma concentrations of the compound in intravenously administered (IV) ICR mice from 0 to 24 hours, pharmacokinetic parameters such as in vivo exposure, half-life, and Tmax were calculated. ICR mice were obtained from Hunan Slack Jingda Experimental Animal Co., Ltd., and weighed 20–30 g.

[1146] 1. Materials and Supplies

[1147] The main reagents and consumables used include: DMSO, Tween 80, anhydrous ethanol, physiological saline, syringes and blood collection needles, EDTA-K2 anticoagulant blood collection tubes, 96-well plates, acetonitrile, etc.

[1148] The main experimental instruments used included: a 4℃ constant temperature high-speed centrifuge, a -80℃ freezer, and LC-MS / MS.

[1149] 2. Operating Procedures

[1150] In vivo drug administration study:

[1151] Experimental animals were grouped and numbered. Mice were administered the drug intravenously. The drug solution was prepared at a specified concentration using DMSO, Tween 80, and physiological saline in a specific ratio. The dosage was 10 mg / kg. Nine mice were used for each compound, with three mice at each time point. Blood samples were collected from each mouse in crossover, and the parent drug and drug toxin (durg payload) were detected using LC-MS / MS.

[1152] The specific experimental design is shown in the table below:

[1153] The test results are shown in the table below:

[1154] Biological Test Example 5: Biodistribution of Compounds

[1155] 5.1 Tissue distribution of compound 23 in rats

[1156] Experimental Methods: SD rats, weighing 150–250 g, were obtained from Hunan Slack Jingda Experimental Animal Co., Ltd. Nine healthy male rats were selected and administered a single tail vein dose of compound 2310 mg / kg. At different time points after administration (0.167, 1, and 4 h, 3 rats at each time point), the animals were euthanized under isoflurane anesthesia, and plasma, liver, and kidneys were collected. Plasma (1 mL) was collected via the jugular vein or other suitable vein and placed in a labeled EDTA-K2 anticoagulant tube. After gentle inversion to ensure thorough mixing of the anticoagulant (EDTA-K2) with the blood, the tube was immediately placed on wet ice and centrifuged as quickly as possible at 4°C, 6800 g, and 6 minutes. The animals were anesthetized with isoflurane and bled from the abdominal aorta. After bledling from the abdominal aorta, the liver and kidneys were collected and washed immediately with physiological saline. After washing, the liver and kidneys were stored at a temperature not exceeding -20°C. The parent drug (compound 23) and drug toxicity were detected using LC-MS / MS.

[1157] Experimental results: See Tables 5.1.1 to 5.2.4 below (SD represents standard deviation; CV represents relative standard deviation).

[1158] Table 5.1.1 Concentrations of compound 23 in plasma, liver, and kidney of rats after intravenous administration of 10 mg / kg

[1159] Table 5.1.2 Concentrations of drug toxins in plasma, liver, and kidneys in rats after intravenous administration of 10 mg / kg.

[1160] Table 5.1.3 Concentration ratios of Compound 23 and drug toxins in different tissues and plasma at different time points.

[1161] Table 5.1.4 AUC of Compound 23 and Drug Toxin in Blood, Liver and Kidney of Rats in PK 0-t

[1162] 5.2 Tissue distribution of compound 30 in rats

[1163] Experimental Methods: SD rats, weighing 150–250 g, were obtained from Hunan Slack Jingda Experimental Animal Co., Ltd. Nine healthy male rats were selected and administered a single tail vein dose of compound 3010 mg / kg. At different time points after administration (0.167, 1, and 4 h, with 3 rats at each time point), the animals were euthanized under isoflurane anesthesia. Whole blood, liver, and kidneys were collected. Blood was excised from the abdominal aorta under isoflurane anesthesia. After excising blood from the abdominal aorta, the liver and kidneys were collected and washed immediately with physiological saline. After washing, they were stored at a temperature not exceeding -20°C. The parent drug (compound 30) and drug toxicity were detected using LC-MS / MS.

[1164] Experimental results: See Tables 5.2.1 to 5.2.4 below (SD represents standard deviation; CV represents relative standard deviation).

[1165] Table 5.2.1 Concentrations of compound 30 in plasma, liver, and kidney of rats after intravenous administration of 10 mg / kg

[1166] Table 5.2.2 Concentrations of drug toxins in plasma, liver, and kidneys in rats after intravenous administration of 30 mg / kg.

[1167] Table 5.2.3 Concentration ratios of Compound 30 and drug toxins in different tissues and plasma at different time points.

[1168] Table 5.2.4 AUC of Compound 30 and Drug Toxin in Blood, Liver and Kidney of Rats in PK 0-t Note: Plasma AUC 0-t The unit is: h*ng / mL; tissue AUC 0-t The unit is h*ng / g. NA: Not applicable.

[1169] Biological Test Example 6: In vivo anti-tumor effect

[1170] Biological assay 6.1: Effect on the growth of human gastric cancer NCI-N87 cell line CB17 SCID mouse...

Claims

A compound of formula I' or a pharmaceutically acceptable salt thereof: in, A is a drug payload, preferably a cytotoxic agent; more preferably, the cytotoxic agent is CPT, wherein CPT is camptothecin or camptothecin derivatives. The B mentioned is taxane; L is a linker, with its a-end covalently linked to a drug toxin and its b-end covalently linked to taxane. The linker enables the compound to release a drug payload in vivo. A compound of Formula I or a pharmaceutically acceptable salt thereof: in, L stands for connector; R 1 Hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R o replace; Each R o Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R p replace; Each R p Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R q replace; Each R q Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; wherein -OH, -SH, -NH2, -C(=O)H, -S(=O)2H, -S(=O)H, -P(=O)H2, -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 The aromatic group and 5-20 heteroaryl group are optionally surrounded by one or more R r replace; Each R r Independently, it can be deuterium, halogen, nitro, cyano, =O, -OH, -SH, -NH2, -C(=O)H, -C(=O)OH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2, -S(=O)OH, -S(=O)NH2, -P(=O)(OH)2, -P(=O)NH2(OH), -P(=O)(NH2)2, -PH(=O)OH, -PH(=O)NH2, -PH2(=O), -SiH3, HN=CH-, C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, 3-20 heteroalkyl, 4-20 heteroenyl, 4-20 heteroalkynyl, 3-20 heterocycloalkyl, 3-20 heterocycloenyl, 3-20 heterocycloalkynyl, C 6-20 Aromatic groups or 5-20 heteroaryl groups; The terms heteroalkyl, heteroalkenyl, heteroynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloynyl, and heteroaromatic groups indicate that the group contains a heteroatom, wherein the heteroatom is independently selected from one, two, three, or four of O, P, S, and N; and the number of heteroatoms is independently one, two, three, or four. R 2 R 3 R 4 R 5a R 5b R 6 R 7 R 8 R 11 R 12 R 13 Each independently as above R 1 Defined; Or, R 1 and R 2 Together with the atoms it is attached to, it forms a ring structure E1; the ring structure E1 is optionally bounded by one or more R... 26 Replace; each R 26 Independently as above R 1 Defined; Or, R 2 and R 3 Together with the atoms it is attached to, it forms a ring structure E2; the ring structure E2 is optionally bounded by one or more R atoms. 27 Replace; each R 27 Independently as above R 1 Defined; Or, R 3 and R 4 Together with the atoms it is attached to, it forms a ring structure E3; the ring structure E3 is optionally bounded by one or more R atoms. 28 Replace; each R 28 Independently as above R 1 Defined. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of formula II, III, IV, or V, or a pharmaceutically acceptable salt thereof. in, The W mentioned A It is a releasable linker, capable of releasing the following chemical structure from the compound in vivo: Q is a spacer group; m can be 0, 1, 2, 3, or 4; T is O or NR 33 Preferably, T is 0; R 15a R 15b R 16 R 17 R 33 Each independently as above R 1 Defined; Q 1 Spacer group 1; X is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- Or -P(=S)(OH)-; The Y is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- or -P(=S)(OH)-. A compound of formula VI or a pharmaceutically acceptable salt thereof: in, L stands for connector; R 6 R 7 R 8 R 11 R 12 R 13 R independently 1 Defined; R 3a Selected from hydrogen, deuterium, and -C(=O)R a -S(=O)2R a -S(=O)R a -P(=O)R a R b 、-Si(R a 3. -C 1-20 Alkylene-Si(R) a 3. C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene-NR a R b -C 1-20 alkylene-3-20-membered heterocyclic group, -C 1-20 Alkylene-OC(=O)-C 1-20 Alkylene-C(=O)-OR a and -C 1-20 Alkylene-NR a -C(=O)-OR a The C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Alkylene, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace; Each R a and R b Each is independently selected from hydrogen, deuterium, halogen, -OH, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group, wherein the 3-7-membered heterocyclic group is optionally surrounded by one or more R c replace; Each R c Selected from deuterium, halogens, -OH, =O, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -OC 1-6 Alkylene-NH2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, -C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NH(C) 1-6 Alkyl), -C 1-6 Alkylene-N(C) 1-6 alkyl)2 and -C 1-6 Alkylene-3-7-membered heterocyclic group. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, is a compound of formula VII, VIII, IX, or XI, or a pharmaceutically acceptable salt thereof. in, The W mentioned A It is a releasable linker, capable of releasing the following chemical structure from the compound in vivo: Q is a spacer group; m can be 0, 1, 2, 3, or 4; T is O or NR 33 Preferably, T is 0; R 15a R 15b R 16 R 17 R 33 Each independently as above R 1 Defined; Q 1 Spacer group 1; X is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- Or -P(=S)(OH)-; The Y is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- or -P(=S)(OH)-. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, and 4 in, L is -W A -Q-、 The W mentioned A It is a releaseable linker. Q is a spacer group; m can be 0, 1, 2, 3, or 4; T is O or NR 33 Preferably, T is 0; R 15a R 15b R 16 R 17 R 33 Each independently as above R 1 Defined; Q 1 Spacer group 1; X is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- Or -P(=S)(OH)-; The Y is -C(=O)-, -S(=O)2-, -S(=O)-, -P(=O)(OH)-, -P(=O)(H)-, -C(=S)-, -S(=S)2-, -S(=S)(=O)-, -S(=S)- or -P(=S)(OH)-. According to claim 2, the compound or a pharmaceutically acceptable salt thereof, Selected from: in, R 121 For H or optionally by one or more R 123 Replacement C 1-6 Alkyl groups; R 122 -C(=O)R 124 ; The R 123 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 101 -NHR 101 -NR 101 R 101 -SR 101 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is independently and optionally surrounded by one or more R 102 Substitution; the aryl and heteroaryl groups are each independently and optionally replaced by one or more R 103 replace; The R 101 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; The R 102 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 104 -NHR 104 -NR 104 R 104 -SR 104 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-0 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; The R 103 Each can be independently classified as deuterium, halogen, nitro, cyano, or -OR. 104 -NHR 104 -NR 104 R 104 -SR 104 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; The R 104 Each is independently hydrogen, deuterium, and C. 1-20 Alkyl, 3-20 heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl; The R mentioned 124 For -OR 201 -NHR 201 -NR 201 R 201 -SR 201 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is independently and optionally surrounded by one or more R 202 Substitution; the aryl and heteroaryl groups are each independently and optionally replaced by one or more R 203 replace; The R 201 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; The R 202 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or -OR. 204 -NHR 204 -NR 204 R 204 -SR 204 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-0 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; The R 203 Each can be independently classified as deuterium, halogen, nitro, cyano, or -OR. 204 -NHR 204 -NR 204 R 204 -SR 204 C 1-10 Alkyl, 3-10 heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl; the alkyl and cycloalkyl groups are each optionally and independently bound by one or more R groups. 205 Substitution; the aryl group is optionally replaced by one or more R 206 replace; The R 204 Each is independently hydrogen, deuterium, and C. 1-20 Alkyl, 3-20 heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl; The R 205 Each can be independently represented as deuterium, halogen, nitro, cyano, =O, or C. 1-10 Alkyl, C 3-10 cycloalkyl or C 6-10 Aryl; The R 206 Each is independently a deuterium, halogen, nitro, cyano, or C group. 1-10 Alkyl, C 3-10 cycloalkyl or C 6-10 Aryl; R 3b Selected from hydrogen, deuterium, halogen, nitro, cyano, -OH, -SH, -NH2, -NH(C) 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 alkylene-3-20-membered heterocyclic group, wherein C 1-20 Alkyl, C 1-20 Alkylene, C 1-20 Heteroalkyl, C 1-20 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 The aryl and 5-20 heteroaryl groups are each independently and optionally bounded by one or more R groups. c replace; Each R c Independently selected from deuterium, halogen, nitro, cyano, =O, -OH, =O, -SH, -NH2, -NH(C 1-20 alkyl), -N(C) 1-20 Alkyl)2, -OC 1-20 Alkylene -NH2, -OC 1-20 Alkylene-NH(C) 1-20 alkyl), -OC 1-20 Alkylene-N(C) 1-20 Alkyl group 2, -C(=O)OH, -C(=O)H, -Si(C 1-20 Alkyl)3, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 1-20 Hydroxyalkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkoxy groups, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 Aryl, 5-20 heteroaryl, -C 1-20 Alkylene -NH2, -C 1-20 Alkylene-NH(C) 1-20 Alkyl), -C 1-20 Alkylene-N(C) 1-20 alkyl)2 and -C 1-20 Alkylene-3-20-membered heterocyclic group. A compound or a pharmaceutically acceptable salt thereof:

Images