Camptothecin analogs, conjugates, and methods of use

Abstract

Camptothecin analogs of formula (I), (II), (III) are described, as well as conjugates comprising these camptothecin analogs. These camptothecin analogs and conjugates are useful as therapeutic agents, particularly for the treatment of cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and immunodeficiency diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to PCT application PCT / CN2024 / 073046, filed on January 18, 2024, and PCT application PCT / CN2024 / 143223, filed on December 27, 2024, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This disclosure relates to the field of therapeutics, and in particular to camptothecin analogues, conjugates comprising these camptothecin analogues, and their use in therapy. Background Technology

[0004] Camptothecin is a natural product that inhibits topoisomerase I and possesses broad-spectrum antitumor activity. However, camptothecin has poor solubility, making it unsuitable for clinical development. Therefore, considerable efforts have been made to find analogs or derivatives of camptothecin with properties more suitable for therapeutic use. Irinotecan and topotecan, two derivatives, have been approved for the treatment of cancer. Irinotecan is a prodrug that is converted in vivo into the more potent analog SN-38. A third derivative, beloteccan, has been approved in South Korea.

[0005] Camptothecin analogues have also been developed as payloads for antibody-drug conjugates (ADCs). Two such ADCs have been approved for cancer treatment. In trastuzumab (Enhertu™), the camptothecin analogue derutecan (Dxd) is conjugated to the anti-HER2 antibody trastuzumab via a cleavable tetrapeptide linker, while in goxatuzumab (Trodelvy™), the camptothecin analogue SN-38 is conjugated to the anti-Trop-2 antibody saltuzumab via a hydrolyzable pH-sensitive linker.

[0006] Other camptothecin analogues and derivatives, as well as ADCs containing them, have been described. See, for example, International (PCT) Publications WO 2019 / 195665; WO 2019 / 236954 and WO 2020 / 219287.

[0007] The purpose of providing this background information is to make the applicant believe that information that may be relevant to this disclosure is known. It does not necessarily imply an admission, nor should it be construed as, any of the foregoing information constituting prior art to the claimed invention. Summary of the Invention

[0008] This article describes camptothecin analogues, conjugates comprising these compounds, and therapeutic applications using these compounds and conjugates. In particular, we introduce the development of novel camptothecin compounds designed as ADC payloads. The novel camptothecin compounds focus on structure-activity relationships and the scope of preclinical ADC studies to improve potency without increasing toxicity. The disclosed compounds are elaborated into drug linkers, conjugated to form ADCs, and evaluated in vitro and in vivo. The novel camptothecin compounds disclosed exhibit excellent inhibitory activity, impressive efficacy in various cell line-derived xenograft models, and significant tolerability in healthy mice and other animals, paving the way for potential therapeutic advances in cancer.

[0009] In a first aspect, a compound having formula (I) is provided, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (I) in, X is CR x Or N, for example CH or N; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R2 is selected from NR 2b R 2c -(CH2) m -C(O)R 2a -(CH2) m -C(O)OR 2a -(CH2) m -OC(O)R 2a -(CH2) m -S(O)2-R 2a -(CH2) m -S(O)-R 2a -(CH2) m -NHC(O)-R 2a -(CH2) m -C(O)NR 2b R2c -(CH2) m -NHC(O)OR 2a and -(CH2) m -OC(O)NR 2b R 2c and -(CH2) m -NHC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p OC(O)R 3a -(CH2) p -S(O)2-R 3a -(CH2) p -S(O)-R 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a -(CH2) p -OC(O)NR 3b R 3c and -(CH2) p -NHC(O)NR 3b R 3c ; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; Each p is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; In this embodiment, R2 and R3 are optionally substituted by 1, 2, 3, 4, or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0010] On the other hand, this disclosure provides the coupling disclosed herein, which can be generated by L1-(D1). x Preferably, the coupling agent can be composed of T1-[L1'-(D1)]. x ] w express; T1 is the target portion; L1 is a linker, and L1' is a divalent group formed by connecting T1 and L1; D1 is the drug fraction, which is selected from compounds having formula (I); x is an integer between 1 and 10; w is an integer between 1 and 10.

[0011] On the other hand, a compound having formula (II) is provided, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II) in, R4 and R5 are independently selected from H, halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6 is selected from H, -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -S(O)2-R 6a -(CH2) n -S(O)-R 6a -(CH2) n -OP(O)(OH)-OR 6a -(CH2) n -OP(S)(OH)-OR 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -NHC(O)NR 6b R 6c -(CH2) n -NHC(O)OR 6a -(CH2) n -OC(O)NR 6b R 6c -(CH2) n -C(O)NR 6b R 6c -(CH2) n -CH2NR 6b R 6c -(CH2) n -3-7-membered heterocyclic group-(CH2) n -OR 6a and -(CH2) n -3-7-membered heterocyclic group-(CH2) n -R 6a ; R 6a R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0012] On the other hand, this disclosure provides for the coupling disclosed herein, which can be made from L2-(D2). y Preferably, the coupling agent can be composed of T2-[L2'-(D2)]. y ] u express; T2 is the target component; L2 is a linker, and L2' is a divalent group formed by connecting L2 and T2; D2 is the drug fraction, which is selected from compounds having formula (II); y is an integer between 1 and 10; u is an integer between 1 and 10.

[0013] On the other hand, a compound having formula (III) is provided, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III) in, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -NHC(O)OR 7a -(CH2) k -OC(O)NH-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each k is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R 10c -(CH2) q -C(O)R 10a -(CH2) q -C(O)OR10a -(CH2) q -OC(O)R 10a -(CH2) q -S(O)2-R 10a -(CH2) q -S(O)-R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R7, R8, R9 and R 10 Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0014] On the other hand, this disclosure provides for the coupling disclosed herein, which can be made from L3-(D3). z Preferably, the coupling compound can be composed of T3-[L3'-(D3)]. z ] r express; T3 is the target component; L3 is a linker, and L3' is a divalent group formed by the connection of T3 and L3; D3 is the drug fraction, which is selected from compounds having formula (III); z is an integer between 1 and 10; r is an integer between 1 and 10.

[0015] On the other hand, this disclosure provides the coupling disclosed herein, which may be an ADC or an LDC, preferably an ADC.

[0016] In another aspect, this disclosure provides a composition comprising the compound described herein, or a pharmaceutically acceptable salt, isotopically labeled analogue, crystalline form, hydrate, solvate, enantiomer, diastereomer, and optionally a pharmaceutically acceptable carrier or excipient.

[0017] On the other hand, this disclosure provides for the use of the compounds described herein, or pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, or the compositions described herein, in the manufacture of medicaments for the treatment and / or prevention of diseases.

[0018] On the other hand, this disclosure provides the compounds described herein, or pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, or compositions described herein, for use in the treatment and / or prevention of diseases.

[0019] On the other hand, this disclosure provides a method for preventing and / or treating a disease in a subject in need, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, or a composition described herein.

[0020] In a particular embodiment, the method further includes administering a second therapeutic agent to the subject, preferably wherein the second therapeutic agent is selected from antibodies, chemotherapeutic agents, and small molecule drugs.

[0021] In a specific embodiment, the disease is selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and immunodeficiency diseases.

[0022] In a specific embodiment, the cancer is selected from head and neck cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, ovarian cancer, prostate cancer, breast cancer, leukemia, myeloma, squamous cell carcinoma, melanoma, brain cancer, cervical cancer, liver cancer, bladder cancer, breast cancer, kidney cancer, testicular cancer, and thyroid cancer. In a particular embodiment, the autoimmune disease is selected from systemic sclerosis and atherosclerosis.

[0023] It should be understood that one, some, or all of the features of the various embodiments described herein can be combined to form other embodiments of this disclosure. These and other aspects of this disclosure will become apparent to those skilled in the art. These and other embodiments of this disclosure are further described in the following detailed description.

[0024] definition

[0025] The following lists the definitions of various terms used to describe the invention. Unless otherwise limited individually or as part of a larger group in a particular case, these definitions apply to the terms used throughout the specification and claims.

[0026] Chemical definition

[0027] When listing a range of values, the aim is to cover every value within that range and its subranges. For example, "C 1-6 "Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 And C 5-6 alkyl.

[0028] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with alkyl groups. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may optionally be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (CH2CH(CH3)2).

[0029] Unless otherwise stated, "C" is used alone or in combination with other terms. 1-6 "Alkoxy" refers to an alkyl group having 1 to 6 carbon atoms connected to the rest of the molecule by an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologues and isomers. In some embodiments, C 1-4 Alkyl groups are preferred.

[0030] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may optionally be substituted by one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkyne groups are preferred. C 2-6Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), and hexynyl (C6). The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be substituted by one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] “C 0-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a bond or divalent group formed by another hydrogen atom of the alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 Alkylene is preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0033] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, and it can be a substituted or unsubstituted alkenyl group. In some embodiments, C 2-4Alkenyl groups are preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0034] “C 2-6 "Iso-ynyl" refers to the group that has the C group removed. 2-6 The other hydrogen atom of the alkynyl group forms a divalent group, and it can be a substituted or unsubstituted alkynyl group. In some embodiments, C 2-4 The ynylene group is preferred. Exemplary ynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc.

[0035] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0036] “C 1-6 "Halogenated alkyl" refers to the above "C" group that has been substituted with one or more halogen groups. 1-6 Alkyl group. "C" 1-6 "Haloalkoxy" refers to the above "C" group that has been substituted with one or more halogen groups. 1-6 "Alkoxy group". Examples include monohalogenated, dihalogenated, and polyhalogenated alkyl groups, including perhalogenated alkyl groups. The monohalogen substituent in this group can be an iodine, bromine, chlorine, or fluorine atom; the dihalogenated and polyhalogenated substituents can be two or more identical halogen atoms or combinations of different halogens. Preferred examples of haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The haloalkyl group can be substituted at any available attachment point, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl groups are particularly preferred, C4-6 Cycloalkyl groups are preferred, and C... 3-5 Cycloalkyl is even more preferred. Cycloalkyl also includes a ring system in which the cycloalkyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the cycloalkyl ring, and in this case, the number of carbons continues to represent the number of carbons in the cycloalkyl ring system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), etc.

[0038] The terms “heterocyclic,” “heterocyclic group,” or “heterocyclic alkyl” are used interchangeably and refer to a fused, bridged, or spirocyclic system of non-aromatic rings, bicyclic, or tricyclic groups, wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen; (ii) each ring system may be saturated or unsaturated; (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized; (iv) the nitrogen heteroatom may optionally be quaternized; (v) any of the above rings may be fused to an aromatic ring; and (vi) the remaining ring atoms are carbon atoms that may optionally be oxo-substituted or optionally substituted with exocyclic alkene, imine, or oxime double bonds.

[0039] "3-12 membered heterocyclic group" refers to a group having a 3- to 12-membered non-aromatic ring system with a cyclic carbon atom and 1 to 6 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. In some embodiments, 5- to 10 membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms in a 5- to 10-membered non-aromatic ring system; in some embodiments, 5- to 6 membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 4 cyclic heteroatoms in a 5- to 6-membered non-aromatic ring system. Heterocyclic groups also include ring systems in which the heterocyclic ring as defined above is fused with one or more cycloalkyl groups and the attachment point is on the cycloalkyl ring; or in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups and the attachment point is on the heterocyclic ring; and in this case, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclic butyl, oxacyclic butyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxasulfuron, dithiofuran, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazine. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxasulfuronyl, and thiasulfuronyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0040] 3- to 12-membered heterocyclic groups also include spiroheterocyclic groups, i.e., groups in which two rings (e.g., a heterocyclic group and a carbocyclic group) share a single carbon atom, wherein at least one ring is a heterocyclic group as defined above. More particularly, the spiroheterocyclic group is a spirocycle formed by two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, wherein at least one ring is a 4- to 6-membered heterocyclic group as defined above. 4- to 6-membered heterocyclic groups containing 1, 2, or 3 O, N, or S heteroatoms are preferred, and 4- to 6-membered heterocyclic groups containing 1 N heteroatom are more preferred. Specific spiroheterocyclic groups include, but are not limited to: , , , , , , , , , , , , , , , , , , , , , , ,and .

[0041] “C 6-10 "Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a ring array) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups and the attachment point is on the aryl ring, and in this case, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.

[0042] "5- to 12-membered heteroaryl" refers to a group having a 5- to 12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-6 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, where the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. Heteroaryl groups further include cyclic systems in which the heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups and the attachment point is on the heteroaryl ring, and in this case, the number of ring members continues to represent the number of ring members in the heteroaryl cyclic system. In some embodiments, 5- to 10-membered heteroaryl groups are particularly preferred, which are groups having a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having a cyclic carbon atom and 1-6 cyclic heteroatoms. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are groups having a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indole, isoindole, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indoleazinyl, and purine. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl.

[0043] It should be understood that any alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, etc., described herein may also be divalent or polyvalent groups when used as bonds connecting two or more groups or substituents (which may be located on the same or different atoms). Those skilled in the art can readily determine the valence of any such group from the context in which it appears.

[0044] As used herein, the term "optionally substituted" means that the mentioned group may be substituted or unsubstituted. In one embodiment, the mentioned group is optionally substituted with zero substituents, i.e., the mentioned group is unsubstituted. In another embodiment, the mentioned group is optionally substituted with one or more additional groups, which are individually and independently selected from the groups described herein.

[0045] The term "hydrogen" includes both hydrogen and deuterium. Additionally, the description of an atom includes other isotopes of that atom, provided the resulting compound is pharmaceutically acceptable.

[0046] Alkyl, alkoxy, alkenyl, alkynylene, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted groups. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permitted substituent (e.g., a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions)). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position can be the same or different. The term "substituted" is considered to include substitution with all permitted substituents of an organic compound (any substituent described herein that results in the formation of a stable compound). For the purposes of this invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and / or any suitable substituent as described herein, which satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0047] Exemplary substituents on carbon atoms include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa-OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; Or two hydrogen atom on a carbon atom are surrounded by =O, =S, =NN(R) groups. bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc Substitute; R aa Each instance is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. aa Groups are linked to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R bb Each instance is independently selected from hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa-C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are linked to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R cc Each instance is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. cc Groups are linked to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; R dd Each instance is independently selected from halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2Ree -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groups dd Substituents can be linked to form =O or =S; R eeEach instance is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently represented by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; R ff Each instance is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. ff Groups are linked to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and R gg Each instance is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3-C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 carbon cyclogroup, C 6- C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0048] Exemplary substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, and -OR. aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc Groups are linked to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd As defined above.

[0049] Other definitions

[0050] In some embodiments, the compound of each formula herein is defined as including an isotopically labeled compound. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched with respect to a specific isotope of a specified element to a level significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound may be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, such as enrichment to at least 1%, preferably at least 20%, or at least 50%. For example, such deuterated compounds may be metabolized more slowly than their non-deuterated analogues, and thus exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, such as by employing deuterated starting materials. Unless otherwise stated, isotopically labeled compounds are pharmaceutically acceptable.

[0051] As used herein, “cancer” means any disease caused or resulting from an inappropriately high level of cell division, an inappropriately low level of cell apoptosis, or both. Examples of cancer include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenström macroglobulinemia, heavy chain disease, and solid tumors.

[0052] Unless otherwise stated, the term "treatment" as used herein includes effects on a subject suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or delay or slow its progression ("therapeutic treatment"). The term also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or condition ("preventive treatment").

[0053] As used herein, the term “treating” refers to reversing, alleviating, inhibiting, or preventing the progression of the following: the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term “treating” as used herein refers to the action of treatment, which is a verb, and the latter is as defined above.

[0054] The terms “disease,” “disorder,” and “symptom” can be used interchangeably in this article.

[0055] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a target biological response. As those skilled in the art will understand, the effective amount of the compounds disclosed herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health status, and symptoms of the subject. Effective amounts include therapeutically effective amounts and prophylacticly effective amounts.

[0056] Unless otherwise stated, the term "therapeuticly effective amount" as used herein refers to an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount by which a therapeutic agent, when used alone or in combination with other therapies, provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0057] The term "combination" and related terms refer to the simultaneous or sequential administration of the disclosed compounds with other therapeutic agents. For example, the disclosed compounds may be administered simultaneously or sequentially with other therapeutic agents at separate unit doses, or simultaneously with other therapeutic agents at a single unit dose.

[0058] As used herein, the term “pharmaceutically acceptable” means that, within reasonable medical judgment, these substances are suitable for contact with a patient’s tissues without undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use, including (where possible) the zwitterionic forms of the compounds disclosed herein.

[0059] The term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed herein. These salts can be prepared in situ during the final separation and purification of the compounds, or by separating the salts produced by reacting the purified compounds in free base form with suitable organic or inorganic acids, respectively.

[0060] Pharmaceutically acceptable base addition salts are formed from metals or amines (e.g., alkali metal and alkaline earth metal hydroxides or organic amines). Examples of metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0061] Salts can be prepared from inorganic acids, including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucono-p-ethylate, lacturonate, lauryl sulfonate, and hydroxyethyl sulfonate. Salts can also be prepared from organic acids, including aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acids, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoate, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals (e.g., sodium, lithium, potassium, calcium, magnesium, etc.) as well as non-toxic ammonium, quaternary ammonium, and amine cations (including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.). This also includes salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (e.g., see Berge SM et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66: 1–19, which is incorporated herein by reference).

[0062] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with tissues of humans and lower animals within the bounds of reasonable medical judgment without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting a free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts with amino groups formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts with amino groups formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. When appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1 to 6 carbon atoms, sulfonates, and aryl sulfonates.

[0063] In some embodiments, the compound of each formula herein is defined as including an isotopically labeled compound. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched with respect to a specific isotope of a specified element to a level significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound may be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, such as enrichment to at least 1%, preferably at least 20%, or at least 50%. For example, such deuterated compounds may be metabolized more slowly than their non-deuterated analogues, and thus exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, such as by employing deuterated starting materials. Unless otherwise stated, isotopically labeled compounds are pharmaceutically acceptable.

[0064] The combinations of substituents and variables contemplated by this invention are only those combinations that result in the formation of stable compounds. As used herein, the term "stable" means a compound that has sufficient stability to allow for manufacture and maintains the integrity of the compound for a sufficient period of time for use for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0065] The synthesized compounds can be isolated from the reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. Other methods for synthesizing compounds having the formula described herein will be apparent to those skilled in the art, as will be understood by those skilled in the art. Furthermore, various synthetic steps can be performed in an alternating order or sequence to give the desired compound. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) used to synthesize the compounds described herein are known in the art and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations , 2nd edition Wiley-VCH [Wiley-VCH Publishers] (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis [ Protecting groups in organic synthesis ], 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis [Fieser and Fieser's Organic Synthesis Reagents] John Wiley and Sons (1994); and L. Paquette, editor. Encyclopedia of Reagents for Organic Synthesis [An Encyclopedia of Organic Synthesis Reagents] John Wiley and Sons (1995) and its subsequent editions.

[0066] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subjects also refer to animals such as dogs, cats, horses, cattle, pigs, guinea pigs, fish, birds, etc.

[0067] The compounds of the present invention can be modified to enhance selective biological properties by adding appropriate functional groups. Such modifications are known in the art and may include those that increase biopermeability to a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism, and change the rate of excretion.

[0068] The compounds described herein contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-, or (D)- or (L)-. This invention aims to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above or by resolving racemic mixtures. Resolution can be performed in the presence of a resolving agent by chromatography or by repeated crystallization or by some combination of these techniques known to those skilled in the art. Further details regarding resolution can be found in: Jacques et al., Enantiomers, Racemates, and Resolutions (John Willie & Sons, 1981). When the compounds described herein contain an alkene double bond, other degrees of unsaturation, or other geometrically asymmetric centers, and unless otherwise stated, these compounds are intended to include... E and Z Geometric isomers or cis and trans isomers. Similarly, all tautomers are intended to be included. Tautomers can be cyclic or acyclic. Any carbon-carbon double bond configuration appearing herein is chosen for convenience only and is not intended to specify a particular configuration unless stated herein; therefore, any carbon-carbon double bond or carbon heteroatom double bond arbitrarily described herein as trans can be cis. 、 Trans, or a mixture of both in any proportion.

[0069] As used herein, the term "antibody" refers to an immunoglobulin molecule that has the ability to specifically bind to an antigen. Antibodies typically include a variable region and a constant region in each of their heavy and light chains. The variable regions of both the heavy and light chains contain binding domains that interact with the antigen. The constant regions of an antibody mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and components of the complement system (e.g., C1q, the first component in the classical pathway of complement activation). Most antibodies have a heavy chain variable region (VH) and a light chain variable region (VL), which together form the antigen-binding portion of the antibody.

[0070] The light chain variable region (VL) or heavy chain variable region (VH) consists of four frame regions separated by three complementarity-determining regions (CDRs). The frame regions align the CDRs to specifically bind to the epitopes of the antigen. The CDRs contain the amino acid residues of the antibody primarily responsible for antigen binding. From the amino terminus to the carboxyl terminus, both the VL and VH domains contain the following frame (FR) regions and CDRs: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs 1, 2, and 3 of the VL domain are also referred to herein as LCDR1, LCDR2, and LCDR3, respectively; and CDRs 1, 2, and 3 of the VH domain are also referred to herein as HCDR1, HCDR2, and HCDR3, respectively.

[0071] As used herein, the term "antibody" should be understood in its broadest sense and includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, antibody fragments, and multispecific antibodies (e.g., bispecific antibodies) containing at least two distinct antigen-binding regions. Antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations in glycosylation sites. Antibodies also include post-translational modified antibodies, fusion proteins containing antibody antigenic determinants, and any other modified immunoglobulin molecules containing antigen recognition sites, provided that these antibodies exhibit the desired biological activity.

[0072] As used herein, the term "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to bind specifically to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0073] Examples of antigen-binding fragments of antibodies include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge via a hinge region; (iii) Fab' fragments, which are essentially Fab fragments with a partially hinge region (see Fundamental Immunology (Paul, ed., 3.sup.rd ed. 1993)); (iv) Fd fragments consisting of VH and CH1 domains; (v) Fd' fragments having VH and CH1 domains and one or more cysteine ​​residues at the C-terminus of the CH1 domain; (vi) Fv fragments consisting of the VL and VH domains of a single antibody arm; (vii) dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); (viii) Separate complementarity-determining regions (CDRs); and (ix) nanobodies containing a heavy chain variable region with a single variable domain and two constant domains. Furthermore, although the two domains VL and VH of an Fv fragment are encoded by separate genes, they can be linked together using recombinant methods via synthetic linkers to form a single protein chain, where the VL and VH regions pair to form a monovalent molecule (called a single-chain Fv (scFv)); see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be covered in the term "antigen-binding fragment" in antibody terminology. Additionally, the term also includes "linear antibodies" comprising a pair of tandem Fd fragments (VH-CH1-VH-CH1) forming an antigen-binding region together with a complementary light chain polypeptide, and modified forms of any of the above fragments that retain antigen-binding activity.

[0074] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies. That is, each antibody that makes up the population is identical, except for a small number that may mutate naturally. Monoclonal antibodies are highly specific and target a single antigen. The term "monoclonal antibody" as used herein is not limited to antibodies produced by hybridoma technology and should not be construed as requiring antibodies to be produced by any particular method.

[0075] In the context of this invention, the term "bispecific antibody" is understood to refer to an antibody having two distinct antigen-binding regions defined by different antibody sequences. This can be understood as binding to different targets, but also includes binding to different epitopes within a single target.

[0076] Some compounds of the present invention may also exist in separable, different stable conformations. Torsional asymmetry due to restricted rotation around asymmetric single bonds (e.g., due to steric hindrance or ring strain) may allow for the separation of different conformational isomers. The present invention includes each conformational isomer of these compounds and mixtures thereof. It should also be understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric, and optically active forms. It should still be understood that some compounds of the present invention may exist in different tautomeric forms. All tautomeric forms are considered to be within the scope of the present invention.

[0077] abbreviation

[0078] The abbreviations that may be used in the scheme description and the following examples are: Ac represents acetyl; AcOH represents acetic acid; AIBN represents azobisisobutyronitrile; aq. represents aqueous; BINAP represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc2O represents ditert-butyl dicarbonate; Boc represents tert-butoxycarbonyl; Bpoc represents 1-methyl-1-(4-biphenyl)ethylcarbonyl; Bz represents benzoyl; Bn represents benzyl; BocNHOH represents tert-butyl N-hydroxycarbamate. t-BuOK represents potassium tert-butoxide; Bu3SnH represents tributyltin hydride; BOP represents (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; brine represents sodium chloride aqueous solution; BSA represents N,O-bis-(trimethylsilyl)acetamide; Bz represents benzoyl; CDI represents carbonyl diimidazole; CH2Cl2 (DCM) represents dichloromethane; CH3 represents methyl; CH3CN represents acetonitrile; CO2 represents carbon dioxide; COMU represents (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomonium hexafluorophosphate; Cs2CO3 represents carbon Cesium acid; CuCl represents copper chloride (I); CuI represents copper iodide (I); dba represents dibenzylacetone; dppb represents diphenylphosphine-phosphonobutane; DBU represents 1,8-diazabicyclo[5.4.0]-undecyl-7-ene; DCC represents N,N'-dicyclohexyl-carbodiimide; DCDMH represents 1,3-dichloro-5,5-dimethylhydantoin; DCE represents 1,1-dichloroethane; DEAD represents diethyl azodicarboxylate; DIAD represents diisopropyl azodicarboxylate; DIPEA (DIEA) or (i-Pr)2EtN represents N,N'-diisopropylethylamine; DIS-Martin high iodine Alkane represents 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzioyl-3-(1H)-one; DMAP represents 4-dimethylamino-pyridine; DME represents 1,2-dimethoxyethane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; DMT represents di(p-methoxyphenyl)phenylmethyl or dimethoxytriphenylmethyl; DMTMM represents 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-onium chloride; DPPA represents diphenylphosphoazide; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbon Diimine; EDC●HCl represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimine hydrochloride; EDTA represents ethylenediaminetetraacetic acid; EtOAc represents ethyl acetate; EtOH represents ethanol; Et2O represents diethyl ether; Fmoc represents 9-fluorenylmethoxycarbonyl; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethylureon hexafluorophosphate; HCl represents hydrogen chloride; HOBT (HOBt) represents 1-hydroxybenzotriazole; hr represents hour; K2CO3 represents potassium carbonate; K4[Fe(CN)6] represents tetrapotassium hexacyanoferrate trihydrate; n -BuLi represents n-butyllithium; i -BuLi represents isobutyllithium; t-BuLi represents tert-butyllithium; PhLi represents phenyllithium; LDA represents diisopropylamide lithium; LiTMP represents 2,2,6,6-tetramethylpiperidinium; MeOH represents methanol; Mg represents magnesium; min represents minutes; MOM represents methoxymethyl; Ms represents methanesulfonyl or -SO2-CH3; Ms2O represents methanesulfonic anhydride or methanesulfonyl anhydride; MTBE represents tert-butyl methyl ether; NaN(TMS)2 represents sodium bis(trimethylsilyl)amide; NaCl represents sodium chloride; NaH represents sodium hydride; NaHCO3 represents sodium bicarbonate or sodium hydrogencarbonate; Na2CO3 represents sodium carbonate; NaOH represents sodium hydroxide; Na2SO4 represents sodium sulfate; NaHSO3 represents sodium bisulfite or sodium hydrogen sulfite; Na2S2O3 represents sodium thiosulfate; NBS represents... N- Bromosuccinimide; NH2NH2 represents hydrazine; NH4HCO3 represents ammonium bicarbonate; NH4Cl represents ammonium chloride; NMO represents N-methylmorpholine N-oxide; NaIO4 represents sodium periodate; Ni represents nickel; NSFI represents N-fluorobenzenesulfonylimide; OH represents hydroxyl; o / n represents overnight; OsO4 represents osmium tetroxide; PE represents petroleum ether; PTSA represents p-toluenesulfonic acid; PPTS represents pyridinium p-toluenesulfonic acid; TBAF represents tetrabutylammonium fluoride; TBDMS (TBS) represents tert-butyldimethylsilyl; TBDPS represents tert-butyldiphenylsilyl; TCFH represents N,N,N',N'-tetramethylchloromethanemida hexafluorophosphate; TEA or Et3N represents triethylamine; TES represents triethylsilyl; TESCl represents triethylsilyl chloride; TESOTf represents triethyl... Silicyl trifluoromethanesulfonate; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran; TMEDA represents N,N,N',N'-tetramethylethylenediamine; TPP or PPh3 represents triphenylphosphine; Troc represents 2,2,2-trichloroethylcarbonyl; Ts represents toluenesulfonyl or -SO2-C6H4CH3; Ts2O represents toluenesulfonic anhydride or toluenesulfonyl anhydride; TsOH represents p-toluenesulfonic acid; Pb(OAc)4 represents lead acetate (IV); Pd represents palladium; Ph represents phenyl; PdOH represents palladium hydroxide; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(O); Pd(PPh3)4 represents tetra(triphenylphosphine)palladium(O); PdCl2(PPh3)2 represents trans-dichlorobis(triphenylphosphine)palladium(II); Pt represents platinum; Rh represents rhodium; rt represents room temperature; Ru represents ruthenium; satd. Saturated represents; SFC represents supercritical fluid chromatography; TBS represents tert-butyldimethylsilyl; TMS represents trimethylsilyl; or TMSCl represents trimethylsilyl chloride; Zn represents zinc (powder); ZnBr2 represents zinc bromide; Zn(CN)2 represents zinc cyanide; Xphos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Attached Figure Description

[0079] Figure 1 The following data show the changes in tumor volume and body weight in an A431 cell mouse tumor model after administration of ADCs of RP007T2-LP2-1-c, RP007T2-LP2-1-d, and RP007T2-MC-GGFG-DXd.

[0080] Figure 2 The changes in body weight in female and male BALB / c mice after administration of ADCs of RP007T2-LP2-1-c or RP007T2-LP2-1-d are shown.

[0081] Figure 3 Hematological results of female and male BALB / c mice after administration of ADCs of RP007T2-LP2-1-c or RP007T2-LP2-1-d are shown. Detailed Implementation

[0082] As used herein, the term “compound disclosed herein” means a compound having formula (I), (II), (III), or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, or mixture thereof.

[0083] In this disclosure, compounds are generally named using standard nomenclature. For compounds with asymmetric centers, it should be understood that, unless otherwise stated, all optical isomers and mixtures thereof are included. Furthermore, unless otherwise stated, all isomers and carbon-carbon double bonds included in this disclosure may appear in the forms of Z and E, or in the forms of (R)- or (S)-. One of the compounds existing in different tautomeric forms is not limited to any particular tautomer, but is intended to cover all tautomeric forms.

[0084] I. Camptothecin analogues

[0085] In one embodiment, this disclosure refers to camptothecin analogs having formulas (I), (II), and (III), or pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof: (I) (II) (III) The variables are defined as in the context.

[0086] 1.1 Variables

[0087] X

[0088] In a specific embodiment, X is CR x For example, CH; in another specific embodiment, X is N. In the above embodiments, R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0089] R1

[0090] In a particular embodiment, R1 is a halogen, such as F; in another particular embodiment, R1 is C. 1-6Alkyl; in another particular embodiment, R1 is C 1-6 Halogenated alkyl; in another specific embodiment, R1 is C 1-6 Alkyl groups, such as OMe; in another particular embodiment, R1 is C 1-6 Halogenated alkoxy groups.

[0091] R2

[0092] In a particular embodiment, R2 is NR 2b R 2c In another specific embodiment, R2 is -(CH2). m -C(O)R 2a For example, C(O)R 2a In another specific embodiment, R2 is -(CH2). m -C(O)OR 2a In another specific embodiment, R2 is -(CH2). m -OC(O)R 2a In another specific embodiment, R2 is -(CH2). m -S(O)2-R 2a In another specific embodiment, R2 is -(CH2). m -S(O)-R 2a In another specific embodiment, R2 is -(CH2). m -NHC(O)-R 2a For example, NHC(O)-R 2a In another specific embodiment, R2 is -(CH2). m -C(O)NR 2b R 2c For example, C(O)NR 2b R 2c In another specific embodiment, R2 is -(CH2). m -NHC(O)OR 2a For example, NHC(O)OR 2a In another specific embodiment, R2 is -(CH2). m -OC(O)NR 2b R 2c For example, OC(O)NR 2b R 2c In another specific embodiment, R2 is -(CH2). m -NHC(O)NR 2b R 2c .

[0093] In a particular embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is In another specific embodiment, R2 is .

[0094] In a more specific embodiment, R2 is In another, more specific embodiment, R2 is In another, more specific embodiment, R2 is In another, more specific embodiment, R2 is In another, more specific embodiment, R2 is In another, more specific embodiment, R2 is In another, more specific embodiment, R2 is .

[0095] In a particular embodiment, R2 is unsubstituted; in another particular embodiment, R2 is substituted by 1, 2, 3, 4 or 5 R groups.

[0096] R 2a R 2b and R 2c

[0097] In a particular embodiment, R 2a It is H; in another particular embodiment, R 2a It is C 1-6 Alkyl; in another particular embodiment, R 2a It is C 1-6 Halogenated alkyl; in another specific embodiment, R 2a It is C 1-6 alkylene-OH; in another specific embodiment, R 2a It is C 1-6 Alkylene-NH2.

[0098] In a particular embodiment, R 2b It is H; in another particular embodiment, R 2b It is C 1-6 Alkyl; in another particular embodiment, R 2b It is C 1-6 Halogenated alkyl; in another specific embodiment, R 2b It is C 1-6 alkylene-OH; in another specific embodiment, R 2b It is C 1-6 Alkylene-NH2.

[0099] In a particular embodiment, R 2c It is H; in another particular embodiment, R 2c It is C 1-6 Alkyl; in another particular embodiment, R 2c It is C 1-6 Halogenated alkyl; in another specific embodiment, R 2c It is C 1-6 alkylene-OH; in another specific embodiment, R 2c It is C 1-6 Alkylene-NH2.

[0100] R3

[0101] In a particular embodiment, R3 is H; in another particular embodiment, R3 is -(CH2). p OR 3a In another specific embodiment, R3 is -(CH2). p C(O)R 3a In another specific embodiment, R3 is -(CH2). p C(O)OR 3a In another specific embodiment, R3 is -(CH2). p OC(O)R 3a In another specific embodiment, R3 is -(CH2). p -S(O)2-R 3a In another specific embodiment, R3 is -(CH2). p -S(O)-R 3a In another specific embodiment, R3 is -(CH2). p -NR 3b R 3c In another specific embodiment, R3 is -(CH2). p -NHC(O)-R 3a In another specific embodiment, R3 is -(CH2). p -C(O)NR 3b R 3c In another specific embodiment, R3 is -(CH2). p -NHC(O)OR 3a In another specific embodiment, R3 is -(CH2). p -OC(O)NR 3b R 3c In another specific embodiment, R3 is -(CH2). p -NHC(O)NR 3bR 3c .

[0102] In a particular embodiment, R3 is H; in another particular embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is .

[0103] In a more specific embodiment, R3 is H; in another more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is In another, more specific embodiment, R3 is .

[0104] In a particular embodiment, R3 is unsubstituted; in another particular embodiment, R3 is substituted by 1, 2, 3, 4 or 5 R groups.

[0105] R 3a R 3b and R 3c

[0106] In a particular embodiment, R 3a It is H; in another particular embodiment, R 3a It is C 1-6 Alkyl; in another particular embodiment, R 3a It is C 1-6 Halogenated alkyl; in another specific embodiment, R 3a It is C 1-6alkylene-OH; in another specific embodiment, R 3a It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 3a It is C 1-6 Alkylene-NH2; in another specific embodiment, R 3a It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 3a It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0107] In a particular embodiment, R 3b It is H; in another particular embodiment, R 3b It is C 1-6 Alkyl; in another particular embodiment, R 3b It is C 1-6 Halogenated alkyl; in another specific embodiment, R 3b It is C 1-6 alkylene-OH; in another specific embodiment, R 3b It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 3b It is C 1-6 Alkylene-NH2; in another specific embodiment, R 3b It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 3b It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0108] In a particular embodiment, R 3c It is H; in another particular embodiment, R 3c It is C 1-6 Alkyl; in another particular embodiment, R 3c It is C 1-6 Halogenated alkyl; in another specific embodiment, R 3c It is C 1-6 alkylene-OH; in another specific embodiment, R 3c It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 3c It is C 1-6 Alkylene-NH2; in another specific embodiment, R3c It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 3c It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0109] In a particular embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 cycloalkyl; in another particular embodiment, R 3b R 3c Together with the nitrogen atoms attached to them, they form 3-12 membered heterocyclic groups, such as 5-12 membered heterocyclic groups or 5-10 membered heterocyclic groups, preferably 5-6 membered heterocyclic groups. 6-10 aryl; in another particular embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-12 heteroaryl groups.

[0110] R2'

[0111] In a particular embodiment, R2' is a divalent group formed by connecting R2 to the rest of the compound.

[0112] In a particular embodiment, R2' is -NR 2b R 2c In another specific embodiment, R2' is -(CH2). m -C(O)R 2a '-, for example -C(O)R 2a In another specific embodiment, R2' is -(CH2). m -C(O)OR 2a In another specific embodiment, R2' is -(CH2). m -OC(O)R 2a In another specific embodiment, R2' is -(CH2). m -S(O)2-R 2a In another specific embodiment, R2' is -(CH2). m -S(O)-R 2a In another specific embodiment, R2' is -(CH2). m -NHC(O)-R 2a '-, for example -NHC(O)-R 2a In another specific embodiment, R2' is -(CH2). m -C(O)NR 2bR 2c '-, for example -C(O)NR 2b R 2c In another specific embodiment, R2' is -(CH2). m -NHC(O)OR 2a '-, for example -NHC(O)OR 2a In another specific embodiment, R2' is -(CH2). m -OC(O)NR 2b R 2c '-, for example -OC(O)NR 2b R 2c In another specific embodiment, R2' is -(CH2). m -NHC(O)NR 2b R 2c '-.

[0113] In a particular embodiment, R2' is In another specific embodiment, R2' is In another specific embodiment, R2' is In another specific embodiment, R2' is In another specific embodiment, R2' is In another specific embodiment, R2' is .

[0114] In a more specific embodiment, R2' is In another more specific embodiment, R2' is In another more specific embodiment, R2' is In another more specific embodiment, R2' is In another more specific embodiment, R2' is In another more specific embodiment, R2' is In another more specific embodiment, R2' is .

[0115] In a particular embodiment, R2' is unsubstituted; in another particular embodiment, R2' is substituted by 1, 2, 3, 4 or 5 R groups.

[0116] R 2a 'and R 2c '

[0117] In a particular embodiment, R 2a 'is a key; in another particular embodiment, R 2a 'Is C 1-6Alkylene; in another specific embodiment, R 2a 'Is C 1-6 Halogenated alkylene; in another specific embodiment, R 2a 'Is C 1-6 alkylene-O-; in another particular embodiment, R 2a 'Is C 1-6 Alkylene-NH-.

[0118] In a particular embodiment, R 2c 'is a key; in another particular embodiment, R 2c 'Is C 1-6 Alkylene; in another specific embodiment, R 2c 'Is C 1-6 Halogenated alkylene; in another specific embodiment, R 2c 'Is C 1-6 alkylene-O-; in another particular embodiment, R 2c 'Is C 1-6 Alkylene-NH-.

[0119] R3'

[0120] In a particular embodiment, R3' is a divalent group formed by connecting R3 to the rest of the compound.

[0121] In a particular embodiment, R3' is a bond; in another particular embodiment, R3' is -(CH2). p OR 3a In another specific embodiment, R3' is -(CH2). p C(O)R 3a In another specific embodiment, R3' is -(CH2). p C(O)OR 3a In another specific embodiment, R3' is -(CH2). p OC(O)R 3a In another specific embodiment, R3' is -(CH2). p -S(O)2-R 3a In another specific embodiment, R3' is -(CH2). p -S(O)-R 3a In another specific embodiment, R3' is -(CH2). p -NR 3b R 3c In another specific embodiment, R3' is -(CH2). p -NHC(O)-R 3aIn another specific embodiment, R3' is -(CH2). p -C(O)NR 3b R 3c In another specific embodiment, R3' is -(CH2). p -NHC(O)OR 3a In another specific embodiment, R3' is -(CH2). p -OC(O)NR 3b R 3c In another specific embodiment, R3' is -(CH2). p -NHC(O)NR 3b R 3c '-.

[0122] In a particular embodiment, R3' is a key; in another particular embodiment, R3' is... In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is .

[0123] In a particular embodiment, R3' is a key; in another particular embodiment, R3' is... In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is In another specific embodiment, R3' is .

[0124] In a particular embodiment, R3' is unsubstituted; in another particular embodiment, R3' is substituted by 1, 2, 3, 4 or 5 R groups.

[0125] R 3a '、R 3b and R 3c '

[0126] In a particular embodiment, R 3a ' is a key; in another particular embodiment, R3' is C 1-6 Alkylene; in another specific embodiment, R3' is C 1-6 Alkyl halide; in another specific embodiment, R3' is -C 1-6 alkylene-O-; in another particular embodiment, R3' is -C 1-6 Alkylene-OC 1-6 alkylene-; in another particular embodiment, R3' is -C 1-6 alkylene-NH-; in another specific embodiment, R3' is -C 1-6 Alkylene-N(C) 1-6 alkyl)- or -C 1-6 Alkylene-NH-C 1-6 alkylene-; in another particular embodiment, R3' is -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 Alkylene-.

[0127] R 3b As defined in the context.

[0128] In a particular embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene; in another specific embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups, such as 3-10 membered heterocyclic groups or 5-10 membered heterocyclic groups; in another particular embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 6-10 aryl; in another particular embodiment, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-12 heteroaryl groups.

[0129] m and p

[0130] In a particular embodiment, each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0131] In a particular embodiment, each p is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0132] R

[0133] In a particular embodiment, R is H; in another particular embodiment, R is NH2; in yet another particular embodiment, R is OH; in yet another particular embodiment, R is CN or a halogen; in yet another particular embodiment, R is C. 1-6 Alkyl; in another particular embodiment, R is C 1-6 Halogenated alkyl; in another specific embodiment, R is C 1-6 alkoxy group; in another particular embodiment, R is C 1-6 Halogenated alkoxy groups.

[0134] R4 and R5

[0135] In a particular embodiment, R4 is H; in another particular embodiment, R4 is a halogen, such as F; in yet another particular embodiment, R4 is OH; in yet another particular embodiment, R4 is NH2; in yet another particular embodiment, R4 is N(C) 1-6 Alkyl group 2; in another specific embodiment, R4 is NH-C 1-6 Alkyl; in another particular embodiment, R4 is C 1-6 Alkyl; in another particular embodiment, R4 is C 1-4 Alkyl, such as Me; in another particular embodiment, R4 is C 1-6 Haloalkyl; in another specific embodiment, R4 is C 1-6 alkoxy group; in another specific embodiment, R4 is C 1-4 Alkyl groups, such as OMe; in another specific embodiment, R4 is C 1-6 Halogenated alkoxy groups.

[0136] In a particular embodiment, R5 is H; in another particular embodiment, R5 is a halogen, such as F; in yet another particular embodiment, R5 is OH; in yet another particular embodiment, R5 is NH2; in yet another particular embodiment, R5 is N(C) 1-6 Alkyl group 2; in another specific embodiment, R5 is NH-C 1-6 Alkyl; in another specific embodiment, R5 is C 1-6 Alkyl; in another specific embodiment, R5 is C 1-4Alkyl group, such as Me; in another particular embodiment, R5 is C. 1-6 Halogenated alkyl; in another specific embodiment, R5 is C 1-6 alkoxy group; in another specific embodiment, R5 is C 1-4 Alkyl groups, such as OMe; in another specific embodiment, R5 is C 1-6 Halogenated alkoxy groups.

[0137] In certain embodiments, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl; in another specific embodiment, R4, R5 together with the carbon atoms to which they are attached form a 3-12 membered heterocyclic group, such as a 3-12 membered heterocyclic group or a 5-10 membered heterocyclic group, with a 5-6 membered heterocyclic group being preferred; in another specific embodiment, R4, R5 together with the carbon atoms to which they are attached form a C 6-10 Aryl group; in another specific embodiment, R4, R5 together with the carbon atoms to which they are attached form a 5-12 membered heteroaryl group; in another specific embodiment, the aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups are unsubstituted; in another specific embodiment, the aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups are selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with 1, 2, 3, 4 or 5 substituents.

[0138] In a more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form In another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form In another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form .

[0139] R6

[0140] In a particular embodiment, R6 is H; in another particular embodiment, R6 is -(CH2). n -OR 6a In another specific embodiment, R6 is -(CH2). n -C(O)OR 6a In another specific embodiment, R6 is -(CH2). n -OC(O)R 6a In another specific embodiment, R6 is -(CH2). n -C(O)R 6a In another specific embodiment, R6 is -(CH2). n -S(O)2-R 6aIn another specific embodiment, R6 is -(CH2). n -S(O)-R 6a In another specific embodiment, R6 is -(CH2). n -NHC(O)-R 6a In another specific embodiment, R6 is -(CH2). n -NHC(O)NR 6b R 6c In another specific embodiment, R6 is -(CH2). n -NHC(O)OR 6a In another specific embodiment, R6 is -(CH2). n -OC(O)NR 6b R 6c In another specific embodiment, R6 is -(CH2). n -C(O)NR 6b R 6c In another specific embodiment, R6 is -(CH2). n -CH2NR 6b R 6c In another specific embodiment, R6 is -(CH2). n -OP(O)(OH)-OR 6a For example, -CH2-OP(O)(OH)-OH; in another specific embodiment, R6 is -(CH2). n -OP(S)(OH)-OR 6a For example, -CH2-OP(S)(OH)-OH; in another specific embodiment, R6 is -(CH2). n -3-7-membered heterocyclic group-(CH2) n -OR 6a In another specific embodiment, R6 is -(CH2). n -3-7-membered heterocyclic group-(CH2) n -R 6a .

[0141] In a particular embodiment, R6 is In another specific embodiment, R6 is In another specific embodiment, R6 is In another specific embodiment, R6 is In another specific embodiment, R6 is In another specific embodiment, R6 is .

[0142] In a more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is .

[0143] In a particular embodiment, R6 is unsubstituted; in another particular embodiment, R6 is replaced by 1, 2, 3, 4, or 5 R6s. Group substitution.

[0144] R 6a R 6b and R 6c

[0145] In a particular embodiment, R 6a It is H; in another particular embodiment, R 6a It is C 1-6 Alkyl groups, such as CH3; in another particular embodiment, R 6a It is C 1-6 Halogenated alkyl; in another specific embodiment, R 6a It is C 3-7 cycloalkyl; in another particular embodiment, R 6a It is a 3-7 membered heterocyclic group; in another specific embodiment, R6a It is C 1-6 Alkylene-OH, such as CH2OH and CH2CH2OH; in another specific embodiment, R 6a It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 6a It is C 1-6 Alkylene-NH2; in another specific embodiment, R 6a It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 6a It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0146] In a particular embodiment, R 6b It is H; in another particular embodiment, R 6b It is C 1-6 Alkyl groups, such as CH3; in another particular embodiment, R 6b It is C 1-6 Halogenated alkyl; in another specific embodiment, R 6b It is C 3-7 cycloalkyl; in another particular embodiment, R 6b It is a 3-7 membered heterocyclic group; in another specific embodiment, R 6b It is C 1-6 Alkylene-OH, such as CH2OH and CH2CH2OH; in another specific embodiment, R 6b It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 6b It is C 1-6 Alkylene-NH2; in another specific embodiment, R 6b It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 6b It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0147] In a particular embodiment, R 6c It is H; in another particular embodiment, R 6c It is C 1-6 Alkyl groups, such as CH3; in another particular embodiment, R 6c It is C 1-6 Halogenated alkyl; in another specific embodiment, R6c It is C 3-7 cycloalkyl, such as C 3-5 cycloalkyl, such as cyclopropyl; in another particular embodiment, R 6c It is a 3-7 membered heterocyclic group; in another specific embodiment, R 6c It is C 1-6 Alkylene-OH, such as CH2OH and CH2CH2OH; in another specific embodiment, R 6c It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 6c It is C 1-6 Alkylene-NH2; in another specific embodiment, R 6c It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 6c It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0148] R6'

[0149] In a particular embodiment, R6' is a divalent group formed by connecting R6 to the rest of the compound.

[0150] In a particular embodiment, R6' is a bond; in another particular embodiment, R6' is -(CH2). n -OR 6a In another specific embodiment, R6' is -(CH2). n -C(O)OR 6a In another specific embodiment, R6' is -(CH2). n -OC(O)R 6a In another specific embodiment, R6' is -(CH2). n -C(O)R 6a In another specific embodiment, R6' is -(CH2). n -S(O)2-R 6a In another specific embodiment, R6' is -(CH2). n -S(O)-R 6a In another specific embodiment, R6' is -(CH2). n -OP(O)(OH)-OR 6a '-, for example -CH2-OP(O)(OH)-O-; in another particular embodiment, R6' is -(CH2) n-OP(S)(OH)-OR 6a '-, for example -CH2-OP(S)(OH)-O-; in another particular embodiment, R6' is -(CH2) n -NHC(O)-R 6a In another specific embodiment, R6' is -(CH2). n -NHC(O)NR 6b R 6c In another specific embodiment, R6' is -(CH2). n -NHC(O)OR 6a In another specific embodiment, R6' is -(CH2). n -OC(O)NR 6b R 6c In another specific embodiment, R6' is -(CH2). n -C(O)NR 6b R 6c In another specific embodiment, R6' is -(CH2). n -CH2NR 6b R 6c In another specific embodiment, R6' is -(CH2). n -3-7-membered heterocyclic group-(CH2) n -OR 6a In another specific embodiment, R6' is -(CH2). n -3-7-membered heterocyclic group-(CH2) n -R 6a '-.

[0151] In a particular embodiment, R6' is In another specific embodiment, R6' is In another specific embodiment, R6' is In another specific embodiment, R6' is In another specific embodiment, R6' is In another specific embodiment, R6' is .

[0152] In a more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another more specific embodiment, R6' is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is In another, more specific embodiment, R6 is .

[0153] In a particular embodiment, R6' is unsubstituted; in another particular embodiment, R6' is replaced by 1, 2, 3, 4, or 5 R's. Group substitution.

[0154] R 6a 'and R 6c '

[0155] In a particular embodiment, R 6a 'is a key; in another particular embodiment, R 6a 'Is C 1-6 Alkylene; in another specific embodiment, R 6a 'is -CH2-; in another particular embodiment, R 6a 'Is C 1-6 Halogenated alkylene; in another specific embodiment, R 6a 'Is C 3-7 Cycloalkylene; in another specific embodiment, R 6a 'It is a 3-7 member subheterocyclic group; in another specific embodiment, R 6a 'is-C 1-6 Alkylene-O-, such as -CH2O- and -CH2CH2O-; in another particular embodiment, R 6a 'is-C 1-6 Alkylene-OC 1-6alkylene-; in another particular embodiment, R 6a 'is-C 1-6 Alkylene-NH-, for example -CH2CH2NH-; in another particular embodiment, R 6a 'is-C 1-6 Alkylene-N(C) 1-6 alkyl)- or -C 1-6 Alkylene-NH-C 1-6 alkylene-; in another particular embodiment, R 6a 'is-C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 Alkylene-.

[0156] In a particular embodiment, R 6c 'is a key; in another particular embodiment, R 6c 'Is C 1-6 Alkylene; in another specific embodiment, R 6c 'is -CH2-; in another particular embodiment, R 6c 'Is C 1-6 Halogenated alkylene; in another specific embodiment, R 6c 'Is C 3-7 Cycloalkylene, such as C 3-5 Cycloalkylene, such as cyclopropylene; in another particular embodiment, R 6c 'It is a 3-7 member subheterocyclic group; in another specific embodiment, R 6c 'is-C 1-6 Alkylene-O-, such as -CH2O- and -CH2CH2O-; in another particular embodiment, R 6c 'is-C 1-6 Alkylene-OC 1-6 alkylene-; in another particular embodiment, R 6c 'is-C 1-6 Alkylene-NH-, for example -CH2CH2NH-; in another particular embodiment, R 6c 'is-C 1-6 Alkylene-N(C) 1-6 alkyl)- or -C 1-6 Alkylene-NH-C 1-6 alkylene-; in another particular embodiment, R 6c 'is-C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 Alkylene-.

[0157] n

[0158] In a particular embodiment, each n is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0159] R

[0160] In a particular embodiment, R It is H; in another particular embodiment, R It is NH2; in another specific embodiment, R It is OH; in another specific embodiment, R It is CN; in another specific embodiment, R It is a halogen; in another specific embodiment, R It is C 1-6 Alkyl; in another particular embodiment, R It is C 1-6 Halogenated alkyl; in another specific embodiment, R It is C 1-6 Alkoxy; in another particular embodiment, R It is C 1-6 Halogenated alkoxy groups.

[0161] R7

[0162] In a particular embodiment, R7 is C 1-6 Alkyl; in another particular embodiment, R7 is C 1-6 Halogenated alkyl; in another specific embodiment, R7 is C 1-6 Alkenyl; in another specific embodiment, R7 is C 1-6 Alkyne group; in another specific embodiment, R7 is -(CH2). k -OR 7a In another specific embodiment, R7 is -(CH2). k -NR 7b R 7c In another specific embodiment, R7 is -(CH2). k -C(O)R 7a In another specific embodiment, R7 is -(CH2). k -C(O)OR 7a In another specific embodiment, R7 is -(CH2). k -OC(O)-R 7a In another specific embodiment, R7 is -(CH2). k -NHC(O)-R 7a In another specific embodiment, R7 is -(CH2). k-NHC(O)OR 7a In another specific embodiment, R7 is -(CH2). k -OC(O)NH-R 7a In another specific embodiment, R7 is -(CH2). k -C(O)NR 7b R 7c .

[0163] In a particular embodiment, R7 is In another specific embodiment, R7 is In another specific embodiment, R7 is In another specific embodiment, R7 is In another specific embodiment, R7 is .

[0164] In a more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is In another, more specific embodiment, R7 is .

[0165] In a particular embodiment, R7 is unsubstituted; in another particular embodiment, R7 is substituted by 1, 2, 3, 4 or 5 R# groups.

[0166] R 7a R 7b and R 7c

[0167] In a particular embodiment, R 7a It is H; in another particular embodiment, R 7a It is C 1-6 Alkyl groups, such as CH3; in another particular embodiment, R 7a It is C 1-6 alkenyl; in another specific embodiment, R 7a It is C 1-6 alkynyl group; in another specific embodiment, R 7a It is C 1-6Halogenated alkyl; in another specific embodiment, R 7a It is C 1-6 alkylene-OH; in another specific embodiment, R 7a It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 7a It is C 1-6 Alkylene-NH2; in another specific embodiment, R 7a It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 7a It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0168] R8

[0169] In a particular embodiment, R8 is C 1-6 Alkyl, such as C 1-4 Alkyl; in another particular embodiment, R8 is C 1-6 Haloalkyl; in another specific embodiment, R8 is C 1-6 alkenyl groups, such as C 1-4 Alkenyl; in another specific embodiment, R8 is C 1-6 Alkyne groups, such as C 1-4 Alkyne group; in another specific embodiment, R8 is -(CH2). k -OR 7a For example, C 1-4 Alkylene-OH; in another specific embodiment, R8 is -(CH2). k -NR 7b R 7c For example, C 1-4 Alkylene-NH2; in another specific embodiment, R8 is -(CH2). k -C(O)R 7a In another specific embodiment, R8 is -(CH2). k -C(O)OR 7a In another specific embodiment, R8 is -(CH2). k -OC(O)-R 7a In another specific embodiment, R8 is -(CH2). k -NHC(O)-R 7a In another specific embodiment, R8 is -(CH2). k -NHC(O)OR 7a In another specific embodiment, R8 is -(CH2).k -OC(O)NH-R 7a In another specific embodiment, R8 is -(CH2). k -C(O)NR 7b R 7c .

[0170] In a more specific embodiment, R8 is CH3; in another specific embodiment, R8 is In another specific embodiment, R8 is In another specific embodiment, R8 is .

[0171] In a particular embodiment, R8 is unsubstituted; in another particular embodiment, R8 is substituted by 1, 2, 3, 4 or 5 R# groups.

[0172] R9

[0173] In a particular embodiment, R9 is H; in another particular embodiment, R9 is OH; in yet another particular embodiment, R9 is CN; in yet another particular embodiment, R9 is NH2; in yet another particular embodiment, R9 is NH(C) 1-6 Alkyl); in another specific embodiment, R9 is N(C) 1-6 Alkyl)2.

[0174] In a particular embodiment, R9 is unsubstituted; in another particular embodiment, R9 is substituted by 1, 2, 3, 4 or 5 R# groups.

[0175] R 10

[0176] In a particular embodiment, R 10 It is H; in another particular embodiment, R 10 It is -(CH2) q -OR 10a In another specific embodiment, R 10 It is -(CH2) q -NR 10b R 10c In another specific embodiment, R 10 It is -(CH2) q -C(O)R 10a In another specific embodiment, R 10 It is -(CH2) q -C(O)OR 10a In another specific embodiment, R 10 It is -(CH2) q -OC(O)R10a In another specific embodiment, R 10 It is -(CH2) q -S(O)2-R 10a In another specific embodiment, R 10 It is -(CH2) q -S(O)-R 10a In another specific embodiment, R 10 It is -(CH2) q -NHC(O)-R 10a In another specific embodiment, R 10 It is -(CH2) q -C(O)NR 10b R 10c In another specific embodiment, R 10 It is -(CH2) q -NHC(O)-OR 10a In another specific embodiment, R 10 It is -(CH2) q -OC(O)NR 10b R 10c .

[0177] In a particular embodiment, R 10 It is H; in another particular embodiment, R 10 yes In another specific embodiment, R 10 yes In another specific embodiment, R 10 yes In another specific embodiment, R 10 yes In another specific embodiment, R 10 yes In another specific embodiment, R 10 yes .

[0178] In a more specific embodiment, R 10 It is H; in another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes In another, more specific embodiment, R 10 yes .

[0179] In a particular embodiment, R 10 It is not replaced; in another particular embodiment, R 10 It can be replaced by 1, 2, 3, 4 or 5 R# groups.

[0180] R 10a R 10b and R 10c

[0181] In a particular embodiment, R 10a It is H; in another particular embodiment, R 10a It is C 1-6 Alkyl; in another particular embodiment, R 10a It is C 1-6 Halogenated alkyl; in another specific embodiment, R 10a It is C 1-6 alkylene-OH; in another specific embodiment, R 10a It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 10a It is C 1-6 Alkylene-NH2; in another specific embodiment, R 10a It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 10a It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0182] In a particular embodiment, R 10b It is H; in another particular embodiment, R 10b It is C 1-6 Alkyl; in another particular embodiment, R 10b It is C 1-6 Halogenated alkyl; in another specific embodiment, R 10b It is C1-6 alkylene-OH; in another specific embodiment, R 10b It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 10b It is C 1-6 Alkylene-NH2; in another specific embodiment, R 10b It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 10b It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0183] In a particular embodiment, R 10c It is H; in another particular embodiment, R 10c It is C 1-6 Alkyl; in another particular embodiment, R 10c It is C 1-6 Halogenated alkyl; in another specific embodiment, R 10c It is C 1-6 alkylene-OH; in another specific embodiment, R 10c It is C 1-6 Alkylene-OC 1-6 Alkyl; in another particular embodiment, R 10c It is C 1-6 Alkylene-NH2; in another specific embodiment, R 10c It is C 1-6 Alkylene-NH(C) 1-6 Alkyl); in another specific embodiment, R 10c It is C 1-6 Alkylene-N(C) 1-6 Alkyl)2.

[0184] In a particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 cycloalkyl; in another particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups; in another particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-12 membered heterocyclic groups or 5-10 membered heterocyclic groups, such as 5-6 membered heterocyclic groups; in another particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C6-10 aryl; in another particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-12 membered heteroaryl groups; in another specific embodiment, the aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups are unsubstituted; in another specific embodiment, the aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups are selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with 1, 2, 3, 4 or 5 substituents.

[0185] k and q

[0186] In a particular embodiment, each k is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0187] In a particular embodiment, each q is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0188] R7'

[0189] In a particular embodiment, R7' is selected from C. 1-6 Alkylene; in another specific embodiment, R7' is C 1-6 Alkyl halide; in another specific embodiment, R7' is C 1-6 alkenyl; in another specific embodiment, R7' is C 1-6 Alynyl group; in another specific embodiment, R7' is -(CH2). k -OR 7a In another specific embodiment, R7' is -(CH2). k -NR 7b R 7c In another specific embodiment, R7' is -(CH2). k -C(O)R 7a In another specific embodiment, R7' is -(CH2). k -C(O)OR 7a In another specific embodiment, R7' is -(CH2). k -OC(O)-R 7a In another specific embodiment, R7' is -(CH2). k -NHC(O)-R 7a In another specific embodiment, R7' is -(CH2). k -C(O)NR 7b R 7c In another specific embodiment, R7' is -(CH2). k -NHC(O)OR7a In another specific embodiment, R7' is -(CH2). k -OC(O)NH-R 7a '-.

[0190] In a particular embodiment, R7' is In another specific embodiment, R7' is In another specific embodiment, R7' is In another specific embodiment, R7' is In another specific embodiment, R7' is .

[0191] In a more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is In another, more specific embodiment, R7' is .

[0192] In a particular embodiment, R7' is unsubstituted; in another particular embodiment, R7' is substituted by 1, 2, 3, 4 or 5 R# groups.

[0193] R 7a 'and R 7c '

[0194] In a particular embodiment, R 7a 'is a key; in another particular embodiment, R 7a 'Is C 1-6 Alkylene; in another specific embodiment, R 7a 'Is C 1-6 alkenyl; in another specific embodiment, R 7a 'is-C 1-6 alkylene-O-; in another particular embodiment, R 7a 'is-C 1-6 Alkylene-NH-.

[0195] In a particular embodiment, R 7c 'is a key; in another particular embodiment, R7c 'Is C 1-6 Alkylene; in another specific embodiment, R 7c 'Is C 1-6 alkenyl; in another specific embodiment, R 7c 'is-C 1-6 alkylene-O-; in another particular embodiment, R 7c 'is-C 1-6 Alkylene-NH-.

[0196] R 10 '

[0197] In a particular embodiment, R 10 'is a key; in another particular embodiment, R 10 'is-(CH2)' q -OR 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -NR 10b R 10c '-; In another particular embodiment, R 10 'is-(CH2)' q -C(O)R 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -C(O)OR 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -OC(O)R 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -S(O)2-R 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -S(O)-R 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -NHC(O)-R 10a '-; In another particular embodiment, R 10 'is-(CH2)' q -C(O)NR 10b R 10c '-; In another particular embodiment, R 10 'is-(CH2)' q -NHC(O)-OR 10a'-; In another particular embodiment, R 10 'is-(CH2)' q -OC(O)NR 10b R 10c '-.

[0198] In a particular embodiment, R 10 'is a key; in another particular embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes .

[0199] In a particular embodiment, R 10 'is a key; in another particular embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes In another specific embodiment, R 10 'yes .

[0200] In a particular embodiment, R 10 'Is not replaced; in another particular embodiment, R 10 It can be replaced by 1, 2, 3, 4 or 5 R# groups.

[0201] R10a '、R 10b and R 10c '

[0202] In a particular embodiment, R 10a 'is a key; in another particular embodiment, R 10a 'Is C 1-6 Alkylene; in another specific embodiment, R 10a 'is-C 1-6 alkylene-O-; in another particular embodiment, R 10a 'is-C 1-6 Alkylene-NH-.

[0203] In a particular embodiment, R 10c 'is a key; in another particular embodiment, R 10c 'Is C 1-6 Alkylene; in another specific embodiment, R 10c 'is-C 1-6 alkylene-O-; in another particular embodiment, R 10c 'is-C 1-6 Alkylene-NH-.

[0204] R 10b As defined in the context.

[0205] In a particular embodiment, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene, 3-12 quinone (e.g., 5-10 or 5-6 quinone) heterocyclic alkylene, C 6-10 Arylene or 5-12-membered heteroarylene (e.g., 5-10-membered or 5-6-membered); in another specific embodiment, the above-mentioned cycloalkylene, heterocyclic, arylene or heteroarylene is optionally selected from H, D, halogen and C. 1-6 Alkyl groups are substituted with 1, 2, 3, 4 or 5 substituents.

[0206] R#

[0207] In a particular embodiment, R# is H; in another particular embodiment, R# is NH2; in yet another particular embodiment, R# is OH; in yet another particular embodiment, R# is CN; in yet another particular embodiment, R# is a halogen or C. 1-6 Alkyl; in another particular embodiment, R# is C 1-6 Haloalkyl; in another specific embodiment, R# is C 1-6 Alkyl group; in another specific embodiment, R# is C 1-6 Halogenated alkoxy groups.

[0208] T1, T2 and T3

[0209] In a particular embodiment, T1, T2, and T3 are independently target portions.

[0210] In a specific embodiment, the targeting portion binds to a tumor-associated antigen.

[0211] In certain embodiments, the targeting portion is an antibody or an antigen-binding antibody fragment.

[0212] In certain embodiments, the antibody is a bispecific antibody or a multispecific antibody.

[0213] L1, L2 and L3

[0214] In a particular embodiment, L1, L2, and L3 are independently connectors.

[0215] In a particular embodiment, the connector is a detachable connector.

[0216] In a particular embodiment, the linker is a protease-cleavable linker.

[0217] In certain embodiments, the linker comprises a dipeptide, a tripeptide, or a tetrapeptide.

[0218] D1, D2 and D3

[0219] In a particular embodiment, D1, D2, and D3 are independently pharmaceutical portions.

[0220] In certain embodiments, the pharmaceutical portion is as defined in the context.

[0221] x, y, and z

[0222] In a particular embodiment, x is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1.

[0223] In a particular embodiment, y is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1.

[0224] In a particular embodiment, z is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1.

[0225] w, u and r

[0226] In a particular embodiment, w is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; in another particular embodiment, w is an integer between 2 and 8, preferably 3, 4, 5, 6, 7, or 8.

[0227] In a particular embodiment, u is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; in another particular embodiment, u is an integer between 2 and 8, preferably 3, 4, 5, 6, 7, or 8.

[0228] In a particular embodiment, r is an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; in another particular embodiment, r is an integer between 2 and 8, preferably 3, 4, 5, 6, 7, or 8.

[0229] Any technical solution or any combination thereof in any of the specific embodiments described above can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof in R1 can be combined with R1-R 10 R2', R3', R6', R7', R 10 '、R、R#、R This disclosure refers to any combination of technical solutions, including L1-L3, D1-D3, x, y, z, w, u, and r. This disclosure aims to include all combinations of such technical solutions; for the sake of brevity, a complete list is not provided here.

[0230] 1.2 Examples - Compounds having formula (I)

[0231] In one embodiment, this disclosure refers to a compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (I) in, X is CR x Or N, for example CH or N; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R2 is selected from NR 2b R 2c -(CH2) m -C(O)R 2a -(CH2) m -C(O)OR 2a -(CH2) m -OC(O)R 2a -(CH2) m -S(O)2-R 2a -(CH2) m -S(O)-R 2a -(CH2) m -NHC(O)-R 2a -(CH2) m -C(O)NR 2b R 2c -(CH2) m -NHC(O)OR 2a and -(CH2) m -OC(O)NR 2b R 2c and -(CH2) m -NHC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p OC(O)R 3a -(CH2) p -S(O)2-R 3a -(CH2) p -S(O)-R 3a -(CH2) p -NR 3b R 3c -(CH2) p-NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a -(CH2) p -OC(O)NR 3b R 3c and -(CH2) p -NHC(O)NR 3b R 3c ; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; Each p is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; In this embodiment, R2 and R3 are optionally substituted by 1, 2, 3, 4, or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0232] In some embodiments, this disclosure refers to a compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: X is CH or N; R1 is selected from halogen and C. 1-6 Alkoxy; R2 is selected from NR 2b R 2c C(O)R2a ,NHC(O)-R 2a C(O)NR 2b R 2c ,NHC(O)OR 2a and OC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a and -(CH2) p -OC(O)NR 3b R 3c Preferably, R3 is not H; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl or 5-10 membered heterocyclic groups; Each p is independently selected from 0, 1, 2, 3, and 4.

[0233] In some embodiments, this disclosure refers to a compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: X is CH or N, preferably X is CH; R1 is selected from halogen and C. 1-6 Alkoxy group, preferably, R1 is a halogen; R2 is selected from , , , , and Preferably, R2 is ; R 2a R 2b and R 2c Independently selected from H and C 1-6 alkyl; Each m is independently 1, 2, or 3; R3 is selected from H, , , , , and Preferably, R3 is H; R 3a R 3b and R 3c Independently selected from H and C 1-6 alkyl; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-6 membered heterocyclic groups; Each p is independently 0, 1, 2, or 3; Alternatively, R3 is selected from H, , , , , , , , , , , , and .

[0234] In some embodiments, this disclosure refers to a compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: X is CH or N; R1 is F or OMe; R2 is , , , , , and ; R3 is selected from H, , , , , , , , , , , , and Preferably, R3 is not H.

[0235] In some embodiments, this disclosure refers to compounds having formula (Ia) or (Ib), or pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof: (Ia) (Ib) in, X, R2, R 2b R 2c R3 is as defined in the context.

[0236] In some embodiments, this disclosure refers to compounds having formula (Ic) or (Id), or pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof: (Ic) (Id) in, X is CR x Or N, for example CH or N; R x Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-6 Alkoxy; R2 is NR 2b R 2c ; R 2b and R 2c Independently selected from H and C 1-6 alkyl; Alternatively, X is CRx For example, CH; R x Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-4 Alkoxy groups, preferably halogens, such as F; R2 is NR 2b R 2c Preferably, it is NH2; R 2b and R 2c Independently selected from H and C 1-4 Alkyl groups, such as H or CH3.

[0237] In some embodiments, this disclosure refers to a compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is selected from: 1-1、 1-2, 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10 1-11 1-12 1-13 1-14 1-15 1-16 1-17 1-18 1-19 1-20 1-21 and 1-22.

[0238] 1.3 Examples - Compounds having formula (II)

[0239] In one embodiment, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II) in, R4 and R5 are independently selected from H, halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6 is selected from H, -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -S(O)2-R 6a -(CH2) n -S(O)-R 6a -(CH2) n -OP(O)(OH)-OR 6a -(CH2) n -OP(S)(OH)-OR 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -NHC(O)NR 6b R 6c -(CH2) n -NHC(O)OR 6a -(CH2) n -OC(O)NR 6b R 6c -(CH2) n -C(O)NR 6b R 6c -(CH2) n -CH2NR 6b R 6c -(CH2) n-3-7-membered heterocyclic group-(CH2) n -OR 6a and -(CH2) n -3-7-membered heterocyclic group-(CH2) n -R 6a ; R 6a R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6 is selected from H, -(CH2). n -OR 6a-(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -S(O)2-R 6a -(CH2) n -S(O)-R 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -NHC(O)NR 6b R 6c -(CH2) n -NHC(O)OR 6a -(CH2) n -OC(O)NR 6b R 6c -(CH2) n -C(O)NR 6b R 6c and -(CH2) n -CH2NR 6b R 6c ; R 6a R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0240] In some embodiments, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -S(O)2-R 6a -(CH2) n -S(O)-R 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -NHC(O)NR 6b R 6c and -(CH2) n -C(O)NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2, such as H, CH3, CH2OH and CH2CH2OH; R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6Alkylene-NH2, such as H and CH3; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -C(O)NR 6b R 6c and -(CH2) n -CH2NR 6b R 6c ; Alternatively, R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -NHC(O)-R 6a and -(CH2) n -C(O)NR 6b R 6c .

[0241] In some embodiments, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, and preferably, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -NHC(O)-R 6a and -(CH2) n -CH2NR 6b R 6c ; R6 is preferably selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a and -(CH2) n -NHC(O)-R 6a ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-NH2, such as H, CH3, CH2OH, CH2CH2OH and CH2CH2NH2; R 6b and R 6c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3; Each n is independently 0, 1, 2, 3, 4, 5, or 6.

[0242] In some embodiments, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, preferably, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group; R6 is selected from , , , , and Preferably, R6 is ; R 6a R 6b and R 6c Independently selected from H and C 1-6 alkyl; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R4 is C 1-4 Alkyl or C 1-4 Alkyl groups, such as Me or OMe; R5 is a halogen, such as F; Alternatively, preferably, R4, R5 together with the carbon atoms to which they are attached form , or ; R6 is selected from , , , , , , , , and .

[0243] In some embodiments, this disclosure refers to a compound having formula (II-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein R6 is selected from... , ,and .

[0244] In some embodiments, this disclosure refers to a compound having formula (II-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein R6 is selected from... , , , , , , , , , , , , , , , , , , ,and .

[0245] In some embodiments, this disclosure refers to a compound having formula (II-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II-a) R6 is defined as in the context.

[0246] In some embodiments, this disclosure refers to compounds having formula (II), wherein the compound has the structure of formula (II), (II-b) or (II-c), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II) (II-b) (II-c) in, R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 6b It is H; R 6c Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each n is independently 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is a halogen, and can be replaced by other halogens such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6 is -(CH2) n -OR 6a Or -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl and C 2-6 Alkylene-OH, such as H, CH3, CH2CH2OH or CH2CH2CH2OH; R 6b It is H; R 6c It is C 1-6 Alkyl groups, such as CH3, CH2CH3, or isopropyl; Each n is independently 0, 1, 2, or 3, preferably 0, 1, or 2.

[0247] In some embodiments, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II) in, R4 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, which may alternatively be selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from H, halogens, and C. 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy groups can be alternatively selected from halogens, C... 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OP(O)(OH)-OR 6a -(CH2) n -OP(S)(OH)-OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6c Selected from C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Each n is independently 0, 1, 2, 3 or 4; Alternatively, R4 is H, C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is H, a halogen, and can be replaced by a halogen, such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6 is selected from -(CH2). n -OP(O)(OH)-OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H and C 1-6 Alkyl groups, preferably H; R6b Selected from H and C 1-6 Alkyl groups, preferably H; R 6c Selected from C 3-5 Cycloalkyl groups, such as cyclopropyl groups; Each n is independently 0, 1, 2, or 3, preferably 0 or 1.

[0248] In some embodiments, this disclosure refers to a compound having formula (II-d), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II-d) in, R6 is -(CH2) n -OR 6a ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2, such as H, CH3, CH2OH and CH2CH2OH; Each n is independently 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R6 is -(CH2) n -OR 6a ; R 6a Selected from H and C 1-6 Alkyl groups, such as H or CH3, preferably H; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

[0249] In some embodiments, this disclosure refers to a compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is selected from: 2-1 2-2、 2-3 2-4 2-5 2-6 2-7 2-8 2-9 2-10 2-11 2-12 2-13 2-14 2-15 2-16 2-17 2-18 2-19 2-20 2-21 2-22、 2-23 2-24 2-25 2-26 2-27 2-28 2-29 2-30 2-31 2-32, or 2-33.

[0250] 1.4 Examples - Compounds having formula (III)

[0251] In one embodiment, this disclosure refers to a compound having formula (III), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III) in, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2)k -NHC(O)-R 7a -(CH2) k -NHC(O)OR 7a -(CH2) k -OC(O)NH-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each k is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R 10c -(CH2) q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -S(O)2-R 10a -(CH2) q -S(O)-R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2)q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R7, R8, R9 and R 10 Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0252] In some embodiments, this disclosure refers to a compound having formula (III), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: R7 is selected from -(CH2). k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R 10c -(CH2) q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Among them, R7, R8, R9 and R 10 Optionally substituted with 1, 2, or 3 R# groups, where R# is selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0253] In some embodiments, this disclosure refers to a compound having formula (III-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III-a) in, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -C(O)NR 7b R 7c -(CH2) k -NHC(O)OR 7a and -(CH2) k -OC(O)NH-R 7a ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, 3, 4, 5, or 6; In this embodiment, R7 and R8 are optionally substituted by 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R7 is selected from -(CH2). k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2.

[0254] In some embodiments, this disclosure refers to a compound having formula (III-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: R7 is selected from , , , and ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3, k is 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; Alternatively, R7 is selected from , , , , , , , and ; R8 is selected from C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 1-4 alkylene-OH and C 1-4 Alkylene-NH2, such as CH3, , and .

[0255] In some embodiments, this disclosure refers to a compound having formula (III-b), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III-b) in, R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R 10c-(CH2) q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -S(O)2-R 10a -(CH2) q -S(O)-R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, or 6; Among them, R 10 Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R 10 Selected from H, -(CH2) q -OR 10a-(CH2) q -NR 10b R 10c -(CH2) q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Among them, R 10 Optionally substituted with 1, 2, or 3 R# groups, where R# is selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0256] In some embodiments, this disclosure refers to a compound having formula (III-b), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: R 10 Selected from H, , , , and ; R 10a R 10b and R 10c Independently selected from H and C 1-6 alkyl; Or, R 10b R 10c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, or 3; Alternatively, R 10 Selected from H, , , , , , , , , and .

[0257] In some embodiments, this disclosure refers to a compound having formula (III), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, preferably, R 10a Not H.

[0258] In some embodiments, this disclosure refers to a compound having formula (III), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is selected from: 3-1 , , 3-2, 3-3 3-4 3-5 3-6 3-7 3-8 3-9 3-10 3-11 3-12 , , 3-13 3-14 3-15 3-16 3-17 3-18 3-19 3-20 , , 3-21 3-22 and 3-23.

[0259] II. Couplings

[0260] Some embodiments of this disclosure relate to conjugates of compounds having formula (I), (II), or (III), comprising one or more compounds having formula (I) coupled to a target portion via one or more linkers.

[0261] The conjugates disclosed herein may comprise one or more compounds having formula (I), (II), or (III) coupled to the target moiety. For example, multiple compounds having formula (I) may be coupled to the target moiety by attaching the compounds to multiple different sites on the target moiety. Alternatively or additionally, multiple compounds having formula (I) may be coupled to the target moiety by employing one or more multivalent linkers, each multivalent linker allowing multiple compounds to be attached to a single site on the target moiety.

[0262] Therefore, certain embodiments of this disclosure relate to conjugates of compounds having formula (I), which are composed of L1-(D1). x This indicates that it is preferably composed of T1-[L1'-(D1)]. x ] w express, T1 is the target portion; L1 is a linker, and L1' is a divalent group formed by connecting T1 and L1; D1 is the pharmaceutical part, which is a camptothecin analogue as described herein and selected from compounds having formula (I) (e.g., formula (I-1) or (I-2)). x is an integer between 1 and 10; w is an integer between 1 and 10.

[0263] In some embodiments, x is between 1 and 2. In some embodiments, x is 1.

[0264] In some embodiments, w is between 1 and 8, for example, between 2 and 8, or between 2 and 6. In some embodiments, w is between 2 and 4.

[0265] As described above, the target moiety “T” can be conjugated with more than one compound “D” having formula (I). Those skilled in the art will understand that although any particular target moiety T is conjugated with an integer number of compounds D, analyzing the conjugate formulation to determine the ratio of compound D to target moiety T may yield non-integer results, reflecting a statistical average. This ratio of compound D to target moiety T is commonly referred to as the drug-antibody ratio or “DAR”. Therefore, it is intended to cover conjugate formulations with non-integer DARs. Those skilled in the art should understand that the term “DAR” can be used to define conjugates containing a target moiety other than an antibody.

[0266] 2.1 Camptothecin analogue D

[0267] According to this disclosure, the conjugate contains a camptothecin analog as pharmaceutical part D, wherein the camptothecin analog is a compound having formula (I), (II) or (III).

[0268] 2.2 Examples - Compounds having formula (I)

[0269] In the embodiments, this disclosure refers to compounds comprising the structure of formula (I-1) or (I-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof: (I-1) (I-2) in, The attachment point between formula (I-1) or (I-2) and the rest of the compound; R2' is a divalent group formed by R2 being attached to the rest of the compound; R3' is a divalent group formed by R3 being attached to the rest of the compound; X, R1, R2, and R3 are as defined in the context; Alternatively, X is CH or N; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups can be alternatively selected from halogens and C. 1-6 Alkyl groups, such as F and OMe; R2 and R3 are defined as in the context.

[0270] In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1) or (I-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R2 is selected from NR 2b R 2c -(CH2) m -C(O)R 2a -(CH2) m -C(O)OR 2a -(CH2) m -OC(O)R 2a -(CH2) m -S(O)2-R 2a -(CH2) m -S(O)-R 2a -(CH2) m -NHC(O)-R 2a -(CH2) m -C(O)NR 2b R 2c -(CH2) m -NHC(O)OR 2a and -(CH2) m -OC(O)NR 2b R 2c and -(CH2) m -NHC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Alternatively, R2 is selected from NR 2b R 2c C(O)R 2a ,NHC(O)-R 2a C(O)NR 2b R 2c ,NHC(O)OR 2a and OC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Alternatively, R2 is selected from , , , , and ; R 2a R 2b and R 2c Independently selected from H and C 1-6 alkyl; Alternatively, R2 is , , , , , and .

[0271] In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1) or (I-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R2' is selected from -NR 2b R 2c '-、-(CH2) m -C(O)R 2a '-、-(CH2) m -C(O)OR 2a '-、-(CH2) m -OC(O)R 2a '、-(CH2) m -S(O)2-R 2a '-、-(CH2) m -S(O)-R 2a '-、-(CH2) m -NHC(O)-R 2a '-、-(CH2) m -C(O)NR 2b R 2c '-、-(CH2) m -NHC(O)OR 2a '- and -(CH2) m -OC(O)NR 2b R 2c '- and -(CH2) m-NHC(O)NR 2b R 2c '-; R 2a 'and R 2c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 Alkylene-O- and C 1-6 alkylene-NH-; R 2b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R2' is optionally substituted with 1, 2, 3, 4 or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R2' is selected from -NR 2b R 2c '、-C(O)R 2a '-、-NHC(O)-R 2a '-、-C(O)NR 2b R 2c '-、-NHC(O)OR 2a '- and -OC(O)NR 2b R 2c '-; R 2a 'and R 2c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 2b Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R2' is selected from , , , , and ; R 2a 'and R2c 'Independently selected from key and C 1-6 Alkylene; R 2b Selected from H and C 1-6 alkyl; Each m is independently 1, 2, or 3; Alternatively, R2' is , , , , , and .

[0272] In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1) or (I-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p OC(O)R 3a -(CH2) p -S(O)2-R 3a -(CH2) p -S(O)-R 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a -(CH2) p -OC(O)NR 3b R 3c and -(CH2) p -NHC(O)NR 3b R 3c ; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl groups; Alternatively, R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a and -(CH2) p -OC(O)NR 3b R 3c Preferably, R3 is not H; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Alternatively, R3 is selected from H, , , , , and ; R 3a R 3b and R 3c Independently selected from H and C1-6 alkyl; Alternatively, R3 is selected from H, , , , , , , , , , , , and .

[0273] In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1) or (I-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R3' is selected from the bond, -(CH2). p OR 3a '-、-(CH2) p C(O)R 3a '-、-(CH2) p C(O)OR 3a '-、-(CH2) p OC(O)R 3a '-、-(CH2) p -S(O)2-R 3a '-、-(CH2) p -S(O)-R 3a '-、-(CH2) p -NR 3b R 3c '-、-(CH2) p -NHC(O)-R 3a '-、-(CH2) p -C(O)NR 3b R 3c '-、-(CH2) p -NHC(O)OR 3a '-、-(CH2) p -OC(O)NR 3b R 3c '- and -(CH2) p -NHC(O)NR 3b R 3c '-; R 3a 'and R 3c 'Independently selected from key, C 1-6Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-N(C) 1-6 alkyl)-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 3b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene, 5-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 heteroarylene; Each p is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R3' is optionally substituted with 1, 2, 3, 4 or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R3' is selected from the bond, -(CH2). p OR 3a '-、-(CH2) p C(O)R 3a '-、-(CH2) p C(O)OR 3a '-、-(CH2) p -NR 3b R 3c '-、-(CH2) p -NHC(O)-R 3a'-、-(CH2) p -C(O)NR 3b R 3c '-、-(CH2) p -NHC(O)OR 3a '- and -(CH2) p -OC(O)NR 3b R 3c '-; R 3a 'and R 3c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 3b Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene or 5-10 membered heterocyclic alkylene; Each p is independently selected from 0, 1, 2, 3, and 4; Alternatively, R3' is selected from the key, , , , , and ; R 3a 'and R 3c 'Independently selected from key and C 1-6 Alkylene; R 3b Selected from H and C 1-6 alkyl; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-6 membered heterocyclic groups; Each p is independently 0, 1, 2, or 3; Alternatively, R3' is selected from the key, , , , , , , , , , , , and Preferably, R3' is not a bond.

[0274] In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1a), (I-2a), (I-1b), or (I-2b), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (I-1a) (I-2a) (I-1b) (I-2b) in, X, R2, R2', R 2b R 2c R 2c ', R3, and R3' are as defined in the context; In some embodiments, this disclosure refers to compounds comprising the structure of formula (I-1c) or (I-1d), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (I-1c) (I-1d) in, X is CR x Or N, for example CH or N; R x Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-6 Alkoxy; R2' is -NR 2b R 2c '-; R 2b Selected from H and C 1-6 alkyl; R 2c 'Selected from key and C' 1-6 Alkylene; Alternatively, X is CR x For example, CH; R x Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-4 Alkoxy groups, preferably halogens, such as F; R2' is -NR 2b R 2c '-, and R2' is preferably -NH-; R 2b Independently selected from H and C 1-4 alkyl; R 2c 'Independently selected from key and C 1-4 Alkylene.

[0275] In some embodiments, this disclosure refers to a compound, a pharmaceutically acceptable salt, an isotopically labeled analog, a crystalline form, a hydrate, a solvate, an enantiomer, a diastereomer, or a mixture thereof, wherein the compound comprises a structure selected from: 1-1'、 1-2'、 1-3'、 1-4'、 1-5' 1-6'、 1-7'、 1-8' 1-9' 1-10a'、 1-10b'、 1-11a'、 1-11b'、 1-12a'、 1-12b'、 1-13a'、 1-13b'、 1-14a'、 1-14b'、 1-15a'、 1-15b'、 1-16a'、 1-16b'、 1-17a'、 1-17b'、 1-18a'、 1-18b'、 1-19a'、 1-19b'、 1-20a'、 1-20b'、 1-21a'、 1-21b'、 1-22a' and 1-22b'.

[0276] In some embodiments, this disclosure refers to L1-(D1) x This indicates that it is preferably composed of T1-[L1'-(D1)]. x ] w The coupling element indicated; T1 is the target portion; L1 is a linker, and L1' is a divalent group formed by connecting T1 and L1; D1 is the drug portion, which is selected from compounds having formula (I) as defined in the context (e.g., formula (I-1) or (I-2)). x is an integer between 1 and 10, or alternatively, 1; w is an integer between 1 and 10.

[0277] In some embodiments, this disclosure refers to a coupling, wherein L1-(D1) x The coupling element represented is selected from: LD 1-1-a; LD 1-1-b; LD 1-1-c; LD 1-1-d; LD 1-6-a; LD 1-6-b; LD 1-7-a; LD 1-7-b; LD 1-7-c; LD 1-7-d; LD 1-9-a; LD 1-9-b; LD 1-10-a; LD 1-10-a LD 1-10-b; LD 1-10-c; LD 1-10-d; LD 1-15-a; LD 1-15-b; LD 1-15-c; LD 1-15-d; LD 1-22-a; LD 1-22-b; LD 1-22-c; and LD 1-22-d.

[0278] In some embodiments, this disclosure refers to a coupling wherein T1-[L1'-(D1)] x ] w The coupling element represented is selected from: TDC 1-1-a; TDC 1-1-b; TDC 1-1-c; TDC 1-1-d; TDC 1-6; TDC 1-7; TDC 1-7-a; TDC 1-7-b; TDC 1-9-a; TDC 1-9-b; TDC 1-10-a; TDC 1-10-b; TDC 1-15-a; TDC 1-15-b; TDC 1-22-a; TDC 1-22-d; T1 and w are defined as in the context.

[0279] 2.3 Examples - Compounds having formula (II)

[0280] In one embodiment, this disclosure refers to a compound comprising the structure of formula (II-1), a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II-1) in, The attachment point between formula (II-1) and the rest of the compound; R6' is a divalent group formed by R6 being attached to the rest of the compound; R4, R5, and R6 are as defined in the context; Alternatively, R4 and R5 are independently selected from H, halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6' is selected from the bond, -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -S(O)2-R 6a '-、-(CH2) n -S(O)-R 6a '-、-(CH2) n -OP(O)(OH)-OR 6a'-、-(CH2) n -OP(S)(OH)-OR 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -NHC(O)NR 6b R 6c '-、-(CH2) n -NHC(O)OR 6a '-、-(CH2) n -OC(O)NR 6b R 6c '-、-(CH2) n -C(O)NR 6b R 6c '-、-(CH2) n -CH2NR 6b R 6c '-、-(CH2) n -3-7-membered heterocyclic group-(CH2) n -OR 6a '- and -(CH2) n -3-7-membered heterocyclic group-(CH2) n -R 6a '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 3-7 Cycloalkylene, 3-7 membered heterocyclic alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0281] Alternatively, R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6' is selected from the bond, -(CH2). n -OR 6a '、-(CH2) n -C(O)OR 6a '、-(CH2) n -OC(O)R 6a '、-(CH2) n -C(O)R 6a '、-(CH2) n -S(O)2-R 6a '、-(CH2) n -S(O)-R 6a '、-(CH2) n -NHC(O)-R 6a '、-(CH2) n -NHC(O)NR 6b R 6c '、-(CH2) n -NHC(O)OR6a '、-(CH2) n -OC(O)NR 6b R 6c '、-(CH2) n -C(O)NR 6b R 6c 'and-(CH2)' n -CH2NR 6b R 6c '; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene-O-, C 1-6 Alkylene-OC 1-6 Alkylene, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0282] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Alternatively, R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group.

[0283] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R6' is selected from the bond, -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2)n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -S(O)2-R 6a '-、-(CH2) n -S(O)-R 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -NHC(O)NR 6b R 6c '-、-(CH2) n -NHC(O)OR 6a '-、-(CH2) n -OC(O)NR 6b R 6c '-、-(CH2) n -C(O)NR 6b R 6c '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-N(C) 1-6 alkyl)-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C)1-6 Alkyl)2; Among them, R6' is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, R6' is selected from -(CH2) n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -C(O)NR 6b R 6c '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, R6' is selected from -(CH2) n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -NHC(O)-R 6a '- and -(CH2) n -CH2NR6b R 6c '-; R6' is preferably selected from -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '- and -(CH2) n -NHC(O)-R 6a '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 Alkylene -NH-, such as bond, -CH2-, -CH2O-, -CH2CH2O- and -CH2CH2NH-; R 6b Selected from H and C 1-6 Alkyl groups, such as H and CH3; R 6c 'Selected from key and C' 1-6 Alkyl groups, such as bonds and -CH2-; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R6' is selected from , , , , and ,For example, , , , , , , , , and ; R 6a 'and R 6c 'Independently selected from key and C 1-6 Alkylene; R 6b Selected from H and C 1-6 alkyl; Each n is independently 0, 1, 2, 3, 4, 5, or 6.

[0284] In some embodiments, this disclosure refers to a compound having formula (II-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein R6' is selected from... , ,and .

[0285] In some embodiments, this disclosure refers to a compound having formula (II-a), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein R6' is selected from... , , , , , , , , , , , , , , , , , , , .

[0286] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1a), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (II-1a) R6' is defined as in the context.

[0287] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1), (II-1b), or (II-1c), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (II-1) (II-1b) (II-1c) in, The attachment point of formula (II-1), (II-1b), or (II-1c) to the rest of the compound; R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6' is selected from -(CH2) n -OR 6a '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 6b It is H; R 6c 'Selected from C' 1-6 Alkylene and C 1-6 Halogenated alkylene; Each n is independently 0, 1, 2, 3, or 4; Among them, R6' is optionally divided by 1, 2 or 3 R Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is a halogen, and can be replaced by other halogens such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6' is -(CH2) n -OR 6a '-or-(CH2)' n -CH2NR 6b R 6c '-; R 6a 'Selected from key, C 1-6 alkylene and -C 2-6Alkylene -O-, such as bond, -CH2-, -CH2CH2O- or -CH2CH2CH2O- R 6b It is H; R 6c 'Is C 1-6 Alkyl groups, such as -CH2-, -CH2CH2-, or -CH(CH3)CH2-; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

[0288] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (II-1) in, The attachment point between formula (II) and the rest of the compound; R4 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, which may alternatively be selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from H, halogens, and C. 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy groups can be alternatively selected from halogens, C... 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6' is selected from -(CH2) n -OP(O)(OH)-OR 6a '-、-(CH2) n -OP(S)(OH)-OR 6a '-、and-(CH2) n -CH2NR 6b R 6c '-; R6a 'Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; R 6b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6c 'Selected from C' 3-7 Cycloalkylene and 3-7 membered heterocyclic alkylene groups; Each n is independently 0, 1, 2, 3 or 4; Alternatively, R4 is H, C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is H, a halogen, and can be replaced by a halogen, such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6' is selected from -(CH2) n -OP(O)(OH)-OR 6a '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'Selected from key and C' 1-6 Alkyl groups, preferably bonds; R 6b Selected from H and C 1-6 Alkyl groups, preferably H; R 6c 'Is C 3-5 Cycloalkylene compounds, such as cyclopropylene compounds; Each n is independently 0, 1, 2, or 3, preferably 0 or 1.

[0289] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1d), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (II-1d) in, The attachment point between formula (II-1d) and the rest of the compound; R6' is -(CH2) n -OR 6a '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 Alkylene -NH-, such as bond, -CH2-, -CH2O- and -CH2CH2O-; Each n is independently 0, 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R6' is -(CH2) n -OR 6a '-; R 6a 'Selected from key and C' 1-6 Alkylene, such as a bond or -CH2-; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

[0290] In some embodiments, this disclosure refers to compounds comprising the structure of formula (II-1), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein the structure of formula (II-1) is selected from the following: 2-1'、 2-2'、 2-3'、 2-4'、 2-5'、 2-6'、 2-7'、 2-8' 2-9' 2-10' 2-11'、 2-12'、 2-13'、 2-14' 2-15' 2-16' 2-17' 2-18' 2-19' 2-20'、 2-21'、 2-22'、 2-23'、 2-24'、 2-25'、 2-26'、 2-27'、 2-28'、 2-29'、 2-30'、 2-31'、 2-32', or 2-33'.

[0291] In some embodiments, this disclosure refers to L2-(D2) y This indicates that it is preferably composed of T2-[L2'-(D2)]. y ] u The coupling element indicated; T2 is the target component; L2 is a linker, and L2' is a divalent group formed by connecting L2 and T2; D2 is the drug component, which is selected from compounds having formula (II) as defined in the context (e.g., formula (II-1)). y is an integer between 1 and 10, or alternatively, 1; u is an integer between 1 and 10.

[0292] In some embodiments, this disclosure refers to a coupling, wherein L2-(D2) y The coupling element represented is selected from: LD 2-1-a; LD 2-1-b; LD 2-2-a; LD 2-2-b; LD 2-5-a; LD 2-5-b; LD 2-6-a; LD 2-6-b; LD 2-9-a; and LD 2-9-b.

[0293] In some embodiments, this disclosure refers to a coupling wherein T2-[L2'-(D2)] y ] uThe coupling element represented is selected from: TDC 2-1-a; TDC 2-1-b; TDC 2-2; TDC 2-5; TDC 2-6; TDC 2-9; T2 and u are defined as in the context.

[0294] 2.4 Examples - Compounds having formula (III)

[0295] In one embodiment, this disclosure refers to a compound comprising a structure of formula (III-1) or (III-2), a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III-1) (III-2) in, The attachment point of formula (III-1) or (III-2) to the rest of the compound; R7' is a divalent group formed by R7 being attached to the rest of the compound; R 10 ' is by R 10 Divalent groups formed by attaching to the rest of the compound; R7, R8, R9 and R 10 As defined in the context.

[0296] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1) or (III-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -NHC(O)OR 7a -(CH2) k -OC(O)NH-R 7a and -(CH2) k -C(O)NR 7b R 7c ; Each k is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Alternatively, R7 is selected from -(CH2). k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6alkylene-OH and C 1-6 Alkylene-NH2; Alternatively, R7 is selected from , , , and ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3, R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; Alternatively, R7 is selected from , , , , , , , and ; R8 is selected from C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 1-4 alkylene-OH and C 1-4 Alkylene-NH2, such as CH3, , and .

[0297] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1) or (III-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R7' is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 imidene group, C 1-6 Alynyl group, -(CH2) k -OR 7a '-、-(CH2) k -NR 7b R 7c '-、-(CH2) k -C(O)R 7a'-、-(CH2) k -C(O)OR 7a '-、-(CH2) k -OC(O)-R 7a '-、-(CH2) k -NHC(O)-R 7a '-、-(CH2) k -C(O)NR 7b R 7c '-、-(CH2) k -NHC(O)OR 7a '- and -(CH2) k -OC(O)NH-R 7a '-; R 7a 'and R 7c 'Independently selected from key, C 1-6 Alkylene, C 1-6 imidene group, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 7b Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, 3, 4, 5, or 6; In this embodiment, R7' is optionally substituted by 1, 2, 3, 4, or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0298] Alternatively, R7' is selected from -(CH2) k -OR 7a '-、-(CH2) k -NR 7b R 7c '-、-(CH2) k -C(O)OR 7a '-、-(CH2) k -OC(O)-R 7a '-、-(CH2) k -NHC(O)-R 7a '- and -(CH2) k -C(O)NR 7b R 7c '-; R 7a 'and R 7c 'Selected from key, C 1-6 Alkylene, C 1-6 Ethyne group, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 7b Selected from H, C 1-6 Alkyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, or 3; Alternatively, R7' is selected from , , , and ; R 7a 'and R 7c 'Selected from key and C' 1-6 Alkyl groups, such as bonds and CH2, R 7b Selected from H and C 1-6 Alkyl groups, such as H and CH3, k is 0, 1, 2, or 3; Alternatively, R7' is selected from , , , , , , , and .

[0299] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1) or (III-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R10c -(CH2) q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -S(O)2-R 10a -(CH2) q -S(O)-R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Alternatively, R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, -(CH2) q -OR 10a -(CH2) q -NR 10b R 10c -(CH2)q -C(O)R 10a -(CH2) q -C(O)OR 10a -(CH2) q -OC(O)R 10a -(CH2) q -NHC(O)-R 10a -(CH2) q -C(O)NR 10b R 10c -(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Alternatively, R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, , , , and ; R 10a R 10b and R 10c Independently selected from H and C 1-6 alkyl; Preferably, R 10a Not H; Or, R 10b R 10cTogether with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Alternatively, R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, , , , , , , , , and .

[0300] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1) or (III-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: R 10 Selected from the key, -(CH2) q -OR 10a '-、-(CH2) q -NR 10b R 10c '-、-(CH2) q -C(O)R 10a '-、-(CH2) q -C(O)OR 10a '-、-(CH2) q -OC(O)R 10a '-、-(CH2) q -S(O)2-R 10a '-、-(CH2) q -S(O)-R 10a '-、-(CH2) q -NHC(O)-R 10a '-、-(CH2) q -C(O)NR 10b R 10c '-、-(CH2) q -NHC(O)-OR 10a '-、and-(CH2) q -OC(O)NR 10b R 10c '-; R 10a 'and R 10c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 10b Selected from C 1-6 Alkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene, 5-12 membered heterocyclic alkylene, C 6-10 arylene or 5-12 quinone heteroarylene, wherein the C 3-10 Cycloalkylene, 5-12 membered heterocyclic alkylene, C 6-10 The arylene and 5-12 heteroarylene groups are optionally selected from H, D, halogen, and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, or 6; Among them, R 10 'Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R 10 Selected from the key, -(CH2) q -OR 10a '-、-(CH2) q -NR 10b R 10c '-、-(CH2) q -C(O)R 10a '-、-(CH2) q -C(O)OR 10a '-、-(CH2) q -OC(O)R 10a '-、-(CH2) q -NHC(O)-R 10a '-、-(CH2) q -C(O)NR 10b R 10c '-、-(CH2) q -NHC(O)-OR10a '-、and-(CH2) q -OC(O)NR 10b R 10c '-; R 10a 'and R 10c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 10b Selected from H, C 1-6 Alkyl, -C 1-6 alkylene -OH and -C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form C 3-10 Cycloalkylene or 5-10 membered heterocyclic alkylene, wherein the C 3-10 The cycloalkylene group and the 5-10-membered heterocyclic group are optionally selected from H, D, halogen and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Alternatively, R 10 'Selected from key, , , , and ; R 10a '、R 10b and R 10c 'Selected independently from H and C 1-6 Alkylene; Or, R 10b R 10c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, or 3; Alternatively, R 10 'Selected from key, , , , , , , , , and .

[0301] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1a), (III-1b), or (III-2b), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein: (III-1a) (III-1b) (III-2b) Among them, R7', R8, R 10 and R 10 As defined in the context; Alternatively, The compound contains the structure of formula (III-1a): (III-1a) in, R7' is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 imidene group, C 1-6 Alynyl group, -(CH2) k -OR 7a '-、and-(CH2) k -NR 7b R 7c '-; R8 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a and -(CH2) k -NR 7b R 7c ; R 7a 'and R 7c 'Independently selected from key, C 1-6 Alkylene, C 1-6 imidene group, and C 1-6 Ethyne group; R 7b Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl and C 1-6 alkynyl group; Each k is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R7' is selected from -(CH2) k -OR 7a '- and -(CH2) k -NR 7b R 7c '-; R 7a 'and R 7c 'Independently selected from key and C 1-6 Alkyl groups, such as bonds and CH2; R 7b Independently selected from H and C 1-6 Alkyl groups, such as H and CH3; Each k is independently 0, 1, 2, or 3; R8 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Alternatively, R7' is selected from , , , ,and Alternatively, , or ; R8 is C 1-6 Alkyl groups, such as CH3.

[0302] In some embodiments, this disclosure refers to compounds comprising the structure of formula (III-1) or (III-2), pharmaceutically acceptable salts, isotopically labeled analogs, crystalline forms, hydrates, solvates, enantiomers, diastereomers, or mixtures thereof, wherein the structure of formula (III-1) or (III-2) is selected from the following: 3-1'、 , , 3-2'、 3-3'、 3-4' 3-5' 3-6' 3-7' 3-8' 3-9' 3-10' 3-11a'、 3-11b'、 3-12'、 , , 3-13a'、 3-13b'、 3-14a'、 3-14b' 3-15a'、 3-15b' 3-16a'、 3-16b' 3-17a'、 3-17b' 3-18a'、 3-18b' 3-19a'、 3-19b' 3-20a'、 , , 3-20b' , , 3-21a'、 3-21b'、 3-22a'、 3-22b'、 3-23a' and 3-23b'.

[0303] In some embodiments, this disclosure refers to L3-(D3) z This indicates that it is preferably composed of T3-[L3'-(D3)]. z ] r The couplings indicated T3 is the target component; L3 is a linker, and L3' is a divalent group formed by the connection of T3 and L3; D3 is the drug part, which is selected from compounds having formula (III) as defined in the context (e.g., formula (III-1) or (III-2)). z is an integer between 1 and 10, or alternatively, 1; r is an integer between 1 and 10.

[0304] In some embodiments, this disclosure refers to a coupling, wherein L3-(D3) z The coupling element represented is selected from: LD 3-1-a; LD 3-1-b; LD 3-3-a LD 3-3-b LD 3-6-a LD 3-6-b LD 3-12; LD 3-12-a; LD 3-12-b; LD 3-13-a; LD 3-13-b; LD 3-13-c; LD 3-13-d; LD 3-14-a; LD 3-14-b; LD 3-14-c; LD 3-14-d; LD 3-20-a; LD 3-20-b; LD 3-20-c; and LD 3-20-d.

[0305] In some embodiments, this disclosure refers to a coupling wherein T3-[L3-(D3)] z ] r The coupling element represented is selected from: TDC 3-1-a; TDC 3-1-b; TDC 3-3; TDC 3-3-b TDC 3-6; TDC 3-6-b TDC 3-12; TDC 3-12a; TDC 3-13-a; TDC 3-13-b; TDC 3-14-a; TDC 3-14-b; TDC 3-20-a; TDC 3-20-b; T3 and r are defined as in the context.

[0306] III. Targeted Part

[0307] The targeting moiety T contained in a conjugate is a molecule that binds to, reactively associates with, or complexes with a receptor, antigen, or other acceptor moiety associated with a given target cell population. Typically, the function of the targeting moiety T is to deliver camptothecin analogue D to a specific target cell population that responds to the targeting moiety T. Examples of targeting moieties include, but are not limited to, proteins (e.g., antibodies, antibody fragments, and growth factors), glycoproteins, peptides (e.g., bufotinide and gastrin-releasing peptide), lectins, vitamins (e.g., folic acid), and nutrient transport molecules (e.g., transferrin).

[0308] Typically, the targeting moiety T is bound to the linker L via heteroatoms of the targeting moiety T, such as sulfur (e.g., from a thiol group), oxygen (e.g., from a carbonyl, carboxyl, or hydroxyl group), or nitrogen (e.g., from a primary or secondary amino group). These heteroatoms may be naturally present on the targeting moiety T, or may be introduced by engineering and / or expression, or may be introduced by chemical or enzymatic modification using techniques known in the art.

[0309] In some embodiments, the targeting portion T is an antibody. Therefore, certain embodiments of this disclosure relate to antibody-drug conjugates (ADCs) in which the targeting portion T is an antibody.

[0310] When the conjugate is an ADC, the antibody contained in the targeting portion T can be a full-size polyclonal or monoclonal antibody, an antigen-binding antibody fragment (e.g., Fab, scFab, Fab', F(ab')2, Fv, or scFv), a domain antibody (dAb), or an antibody mimic (e.g., affibody, DARPin, anticalin, versabody, duocalin, lipocalin, or avimer). Antibodies typically target specific antigens, such as disease-associated antigens (e.g., tumor-associated antigens), antigens associated with autoimmune diseases, or viral antigens.

[0311] In some embodiments where the conjugate is an ADC, the targeting portion T is a monoclonal antibody, an antigen-binding antibody fragment (e.g., Fab, scFab, Fab', F(ab')2, Fv, or scFv), or a domain antibody (dAb).

[0312] Methods for producing polyclonal and monoclonal antibodies are known in the art. For example, monoclonal antibodies can be produced by methods including, but not limited to, hybridoma techniques originally described by Kohler and Milstein (1975, Nature 256:495-497), human B-cell hybridoma techniques (Kozbor et al., 1983, Immunology Today 4:72), EBV-hybridoma techniques (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, pp. 77-96), and selective lymphocyte antibody methods (SLAM) (Babcook et al., 1996, Proc Natl Acad Sci USA, 93(15):7843-8; McLean et al., 2005, J Immunol, 174(8):4768-4778). Antibodies of various immunoglobulin classes, including IgG, IgM, IgE, IgA, and IgD and their subclasses, can be used as the targeting portion in various embodiments. In some embodiments, the targeting portion is an IgG antibody.

[0313] In some embodiments, the targeting portion T may be a monoclonal antibody. The monoclonal antibody may be, for example, a non-human monoclonal antibody (e.g., a mouse antibody), a human monoclonal antibody, a humanized monoclonal antibody, or a chimeric antibody (e.g., a human-mouse antibody). Human monoclonal antibodies may be prepared using any of a variety of techniques known in the art (see, for example, Teng et al., 1983, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 80:7308-7312; Kozbor et al., 1983, Immunology Today [Immunology Today] 4:72-79; Olsson et al., 1983, Meth. Enzymol. [Enzymological Methods] 92:3-16; Huse et al., 1989, Science [Science] 246:1275-1281 and U.S. Patent No. 8,012,714). Chimeric and humanized monoclonal antibodies can be produced using recombinant DNA techniques known in the art, such as those described below: International Patent Publications WO 87 / 02671 and WO 86 / 01533; European Patent Publications 0184187, 0171496 and 0173494; US Patents 4,816,567 and 5,225,539; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Wood et al., 1985, Nature. 314:446-449; Shaw et al., 1988, J. Natl. Cancer Inst., 80:1553-1559; Oi et al., 1986, BioTechniques, 4:214; Jones et al., 1986, Nature, 321:552-525; and Beidler et al., 1988, J. Immunol., 141:4053-4060). Immunospecific antibodies against a given target antigen are also commercially available.

[0314] In some embodiments, the antibody contained in the conjugate may be a bispecific antibody or a multispecific antibody. Methods for preparing bispecific and multispecific antibodies are known in the art (see, for example, Milstein et al., 1983, Nature, 305:537-539; Traunecker et al., 1991, EMBO J, 10:3655-3659; Suresh et al., 1986, Meth. Enzymol, 121:210; Rodrigues et al., 1993, J. Immunol, 151:6954-6961; Carter et al., 1992, Bio / Technology, 10:163-167; Carter et al., 1995, J. Hematotherapy, 4:463-470; Merchant et al., 1998, Nature Biotechnology). 16:677-681, and international (PCT) publications WO 94 / 04690, WO 2012 / 032080, WO 2012 / 058768 and WO 2013 / 063702.

[0315] In some embodiments, the targeting portion T of the conjugate is an antibody or antigen-binding antibody fragment that binds to a tumor-associated antigen (TAA). Examples of tumor-associated antigens include, but are not limited to, 5T4, ADAM-9, ALK, AMHRII, ASCT2, Axl, B7-H3, BCMA, C4.4a, CA6, CA9, CanAg, CD123, CD138, CD142, CD166, CD184, CD19, CD20, CD205, CD22, CD248, CD25, CD3, CD30, CD33, CD352, CD37, CD38, CD40L, CD44v6, CD45, CD46, CD48, CD51, CD56, CD7, CD70, CD71, CD74, CD79b, CDH6, and CE. ACAM5, CEACAM6, cKIT, CLDN18.2, CLDN6, CLL-1, c-MET, Cripto, CSP-1, CXCR5, DLK-1, DLL3, DPEP3, Dysadherin, EFNA4, EGFR, EGFRviii, ENPP3, EpCAM, EphA2, EphA3, ETBR, FGFR2, FGFR3, FLT3, FRα, FSH, GCC, GD2, GD3, Globo H, GPC-1, GPC 3, gpNMB, HER-2, HER-3, HLA-DR, HSP90, IGF-1R, IL-13R, IL1RAP, IL7R, IL4R, KAAG-1, LAMP-1, Lewis Y antigen, LGALS3BP, LGR5, LH / hCG, LHRH, LIV-1, LRP-1, LRRC 1 5. Ly6E, MAGE, MSLN, MET, MICA, MICB, MT1-MMP, MTX3, MTX5, MUC 1, MUC 1 6, NaPi2b, Nectin-4, NOTCH 3. OAcGD2, OX001L, p-cadherin, PD-1, PD-L1, phosphatidylserine (PS), polymorphic epithelial mucin (PEM), prolactin receptor (PRLR), PSMA, PTK7, RNF43, ROR1, ROR2, SAIL, SLAMF7, SLC44A4, SLITRK6, SSTR2, STEAP-1, STING, sialyl-Tn, TIM-1, TM4SF1, TNFα, TRA, TROP-2, TAG-72, TA-MUC 1, TIM-3, UPK2 and UPK1b.

[0316] In some embodiments of any of the above conjugates, Ab is an antibody or antigen-binding fragment thereof that binds to a tumor antigen, tumor-associated antigen, or immune cell antigen or T cell antigen.

[0317] In some embodiments of any of the above conjugates, Ab is an antibody or antigen-binding fragment thereof that binds to a tumor-associated antigen (TAA); the tumor-associated antigen (TAA) includes, but is not limited to, HER2, TROP2, EGFR, FLOR2, MUC16, CEACAM, nectin4, CD19, CD33, MSLN, EpCAM, NaPi2b, ROR1, CLDN6, CLDN18.2, ROR2, LY6G6D, fibronectin, B7H3, B7H4, BCMA, TF, MET, and others.

[0318] In some embodiments of any of the above conjugates, Ab is a TROP2 antibody.

[0319] In some embodiments, the Trop2 antibody comprises a heavy chain (HC) and a light chain (LC), wherein: The HC contains an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 1, and the LC contains an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity with SEQ ID NO: 2.

[0320] IV. Connector

[0321] The conjugate includes a linker L, which is a bifunctional or multifunctional moiety capable of linking one or more camptothecin analogs D to a target moiety T. A bifunctional (or monovalent) linker L links a single compound D to a single site on the target moiety T, while a multifunctional (or polyvalent) linker L links more than one compound D to a single site on the target moiety T. In some embodiments, linkers that link a compound D to more than one site on the target moiety T may also be considered multifunctional.

[0322] Linker L includes a functional group capable of reacting with one or more target groups on the target moiety T, and at least one functional group capable of reacting with a target group on the camptothecin analog D. Suitable functional groups are known in the art and include, for example, those described in Bioconjugate Techniques (GT Hermanson, 2013, AcademicPress). The groups on the target moiety T and the camptothecin analog D that can serve as target groups for linker attachment include, but are not limited to, thiols, hydroxyl groups, carboxyl groups, amine groups, aldehyde groups, and ketone groups.

[0323] Non-limiting examples of functional groups capable of reacting with thiols include maleimides, haloacetamides, haloacetyl groups, active esters (e.g., succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, and tetrafluorophenyl esters), acid anhydrides, acyl chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Also useful in this context are “self-stabilized” maleimides, as described in Lyon et al., 2014, Nat. Biotechnol. [Nature Biotechnology] 32:1059-1062.

[0324] Non-limiting examples of functional groups capable of reacting with amines include reactive esters (e.g., N-hydroxysuccinamide (NHS) esters, sulfonated NHS esters, imide esters such as Traut reagent, tetrafluorophenyl (TFP) ester, and sulfodichlorophenyl ester), isothiocyanates, aldehydes, and acid anhydrides (e.g., diethylenetriaminepentaacetic anhydride (DTPA)). Other examples include succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU) and benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate (PyBOP).

[0325] Non-limiting examples of functional groups capable of reacting with electrophilic groups (such as aldehyde or ketone carbonyl groups) include acyl hydrazides, oximes, amino groups, hydrazines, thioureas, hydrazide carboxylates, and aryl acyl hydrazides.

[0326] In some embodiments where the targeting portion T is an antibody, the linker L may include a functional group that allows bridging of two interchain cysteine ​​residues on the antibody, such as the ThioBridge™ linker (Badescu et al., 2014, Bioconjug. Chem. 25:1124-1136), the dithiomaleimide (DTM) linker (Behrens et al., 2015, Mol. Pharm. 12:3986-3998), the dithioaryl (TCEP) pyridazinedione-based linker (Lee et al., 2016, Chem. Sci. 7:799-802), or the dibromopyridazinedione-based linker (Maruani et al., 2015, Nat. Commun. 6:6645).

[0327] Alternatively, the target moiety T can be modified to include non-natural reactive groups, such as azides, which allow coupling with the linker via complementary reactive groups on the linker. For example, coupling of the linker to the target moiety can utilize click chemistry reactions (see, for example, Chio and Bane, 2020, Methods Mol. Biol., 2078:83-97), such as the azide-alkyne cycloaddition (AAC) reaction, which has been successfully used in the development of antibody-drug conjugates. The AAC reaction can be a copper-catalyzed AAC (CuAAC) reaction involving the coupling of an azide to a linear alkyne, or a strain-promoted AAC (SPAAC) reaction involving the coupling of an azide to a cyclooctyne.

[0328] Linker L can be either cleavable or non-cleavable. A cleavable linker is one that is susceptible to cleavage under specific conditions, such as intracellular conditions (e.g., in endosomes or lysosomes) or near target cells (e.g., in the tumor microenvironment). Examples include linkers that are sensitive to proteases, acids, or reductions. In contrast, non-cleavable linkers depend on antibody degradation in the cell, which typically results in the release of the amino acid-linker-drug moiety. In some embodiments, the linker contains MC (maleimide hexanoyl group, ...). ) or MsP ( ).

[0329] Examples of cleavable linkers include, for example, linkers containing an amino acid sequence that serves as a protease cleavage recognition sequence. Many such cleavage recognition sequences are known in the art. For conjugates not intended for internalization, for example, an amino acid sequence that is recognized and cleaved by proteases present in the extracellular matrix near the target cell (e.g., cancer cell) may be employed. Examples of extracellular tumor-associated proteases include, for example, plasminogen activators, matrix metalloproteinases (MMPs), elastases, and kallikrein-related peptidases.

[0330] For conjugates intended for internalization, the linker L may contain an amino acid sequence that is recognized and cleaved by endosomal or lysosomal proteases. Examples of such proteases include, for example, cathepsins B, C, D, H, L, and S, as well as asparagine endopeptidase.

[0331] The cleavage recognition sequence can be, for example, a dipeptide, tripeptide, or tetrapeptide. Non-limiting examples of dipeptide recognition sequences that may be included in the cleavable linker include, but are not limited to, Ala-(D)Asp, Ala-Lys, Ala-Phe, Asn-Lys, Asn-(D)Lys, Asp-Val, His-Val, Ile-Cit, Ile-Pro, Ile-Val, Leu-Cit, Me3Lys-Pro, Met-Lys, Met-(D)Lys, NorVal-(D)Asp, Phe-Arg, Phe-Cit, Phe-Lys, phenyl Gly-(D)Lys, Pro-(D)Lys, Trp-Cit, Val-Ala, Val-(D)Asp, Val-Cit, Val-Gly, Val-Gln, and Val-Lys. Examples of tripeptide and tetrapeptide cleavage sequences include, but are not limited to, Ala-Ala-Asn, Ala-Val-Cit, (D)Ala-Phe-Lys, Asp-Val-Ala, Asp-Val-Cit, Gly-Cit-Val, Lys-Val-Ala, Lys-Val-Cit, Met-Cit-Val, (D)Phe-Phe-Lys, Asn-Pro-Val, Ala-Leu-Ala-Leu, Gly-Phe-Leu-Gly, Gly-Gly-Phe-Gly, and Gly-Phe-Gly-Gly.

[0332] Other examples of cleavable linkers include disulfide-containing linkers, such as N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) and N-succinimidyl-4-(2-pyridyldithio)-2-sulfonylbutyrate (sulfon-SPDB). Disulfide-containing linkers may optionally include additional groups to provide steric hindrance adjacent to the disulfide bond, thereby improving the extracellular stability of the linker; for example, including a gem-dimethyl group. Other cleavable linkers include linkers that are hydrolyzable at or within a specific pH range, such as hydrazone linkers. Linkers containing combinations of these functional groups may also be useful; for example, linkers containing both hydrazone and disulfide are known in the art.

[0333] Another example of a cleavable linker is a linker containing a β-glucuronide, which can be cleaved by β-glucuronidase (an enzyme present in lysosomes and tumor stroma) (see, for example, De Graaf et al., 2002, Curr. Pharm. Des. [Current Drug Design] 8:1391-1403, and International Patent Publication No. WO 2007 / 011968). The β-glucuronide can also enhance the hydrophilicity of the linker L.

[0334] Another example of linkers that cleave inside the cell and increase hydrophilicity is a linker containing a pyrophosphate diester moiety (see, for example, Kern et al., 2016, J Am Chem Soc., 138:2430-1445).

[0335] In some embodiments, the linker L included in the conjugate is a cleavable linker. In some embodiments, the linker L includes a cleavage recognition sequence. In some embodiments, the linker L may include an amino acid sequence that is recognized and cleaved by lysosomal proteases.

[0336] The cleavable linker may optionally further include one or more additional functional groups, such as self-destructing and self-eliminating groups, stretchers, or hydrophilic portions.

[0337] Self-destructive and self-eliminating groups that can be used as linkers include, for example, p-aminobenzyl (PAB) and p-aminobenzyloxycarbonyl (PABC) groups, as well as methylated ethylenediamine (MED). Other examples of self-destructive groups include, but are not limited to, aromatic compounds that are electronically similar to PAB or PABC groups, such as heterocyclic derivatives, such as the 2-aminoimidazolium-5-methanol derivative described in U.S. Patent No. 7,375,078. Other examples include groups that undergo cyclization after amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., 1995, Chemistry Biology 2:223-227) and 2-aminophenylpropionic acid amides (Amsberry et al., 1990, J. Org. Chem. 55:5867-5877). Self-destructive / self-eliminating groups are typically attached to an amino or hydroxyl group on compound D. Self-destructing / self-eliminating groups (alone or in combination) are typically included in peptide-based linkers, but can also be included in other types of linkers.

[0338] Extension groups that can be used as linkers in drug conjugates include, for example, alkylene groups and extension groups based on fatty acids, diacids, amines, or diamines, such as diglycolate, malonic acid esters, hexanoates, and hexamethylenetetramine. Other extension groups include, for example, glycine-based extension groups and polyethylene glycol (PEG) or monomethoxy polyethylene glycol (mPEG) extension groups.

[0339] PEG and mPEG extension groups can also serve as hydrophilic portions within the linker. For example, PEG or mPEG can be included in the linker “in-line” or as a pendant group to increase the linker’s hydrophilicity (see, for example, U.S. Patent Application Publication No. US 2016 / 0310612). Various PEG-containing linkers are commercially available from companies such as Quanta BioDesign, Ltd. (Plaintown, Ohio). Other hydrophilic groups that may optionally be incorporated into the linker L include, for example, β-glucuronic acid, sulfonate groups, carboxylic acid ester groups, and pyrophosphate diesters.

[0340] In some embodiments, the conjugate may contain a cleavable linker. In some embodiments, the conjugate may contain a peptide-containing linker. In some embodiments, the conjugate may contain a protease-cleavable linker.

[0341] Various non-cleavable linkers are known in the art for linking drugs to target moieties and are used in some embodiments of the conjugate compositions disclosed herein. Examples of non-cleavable linkers include linkers having an N-succinimide or N-sulfosuccinimide moiety for reaction with cell-binding agents, and linkers having a maleimide- or haloacetyl-based moiety for reaction with drugs, or vice versa. An example of such a non-cleavable linker is based on sulfosuccinimide-4-[N-maleimidemethyl]cyclohexane-1-carboxylate (sulfon-SMCC). Sulfon-SMCC conjugation typically occurs via a reaction of the maleimide group with a thiol (thiol, -SH) on compound D, while sulfon-NHS esters are reactive to primary amines on the target moiety T (such as lysine, found at the N-terminus of proteins or peptides). Other non-limiting examples of such linkers include N-succinimide based on 4-(maleimidemethyl)cyclohexanecarboxylic acid (SMCC), N-succinimide-4-(N-maleimidemethyl)-cyclohexane-1-carboxy-(6-amidohexanoate) (“long-chain” SMCC or LC-SMCC), K-maleimide undecanoic acid N-succinimide (KMUA), γ-maleimide butyrate N-succinimide (GMBS), ε-maleimide... N-hydroxysuccinimide ester of aminohexanoate (EMCS), m-maleimide benzoyl-N-hydroxysuccinimide ester (MBS), N-(α-maleimide acetoxy)-succinimide ester (AMAS), succinimide-6-(β-maleimide propionamido)hexanoate (SMPH), 4-(p-maleimide phenyl)-butyrate N-succinimide ester (SMPB), and N-(p-maleimide phenyl)isocyanate (PMPI). Other examples include those containing a halogenated acetyl functional group, such as N-succinimide-4-(iodoacetyl)-aminobenzoate (SIAB), iodoacetic acid N-succinimide ester (SIA), bromoacetic acid N-succinimide ester (SBA), and 3-(bromoacetamido)propionic acid N-succinimide ester (SBAP).

[0342] V. Drugs

[0343] In this article, the terms “drug fraction,” “drug payload,” “cytotoxic payload,” “therapeutic molecule,” “therapeutic payload,” “therapeutic agent,” and “therapeutic fraction” that are used interchangeably refer to the chemical or biological fraction coupled to an antibody or its antigen-binding fragment that binds to α6β4 integrin.

[0344] In some respects, the drug component is a camptothecin analogue as defined in the context.

[0345] VI. Pharmaceutical Composition

[0346] This disclosure also provides compositions, such as pharmaceutical compositions, containing conjugates of this disclosure formulated with pharmaceutically acceptable carriers.

[0347] The therapeutic formulations disclosed herein can be prepared by mixing a conjugate of desired purity with an optional physiologically acceptable carrier, excipient, or stabilizer in the form of a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, or stabilizers are non-toxic to receptors at the doses and concentrations employed and include buffers (e.g., phosphates, citrates, and other organic acids); antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 amino acids). Proteins containing amino acid residues, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as Tween, Pluronics, or PEG.

[0348] The formulation may also contain more than one active compound necessary for the specific indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, the formulation may further contain another antibody or bispecific antibody, cytotoxic agent, chemotherapeutic agent, or ADC. Such molecules are suitably present in a combination in amounts effective for the intended purpose.

[0349] Active ingredients can also be encapsulated in microcapsules, for example, prepared by coagulation techniques or by interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in crude emulsions containing hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (1980).

[0350] The pharmaceutical compositions disclosed herein can be administered in combination therapy, i.e., in combination with other pharmaceutical agents. Examples of therapeutic agents that can be used in combination therapy are described in more detail below.

[0351] Preparations intended for in vivo administration must be sterile. This can be readily achieved through filtration using a sterile filter membrane. Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound with one or more of the ingredients listed above (as needed) into a suitable solvent, followed by sterile microfiltration. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing a base dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying (lyophilization), which produce powders of the active ingredient and any other desired ingredients from their previously sterile filtered solutions.

[0352] VII. Dosage

[0353] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is typically the amount of the composition that produces the therapeutic effect. Generally, this amount ranges from about 0.01% to about 99% of the active ingredient, preferably from about 0.1% to about 70%, and most preferably from about 1% to about 30% of the active ingredient combined with a pharmaceutically acceptable carrier, within one hundred percent.

[0354] Dosing regimens are adjusted to provide the best expected response (e.g., a therapeutic response). For example, the medication may be administered as a single bolus, administered in multiple doses over time, or the dose may be proportionally reduced or increased depending on the urgency of the treatment situation. Formulating parenteral compositions in unit dosage form is particularly advantageous for ease of administration and uniform dosing. As used herein, unit dosage form refers to a physically discrete unit suitable as a single dose to a subject to be treated; each unit contains a predetermined amount of the active compound, calculated to produce the expected therapeutic effect associated with the desired drug delivery. The specifications of the unit dosage form disclosed herein are determined by and directly depend on: (a) the unique characteristics of the active compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the area of ​​sensitivity of the individual to which such active compound is combined for treatment.

[0355] For the administration of the conjugates disclosed herein, the dosage range is from about 0.0001 to 100 mg / kg of host body weight, and more typically from 0.01 to 50 mg / kg of host body weight. For example, the dosage may be 0.3 mg / kg body weight, 1 mg / kg body weight, 3 mg / kg body weight, 5 mg / kg body weight, or 10 mg / kg body weight, or in the range of 1-10 mg / kg. Exemplary treatment regimens require daily administration, twice weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, once every three months, or once every three to six months. Preferred administration regimens of the conjugates disclosed herein include intravenous administration of 1 mg / kg body weight or 3 mg / kg body weight, wherein the conjugate is administered using one of the following dosing schedules: (i) once every four weeks for a total of six doses, followed by once every three months; (ii) once every three weeks; (iii) once 3 mg / kg body weight, followed by 1 mg / kg body weight every three weeks.

[0356] Alternatively, the conjugate can be administered as a sustained-release formulation, in which case a lower frequency of administration is required. The dosage and frequency vary depending on the half-life of the conjugate in the patient. Typically, human antibodies exhibit the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic use, relatively low doses are administered at relatively infrequent intervals over a long period. Some patients continue treatment for the rest of their lives. In therapeutic use, relatively high doses are sometimes required at relatively short intervals until disease progression decreases or ceases, and preferably until the patient shows partial or complete improvement in disease symptoms. Thereafter, a prophylactic regimen can be administered to the patient.

[0357] The actual dose level of the active ingredient in the pharmaceutical compositions disclosed herein can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response and is non-toxic to the patient for a particular patient, composition, and route of administration. The selected dose level will depend on a variety of pharmacokinetic factors, including the activity of the particular composition used herein, the route of administration, the time of administration, the excretion rate of the particular compound used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition used, and factors well known in the medical field such as the age, sex, weight, disease condition, general health status, and medical history of the patient being treated.

[0358] The "therapeutic effective dose" of the conjugate disclosed herein preferably results in a reduction in the severity of disease symptoms, an increase in the frequency and duration of symptom-free periods, or prevention of injury or disability due to disease suffering. For example, in the treatment of tumors, the "therapeutic effective dose" preferably inhibits cell growth or tumor growth or metastasis by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and still more preferably at least about 80%, relative to an untreated subject. The ability of an agent or compound to inhibit tumor growth can be evaluated in animal model systems that predict efficacy against human tumors. Alternatively, this property of the composition can be evaluated by assays known to those skilled in the art to examine the ability of the compound to inhibit (such in vitro inhibition). A therapeutically effective amount of a therapeutic compound can reduce tumor size, metastasis, or otherwise improve symptoms in a subject. Those skilled in the art will be able to determine such amounts based on factors such as the subject's body size, the severity of the subject's symptoms, and the specific composition or route of administration chosen.

[0359] VIII. Application

[0360] The compositions disclosed herein can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be understood by those skilled in the art, the route and / or manner of administration will vary depending on the desired results. Preferred routes of administration for the conjugates disclosed herein include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase “parenteral administration” refers to administration methods that are typically administered by injection, other than enteral and local administration, and includes, but is not limited to, intravenous, intramuscular, intraarticular, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. Alternatively, the conjugates disclosed herein can be administered via non-parenteral routes, such as local, epidermal, or mucosal administration routes, such as intranasal, oral, vaginal, rectal, sublingual, or local administration.

[0361] These active compounds can be prepared using carriers that protect the compound from rapid release, such as controlled-release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are patented or well known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, editor, Marcel Dekker, Inc., New York, 1978.

[0362] The therapeutic compositions can be administered using medical devices known in the art. For example, the therapeutic compositions disclosed herein can be administered using needle-free subcutaneous injection devices, such as those disclosed in US 5399163, US 5383851, US 5312335, US5064413, US 4941880, US 4790824, and US 4596556. Examples of well-known implants and modules used in this disclosure include those described in US 4487603, US 4486194, US 4447233, US 4447224, US 4439196, and US 4475196. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[0363] IX. Treatment methods

[0364] In one aspect, this disclosure relates to treating a subject's disease in vivo using the aforementioned conjugate. In one embodiment, this disclosure provides a method for preventing and / or treating a disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the conjugate or a composition comprising the conjugate.

[0365] In some embodiments, the disease is selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and immunodeficiency diseases.

[0366] In one particular embodiment, the disease is cancer.

[0367] Non-limiting examples of preferred cancers for treatment include head and neck cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, ovarian cancer, prostate cancer, breast cancer, leukemia, myeloma, squamous cell carcinoma, melanoma, brain cancer, cervical cancer, liver cancer, bladder cancer, breast cancer, kidney cancer, testicular cancer, and thyroid cancer.

[0368] Non-limiting examples of preferred autoimmune diseases to be treated include systemic sclerosis and atherosclerosis.

[0369] On the other hand, this disclosure relates to treating a subject in vivo with the aforementioned conjugate to inhibit the growth and / or metastasis of cancerous tumors. In one embodiment, this disclosure provides a method for inhibiting the growth of tumor cells in a subject and / or limiting the metastatic spread of tumor cells, the method comprising administering a therapeutically effective amount of the conjugate to the subject.

[0370] As used herein, the term "subject" is intended to include both humans and non-human animals. Non-human animals include all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cattle, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cattle, and horses. Preferred subjects include human patients who require enhanced immune responses. These methods are particularly suitable for treating human patients with disorders that can be treated by enhancing immune responses.

[0371] The above treatments can also be combined with standard cancer treatments. For example, they can be effectively combined with chemotherapy regimens. In these cases, the dosage of the chemotherapeutic agents can be reduced (Mokyr, M. et al. Cancer Res., 1998, 58, 5301-5304).

[0372] Other antibodies that can activate host immune responses can be used in or in conjunction with the bispecific molecular drug conjugates disclosed herein. These include molecules that target the surface of dendritic cells, activating DC function and antigen presentation. For example, anti-CD40 antibodies can effectively displace T cell helper activity (Ridge, J. et al., Nature, 1998, 393, 474-478) and can be used in combination with the bispecific molecular drug conjugates disclosed herein (Ito, N. et al., Immunobiology, 2000, 201, 527-540). Similarly, antibodies targeting T cell co-stimulatory molecules, such as CTLA-4 (US 5811097), CD28 (Haan, J. et al. Immunol. Lett. [Immunology Letters], 2014, 162, 103-112), OX-40 (Weinberg, A. et al. J. Immunol. [Journal of Immunology], 2000, 164, 2160-2169), 4-1BB (Melero, I. et al. Nature Med. [Nature Medicine], 1997, 3, 682-685) and ICOS (Hutloff, A. et al. Nature [Nature], 1999, 397, 262-266) or antibodies targeting PD-1 (US 8008449) and antibodies targeting PD-L1 (US 8008449) are also effective. 7943743; US8168179) can also provide increased T-cell activation levels. In another instance, the bispecific molecular drug conjugates disclosed herein can be used in combination with antitumor antibodies such as Rituxan (rituximab), Herceptin (trastuzumab), BEXXAR (tosimomab), ZEVALIN (teimomab), CAMPATH (alemumab), LYMPHOCIDE (epizumab), AVASTIN (bevacizumab), and TARCEVA (erlotinib).

[0373] Synthesis method

[0374] The compounds and methods of the present invention can be better understood by referring to the synthetic schemes described below for preparing the compounds of the present invention. These schemes are for illustrative purposes and are not intended to limit the scope of the invention. The specific solvents, reagents, or reaction conditions described herein may be substituted with equivalent, similar, or suitable solvents, reagents, or reaction conditions without departing from the general scope of the synthetic methods.

[0375] Compounds having Formula I can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in Scheme 1. Compounds having Formula I are obtained by alkylation of compound A and compound B under the catalysis of an iron catalyst or other related Minisci reactions.

[0376] Option 1

[0377] Alternatively, compound A is synthesized into compound C via an N-oxidation reaction, and then compound C is treated with a phosphorus oxyhalide to obtain the halogenated product of compound A, compound D. Compounds having formula I can be obtained from compound D through various reactions, such as the Heck reaction, Suzuki reaction, Buchwald reaction, Negishi reaction, Stiele reaction, etc., as shown in scheme 2.

[0378] Option 2

[0379] Different or more complex molecules can be synthesized by various chemical transformations of R3 in compounds having formula I, such as oxidation, reduction, substitution, and other methods commonly found in textbooks.

[0380] Alternatively, compounds of formula I can also be obtained from compounds E and F via a ring-closing reaction, as shown in Scheme 3.

[0381] Option 3

[0382] Compounds having formula II can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 4. Compounds having formula II can also be obtained from compound G and compound F via a ring-closing reaction.

[0383] Option 4

[0384] Compounds having formula II-a can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 5. Compounds having formula II-a can also be obtained from compound N and compound F via a ring-closing reaction.

[0385] Option 5

[0386] Compounds having formula II-b can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 6-1. Compounds having formula II-b can also be obtained from compound O and compound F via a ring-closing reaction. Alternatively, in some respects, using chemistry similar to that described above, compound Q can also be obtained from compound P and compound F via a ring-closing reaction, which can be readily converted to formula II-b by nucleophilic substitution, as shown in scheme 6-2.

[0387] Option 6-1

[0388] Option 6-2

[0389] Compounds having formula II-c can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 7-1. Compounds having formula II-c can also be obtained from compound R and compound F via a ring-closing reaction. Alternatively, in some respects, compound Q can be reacted with various amines S using chemical transformations known to those skilled in the art to provide compounds having formula II-c, as shown in scheme 7-2.

[0390] Option 7-1

[0391] Option 7-2

[0392] Compounds having formula II-d can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 8. Compounds having formula II-d can also be obtained from compound T and compound F via a ring-closing reaction.

[0393] Option 8

[0394] Compounds having formula III can be prepared via several different synthetic routes using chemical transformations known to those skilled in the art. One common synthetic strategy is shown in scheme 9. Compounds having formula III are obtained by alkylation of compound H with compound J under iron catalyst or other related Minich reactions.

[0395] Option 9

[0396] Alternatively, compound H is synthesized into compound K via an N-oxidation reaction, and then compound K is treated with a phosphoryl halide to obtain the halogenated product of compound H, compound L. Compounds having formula III can be obtained from compound L through various reactions, such as the Heck reaction, Suzuki reaction, Buchwald reaction, Negishi reaction, Stieler reaction, etc., as shown in scheme 10.

[0397] Option 10

[0398] By analyzing R in compounds having formula III 10 Various chemical transformations can be performed to synthesize different or more complex molecules, such as oxidation, reduction, substitution, and other methods commonly found in textbooks.

[0399] Alternatively, compounds of formula III can also be obtained from compounds M and F via a ring-closing reaction, as shown in Scheme 11.

[0400] Option 11

[0401] It should be understood that compounds having formulas I, II, and III can be synthesized by means of methods similar to those described in the methods and experimental sections above, through proper manipulation and protection of any chemical functional groups. Suitable protecting groups can be found, but are not limited to, those found by TW Greene and PGM Wuts in “Protective Groups in Organic Synthesis,” 3rd edition (1999), J. Wiley and Sons.

[0402] All references cited in this article, whether in print, electronic, computer-readable storage media or other forms, are expressly incorporated in their entirety by reference, including but not limited to abstracts, articles, journals, publications, texts, papers, websites, databases, patents and patent publications.

[0403] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications (including, but not limited to, those relating to the chemical structure, substituents, derivatives, formulations and / or methods of the invention) can be made without departing from the spirit of the invention and the scope of the appended claims.

[0404] Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather, those skilled in the art will recognize that various changes and modifications can be made within the spirit of the invention and the scope of the appended claims.

[0405] Example

[0406] The compounds and methods of the present invention will be better understood in conjunction with the following examples, which are for illustrative purposes only and not for limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications (including, but not limited to, those involving changes and modifications to the chemical structures, substituents, derivatives, formulations and / or methods of the present invention) can be made without departing from the spirit of the invention and the scope of the appended claims.

[0407] Example 1-1

[0408] (S)-10-amino-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]inzazino[1,2-b]quinoline-3,14(4H)-dione

[0409]

[0410] Step 1-1a. A mixture of 1,3-dibromo-5-fluoro-2-iodobenzene (CAS: 62720-29-0) (5000 mg, 17.74 mmol) cooled to -35°C in toluene (100 mL) was added over 30 minutes to a solution of magnesium chloride (7.9 mL, 15.80 mmol) while maintaining the internal temperature below -25°C, resulting in a clear brown solution, which was stirred for 1.5 hours. Then, anhydrous N,N-dimethylformamide (3.4 mL, 44.10 mmol) was added to the mixture over a 30-minute period, and the temperature of the reaction mixture was raised to -19°C, and then to 10°C over 1 hour. The reaction mixture was stirred at 10°C for 1.5 hours. The mixture was then quenched with a saturated aqueous NH₄Cl solution, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate at a ratio of 50:1 to 20:1) to give the desired compound as a white solid (3000 mg, 10.6 mmol, 81% yield).

[0411] Step 1-1b. A mixture of the compound from Step 1-1a (500 mg, 1.77 mmol), ethylene glycol (0.5 mL, 8.87 mmol), 4-methylbenzenesulfonic acid (30.55 mg, 0.18 mmol), and triethoxymethane (226.05 mg, 1.56 mmol) in a DCE (10 mL) was stirred at 80°C for 16 hours. It was quenched with water (0.5 mL) and extracted with DCM (3 × 10 mL). The combined organic matter was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA, where EA ranged from 0–25%) to give the desired compound as a yellow solid (550 mg, 1.69 mmol, 95% yield).

[0412] Step 1-1c. A mixture of the compound from Step 1-1b (150 mg, 0.46 mmol), diphenylmethyleneimine (175.15 mg, 0.97 mmol), [5-(diphenylphosphine)-9,9-dimethyl-9H-oxanthracene-4-yl]diphenylphosphine (26.63 mg, 0.05 mmol), palladium di(acetic acid) (10.33 mg, 0.05 mmol), and potassium tert-butoxide (132.67 mg, 1.38 mmol) in toluene (10 mL) was stirred at 80°C for 16 hours. The organic solvent was removed under reduced pressure. The residue was concentrated under vacuum and purified by rapid chromatography (PE / EA, where EA ranged from 0-40%) to give the desired compound as a white solid (150 mg, 0.285 mmol, 62% yield). LC-MS: (ESI) m / z (M+H), 527.6.

[0413] Step 1-1. A mixture of the compound from Step 1-1c (100 mg, 0.19 mmol), (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (CAS 110351-94-5) (44.99 mg, 0.17 mmol), and HCl (0.5 mL, 6.00 mmol) in EtOH (5 mL) was stirred at 80°C for 16 hours. The organic solvent was removed under reduced pressure. The residue was purified by preparative HPLC (C18, 18%-48% acetonitrile, in H2O (containing 0.1% formic acid)) to give compound 1-1 (7 mg, 0.018 mmol, 9.7% yield) as a brown solid. LC-MS: (ESI) m / z (M+H), 382.2. 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 7.29 (s, 1H), 7.01 (dd, J = 10.4, 2.4 Hz, 1H), 6.68 - 6.53 (m, 3H), 6.51 (s, 1H), 5.43 (s,2H), 5.26 (s, 2H), 1.93 - 1.79 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0414] Examples 1-6

[0415] (S)-4-Ethyl-8-fluoro-4-hydroxy-10-((2-hydroxyethyl)amino)-1,12-dihydro-14H-pyrano[3',4':6,7]inzazino[1,2-b]quinoline-3,14(4H)-dione

[0416]

[0417] Steps 1-6a. A mixture of the compound from Steps 1-1b (5.0 g, 15.339 mmol) and diphenylmethyleneimine (3.06 g, 16.873 mmol), [5-(diphenylphosphine)-9,9-dimethyl-9H-oxanthracene-4-yl]diphenylphosphine (0.89 g, 1.534 mmol), Pd(OAc)2 (0.34 g, 1.534 mmol), and sodium 2-methylpropane-2-ol (4.42 g, 46.018 mmol) in toluene (50 mL) was stirred at 100°C for 16 h. The mixture was concentrated under vacuum. The residue was purified by column chromatography (PE / EA, where EA ranged from 0-30%) to give the desired compound as a yellow solid (3.2 g, 49%). LC-MS: (ESI) m / z (M+H), 428.0.

[0418] Steps 1-6b. The mixture of the compound from steps 1-6a (500 mg, 1.173 mmol), 2-aminoethanol (14.33 mg, 0.235 mmol), and copper powder (74.54 mg, 1.173 mmol) in DMSO (15 mL) was stirred at 100°C for 18 h. The mixture was filtered and treated with EA (20 mL). 3) Extraction. The mixture was concentrated under vacuum. The residue was purified by column chromatography (PE / EA, where EA ranged from 0-50%) to give the desired compound as a yellow solid (90 mg, 18%). LC-MS: (ESI) m / z (M+H), 363.2.

[0419] Steps 1-6c. A mixture of the compound from steps 1-6b (90 mg, 0.221 mmol) and (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (CAS 110351-94-5) (58.29 mg, 0.221 mmol) and 4-methylbenzenesulfonic acid (38.13 mg, 0.221 mmol) in toluene (10 mL) was stirred at 120°C for 18 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (C18, 20-50% acetonitrile, in H2O (containing 0.01% TFA)) to give compounds 1-6 (2.9 mg, 3.08%) as the desired yellow solid. (LC-MS: (ESI) m / z (M+H), 426.2. 1 H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 7.32 (s, 1H), 7.02 (dd, J = 10.4, 2.4 Hz, 1H), 6.93 (s, 1H), 6.53 (dd, J = 12.4, 2.4 Hz, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 4.83 (s, 1H), 3.71 (t, J = 6.0 Hz, 2H), 3.40(s, 2H), 1.92-1.81 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0420] Examples 1-7

[0421] (S)-10-((2-aminoethyl)amino)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]inzazino[1,2-b]quinoline-3,14(4H)-dione

[0422]

[0423] Steps 1-7a. The mixture of the compound from steps 1-6a (300 mg, 0.704 mmol), 2-methylpropyl-2-yl [(2-aminoethyl)amino]formic acid (563.77 mg, 3.519 mmol), and Cu (44.74 mg, 0.704 mmol) in DMSO (10 mL) was stirred at 100°C for 18 hr. The mixture was filtered and treated with EA (20 mL). 3) Extraction. The mixture was concentrated under vacuum. The residue was purified by column chromatography (PE / EA, where EA ranged from 0-30%) to give the title compound (50 mg, 14%) as a yellow solid. LC-MS: (ESI) m / z (M+H), 506.2.

[0424] Steps 1-7. A mixture of the compound from Steps 1-7a (50 mg, 0.099 mmol) and (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (26.03 mg, 0.099 mmol) and 4-methylbenzenesulfonic acid (17.03 mg, 0.099 mmol) in toluene (10 mL) was stirred at 120°C for 18 hr. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (C18, 20%-50% acetonitrile, in H2O (containing 0.01% TFA)) to give the title compound (6.7 mg, 16%) as a brown solid. LC-MS: (ESI) m / z (M+H), 436.2. 1 HNMR (400 MHz, DMSO) δ 8.87 (s, 1H), 7.86 (s, 3H), 7.31 (s, 1H), 7.14 -7.05(m, 2H), 6.64 (dd, J = 12.4, 2.3 Hz, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 3.54-3.50 (m, 2H), 3.14-3.12 (m, 2H), 1.93 -1.81 (m, 2H), 0.88 (t, J= 7.2 Hz, 3H).

[0425] Examples 1-9

[0426] (S)-2-amino-N-(4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]inzazino[1,2-b]quinoline-10-yl)acetamide

[0427]

[0428] Steps 1-9a. A mixture of 1-1 (30 mg, 0.08 mmol), N-{[(2-methylpropyl-2-yl)oxy]carbonyl}glycine (41.34 mg, 0.24 mmol), HOAt (32.12 mg, 0.24 mmol), 1-{[3-(dimethylamino)propyl]azalkylylyl]-N-ethylmethylimine hydrochloride (51.59 mg, 0.24 mmol), and copper chloride (42.31 mg, 0.32 mmol) in DMF (0.3 mL) and DCM (2.7 mL) was stirred at 25°C for 18 hours. The resulting mixture was concentrated to give the desired compound as a yellow solid (crude, 30 mg). LC-MS: (ESI) m / z (M+H), 539.3.

[0429] Steps 1-9. The mixture of Step 1-9b (30 mg, 0.028 mmol) and TFA (0.25 mL, 3.265 mmol) in DCM (1 mL) was stirred at 25°C for 16 hours. The resulting mixture was concentrated and the residue was purified by preparative HPLC (C18, 20%-50% acetonitrile, in H2O (containing 0.01% TFA)) to give the desired compounds 1-9 as a grayish-white solid (3 mg, 0.007 mmol, 12.2% yield). LC-MS: (ESI) m / z (M+H), 439.2. 1 H NMR (400 MHz, DMSO)δ 10.85 (s, 1H), 8.93 (s, 1H), 8.21 (s, 2H), 7.94 (dd, J = 10.4, 2.4 Hz, 1H), 7.85 (dd, J = 9.6, 2.4 Hz, 1H), 7.37 (s, 1H), 6.56 (s, 1H), 5.44 (s, 2H), 5.32 (s, 2H), 4.02 (s, 2H), 1.93-1.82 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0430] Example 2-1

[0431] (S)-7-ethyl-7-hydroxy-14-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-10,13-dihydro-11H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0432]

[0433] Step 2-1a. Mix 1-(hydroxymethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (CAS 180464-87-3) (3.0 g, 19.20 mmol), chloro(2-methylpropyl-2-yl)diphenylsilane (5.54 g, 20.16 mmol), and 1... H The mixture of β-imidazole (2.62 g, 38.41 mmol) in DCM (50 mL) was stirred at 25°C for 18 hours. The solution was concentrated and the residue was purified by FC (PE / DCM, where DCM ranged from 0-45%) to give the desired product as a colorless oil (3.0 g, 7.59 mmol, 39.6% yield). LC-MS: (ESI) m / z (M+H), 395.2.

[0434] Step 2-1b. A mixture of the compound from step 2-1a (1.8 g, 4.56 mmol) and lithium hydroxide (0.22 g, 9.12 mmol) in THF (40 mL) and water (10 mL) was stirred at 0°C for 18 hours. It was concentrated, and the residue was purified by RP-FC (H₂O / CH₃CN, where CH₃CN ranged from 0–60%) to give the desired compound as a white solid (0.87 g, 2.16 mmol, 50% yield). LC-MS: (ESI) m / z (M+H), 403.2.

[0435] Step 2-1c. The mixture of the compound from Step 2-1b (0.7 g, 1.84 mmol), N,O-dimethylhydroxylamine hydrochloride (179 mg, 1.84 mmol), HATU (1.4 g, 3.68 mmol), and DIPEA (713 mg, 5.52 mmol) in DCM (20 mL) was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was separated with DCM (20 mL). 2) Extraction was performed, and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography (10 g silica gel column, PE / DCM, where DCM ranged from 0-50%) to give the desired compound as a yellow oil (0.4 g, 0.94 mmol, 51.3% yield). LC-MS: (ESI) m / z (M+H), 424.4.

[0436] Step 2-1d. The mixture of the compound from step 2-1c (450 mg, 1.06 mmol), 5-bromobenzo[d][1,3]dioxane (235 mg, 1.17 mmol), and n-BuLi (177 mg, 2.76 mmol) in THF (10 mL) was stirred at -65°C for 2 hours. It was concentrated, and the residue was purified by FC (PE / EA, where EA ranged from 0-15%) to give the desired compound as a yellow oil (45 mg, 0.089 mmol, 15.5% yield). LC-MS: (ESI) m / z (M+Na), 507.2.

[0437] Step 2-1e. The mixture of the compound from step 2-1d (45 mg, 0.09 mmol) and copper nitrate (35 mg, 0.19 mmol) in acetic anhydride (0.25 mL) was stirred at 0°C for 2 hours. It was concentrated and the residue purified to give the desired product as a white solid (15 mg, 0.028 mmol, 31% yield). LC-MS: (ESI) m / z (M+H), 530.4.

[0438] Step 2-1f. The mixture of the compound from step 2-1e (15 mg, 0.03 mmol), iron (O) (6 mg, 0.11 mmol), and NH4Cl (15 mg, 0.28 mmol) in EtOH (2 mL) and water (0.5 mL) was stirred at 0°C for 2 hours. The solution was diluted with EA (2 mL) and washed with water (2 mL), and the phases were separated. The aqueous layer was extracted four times with EA (2 mL), the combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure to give the desired compound as a colorless oil (crude product, 15 mg). LC-MS: (ESI) m / z (M+H), 500.4.

[0439] Step 2-1g. The mixture of the compound from Step 2-1f (10 mg, 0.02 mmol), (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (CAS110351-94-5) (7 mg, 0.02 mmol), and PPTS (6 mg, 0.02 mmol) in toluene (2 mL) was stirred at 110°C for 18 hours. It was concentrated to give the desired compound as a brown solid (crude, 10 mg), which could be used in the next step without further purification. LC-MS: (ESI) m / z (M+H), 727.2.

[0440] Step 2-1. The mixture of the compound from Step 2-1 g (10 mg, 0.014 mmol) and 4N HCl (50 mg, 0.27 mmol) in 1,4-dioxane (2 mL) was stirred at 0°C for 2 hours. The solvent was removed under vacuum and the residue was purified by preparative HPLC (C18, 20%–60% acetonitrile, in H2O (containing 0.1% TFA)) to give compound 2-1 as a desired yellow solid (1.7 mg, 0.003 mmol, 25.3% yield). LC-MS: (ESI) m / z (M+H), 489.2. 1 HNMR (400 MHz, DMSO) δ 7.74 (s, 1H), 7.52 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.30 (s, 2H), 5.40 - 5.45 (m, 4H), 4.75 - 4.51 (m, 1H), 3.53 (s, 2H), 2.42 (s, 6H), 1.90 - 1.84 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0441] Example 2-4

[0442] (S)-7-ethyl-7-hydroxy-14-(3-(methoxymethyl)bicyclo[1.1.1]pent-1-yl)-10,13-dihydro-11H-[1,3]dioxapentanocene[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0443]

[0444] Steps 2-4. MeI (15 mg, 0.1 mmol) and AgOTf (79 mg, 0.3 mmol) were added to a solution of compound 2-1 in DCM (15 mL), and the mixture was stirred at 20°C for 12 h. The mixture was concentrated and purified by preparative HPLC (column: WELCH Xtimate 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 40% to 70% over 10 min, 30 mL / min) to give compound 2-4 (6.4 mg, 12% yield) as a white solid. LC-MS: ESI-MS m / z = 503.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.73 (s, 1H), 7.51 (s,1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.29 (s, 2H), 5.41 (s, 2H), 5.37 (s, 2H), 3.48 (s, 2H), 3.34 (s, 3H), 2.48 - 2.44 (m, 6H), 1.88 - 1.84 (m, 2H), 0.87 (t, J= 8.0 Hz, 3H).

[0445] The following examples were prepared using a procedure similar to that described above:

[0446] Example 2-6

[0447] (S)-14-(3-(aminomethyl)bicyclo[1.1.1]pent-1-yl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxapentancyclo[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0448]

[0449] Steps 2-6a. Under a nitrogen atmosphere at 25°C, add Desmond-Martin periodane (260 mg, 0.6 mmol) to a stirred mixture of compound 2-1 (200 mg, 0.4 mmol) in DCM (3 mL) and DMF (3 mL). Stir the resulting mixture at 25°C for 2 h. Collect the precipitated solid by filtration and wash with DCM (2 mL × 2). Concentrate the resulting mixture under vacuum. This resulted in the desired yellow solid of compound 2-6a (200 mg, approximately 90% purity, 90% yield). ESI-MS m / z = 487.1 [M+H] + , 505.2 [M+H2O+H] + .

[0450] Steps 2-6. Under a nitrogen atmosphere at 25°C, a mixture of compounds from step 2-6a (200 mg, 0.4 mmol) in MeOH (5 mL) was treated with NH4OAc (1423 mg, 1.9 mmol) and AcOH (23 mg, 0.4 mmol) for 2 h, followed by the addition of NaBH3CN (46 mg, 0.7 mmol) at 25°C. The resulting mixture was stirred at 25°C for another 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by rapid column chromatography (12 g silica gel column, dichloromethane / CH3OH, where CH3OH increased from 0% to 20% within 15 min) to give compounds 2-6 (70 mg, 35% yield) as the desired yellow solid. ESI-MS m / z = 488.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ7.84 (s, 2H), 7.70 (s, 1H),7.55 (s, 1H), 7.25 (s, 1H), 6.50 (s, 1H), 6.32 (s, 2H), 5.46 - 5.40 (m, 4H),3.14 - 3.10 (m, 2H), 2.57 (s, 6H), 1.93 - 1.81 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0451] Example 2-7

[0452] (S)-N-((3-(7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-14-yl)bicyclo[1.1.1]pent-1-yl)methyl)-2-hydroxyacetamide

[0453]

[0454] Steps 2-7. Compounds 2-6 and DIPEA (66 mg, 0.5 mmol) were added to a stirred mixture of 2-hydroxyacetic acid (15 mg, 0.2 mmol) and HATU (78 mg, 0.2 mmol) in DMF (4 mL) under a nitrogen atmosphere at 25°C. The resulting mixture was stirred at 25°C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Ultimate-18C 250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 20% to 50% over 9 min) to give the desired pale yellow solid of compound 2-7 (4.7 mg, 7% yield). ESI-MS m / z = 546.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (t, J = 6.0 Hz, 1H), 7.70 (s,1H), 7.51 (s, 1H), 7.22 (s, 1H), 6.29 (s, 2H), 5.42 (s, 2H), 5.34 (s, 2H), 3.91 (s, 1H), 3.88 (s, 2H), 3.36 (d, J = 6.1 Hz, 2H), 2.67 (s, 1H), 2.41 (s,6H), 1.95 - 1.78 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0455] Example 2-8

[0456] (S)-3-(7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-14-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0457]

[0458] Steps 2-8. Under a nitrogen atmosphere at 25°C, IBX (34 mg, 123 µmol) was added to a solution of compound 2-1 (30 mg, 61 µmol) in DMSO (2 mL). The resulting mixture was stirred at 80°C for 3 h. The residue was purified by preparative HPLC (column: Ultimate-18C 250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 32% to 42% over 10 min) to give compound 2-8 (2.3 mg, 7% yield) as a white solid. ESI-MS m / z = 503.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.29 (s, 2H), 5.41 (s, 2H), 5.38 (s, 2H), 2.70 (s,6H), 1.94 - 1.78 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0459] Example 2-13

[0460] (S)-7-ethyl-7-hydroxy-14-(3-((2-hydroxyethoxy)methyl)bicyclo[1.1.1]pent-1-yl)-10,13-dihydro-11H-[1,3]dioxapentanoctano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0461]

[0462] Step 2-13a. AgOTf (26 mg, 0.1 mmol) was added to a solution of compound 2-1 (25 mg, 0.05 mmol) and [(2-iodoethoxy)methyl]benzene (16.1 mg, 0.0614 mmol) in DCM (10 mL). The resulting mixture was stirred at 20°C for 12 h under N2 atmosphere. The mixture was filtered and concentrated to give a crude product. The residue was purified by rapid column chromatography (4 g silica gel column, petroleum ether / ethyl acetate, where ethyl acetate increased from 10% to 50% within 20 min) to give the desired compound as a white solid (30 mg, 75% yield). LC-MS: ESI-MS m / z = 623.2 [M+H] + .

[0463] Steps 2-13. Pd / C (10 mg, 10%) was added to a solution of the compound from step 2-13a (25 mg, 0.04 mmol) in EtOAc (10 mL). The resulting mixture was stirred at 20°C for 12 h under a H2 atmosphere. The mixture was filtered and purified by preparative HPLC (column: Xbridge-C18 150 × 19 mm, 5 μm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 35% to 45% over 8 min, 20 mL / min) to give the desired white solid compound 2-13 (2.2 mg, 9% yield). LC-MS: ESI-MS m / z = 533.2 [M+H] + . 1 HNMR (400 MHz, DMSO) δ 7.74 (s,1H), 7.51 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.29 (s, 2H), 5.41 (s, 2H),5.38 (s, 2H), 3.57 - 3.51 (m, 6H), 2.48 - 2.44 (m, 6H), 1.88 - 1.84 (m, 2H), 0.87 (t, J= 8.0 Hz, 3H).

[0464] Example 2-14

[0465] Dihydrogen phosphate (S)-(3-(7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-14-yl)bicyclo[1.1.1]pent-1-yl)methyl ester

[0466]

[0467] Step 2-14. Add P2O5 (215 mg, 1.5 mmol) to a solution of compound 2-1 (410 mg, 0.8 mmol) in DMF (5 mL). Stir the reaction mixture at 80°C for 12 h. Purify the reaction mixture by preparative HPLC (column: Welch-18C 250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% TFA); gradient: 25% to 40% over 10 min) to give compound 2-14 (114 mg, 24% yield) as the desired yellow solid. LC-MS: ESI-MS m / z = 569.1 [M+H] + . 1 HNMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 6.28 (s, 2H), 5.41 (s, 2H), 5.36 (s, 2H), 3.97 (d, J =4.0 Hz, 2H), 2.47 - 2.40 (m, 6H), 1.89 - 1.81 (m, 2H), 0.87 (t, J = 4.0 Hz, 3H). 31 P NMR (162 MHz, DMSO) δ -0.84.

[0468] Example 2-15

[0469] (S)-7-ethyl-7-hydroxy-14-(3-(((3-hydroxypropyl)amino)methyl)bicyclo[1.1.1]pent-1-yl)-10,13-dihydro-11H-[1,3]dioxapentanoctano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0470]

[0471] Steps 2-15. A mixture of the compound from Step 2-6a (20 mg, 41 µmol), 3-aminoprop-1-ol (15 mg, 0.2 mmol), and AcOH (3 mg, 41 µmol) in MeOH (5 mL) was stirred at 25°C for 2 h under a nitrogen atmosphere. NaBH3CN (5 mg, 82 µmol) was added to the mixture at 25°C. The resulting mixture was stirred again at 25°C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Ultimate-18C 250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 20% to 40% over 10 min) to give compound 2-15 as a desired white solid. ESI-MS m / z = 546.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ7.70 (s, 1H), 7.49 (s, 1H), 7.21 (s, 1H), 6.49 (s, 1H), 6.27 (s, 2H), 5.39(s, 2H), 5.34 (s, 2H), 3.54 (s, 1H), 3.50 - 3.46 (m, 2H), 2.82 (s, 2H), 2.73(t, J = 7.0 Hz, 2H), 2.46 (s, 6H), 1.92 - 1.75 (m, 2H), 1.69 - 1.59 (m, 2H),0.84 (t, J = 7.3 Hz, 3H).

[0472] The following examples were prepared using a procedure similar to that described above:

[0473] Example 2-18

[0474] (S)-4-ethyl-4-hydroxy-11-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-1,12-dihydro-14H-pyrano[3',4':6,7]inzazo[1,2-b]quinoline-3,14(4H)-dione

[0475]

[0476] Step 2-18a. Under a nitrogen atmosphere at -78°C, a mixture of N-(2-bromophenyl)acetamide (227 mg, 1.0 mmol) in THF (5 mL) was treated with n-BuLi (2.5 mol / L, in hexane) (1.0 mL) for 1.5 h, followed by the addition of a solution of the compound from Step 2-1c in THF (5 mL) at -78°C. The resulting mixture was stirred at -78°C for another 1.5 h. The reaction was quenched at 0°C with saturated NH4Cl (10 mL, aqueous). The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (25 g silica gel column, petroleum ether / ethyl acetate, with ethyl acetate increasing from 0% to 10% over 16 min) to give the desired compound 2-18a as a white solid (170 mg, 46% yield). ESI-MS m / z = 498 [M+H] + .

[0477] Step 2-18b. Under a nitrogen atmosphere at 25°C, HCl (4.0 N) (2 mL) was added to a stirred mixture of the compound from Step 2-18a (170 mg, 341 µmol) in MeOH (2.0 mL) and THF (2.0 mL). The resulting mixture was stirred at 50°C for 16 h. The reaction was quenched at 0°C with saturated NaHCO3 (10 mL, aqueous). The resulting mixture was extracted with dichloromethane (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (12 g silica gel column, dichloromethane / ethyl acetate, where ethyl acetate increased from 15% to 40% within 16 min) to give the desired compound 2-18b (70 g, 92% yield) as a white solid. ESI-MS m / z = 218.1 [M+H] + .

[0478] Step 2-18. Under a nitrogen atmosphere at 25°C, add PPTS (89 mg, 354 µmol) to a stirred mixture of the compound from Step 2-18b (93 mg, 354 µmol) and (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (CAS110351-94-5) (93 mg, 354 µmol) in toluene (10 mL). Stir the resulting mixture at 110°C for 10 h. Concentrate the resulting mixture under vacuum. The residue was purified by preparative MPLC (column: Agela-18C 40 g; mobile phase: CH3CN / H2O (0.1% FA); gradient: 20% to 40% over 18 min) to the desired compound 2-18 (120 mg, 84% yield) as a pale yellow solid. ESI-MS m / z = 445.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.33 (s, 1H),6.54 (s, 1H), 5.51 - 5.35 (m, 4H), 4.71 (s, 1H), 3.55 (d, J = 3.7 Hz, 2H),2.47 (s, 6H), 1.97 - 1.79 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0479] Example 2-19

[0480] (S)-3-(4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]inzazo[1,2-b]quinoline-11-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0481]

[0482] Step 2-19. Under a nitrogen atmosphere at 25°C, IBX (75 mg, 270 µmol) was added to a stirred mixture of compound 2-18 (40 mg, 90 µmol) in DMSO (4 mL). The resulting mixture was stirred at 80°C for 3 h. The residue was purified by preparative HPLC (column: Ultimate-18C 250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 30% to 50% over 10 min) to give compound 2-19 (22.7 mg, 55% yield) as a white solid. ESI-MS m / z = 459.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H),8.52 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H),7.72 (t, J = 7.6 Hz, 1H), 7.33 (s, 1H), 6.54 (s, 1H), 5.47 (s, 2H), 5.44 (s,2H), 2.81 (s, 6H), 1.95 - 1.80 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0483] The following examples were prepared using a procedure similar to that described above:

[0484]

[0485]

[0486] Example 2-28

[0487] ( S )-3-(4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]inzino[1,2-b]quinoline-11-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0488]

[0489] Step 2-28. Under a nitrogen atmosphere at 25°C, IBX (458 mg, 1.6 mmol) was added to a stirred mixture of compound 2-2 (260 mg, 546 µmol) in DMSO (4 mL). The resulting mixture was stirred at 80°C for 3 h. The residue was purified by preparative MPLC (column: Agela-18C 40 g; mobile phase: CH3CN / H2O (0.1% FA); gradient: 20% to 50% over 18 min) to give compound 2-28 (120 mg, 44% yield) as a pale yellow solid. ESI-MS m / z = 491.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.36 (d, J = 8.2 Hz,1H), 7.89 (d, J = 10.7 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.48 - 5.37 (m,4H), 2.83 (s, 6H), 2.54 (s, 3H), 1.93 - 1.79 (m, 2H), 0.87 (t, J = 7.3 Hz,3H). 19F NMR (400 MHz, DMSO-d6) -112.73.

[0490] Example 2-30

[0491] ( S )-3-(4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]inzazido[1,2-b]quinoline-11-yl)-N-(2-hydroxyethyl)bicyclo[1.1.1]pentane-1-carboxamide

[0492]

[0493] Step 2-30a. Under a nitrogen atmosphere at 25°C, 2-((tert-butyldimethylsilyl)oxy)ethyl-1-amine (12 mg, 73 µmol) and DIPEA (24 mg, 0.2 mmol) were added to a stirred mixture of compounds 2-28 (30 mg, 61 µmol) and HATU (28 mg, 73 µmol) in DMF (2 mL). The resulting mixture was stirred at 25°C for 2 h. The resulting mixture was diluted with water (60 mL). The resulting mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (12 g silica gel column, dichloromethane / CH3OH, where CH3OH increased from 0% to 10% over 16 min) to give the desired compound as a pale yellow oil (70 mg, 88% yield, approximately 50% purity). ESI-MS m / z = 648.3 [M+H] + .

[0494] Steps 2-30. Under a nitrogen atmosphere at 25°C, HCl (4.0 N) (0.3 mL) was added to a stirred mixture of the compound from step 2-30a (70 mg, approximately 50% purity, 54 µmol) in THF (3 mL). The resulting mixture was stirred at 25°C for 40 min. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Ultimate-18C250 × 21.2 mm, 10 µm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 32% to 42% over 10 min) to give the desired compound 2-30 (11 mg, 38% yield) as a pale yellow solid. ESI-MS m / z = 534.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.2 Hz, 1H), 7.96 (t, J = 5.7 Hz, 1H), 7.88 (d, J = 10.7 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.41 (s,2H), 4.73 (s, 1H), 3.45 (d, J = 3.8 Hz, 2H), 3.19 (q, J = 6.1 Hz, 2H), 2.78(s, 6H), 2.53 (s, 3H), 1.97 - 1.73 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 19 F NMR (400 MHz, DMSO-d6) -112.82.

[0495] The following examples were prepared using a procedure similar to that described above:

[0496]

[0497] Example 3-1 (3-1-1 and 3-1-2)

[0498] (2S,7S)-7-ethyl-7-hydroxy-2-(hydroxymethyl)-2-methyl-10,13-dihydro-11H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0499] (2R,7S)-7-ethyl-7-hydroxy-2-(hydroxymethyl)-2-methyl-10,13-dihydro-11H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0500] Example 3-20 (3-20-1 and 3-20-2)

[0501] (2S,7S)-7-ethyl-7-hydroxy-2,14-bis(hydroxymethyl)-2-methyl-10,13-dihydro-11H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0502] (2R,7S)-7-ethyl-7-hydroxy-2,14-bis(hydroxymethyl)-2-methyl-10,13-dihydro-11H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-8,11(7H)-dione

[0503]

[0504] Step 3-1a. A mixture of 4,5-dihydroxy-2-nitrobenzene-1-carboxaldehyde (500 mg, 2.73 mmol), 2-(propane-2-alkynyloxy)tetrahydropyran (1.15 mL, 8.19 mmol), PPh3 (72 mg, 0.27 mmol), and dodecyltriruthenium dodecylcarbonyl (87 mg, 0.14 mmol) in toluene (40 mL) was stirred at 120°C for 18 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA, where EA ranged from 0–10%) to give the desired compound as a brown solid (405 mg, 1.25 mmol, 45.9%). LC-MS: (ESI) m / z (M+H), 324.2.

[0505] Step 3-1b. The mixture of Step 3-1a (0.40 g, 1.25 mmol), Fe (2.80 g, 50.11 mmol), and NH4Cl (4.42 g, 82.68 mmol) in EA (20 mL) and H2O (12 mL) was stirred at 25°C for 18 hours. The mixture was filtered and rinsed with EA (20 mL). 3) Extraction. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA, where EA ranged from 0-10%) to give the desired compound as a yellow solid (101 mg, 0.34 mmol, 27.5%). LC-MS: (ESI) m / z (M+H), 294.2.

[0506] Step 3-1. A mixture of step 3-1b (101 mg, 0.34 mmol), (4S)-4-ethyl-4-hydroxy-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indazine-3,6,10-trione (118 mg, 0.45 mmol), and pyridinium-1-onium 4-methylbenzenesulfonate (112.5 mg, 0.45 mmol) in toluene (7 mL) was stirred at 120°C for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (C18, 20%-50% acetonitrile, in H2O (containing 0.01% TFA)) to give the two desired compounds: 3-1-1 as a yellow solid (17.9 mg, 0.041 mmol, 11.9% yield), LC-MS: (ESI) m / z (M+H), 437.2. 1 H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.40 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 5.41 (s, 2H), 5.21 (s, 2H), 3.71 (s, 2H), 1.90 - 1.81 (m, 2H),1.70 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

[0507] 3-1-2 was a grayish-white solid (18.7 mg, 0.043 mmol, 12.46% yield). LC-MS: (ESI) m / z(M+H), 437.2. 1 H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 7.40 (s, 1H), 7.39 (s,1H), 7.24 (s, 1H), 6.47 (s, 1H), 5.48 (s, 1H), 5.41 (s, 2H), 5.21 (s, 2H),3.70 (s, 2H), 1.90-1.81 (m, 2H), 1.70 (s, 3H), 0.87 (t, J = 7.6 Hz, 3H).

[0508] Step 3-20-1. The mixture of Step 3-1-1 (5 mg, 0.011 mmol), FeSO4 (5 mg, 0.033 mmol), H2SO4 (10 μL), H2O2 (0.1 mL, 30%) in H2O (0.1 mL) and MeOH (5 mL) was stirred at 65°C for 0.5 h. The reaction solution was cooled to 25°C and purified by preparative HPLC (C18, 20%–50% acetonitrile, in H2O (containing 0.01% TFA)) to give the desired yellow solid compound 3-20-1 (0.8 mg, 0.002 mmol, 15.59%) with the same chiral center / relative configuration as compound 3-1-1. LC-MS: (ESI) m / z (M+H), 467.4. 1H NMR (400 MHz, DMSO) δ 7.41 (d, J = 1.0 Hz, 2H), 7.24 (s, 1H), 6.46 (s, 1H), 5.72 (t, J =5.6 Hz, 1H), 5.48 (t, J = 6.0 Hz, 1H), 5.41 (s, 2H), 5.35 (s, 2H), 5.12 (d, J= 5.6 Hz, 2H), 3.71 (d, J = 6.0 Hz, 2H), 1.89-1.81 (m, 2H), 1.70 (s, 3H),0.88 (t, J = 7.2 Hz, 3H).

[0509] Step 3-20-2. The mixture of Step 3-1-2 (13 mg, 0.029 mmol), FeSO4 (13 mg, 0.087 mmol), H2SO4 (25 μL), H2O2 (0.3 mL, 30%) in H2O (0.2 mL) and MeOH (10 mL) was stirred at 65°C for 0.5 h. The reaction solution was cooled to 25°C and purified by preparative HPLC (C18, 20%–50% acetonitrile, in H2O (containing 0.01% TFA)) to give the desired yellow solid compound 3-20-2 (4.4 mg, 0.009 mmol, 32.52%) with the same chiral center / relative configuration as compound 3-1-2. LC-MS: (ESI) m / z (M+H), 467.0. 1H NMR (400 MHz, DMSO) δ 7.41 - 7.40 (m, 2H), 7.24 (s, 1H), 6.46 (s, 1H), 5.72 (s, 1H), 5.48(s, 1H), 5.41 (s, 2H), 5.35 (s, 2H), 5.12-5.11 (m, 2H), 3.71 - 3.70 (m, 2H), 1.89 - 1.82 (m, 2H), 1.70 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H).

[0510] The following examples were prepared using a procedure similar to that described above:

[0511] Example LD 1-1-a

[0512] N-(2-((2-(((S)-1-((2-((((S)-4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]inzizo[1,2-b]quinoline-10-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylprop-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-yneamide)

[0513]

[0514] Step 1-1-a1 A mixture of N-[(11S)-11-benzyl-1-(9H-fluorene-9-yl)-3,6,9,12-tetraoxo-2-oxa-4,7,10-triazadodecane-12-yl]glycine CAS (1817857-75-2) (117 mg, 0.21 mmol) and HOAt (42 mg, 0.31 mmol) in a 10% (v / v) mixture of DMF (0.1 mL) and DCM (1 mL), and EDCI (60 mg, 0.31 mmol) was stirred at 25°C for 5 min. Then, compound 1-1 (40 mg, 0.11 mmol) in a 10% (v / v) mixture of DMF (0.2 mL) and DCM (2 mL) was added, followed immediately by CuCl2 (56 mg, 0.42 mmol). The mixture was concentrated and the residue was purified by preparative HPLC (TFA) to obtain the desired product as a yellow solid (30 mg, 0.03 mmol, 31% yield). LC-MS: (ESI) m / z (M+H), 922.4.

[0515] Step 1-1-a2: The mixture of Step 1-1-a1 (30 mg, 0.033 mmol) and diethylamine (47 uL, 0.62 mmol) in DMF (2 mL) was stirred at 0°C for 2 hours. The solution was filtered and concentrated under vacuum to obtain the desired compound as a brown solid (crude, 25 mg), which could be used in the next step without further purification. LC-MS: (ESI) m / z (M+H), 701.2.

[0516] Step 1-1-a: A mixture of Step 1-1-a2 (25 mg, 0.04 mmol), 6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ethynic acid (12 mg, 0.04 mmol), HATU (27 mg, 0.07 mmol), and DIEA (14 mg, 0.11 mmol) in DMF (3 mL) was stirred at 25°C for 2 hours. The mixture was concentrated and the residue was purified by preparative HPLC (C18, 20%–60% acetonitrile, in H2O (containing 0.1% TFA)) to give the desired compound LD 1-1-a (8.5 mg, 0.009 mmol, 28% yield) as a yellow solid. LC-MS: (ESI) m / z (M+H), 950.4 1H NMR (400 MHz, DMSO) δ10.36 (s, 1H), 9.09 (s, 2H), 8.91 (s, 1H), 8.52 - 8.49 (m, 1H), 8.23 ​​- 8.18(m, 2H), 8.11 - 8.08 (m, 1H), 7.96 - 7.94 (m, 1H), 7.81 - 7.78 (m, 1H), 7.37(s, 1H), 7.32 - 7.27 (m, 4H), 7.22 - 7.19 (m, 1H), 6.55 (s, 1H), 5.44 (s,2H), 5.32 (s, 2H), 4.63 - 4.60 (m, 1H), 4.19 - 4.14 (m, 2H), 3.85 - 3.72 (m,4H), 3.40 (s, 3H), 3.15 - 3.13 (m, 1H), 2.91 - 2.88 (m, 1H), 2.60 - 2.55 (m,2H), 2.35 - 2.32 (m, 2H), 1.91 - 1.77 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H).

[0517] Example LD 2-1-c

[0518] N-((6S,12S)-1-(3-((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-14-yl)bicyclo[1.1.1]pent-1-yl)-6-(3-guanidinopropyl)-13-hydroxy-5,8,11-trioxo-2-oxa-4,7,10-triazatridecane-12-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-yneamide

[0519]

[0520] Step 2-1-c1. A mixture of (S,Z)-4-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-9-((tert-butoxycarbonyl)amino)-13,13-dimethyl-3,11-dioxo-12-oxa-2,8,10-triazatetradec-9-en-1-yl ester (200 mg, 0.300 mmol), compound 2-1, and TsOH (25.79 mg, 0.150 mmol) in THF (50 mL) was stirred at 25°C for 16 hr. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH, where EA ranged from 0-15%) to give the desired compound as a yellow solid (65 mg, 20%). LC-MS: (ESI) m / z (M+H), 1092.2.

[0521] Step 2-1-c2. The mixture of the compound from step 2-1-c1 (130 mg, 0.119 mmol) and DEA (53.10 mg, 0.356 mmol) in DMF (2 mL) was stirred at 25°C for 1 hr. The solution was filtered and concentrated under vacuum to obtain the desired compound as a brown solid (120 mg), which could be used in the next step without purification. LC-MS: (ESI) m / z (M+H), 873.5.

[0522] Step 2-1-c3. The mixture of the compound from step 2-1-c2 (100 mg, 0.114 mmol), (6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynyl)-L-serylglycine (47.19 mg, 0.114 mmol), DIPEA (0.057 mL, 0.343 mmol), and HATU (65.26 mg, 0.172 mmol) in DMF (5 mL) was stirred at 15°C for 2 hr. The mixture was concentrated under vacuum and the residue was purified to give the desired product as a yellow solid (30 mg, 20.7% yield). LC-MS: (ESI) m / z (M+H), 1267.2.

[0523] Step 2-1-c. The mixture of the compound from step 2-1-c3 (25 mg, 0.020 mmol) and ZnBr2 (44.38 mg, 0.197 mmol) in DCM (5 mL) was stirred at 15°C for 18 hr. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC (C18, 20%–60% acetonitrile, in H2O (containing 0.1% TFA)) to give the title compound (5.4 mg, 25% yield) as a yellow solid. LC-MS: (ESI) m / z (M+H), 1068.2. 1H NMR (400 MHz, DMSO)δ 9.10 (s, 2H), 8.72 (t, J = 6.8 Hz, 1H), 8.24 (t, J = 5.6 Hz, 1H), 8.08 (d,J = 7.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.47-7.44 (m, 1H), 7.25 (s, 1H), 6.50 (s, 1H), 6.30 (s, 2H), 5.40 (d, J = 16.0 Hz,4H), 5.02 (s, 1H), 4.68 -4.58 (m, 2H), 4.27-4.24 (m, 2H), 3.79-3.76 (m, 2H), 3.63-3.58 (m, 2H), 3.54-3.53 (m, 2H), 3.41 (s, 3H), 3.11-3.11 (m, 2H), 2.58-2.54 (m, 2H), 2.47 (s, 6H), 2.38-2.33 (m, 3H), 1.89-1.74 (m, 6H), 1.57 - 1.46(m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0524] Example LD 2-1-d

[0525] N-((6S,9S,12S)-1-(3-((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxapentano[4,5-g]pyrano[3',4':6,7]inzizo[1,2-b]quinoline-14-yl)bicyclo[1.1.1]pent-1-yl)-6-(3-guanidinopropyl)-9-(hydroxymethyl)-13-(4-hydroxyphenyl)-5,8,11-trioxo-2-oxa-4,7,10-triazatridecane-12-yl)-6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-yneamide

[0526]

[0527] Step 2-1-d1. The compound from Step 2-1-c1 (120 mg, 0.137 mmol) and (6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynyl)-L-tyrosino-L-serine (106.80 mg, 0.206 mmol), DIEA (ethyl diisopropylamine, 0.068 mL, 0.412 mmol), and HATU (78.31 mg, 0.206 mmol) in DMF (5 mL) were stirred at 15°C for 2 hr. The mixture was concentrated under vacuum and the residue was purified to give the desired product as a yellow solid (25 mg, 13.25% yield). LC-MS: (ESI) m / z (M+H), 1373.0.

[0528] Step 2-1-d. The mixture of the compound from step 36a (25 mg, 0.018 mmol) and ZnBr2 (12.29 mg, 0.055 mmol) in DCM (5 mL) was stirred at 15°C for 18 hr. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC (C18, 20%–60% acetonitrile, in H2O (containing 0.1% TFA)) to give the title compound (5.9 mg, 27% yield) as a yellow solid. LC-MS: (ESI) m / z (M+H), 1173.4. 1H NMR (400 MHz, DMSO)δ 9.14 (d, J = 9.2 Hz, 1H), 9.10 (s, 1H), 9.08 (s, 1H), 8.71-8.58 (m, 1H),8.19-8.05 (m, 3H), 7.72 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 3.0 Hz, 1H), 7.53-7.52 (m, 1H), 7.25 (s, 1H), 7.05-7.03 (m, 2H), 6.62-6.60 (m, 2H), 6.50 (s,1H), 6.30 (s, 2H), 5.42 (s, 2H), 5.37 (s, 2H), 4.63-4.61 (m, 2H), 4.56 -4.46(m, 1H), 4.36-4.32 (m, 2H), 3.60 (s, 1H), 3.52 (s, 2H), 3.41 (d, J = 2.8 Hz,3H), 3.13-3.11 (m, 2H), 2.68-2.67 (m, 1H), 2.46 (s, 6H), 2.34-2.22 (m, 4H), 2.24-2.20 (m, 2H), 2.03- 1.97 (m, 1H), 1.88-1.82 (m, 3H), 1.71-1.67 (m, 2H),1.60-1.44 (m, 4H), 1.24 (s, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0529] ADC coupling

[0530] method: Antibodies were conjugated to drug-linkers (examples above) to form antibody-drug conjugates with a DAR of approximately 8. Conjugation was performed as follows: The sample buffer containing the antibody was adjusted to the desired pH and concentration of 5 mg / mL by dialyzing at 4°C for 16 hours. Approximately 10 TCEP (relative to protein) was added to the sample buffer, shaken, and incubated at 25°C for 3 hours. Then, a relative equivalent (relative to protein) of the drug-linker dissolved in DMSO was added directly to the reaction sample and incubated at 25°C for 2 hours. Then, 20 cysteine ​​equivalents (relative to protein) were added to the reaction sample to quench the reaction. Excess small molecules were removed by dialyzing, yielding the ADC conjugated to the drug-linker.

[0531] Characterization of ADC

[0532] DAR determined by LC-MS

[0533] ADCs were deglycosylated using PNG enzyme F (0.5 μL of PNG enzyme F was added to the sample and incubated at 37°C for 3 h). The deglycosylated ADCs were reduced by DTT (DTT was added to the sample to 50 mM and incubated at 37°C for 10 min) and injected into an Agilent 1290 UPLC (Agilent Technologies, INC., Santa Clara, CA) coupled to a time-of-flight mass spectrometer (TOF-MS, X500B, AB Sceix). A Waters ACQUITY UPLC protein BEH C4 column (1.7 μm, 2.1 mm) was used. Heavy and light chains were separated at a flow rate of 0.3 mL / min (100 mm). Qualitative quality analysis was used for deconvolution and data analysis.

[0534] Size exclusion chromatography (SEC-HPLC) analysis

[0535] Analytical SEC was performed using an Agilent Infinity II 1260 HPLC (Agilent Technologies, Santa Clara, CA) and a BioCore column (B213-050030-07830S, BioCore SEC-300), equilibrated with buffer (60 mM Na₂HPO₄, 20 mM NaH₂PO₄, 100 mM arginine, pH 7.0): ACN = 90:10 (v / v). Typically, 20 µg of sample at a concentration of 2–3 mg / mL was eluted isostatically at 1 mL / min for 15 or 20 min, and absorbance was monitored at A280.

[0536]

[0537] The ADC was prepared by cysteine-based conjugation and characterized by LC-MS (or HIC) for DAR determination and SEC-HPLC for purity and aggregation. The RP007T2 antibody is an anti-Trop-2 antibody with the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2.

[0538] Experiment 1: Cytotoxicity of novel drugs on A431 / A549 / PC-3 / HT29 / SKOV3 cells

[0539] Cancer cells were seeded at 2000 cells / well in 96-well plates. After overnight incubation, serially diluted solutions of each novel drug were added. Cell viability was evaluated using a Cell Titer-Glo chemiluminescence cell viability assay (G7572) from Promega, according to the manufacturer's instructions, after 6 days. The results showed that all novel drugs exhibited good cytotoxic activity. The results are shown in Table 1.

[0540] Table 1

[0541] Note: "-" indicates that it has not been tested.

[0542] Experiment 2. Cytotoxicity of novel drugs on A431 / HT29 cells

[0543] Cancer cells were seeded at 2000 cells / well in 96-well plates. After overnight incubation, serially diluted solutions of each novel drug were added. Cell viability was evaluated using a Cell Titer-Glo chemiluminescence cell viability assay (G7572) from Prometheus, according to the manufacturer's instructions, after 6 days. The results showed that all novel drugs exhibited good cytotoxic activity. The results are shown in Table 2.

[0544] Table 2

[0545] Experiment 3: ADC Conjugation: Preparation of Antibody-Drug Conjugates with Novel Payloads

[0546] The novel camptothecin payload 2-1 was coupled with a linker to generate ADCs RP007T2-LP2-1-c, RP007T2-LP2-1-d, and RP007T2-MC-GGFG-DXd (as a control ADC) (MC-GGFG-DXd was purchased from MedChemExpress, CAS: 1599440-13-7). The ADCs were prepared via cysteine-based coupling and characterized by LC-MS for DAR determination and SEC-HPLC for purity and aggregation, as shown in Table 3.

[0547] Table 3. Fabrication and characterization of ADCs using novel payloads

[0548] Experiment 4. Power determination of ADC in A431 xenograft model

[0549] In this experiment, an A431 cell mouse tumor model was used to study the antitumor activity of ADCs. The pharmacodynamics of RP007T2-LP2-1-c and RP007T2-LP2-1-d, and the control ADC RP007T2-MC-GGFG-DXd, administered at 5 mg / kg BIW 3 in an A431 cell mouse model were investigated, and the experimental design for in vivo pharmacodynamics of ADCs is shown in Table 4. A431 cells were subcutaneously inoculated into female Balb / c nude mice. The ADC treatment method was as follows: on day 7 after tumor cell inoculation, the corresponding ADC was injected intraperitoneally into each group of mice. Tumor volume was measured on days 7, 11, 14, 18, 21, and 25 after tumor cell inoculation, and then the mice were euthanized. The results are shown in Table 4. Figure 1 In comparison with the drug control group, the TGI% (RTV) of RP007T2-LP2-1-c and RP007T2-LP2-1-d (5 mg / kg) and the control ADC RP007T2-MC-GGFG-DXd (5 mg / kg) were 76%, 86%, and 34%, respectively. No animal deaths or drug-related abnormalities were observed in any of the treatment groups, and all treatments were well tolerated.

[0550] Table 4. Experimental design for in vivo pharmacodynamics of ADCs

[0551] discuss The conjugation of LP2-1-c and LP2-1-d with antibodies was highly effective in preclinical tumor models, demonstrating superior in vivo efficacy compared to the control MC-GGFG-DXD, paving the way for potential therapeutic advances in cancer.

[0552] Experiment 5. Tolerance of ADC in non-tumor-bearing BALB / c mice

[0553] RP007T2-LP2-1-c and RP007T2-LP2-1-d were administered to female and male BALB / c mice (9–10 weeks old, with female mice weighing 18.2 g to 23.3 g and male mice weighing 24.4 g to 30.7 g at the start of administration, derived from GemPharmatech, via intravenous injection at a dose level of 20 mL / kg via tail vein at dose levels of 40, 80, and 140 mg / kg (12 animals / dose level)). Mice were observed for up to 22 days post-administration. Mice were euthanized if their body weight decreased by ≥20% within 72 hours from pre-administration levels. Weight changes were monitored. Blood samples were collected for hematological testing, specifically for the following parameters: WBC, NEUT, LYM, RBC, HGB, ALT, and UREA.

[0554] discuss Single-dose toxicity was assessed using BALB / c mice and compared with MC-GGFG-DXd (the linker-payload used in Daiichi Pharmaceutical's DS8201), and the results are presented in [the table / incomplete]. Figure 2 and Figure 3 The results showed that the novel ADC with a payload of 2-1 was well-tolerated in mice up to 140 mg / kg and exhibited a safety profile comparable to MC-GGFG-DXd. No significant weight loss was observed at the 40 mpk and 80 mpk dose levels compared to the ADC group. Weight loss was observed in the high-dose groups (140 mpk) of both ADCs and gradually recovered from day 7. No dose-related changes were observed in hematological tests, such as... Figure 3 As shown. No other anomalies were observed in any of the test groups.

Claims

1. A compound having formula (II), or a pharmaceutically acceptable salt, isotopically labeled analogue, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II) in, R4 and R5 are independently selected from H, halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6 is selected from H, -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -S(O)2-R 6a -(CH2) n -S(O)-R 6a -(CH2) n -OP(O)(OH)-OR 6a -(CH2) n -OP(S)(OH)-OR 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -NHC(O)NR 6b R 6c -(CH2) n -NHC(O)OR 6a -(CH2) n -OC(O)NR 6b R 6c -(CH2) n -C(O)NR 6b R 6c -(CH2) n -CH2NR 6b R 6c -(CH2) n -3-7-membered heterocyclic group-(CH2) n -OR 6a and -(CH2) n -3-7-membered heterocyclic group-(CH2) n -R 6a ; R 6a R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6 is selected from H, -(CH2) n -OR 6a 、-(CH2) n -C(O)OR 6a 、-(CH2) n -OC(O)R 6a 、-(CH2) n -C(O)R 6a 、-(CH2) n -S(O)2-R 6a 、-(CH2) n -S(O)-R 6a 、-(CH2) n -NHC(O)-R 6a 、-(CH2) n -NHC(O)NR 6b R 6c 、-(CH2) n -NHC(O)OR 6a 、-(CH2) n -OC(O)NR 6b R 6c 、-(CH2) n -C(O)NR 6b R 6c and -(CH2) n -CH2NR 6b R 6c ; R 6a R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2) n -OR 6a 、-(CH2) n -C(O)OR 6a 、-(CH2) n -OC(O)R 6a 、-(CH2) n -C(O)R 6a 、-(CH2) n -S(O)2-R 6a 、-(CH2) n -S(O)-R 6a 、-(CH2) n -NHC(O)-R 6a 、-(CH2) n -NHC(O)NR 6b R 6c and -(CH2) n -C(O)NR 6b [[ID = 38]]R 6c ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2, such as H, CH3, CH2OH and CH2CH2OH; R 6b and R 6c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2, such as H and CH3; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -NHC(O)-R 6a -(CH2) n -C(O)NR 6b R 6c and -(CH2) n -CH2NR 6b R 6c ; Alternatively, R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -OC(O)R 6a -(CH2) n -C(O)R 6a -(CH2) n -NHC(O)-R 6a and -(CH2) n -C(O)NR 6b R 6c .

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, and preferably, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a -(CH2) n -NHC(O)-R 6a and -(CH2) n -CH2NR 6b R 6c ; R6 is preferably selected from -(CH2). n -OR 6a -(CH2) n -C(O)OR 6a and -(CH2) n -NHC(O)-R 6a ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-NH2, such as H, CH3, CH2OH, CH2CH2OH and CH2CH2NH2; R 6b and R 6c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3; Each n is independently 0, 1, 2, 3, 4, 5, or 6.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, preferably, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group; R6 is selected from , , , , and ; R 6a R 6b and R 6c Independently selected from H and C 1-6 alkyl; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R4 is C 1-4 Alkyl or C 1-4 Alkyl groups, such as Me or OMe; R5 is a halogen, such as F; Alternatively, preferably, R4, R5 together with the carbon atoms to which they are attached form , or ; R6 is selected from , , , , , , , , and .

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II-a): (II-a) R6 is defined as in any one of claims 1-4.

6. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II), (II-b), or (II-c): (II) (II-b) (II-c) in, R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 6b It is H; R 6c Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each n is independently 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is a halogen, and can be replaced by other halogens such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6 is -(CH2) n -OR 6a Or -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl and C 2-6 Alkylene-OH, such as H, CH3, CH2CH2OH or CH2CH2CH2OH; R 6b It is H; R 6c It is C 1-6 Alkyl groups, such as CH3, CH2CH3, or isopropyl; Each n is independently 0, 1, 2, or 3, preferably 0, 1, or 2.

7. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II): (II) in, R4 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, which may be selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from H, halogens, and C. 1-6 Halogenated alkyl and C 1-6 Haloalkoxy groups can be alternatively selected from halogens, C... 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6 is selected from -(CH2). n -OP(O)(OH)-OR 6a -(CH2) n -OP(S)(OH)-OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6c Selected from C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Each n is independently 0, 1, 2, 3 or 4; Alternatively, R4 is H, C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is H, a halogen, and can be replaced by a halogen, such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6 is selected from -(CH2). n -OP(O)(OH)-OR 6a and -(CH2) n -CH2NR 6b R 6c ; R 6a Selected from H and C 1-6 Alkyl groups, preferably H; R 6b Selected from H and C 1-6 Alkyl groups, preferably H; R 6c Selected from C 3-5 Cycloalkyl groups, such as cyclopropyl groups; Each n is independently 0, 1, 2, or 3, preferably 0 or 1.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II-d): (II-d) in, R6 is -(CH2) n -OR 6a ; R 6a Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2, such as H, CH3, CH2OH and CH2CH2OH; Each n is independently 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R6 is -(CH2) n -OR 6a ; R 6a Selected from H and C 1-6 Alkyl groups, such as H or CH3, preferably H; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, This compound was selected from: 2-1 2-2、 2-3 2-4 2-5 2-6 2-7 2-8 2-9 2-10 2-11 2-12 2-13 2-14 2-15 2-16 2-17 2-18 2-19 2-20 2-21 2-22、 2-23 2-24 2-25 2-26 2-27 2-28 2-29 2-30 2-31 2-32, or 2-33.

10. A compound comprising the structure of formula (II-1), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (II-1) in, The attachment point between formula (II-1) and the rest of the compound; R6' is a divalent group formed by R6 being attached to the rest of the compound; R4, R5 and R6 are as defined in any one of claims 1-9; Alternatively, R4 and R5 are independently selected from H, halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6' is selected from the bond, -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -S(O)2-R 6a '-、-(CH2) n -S(O)-R 6a '-、-(CH2) n -OP(O)(OH)-OR 6a '-、-(CH2) n -OP(S)(OH)-OR 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -NHC(O)NR 6b R 6c '-、-(CH2) n -NHC(O)OR 6a '-、-(CH2) n -OC(O)NR 6b R 6c '-、-(CH2) n -C(O)NR 6b R 6c '-、-(CH2) n -CH2NR 6b R 6c '-、-(CH2) n -3-7-membered heterocyclic group-(CH2) n -OR 6a '- and -(CH2) n -3-7-membered heterocyclic group-(CH2) n -R 6a '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 3-7 Cycloalkylene, 3-7 membered heterocyclic alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6' is selected from the bond, -(CH2). n -OR 6a '、-(CH2) n -C(O)OR 6a '、-(CH2) n -OC(O)R 6a '、-(CH2) n -C(O)R 6a '、-(CH2) n -S(O)2-R 6a '、-(CH2) n -S(O)-R 6a '、-(CH2) n -NHC(O)-R 6a '、-(CH2) n -NHC(O)NR 6b R 6c '、-(CH2) n -NHC(O)OR 6a '、-(CH2) n -OC(O)NR 6b R 6c '、-(CH2) n -C(O)NR 6b R 6c 'and-(CH2)' n -CH2NR 6b R 6c '; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene-O-, C 1-6 Alkylene-OC 1-6 Alkylene, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6 is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

11. The compound of claim 10, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R4 and R5 are independently selected from halogens, OH, NH2, N(C) 1-6 Alkyl)2, NH-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R6' is selected from the bond, -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -S(O)2-R 6a '-、-(CH2) n -S(O)-R 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -NHC(O)NR 6b R 6c '-、-(CH2) n -NHC(O)OR 6a '-、-(CH2) n -OC(O)NR 6b R 6c '-、-(CH2) n -C(O)NR 6b R 6c '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R6' is optionally divided by 1, 2, 3, 4 or 5 Rs. Group substitution, R Selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R6' is selected from -(CH2) n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -OC(O)R 6a '-、-(CH2) n -C(O)R 6a '-、-(CH2) n -NHC(O)-R 6a '-、-(CH2) n -C(O)NR 6b R 6c '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'and R 6c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 6b Selected from H, C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Alternatively, R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6' is selected from -(CH2) n -OR 6a '-、-(CH2) n -C(O)OR 6a '-、-(CH2) n -NHC(O)-R 6a '- and -(CH2) n -CH2NR 6b R 6c '-; R6' is preferably selected from -(CH2). n -OR 6a '-、-(CH2) n -C(O)OR 6a '- and -(CH2) n -NHC(O)-R 6a '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 Alkylene -NH-, such as bond, -CH2-, -CH2O-, -CH2CH2O- and -CH2CH2NH-; R 6b Selected from H and C 1-6 Alkyl groups, such as H and CH3; R 6c 'Selected from key and C' 1-6 Alkyl groups, such as bonds and -CH2-; Each n is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy; R5 is a halogen; Alternatively, preferably, R4 and R5 together with the carbon atoms to which they are attached form a 5-6 membered heterocyclic group; R6' is selected from , , , , and ,For example, , , , , , , , , and ; R 6a 'and R 6c 'Independently selected from key and C 1-6 Alkylene; R 6b Selected from H and C 1-6 alkyl; Each n is independently 0, 1, 2, 3, 4, 5, or 6.

12. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II-1a): (II-1a) R6' is defined as in claim 11.

13. The compound according to any one of claims 10-12, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II-1), (II-1b), or (II-1c): (II-1) (II-1b) (II-1c) in, The attachment points of formulas (II-1), (II-1b), or (II-1c) to the rest of the compound; R4 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from halogens, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6' is selected from -(CH2) n -OR 6a '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; R 6b It is H; R 6c 'Selected from C' 1-6 Alkylene and C 1-6 Halogenated alkylene; Each n is independently 0, 1, 2, 3, or 4; Among them, R6' is optionally divided by 1, 2 or 3 R Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R4 is C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is a halogen, and can be replaced by other halogens such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6' is -(CH2) n -OR 6a '-or-(CH2)' n -CH2NR 6b R 6c '-; R 6a 'Selected from key, C 1-6 alkylene and -C 2-6 Alkylene -O-, such as bond, -CH2-, -CH2CH2O- or -CH2CH2CH2O-; R 6b It is H; R 6c 'Is C 1-6 Alkyl groups, such as -CH2- or -CH2CH2- or -CH(CH3)CH2-; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

14. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, This compound is a compound having the structure of formula (II-1): (II-1) in, The attachment point between formula (II) and the rest of the compound; R4 is selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups, which may be selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R5 is selected from H, halogens, and C. 1-6 Halogenated alkyl and C 1-6 Haloalkoxy groups can be alternatively selected from halogens, C... 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; Alternatively, preferably, R4, R5, together with the carbon atoms to which they are attached, form C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R6' is selected from -(CH2) n -OP(O)(OH)-OR 6a '-、-(CH2) n -OP(S)(OH)-OR 6a '-、and-(CH2) n -CH2NR 6b R 6c '-; R 6a 'Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; R 6b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 6c 'Selected from C' 3-7 Cycloalkylene and 3-7 membered heterocyclic alkylene groups; Each n is independently 0, 1, 2, 3 or 4; Alternatively, R4 is H, C 1-6 Alkyl or C 1-6 Alkoxy, or alternatively C 1-6 Alkyl or C 1-6 Alkyl groups, such as Me or OMe; R5 is H, a halogen, and can be replaced by a halogen, such as F; Alternatively, R4 and R5 together with the carbon atoms to which they are attached form 5-6 membered heterocyclic groups; R6' is selected from -(CH2) n -OP(O)(OH)-OR 6a '- and -(CH2) n -CH2NR 6b R 6c '-; R 6a 'Selected from key and C' 1-6 Alkyl groups, preferably bonds; R 6b Selected from H and C 1-6 Alkyl groups, preferably H; R 6c 'Is C 3-5 Cycloalkylene compounds, such as cyclopropylene compounds; Each n is independently 0, 1, 2, or 3, preferably 0 or 1.

15. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (II-1d): (II-1d) in, The attachment point between formula (II-1d) and the rest of the compound; R6' is -(CH2) n -OR 6a '-; R 6a 'Selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 Alkylene -NH-, such as bond, -CH2-, -CH2O- and -CH2CH2O-; Each n is independently 0, 1, 2, 3, or 4; Among them, R6 is optionally divided by 1, 2 or 3 Rs Group substitution, R Selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Alternatively, R6' is -(CH2) n -OR 6a '-; R 6a 'Selected from key and C' 1-6 Alkylene, such as a bond or -CH2-; Each n is independently 0, 1, 2, or 3, preferably 1 or 2.

16. The compound according to any one of claims 10-15, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound comprises a structure selected from: 2-1'、 2-2'、 2-3'、 2-4'、 2-5' 2-6'、 2-7'、 2-8' 2-9' 2-10' 2-11'、 2-12'、 2-13'、 2-14' 2-15' 2-16' 2-17' 2-18' 2-19' 2-20'、 2-21'、 2-22'、 2-23'、 2-24'、 2-25'、 2-26'、 2-27'、 2-28'、 2-29' 2-30'、 2-31'、 2-32', or 2-33'.

17. The compound according to any one of claims 10-16, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is derived from L2-(D2). y The coupling compound represented is preferably composed of T2-[L2'-(D2)]. y ] u The coupling element indicated; in, T2 is the target region; L2 is a linker, and L2' is a divalent group formed by connecting L2 and T2; D2 is the pharmaceutical portion, which is selected from the compounds according to any one of claims 10-16; y is an integer between 1 and 10, or alternatively, 1; u is an integer between 1 and 10.

18. The compound according to any one of claims 10-17, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein L2-(D2) is involved. y The compound represented is selected from: LD 2-1-a; LD 2-1-b; LD 2-2; LD 2-5; LD 2-6; LD 2-9; in, From T2-[L2'-(D2)] y ] u The compound represented is selected from: TDC 2-1-a; TDC 2-1-b; TDC 2-2; TDC 2-5; TDC 2-6; TDC 2-9; Wherein, T2 and u are as defined in claim 17.

19. A compound having formula (I), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (I) in, X is CR x Or N, for example CH or N; R x Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R2 is selected from NR 2b R 2c -(CH2) m -C(O)R 2a -(CH2) m -C(O)OR 2a -(CH2) m -OC(O)R 2a -(CH2) m -S(O)2-R 2a -(CH2) m -S(O)-R 2a -(CH2) m -NHC(O)-R 2a -(CH2) m -C(O)NR 2b R 2c -(CH2) m -NHC(O)OR 2a and -(CH2) m -OC(O)NR 2b R 2c and -(CH2) m -NHC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R3 is selected from H, -(CH2) p OR 3a 、-(CH2) p C(O)R 3a 、-(CH2) p C(O)OR 3a 、-(CH2) p OC(O)R 3a 、-(CH2) p -S(O)2-R 3a 、-(CH2) p -S(O)-R 3a 、-(CH2) p -NR 3b R 3c 、-(CH2) p -NHC(O)-R 3a 、-(CH2) p -C(O)NR 3b R 3c 、-(CH2) p -NHC(O)OR 3a 、-(CH2) p -OC(O)NR 3b R 3c and -(CH2) p -NHC(O)NR 3b R 3c ; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups; Each p is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; In this embodiment, R2 and R3 are optionally substituted by 1, 2, 3, 4, or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C, etc. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

20. The compound of claim 19, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein: X is CH or N; R1 is selected from halogen and C. 1-6 Alkoxy; R2 is selected from NR 2b R 2c C(O)R 2a ,NHC(O)-R 2a C(O)NR 2b R 2c ,NHC(O)OR 2a and OC(O)NR 2b R 2c ; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a and -(CH2) p -OC(O)NR 3b R 3c Preferably, R3 is not H; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups; Each p is independently selected from 0, 1, 2, 3, and 4.

21. The compound according to claim 19 or 20, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, X is CH or N; R1 is selected from halogen and C. 1-6 Alkoxy; R2 is selected from , , , , and ; R 2a R 2b and R 2c Independently selected from H and C 1-6 alkyl; Each m is independently 1, 2, or 3; R3 is selected from H, , , , , and ; R 3a R 3b and R 3c Independently selected from H and C 1-6 alkyl; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-6 membered heterocyclic groups; Each p is independently 0, 1, 2, or 3; Alternatively, R3 is selected from H, , , , , , , , , , , , and .

22. The compound according to any one of claims 19-21, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, X is CH or N; R1 is F or OMe; R2 is , , , , , and ; R3 is selected from H, , , , , , , , , , , , and Preferably, R3 is not H.

23. The compound according to any one of claims 19-22, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (Ia) or (Ib): (I-a) (I-b) in, X, R2, R 2b R 2c R3 is as defined in any one of claims 19-22; Alternatively, the compound has the structure of formula (Ic) or (Id): (I-c) (I-d) in, X is CR x Or N, for example CH or N; R x Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-6 Alkoxy; R2 is NR 2b R 2c ; R 2b and R 2c Independently selected from H and C 1-6 alkyl; Alternatively, among them, X is CR x For example, CH; R x Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-4 Alkoxy groups, preferably halogens, such as F; R2 is NR 2b R 2c Preferably, it is NH2; R 2b and R 2c Independently selected from H and C 1-4 Alkyl groups, such as H or CH3.

24. The compound according to any one of claims 19-23, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, This compound was selected from: 1-1、 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10 1-11 1-12 1-13 1-14 1-15 1-16 1-17 1-18 1-19 1-20 1-21 and 1-22.

25. A compound comprising a structure of formula (I-1) or (I-2), a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (I-1) (I-2) in, The attachment point of formula (I-1) or (I-2) to the rest of the compound; R2' is a divalent group formed by R2 being attached to the rest of the compound; R3' is a divalent group formed by R3 being attached to the rest of the compound; X, R1, R2, and R3 are as defined in any one of claims 19-23; Alternatively, X is CH or N; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups can be alternatively selected from halogens and C. 1-6 Alkyl groups, such as F and OMe; R2 and R3 are as defined in any one of claims 19-23.

26. The compound according to claim 25, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R2 is selected from NR 2b R 2c -(CH2) m -C(O)R 2a -(CH2) m -C(O)OR 2a -(CH2) m -OC(O)R 2a -(CH2) m -S(O)2-R 2a -(CH2) m -S(O)-R 2a -(CH2) m -NHC(O)-R 2a -(CH2) m -C(O)NR 2b R 2c -(CH2) m -NHC(O)OR 2a and -(CH2) m -OC(O)NR 2b R 2c and -(CH2) m -NHC(O)NR 2b R 2c ; R2' is selected from -NR 2b R 2c '-、-(CH2) m -C(O)R 2a '-、-(CH2) m -C(O)OR 2a '-、-(CH2) m -OC(O)R 2a '、-(CH2) m -S(O)2-R 2a '-、-(CH2) m -S(O)-R 2a '-、-(CH2) m -NHC(O)-R 2a '-、-(CH2) m -C(O)NR 2b R 2c '-、-(CH2) m -NHC(O)OR 2a '- and -(CH2) m -OC(O)NR 2b R 2c '- and -(CH2) m -NHC(O)NR 2b R 2c '-; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 2a 'and R 2c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 Alkylene-O- and C 1-6 alkylene-NH-; Each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R2' is optionally substituted with 1, 2, 3, 4 or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R2 is selected from NR 2b R 2c C(O)R 2a ,NHC(O)-R 2a C(O)NR 2b R 2c ,NHC(O)OR 2a and OC(O)NR 2b R 2c ; R2' is selected from -NR 2b R 2c '-、-C(O)R 2a '-、-NHC(O)-R 2a '-、-C(O)NR 2b R 2c '-、-NHC(O)OR 2a '- and -OC(O)NR 2b R 2c '-; R 2a R 2b and R 2c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 2a 'and R 2c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Alternatively, R2 is selected from , , , , and ; R2' is selected from , , , , and ; R 2a R 2b and R 2c Independently selected from H and C 1-6 alkyl; R 2a 'and R 2c 'Independently selected from key and C 1-6 Alkylene; Each m is independently 1, 2, or 3; Alternatively, R2 is , , , , , and ; R2' is , , , , , and .

27. The compound according to claim 25 or 26, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R3 is selected from H, -(CH2) p OR 3a 、-(CH2) p C(O)R 3a 、-(CH2) p C(O)OR 3a 、-(CH2) p OC(O)R 3a 、-(CH2) p -S(O)2-R 3a 、-(CH2) p -S(O)-R 3a 、-(CH2) p -NR 3b R 3c 、-(CH2) p -NHC(O)-R 3a 、-(CH)2 p -C(O)NR 3b R 3c 、-(CH2) p -NHC(O)OR 3a 、-(CH2) p -OC(O)NR 3b R 3c and -(CH2) p -NHC(O)NR 3b R 3c ; R3' is selected from the bond, -(CH2). p OR 3a '-、-(CH2) p C(O)R 3a '-、-(CH2) p C(O)OR 3a '-、-(CH2) p OC(O)R 3a '-、-(CH2) p -S(O)2-R 3a '-、-(CH2) p -S(O)-R 3a '-、-(CH2) p -NR 3b R 3c '-、-(CH2) p -NHC(O)-R 3a '-、-(CH2) p -C(O)NR 3b R 3c '-、-(CH2) p -NHC(O)OR 3a '-、-(CH2) p -OC(O)NR 3b R 3c '- and -(CH2) p -NHC(O)NR 3b R 3c '-; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups; R 3a 'and R 3c 'Independently selected from key, C 1-6 Alkylene, C 1-6 Halogenated alkylene, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 alkylene-, -C 1-6 alkylene-NH-, -C 1-6 Alkylene-NH-C 1-6 alkylene- and -C 1-6 Alkylene-N(C) 1-6 alkyl)-C 1-6 alkylene-; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups; Each p is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R3' is optionally substituted with 1, 2, 3, 4 or 5 R groups, where R is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R3 is selected from H, -(CH2). p OR 3a -(CH2) p C(O)R 3a -(CH2) p C(O)OR 3a -(CH2) p -NR 3b R 3c -(CH2) p -NHC(O)-R 3a -(CH2) p -C(O)NR 3b R 3c -(CH2) p -NHC(O)OR 3a and -(CH2) p -OC(O)NR 3b R 3c Preferably, R3 is not H; R3' is selected from the bond, -(CH2). p OR 3a '-、-(CH2) p C(O)R 3a '-、-(CH2) p C(O)OR 3a '-、-(CH2) p -NR 3b R 3c '-、-(CH2) p -NHC(O)-R 3a '-、-(CH2) p -C(O)NR 3b R 3c '-、-(CH2) p -NHC(O)OR 3a '- and -(CH2) p -OC(O)NR 3b R 3c '-; R 3a R 3b and R 3c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 3a 'and R 3c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups; Each p is independently selected from 0, 1, 2, 3, and 4; Alternatively, R3 is selected from H, , , , , and ; R3' is selected from the key, , , , , and ; R 3a R 3b and R 3c Independently selected from H and C 1-6 alkyl; R 3a 'and R 3c 'Independently selected from key and C 1-6 Alkylene; Or, R 3b R 3c Together with the nitrogen atoms to which they are attached, they form 5-6 membered heterocyclic groups; Each p is independently 0, 1, 2, or 3; Alternatively, R3 is selected from H, , , , , , , , , , , , and ; R3' is selected from the key, , , , , , , , , , , , and Preferably, R3' is not a bond.

28. The compound according to any one of claims 25-27, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound comprises a structure of formula (I-1a), (I-2a), (I-1bI-1b), or (I-2b): (I-1a) (I-2a) (I-1b) (I-2b) in, X, R2, R2', R 2b R 2c R 2c R3 and R3' are as defined in any one of claims 25-27; Alternatively, the compound comprises the structure of formula (I-1c) or (I-1d): (I-1c) (I-1d) in, X is CR x Or N, for example CH or N; R x Selected from halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-6 Alkoxy; R2' is -NR 2b R 2c '-; R 2b Selected from H and C 1-6 alkyl; R 2c 'Selected from key and C' 1-6 Alkylene; Alternatively, X is CR x For example, CH; R x Selected from H, halogens, C 1-6 Alkyl and C 1-6 Alkoxy; R1 is selected from halogen and C. 1-4 Alkoxy groups, preferably halogens, such as F; R2' is -NR 2b R 2c '-, and R2' is preferably -NH-; R 2b Independently selected from H and C 1-4 alkyl; R 2c 'Independently selected from key and C 1-4 Alkylene.

29. The compound according to any one of claims 25-28, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound comprises a structure selected from: 1-1'、 1-3'、 1-4'、 1-5' 1-6'、 1-7'、 1-8' 1-9' 1-10a'、 1-10b'、 1-11a'、 1-11b'、 1-12a'、 1-12b'、 1-13a'、 1-13b', 1-14a'、 1-14b'、 1-15a'、 1-15b'、 1-16a'、 1-16b'、 1-17a'、 1-17b'、 1-18a'、 1-18b'、 1-19a'、 1-19b'、 1-20a'、 1-20b'、 1-21a'、 1-21b'、 1-22a' and 1-22b'.

30. The compound according to any one of claims 25-29, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is derived from L1-(D1). x The coupling compound represented is preferably composed of T1-[L1'-(D1)]. x ] w The coupling element indicated; in, T1 is the target region; L1 is a linker, and L1' is a divalent group formed by connecting T1 and L1; D1 is the pharmaceutical portion, which is selected from the compounds as defined in any one of claims 25-29; x is an integer between 1 and 10, or alternatively, 1; w is an integer between 1 and 10.

31. The compound according to any one of claims 25-30, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein L1-(D1) is involved. x The compound represented is selected from: LD 1-1-a; LD 1-1-b; LD 1-1-c; LD 1-1-d; LD 1-6; LD 1-7; LD 1-7-a; LD 1-7-b; LD 1-9-a; LD 1-9-b; LD 1-10-a; LD 1-10-b; LD 1-15-a; LD 1-15-b; LD 1-22-a; LD 1-22-d; Alternatively, where T1-[L1'-(D1)] x ] w The compound represented is selected from: TDC 1-1-a; TDC 1-1-b; TDC 1-1-c; TDC 1-1-d; TDC 1-6; TDC 1-7; TDC 1-7-a; TDC 1-7-b; TDC 1-9-a; TDC 1-9-b; TDC 1-10-a; TDC 1-10-b; TDC 1-15-a; TDC 1-15-b; TDC 1-22-a; TDC 1-22-d; in, T1 and w are as defined in claim 30.

32. A compound having formula (III), or a pharmaceutically acceptable salt, isotopically labeled analogue, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III) in, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -NHC(O)OR 7a -(CH2) k -OC(O)NH-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Each k is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R 10a 、-(CH2) q -S(O)2-R 10a 、-(CH2) q -S(O)-R 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR 10b R 10c 、-(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-NH2, C 1-6 Alkylene-NH(C) 1-6 alkyl) and C 1-6 Alkylene-N(C) 1-6 Alkyl)2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 3-12-membered heterocyclic groups or 5-12-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group and the 5-12-membered heteroaryl group are optionally selected from H, D, halogens and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; Among them, R7, R8, R9 and R 10 Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

33. The compound according to claim 32, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R7 is selected from -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR 10b R 10c 、-(CH2) q -NHC(O)-OR 10a 、and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic groups are optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Among them, R7, R8, R9 and R 10 Optionally substituted with 1, 2, or 3 R# groups, where R# is selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

34. The compound according to claim 32 or 33, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (III-a): (III-a) in, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -C(O)NR 7b R 7c -(CH2) k -NHC(O)OR 7a and -(CH2) k -OC(O)NH-R 7a ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, 3, 4, 5, or 6; In this embodiment, R7 and R8 are optionally substituted by 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R7 is selected from -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Each k is independently 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; Alternatively, R7 is selected from , , , and ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3, k is 0, 1, 2, or 3; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; Alternatively, R7 is selected from , , , , , , , and ; R8 is selected from C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 1-4 alkylene-OH and C 1-4 Alkylene-NH2, such as CH3, , and .

35. The compound according to claim 32 or 33, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound has the structure of formula (III-b): (III-b) in, R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R 10a 、-(CH2) q -S(O)2-R 10a '、-(CH2) q -S(O)-R 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR 10b R 10c 、-(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups, wherein the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally selected from H, D, halogen and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, or 6; Among them, R 10 Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR[[ID=,31]] 10b R 10c 、-(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic groups are optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Among them, R 10 Optionally substituted with 1, 2, or 3 R# groups, where R# is selected from H, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

36. The compound of claim 35, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R 10 Selected from H, , , , and ; R 10a R 10b and R 10c Independently selected from H and C 1-6 alkyl; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, or 3; Alternatively, R 10 Selected from H, , , , , , , , , and .

37. The compound according to any one of claims 32-36, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, This compound was selected from: 3-1 , , 3-2, 3-3 3-4 3-5 3-6 3-7 3-8 3-9 3-10 3-11 3-12 , , 3-13 3-14 3-15 3-16 3-17 3-18 3-19 3-20 , , 3-21 3-22 and 3-23.

38. A compound comprising a structure of formula (III-1) or (III-2), or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof: (III-1) (III-2) in, The attachment point of formula (III-1) or (III-2) to the rest of the compound; R7' is a divalent group formed by R7 being attached to the rest of the compound; R 10 ' is by R 10 Divalent groups formed by connecting with the rest of the compound; R7, R8, R9 and R 10 As defined in any one of claims 32-36.

39. The compound according to claim 38, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R7 and R8 are independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)R 7a -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a -(CH2) k -NHC(O)OR 7a -(CH2) k -OC(O)NH-R 7a and -(CH2) k -C(O)NR 7b R 7c ; Each k is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; R7' is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 imidene group, C 1-6 Alynyl group, -(CH2) k -OR 7a '-、-(CH2) k -NR 7b R 7c '-、-(CH2) k -C(O)R 7a '-、-(CH2) k -C(O)OR 7a '-、-(CH2) k -OC(O)-R 7a '-、-(CH2) k -NHC(O)-R 7a '-、-(CH2) k -C(O)NR 7b R 7c '-、-(CH2) k -NHC(O)OR 7a '- and -(CH2) k -OC(O)NH-R 7a '-; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 7a 'and R 7c 'Independently selected from key, C 1-6 Alkylene, C 1-6 imidene group, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Each k is independently 0, 1, 2, 3, 4, 5, or 6; In this embodiment, R7' is optionally substituted by 1, 2, 3, 4, or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R7 is selected from -(CH2) k -OR 7a -(CH2) k -NR 7b R 7c -(CH2) k -C(O)OR 7a -(CH2) k -OC(O)-R 7a -(CH2) k -NHC(O)-R 7a and -(CH2) k -C(O)NR 7b R 7c ; R7' is selected from -(CH2) k -OR 7a '-、-(CH2) k -NR 7b R 7c '-、-(CH2) k -C(O)OR 7a '-、-(CH2) k -OC(O)-R 7a '-、-(CH2) k -NHC(O)-R 7a '- and -(CH2) k -C(O)NR 7b R 7c '-; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; R 7a 'and R 7c 'Selected from key, C 1-6 Alkylene, C 1-6 Ethyne group, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Each k is independently 0, 1, 2, or 3; Alternatively, R7 is selected from , , , and ; R7' is selected from , , , and ; R 7a R 7b and R 7c Independently selected from H and C 1-6 Alkyl groups, such as H and CH3, R 7a 'and R 7c 'Selected from key and C' 1-6 Alkyl groups, such as bonds and CH2; R8 is selected from C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 0-6 alkylene-OH and C 0-6 Alkylene-NH2; k is 0, 1, 2, or 3; Alternatively, R7 is selected from , , , , , , , and ; R7' is selected from , , , , , , , and ; R8 is selected from C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 1-4 alkylene-OH and C 1-4 Alkylene-NH2, such as CH3, , and .

40. The compound according to claim 38 or 39, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R 10a 、-(CH2) q -S(O)2-R 10a 、-(CH2) q -S(O)-R 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR 10b R 10c 、-(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10 ’ is selected from a bond, -(CH2) q -OR 10a ’-, -(CH2) q -NR 10b R 10c ’-, -(CH2) q -C(O)R 10a ’-, -(CH2) q -C(O)OR 10a ’-, -(CH2) q -OC(O)R 10a ’-, -(CH2) q -S(O)2-R 10a ’-, -(CH2) q -S(O)-R 10a ’-, -(CH2) q -NHC(O)-R 10a ’-, -(CH2) q -C(O)NR 10b R 10c ’-, -(CH2) q -NHC(O)-OR 10a ’-, and -(CH2) q -OC(O)NR 10b R 10c ’; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 3-12-membered heterocyclic groups or 5-12-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group and the 5-12-membered heteroaryl group are optionally selected from H, D, halogens and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; R 10a 'and R 10c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-12-membered heterocyclic groups or 5-12-membered heteroaryl groups, wherein the 5-12-membered heterocyclic group and 5-12-membered heteroaryl group are optionally selected from H, D, halogens and C. 1-6 Alkyl groups may be substituted with 1, 2, 3, 4, or 5 substituents; Each q is independently 0, 1, 2, 3, 4, 5, or 6; Among them, R 10 'Optionally substituted with 1, 2, 3, 4 or 5 R# groups, where R# is selected from H, NH2, OH, CN, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; Alternatively, R9 is selected from H, OH, CN, NH2, NH(C) 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 selected from H, -(CH2) q -OR 10a 、-(CH2) q -NR 10b R 10c 、-(CH2) q -C(O)R 10a 、-(CH2) q -C(O)OR 10a 、-(CH2) q -OC(O)R s 10a 、-(CH2) q -NHC(O)-R 10a 、-(CH2) q -C(O)NR 10b R 10c 、-(CH2) q -NHC(O)-OR 10a and -(CH2) q -OC(O)NR 10b R 10c ; R 10 Selected from the key, -(CH2) q -OR 10a '-、-(CH2) q -NR 10b R 10c '-、-(CH2) q -C(O)R 10a '-、-(CH2) q -C(O)OR 10a '-、-(CH2) q -OC(O)R 10a '-、-(CH2) q -NHC(O)-R 10a '-、-(CH2) q -C(O)NR 10b R 10c '-、-(CH2) q -NHC(O)-OR 10a '-、and-(CH2) q -OC(O)NR 10b R 10c '-; R 10a R 10b and R 10c Independently selected from H and C 1-6 Alkyl, C 1-6 alkylene-OH and C 1-6 Alkylene-NH2; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic groups are optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R 10a 'and R 10c 'Independently selected from key, C 1-6 Alkylene, -C 1-6 alkylene-O- and -C 1-6 alkylene-NH-; Or, R 10b R 10c Together with the nitrogen atoms to which they are attached, they form 5-10 membered heterocyclic groups, wherein the 5-10 membered heterocyclic groups are optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, 3 or 4; Alternatively, R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, , , , and ; R 10 'Selected from key, , , , and ; R 10a R 10b and R 10c Independently selected from H and C 1-6 alkyl; Preferably, R 10a Not H; Or, R 10b R 10c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens, and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; R 10a 'and R 10c 'Independently selected from key and C 1-6 Alkylene; Or, R 10b R 10c Together with the nitrogen atom to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally selected from H, D, halogens and C. 1-6 Alkyl groups are substituted with one, two, or three substituents; Each q is independently 0, 1, 2, or 3; Alternatively, R9 is selected from H, NH2, and NH(C). 1-6 alkyl) and N(C) 1-6 Alkyl group 2, such as H or NH2; R 10 Selected from H, , , , , , , , , and ; R 10 'Selected from key, , , , , , , , , and .

41. The compound according to any one of claims 38-40, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein, The compound contains structures of formula (III-1a), (III-1b), or (III-2b): (III-1a) (III-1b) (III-2b) Among them, R7', R8, R 10 and R 10 'As defined in any one of claims 38-40; Alternatively, The compound contains the structure of formula (III-1a): (III-1a) in, R7' is selected from C 1-6 Alkylene, C 1-6 Halogenated alkylene, C 1-6 imidene group, C 1-6 Alynyl group, -(CH2) k -OR 7a '-、and-(CH2) k -NR 7b R 7c '-; R8 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 Alkyne group, -(CH2) k -OR 7a and -(CH2) k -NR 7b R 7c ; R 7a 'and R 7c 'Independently selected from key, C 1-6 Alkylene, C 1-6 imidene group, and C 1-6 Ethyne group; R 7b Independently selected from H and C 1-6 Alkyl, C 1-6 alkenyl and C 1-6 alkynyl group; Each k is independently 0, 1, 2, 3, 4, 5, or 6; Alternatively, R7' is selected from -(CH2) k -OR 7a '- and -(CH2) k -NR 7b R 7c '-; R 7a 'and R 7c 'Independently selected from key and C 1-6 Alkyl groups, such as bonds and CH2; R 7b Independently selected from H and C 1-6 Alkyl groups, such as H and CH3; Each k is independently 0, 1, 2, or 3; R8 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Alternatively, R7' is selected from , , , ,and Alternatively, , or ; R8 is C 1-6 Alkyl groups, such as CH3.

42. The compound according to any one of claims 38-41, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound comprises a structure selected from: 3-1'、 , , 3-2'、 3-3'、 3-4' 3-5' 3-6' 3-7' 3-8' 3-9' 3-10' 3-11a'、 3-11b'、 3-12'、 , , 3-13a'、 3-13b'、 3-14a'、 3-14b' 3-15a'、 3-15b' 3-16a'、 3-16b' 3-17a'、 3-17b' 3-18a'、 3-18b' 3-19a'、 3-19b' 3-20a'、 , , 3-20b' , , 3-21a'、 3-21b'、 3-22a'、 3-22b'、 3-23a' and 3-23b'.

43. The compound according to any one of claims 38-42, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein the compound is derived from L3-(D3). z The coupling compound represented is preferably composed of T3-[L3'-(D3)]. z ] r The coupling element indicated; in, T3 is the target component; L3 is a linker, and L3' is a divalent group formed by the connection of T3 and L3; D3 is the pharmaceutical part, which is selected from the compounds as defined in any one of claims 38-42; z is an integer between 1 and 10, or alternatively, 1; r is an integer between 1 and 10.

44. The compound according to any one of claims 38-43, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, wherein L3-(D3) is present. z The compound represented is selected from: LD 3-1-a; LD 3-1-b; LD 3-3; LD 3-6; LD 3-12; LD 3-12a; LD 3-13-a; LD 3-13-b; LD 3-14-a; LD 3-14-b; LD 3-20-a; LD 3-20-b; Alternatively, where T3-[L3-(D3)] z ] r The compound represented is selected from: TDC 3-1-a; TDC 3-1-b; TDC 3-3; TDC 3-6; TDC 3-12; TDC 3-12a; TDC 3-13-a; TDC 3-13-b; TDC 3-14-a; TDC 3-14-b; TDC 3-20-a; TDC 3-20-b; in, T3 and r are as defined in claim 43.

45. A composition comprising the compound according to any one of claims 1-44, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, and optionally a pharmaceutically acceptable carrier or excipient.

46. ​​The use of any compound according to any one of claims 1-44, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, or the composition according to claim 45, in the manufacture of a medicament for treating and / or preventing disease.

47. The compound according to any one of claims 1-44, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, or the composition according to claim 45, for use in the treatment and / or prevention of disease.

48. A method for preventing and / or treating a disease in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1-44, or a pharmaceutically acceptable salt, isotopically labeled analog, crystalline form, hydrate, solvate, enantiomer, diastereomer, or mixture thereof, or a composition according to claim 45.

49. The method of claim 48, wherein the method further comprises administering a second therapeutic agent to the subject, preferably wherein the second therapeutic agent is selected from antibodies, chemotherapeutic agents, and small molecule drugs.

50. The use according to claim 46, or the compound or composition for use according to claim 47, or the method according to claim 48, wherein the disease is selected from cancer, infectious diseases, inflammatory diseases, autoimmune diseases, and immunodeficiency diseases; Preferably, the cancer is selected from head and neck cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, ovarian cancer, prostate cancer, breast cancer, leukemia, myeloma, squamous cell carcinoma, melanoma, brain cancer, cervical cancer, liver cancer, bladder cancer, breast cancer, kidney cancer, testicular cancer, and thyroid cancer. Preferably, the autoimmune disease is selected from systemic sclerosis and atherosclerosis.

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